Mucocutaneous Manifestations in Patients Receiving Cancer

MUCOCUTANEOUS MANIFESTATIONS IN PATIENTS RECEIVING CANCER

CHEMOTHERAPY IN REGIONAL CANCER CENTRE OF TIRUNELVELI

MEDICAL COLLEGE

Dissertation Submitted to

THE TAMILNADU DR.M.G.R. MEDICAL UNIVERSITY

IN PARTIAL FULFILMENT FOR THE AWARD OF THE DEGREE OF

DOCTOR OF MEDICINE

DERMATOLOGY, VENEREOLOGY & LEPROSY

BRANCH XII-A

APRIL 2019

DEPARTMENT OF DERMATOLOGY VENEREOLOGY & LEPROSY

TIRUNELVELI MEDICAL COLLEGE

TIRUNELVELI -11

BONAFIDE CERTIFICATE

This is to certify that the dissertation titled as “MUCOCUTANEOUS

MANIFESTATIONS IN PATIENTS RECEIVING CANCER CHEMOTHERAPY IN

REGIONAL CANCER CENTRE OF TIRUNELVELI MEDICAL COLLEGE” submitted by DR. P. SULOCHANA to the Tamil Nadu Dr. M.G.R Medical University, Chennai, in partial fulfilment of the requirement for the award of the Degree of DOCTOR OF

MEDICINE in DERMATOLOGY, VENEREOLOGY & LEPROSY during the academic period 2016-2019 is a bonafide research work carried out by her under direct supervision & guidance.

PROFESSOR & HEAD DEAN

Department of Dermatology, Venereology & Leprosy Tirunelveli Medical college

Tirunelveli Medical college Tirunelveli

Tirunelveli.

CERTIFICATE

This is to certify that the dissertation titled as “MUCOCUTANEOUS

MANIFESTATIONS IN PATIENTS RECEIVING CANCER CHEMOTHERAPY IN

REGIONAL CANCER CENTRE OF TIRUNELVELI MEDICAL COLLEGE” submitted

by DR. P. SULOCHANA is an original work done by her in the Department of Dermatology

Venereology & Leprosy, Tirunelveli Medical college, Tirunelveli for the award of the Degree

of DOCTOR OF MEDICINE in DERMATOLOGY, VENEREOLOGY & LEPROSY

during the academic period 2016-2019.

Place: Tirunelveli GUIDE

Date: PROFESSOR & HEAD

Department of Dermatology, Venereology & Leprosy,

Tirunelveli Medical college,

Tirunelveli.

DECLARATION

I solemnly declare that the dissertation titled “MUCOCUTANEOUS

MANIFESTATIONS IN PATIENTS RECEIVING CANCER CHEMOTHERAPY IN

REGIONAL CANCER CENTRE OF TIRUNELVELI MEDICAL COLLEGE” is done

by me in the Department of Dermatology, Venereology & Leprosy, Tirunelveli Medical

College, Tirunelveli.

The dissertation is submitted to The Tamil Nadu Dr. M.G.R. Medical University in

partial fulfilment for the award of the Degree of Doctor of Medicine in Dermatology

Venereology & Leprosy.

Place: Tirunelveli DR.P.SULOCHANA Post Graduate Student Date: M.D. Dermatology Venereology & Leprosy Dept. of Dermatology Venereology & Leprosy Tirunelveli Medical college Tirunelveli -627011

Acknowledgement

It gives me great pleasure in presenting my dissertation. At first, I must bow down with reverence to almighty God, my parents and my teachers for giving me the opportunity to pursue my aim.

I express my gratitude to Dean, Tirunelveli Medical College Hospital and Medical Superintendent of Tirunelveli Medical College Hospital for permitting me to carry out this research work.

“It is the supreme art of the teacher to awaken joy in creative expression and knowledge.” These words of Albert Einstein, I dedicate to my esteemed teacher and guide Dr. P.Nirmaladevi MD, Professor and Head, Dept of DVL, Tirunelveli Medical College Hospital, whose presence and expert guidance helped in bringing out the best in me. It would not have been possible without her support and guidance. I am very fortunate to have such a kind and outstanding person as my guide, my guru.

I express my deep sense of gratitude to Dr. K.Punithavathi MD, Associate Professor Dept of DVL, for her valuable guidance.

I also want to express my gratitude to Dr.M.Selvakumar MD, Associate Professor, Dept of Venereology for his guidance and valuable suggestions.

I sincerely thank Dr. R. Deivanayagam M.D. D.M., Professor and HOD, Department of Medical Oncology and Dr. V. Arumugam M.D. D.M., Assistant Professor, Department of

Medical Oncology for their support. With deep sense of gratitude, I thank all the faculty member of the Department of Medical Oncology for sharing their implicit knowledge, support and encouragement during the course of this research work.

I have learnt a lot of things and also got immeasurable guidance from my teachers. I sincerely thank Dr.Judith Joy MD., (Late) Dr.R.Karthikeyan MD., Dr.A.N.M. Maalikbabu MD., Dr.P.Kalyanakumar DDVL., Dr.S.Seeniammal MD., for their constant support and encouragement. I am obliged to all my teachers from other departments who encouraged, supported and guided me throughout my endeavor.

Kind words of affection have to be mentioned about all my all colleagues Dr.B.Arun kumar, Dr.M.Aravind Baskar, Dr. P.Karthik raja, Dr.R.Monisha, Dr.S.Soundarya, Dr.Vijay kumar, Dr.P.Jemi singh, Dr.A.Rupan, Dr.Ramasubramanium, Dr.S.Vidhya, Dr.S.Yogeswari for their support at various stages of my research work.

I am thankful to my patients for participating in this study, for their cooperation and for allowing me to learn the skills of Dermatology Venereology & Leprosy.

I am really grateful to my husband Dr.B.Rajesh Kumar and my parents & family members who are the pillar of my strength, providing me emotional support and all the help during my research work.

I express my apologies and gratitude to those wittingly or unwittingly remained unsung during my research work.

Date: . 2018

Place: Tirunelveli Medical College Hospital Dr. P. Sulochana

CERTIFICATE – II

This is to certify that this dissertation work titled “MUCOCUTANEOUS

MANIFESTATIONS IN PATIENTS RECEIVING CANCER CHEMOTHERAPY IN

REGIONAL CANCER CENTRE OF TIRUNELVELI MEDICAL COLLEGE” of the candidate DR. P. SULOCHANA with registration Number 201630251 for the award of M.D. in the branch of Dermatology, Venereology & Leprosy. I personally verified the urkund.com website for the purpose of plagiarism check. I found that the uploaded thesis file contains from introduction to conclusion page and result shows 1 percentage of plagiarism in the dissertation.

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CONTENTS

SL NO TITLE PAGE NO

1 INTRODUCTION 1

2 REVIEW OF LITERATURE 3

3 AIMS &OBJECTIVES 48

4 MATERIALS AND METHODOLOGY 49

5 OBSERVATION & RESULTS 51

6 DISCUSSION 71

7 SUMMARY 89

8 CONCLUSION 93

9 LIMITATION OF THE STUDY 95

10 BIBLIOGRAPHY

ANNEXURES

 PROFORMA

 CLINICAL PHOTOGRAPHS

 MASTER CHART

 CONSENT FORM

LIST OF ABBREVIATIONS USED WHO – World Health Organisation

ADR – Adverse Drug Reaction

CADRs – Cutaneous Adverse Drug Reactions

CA - Carcinoma

AICAR – Aminoimidazole – Carboxamide –Ribonucleotide Transformylase

5FU – 5 Fluorouracil

6MP – 6 Mercaptopurine

6 TG – 6 Thioguanine

ABVD – Adriamycin/ Bleomycin/ Vinblastine/ Dacarbazine

FOLFOX – Folinic acid/ Leucovorin/ Oxaliplatin

TPMT – ThioPurine S Methyl Transferase

AHS – Azathioprine Hypersenstivity Syndrome

DNA – Deoxy Ribonucleic Acid

RNA – Ribonucleic acid

PATEO – Periarticular Thenar Erythema with Onycholysis

HL – Hodgkin’s Lymphoma

NHL- Non Hodgkin’s Lymphoma CML- Chronic Myeloid Leukemia

CLL- Chronic lymphocytic Leukemia

ALL – Acute Lymphoblastic Leukemia

GIST – Gastro Intestinal Stromal Tumour

NSCLC – Non Small Cell Lung Carcinoma

EGFR – Epidemal Growth Factor Receptor

VEGFR – Vascular Endothelial Growth Factor Receptor

PDGFR – Platelet Derived Growth Factor Receptor

SJS – Stevens – Johnson syndrome

TEN – Toxic epidermal Necrolysis

AGEP – Acute Generalised Exanthematous Pustulosis

DRESS – Drug Rash with Eosinophilia and Systemic Symptoms

HFS – Hand – foot syndrome

PPES – PalmoPlantar Erythrodysesthesia

PRIDE syndrome - Papulopustules, paronychia, Regulatory abnormalities of hair growth, Itching and Dryness due to EGFR inhibitor.

GIT – Gastro Intestinal Tract INTRODUCTION

Chemotherapy is a common, widely used treatment for cancer. We started to use Cancer chemotherapy since 1940. First FDA approved drug is Mechlorethamine and it is being used for non small cell lung cancer since 1949(1). Cutaneous adverse reactions (CARs) are the most commonly associated adverse effects with chemotherapy next to haematological toxicity. They range from mild reactions to severe fatal reactions.

Mechanism of drug reaction:

Chemotherapeutic drugs act on tumour by interfering with DNA replication process that affects normal healthy tissues containing rapidly dividing cells such as hair, nails, skin and mucosa(2).Cutaneous complications following chemotherapeutic agents administration are generally due to accidental extravasation of drugs, while systemic toxicity may be caused by

i) A direct toxic effect,

ii) Hypersensitivity reactions and

iii) Dissemination of inflammatory response mediators by

necrotic cells.

Nowadays newer chemotherapeutic agents are introduced to improve the clinical outcome such as targeted therapies which contain small molecule drugs and monoclonal antibodies. Oldest drugs represent

1 cytotoxic agents. Single agent or combination of multiple drugs can be given to target many types of tumour cells.

These agents may be cell cycle specific or cell cycle non specific.

Cell cycle specific agents target one specific phase of cell cycle and can be given more frequently or as continuous infusion. Cell cycle non specific agents act against all proliferating cells regardless of cell cycle and are usually given as a single dose(3).

Most commonly observed adverse effects like xerosis, alopecia, rash, pruritus, mucositis, hand-foot syndrome, dyspigmentation, acneiform eruption, nail changes, and hair changes lead to decreased compliance to the drug and increased morbidity. These adverse effects are common with both cytotoxic drugs and targeted therapies.

Newer anticancer drugs are replacing the older traditional chemotherapy agents. Pattern of adverse cutaneous reactions to chemotherapeutic drugs is changing every year. Hence this study was conducted to study the pattern of adverse drug reactions following cancer chemotherapy.

REVIEW OF LITERATURE

An adverse drug reaction (ADR) is defined by World Health

Organization (WHO) as “Any response to a drug which is noxious, unintended and occurs at doses used in man for prophylaxis, diagnosis or therapy".

They range from mild reactions like xerosis, alopecia, rash, pruritus, mucositis, hand-foot syndrome, dyspigmentation, acneiform eruption, nail changes, and hair changes to severe fatal reactions like Steven-Johnson

Syndrome (SJS), Toxic Epidermal Necrolysis(TEN).

CLASSIFICATION OF CHEMOTHERAPEUTIC AGENTS:

MAJOR CLASS

1. Cytotoxic drugs

2. Targeted drugs

1. CYTOTOXIC DRUGS:

ALKYLATING AGENTS:

Nitrogen mustards: Mechlorethamine, Cyclophosphamide,

Ifosfamide, Chlorambucil, Melphalan.

Ethylenimine: Thiotepa, Altretamine

Alkyl sulfonate: Busulfan

Nitrosoureas: Carmustine, Lomustine, Streptozocin, Bendamustine

Triazine: Dacarbazine

Methyl hydrazine: Procarbazine

PLATINUM COMPOUNDS:

Cisplatin

Carboplatin

Oxaliplatin

ANTIMETABOLITES:

Folate antagonist: Methotrexate, Pemetrexed

Purine antagonist: 6 – Mercaptopurine (6 –MP), 6 –Thioguanine

(6 – TG), Azathioprine, Fludarabine

Pyrimidine antagonist: 5 – Fluorouracil (5 FU),Capecitabine,

Cytarabine

MICROTUBULE DAMAGING AGENTS:

Vinca alkaloids: Vincristine, Vinblastine, Vinorelbine

Taxanes: Paclitaxel, Docetaxel

CAMPTOTHECIN ANALOGUE

Topoisomerase 1 inhibitors: Topotecan, Irinotecan

EPIPODOPHYLLOTOXINS:

Etoposide

Teniposide

ENZYMES:

L-asparaginase

ANTIBIOTICS:

Actinomycin D (dactinomycin), Doxorubicin, Daunorubicin

(Rubidomycin), Mitoxantrone, Bleomycin, Mitomycin C

MISCELLANEOUS:

Hydroxyurea, Tretinoin, Arsenic trioxide

TARGETED DRUGS:

Tyrosine protein kinase inhibitors - Imatinib, Nilotinib

Epidermal growth factor receptor inhibitor - Gefitinib, Erlotinib

Angiogenesis inhibitor - Bevacizumab

Proteasome inhibitor - Bortezomib

Unarmed monoclonal antibody - Rituximab, Trastuzumab

CELL CYCLE:

The cell cycle is series of events by which normal and cancer cells divide and form new cells. Oncogenes and tumour suppressor genes provide the stimulatory and inhibitory signals that regulate the cell cycle.

Five phases of cell cycle:

DNA replication (S phase)

Cell division (M phase)

Two resting phases (G1 and G2)

Nondividing state (G0 phase) - quiescent state

First resting phase G1, the cell grows in size and decides to commit to the cell cycle or remain in a resting state. If the cell is normal at G1S

5 checkpoint, the cell will move into the S phase to synthesize its DNA.

Next, the cell enters the second resting phase G2, in which the cell prepares to divide. In the M phase, the cell enters mitosis and yields two daughter cells. If the cell is not healthy, the cell can stop dividing and undergoes apoptosis.

Apoptosis:

Apoptosis (programmed cell death or suicide) is a normal mechanism of cell death required for tissue homeostasis. This process is regulated by oncogenes and tumour suppressor genes and is also a mechanism of cell death after exposure to cytotoxins. Overexpression of oncogenes decreases apoptosis and may produce an “immortal” cell. This is a potential risk for malignancy.

Cell cycle specific / non specific inhibitors:

• Cell cycle specific:

They act on actively dividing cells

G1 -Vinblastine

S - Methotrexate, 6- MP, 5-FU, 6-TG, Doxorubicin,

Daunorubicin, Mitomycin C, Hydroxyurea

G2 - Bleomycin, Etoposide, Topotecan

M - Vincristine, Vinblastine, Paclitaxel, Docetaxel

• Cell cycle non specific: They act on resting as well as dividing cells.

E.g. Alkylating agents, L- asparaginase, Cisplatin, Actinomycin D

INCIDENCE:

Incidence of drug induced cutaneous reaction to cancer chemotherapy is about 2 to 5% of hospitalised patients(4).Increasing incidence occurs due to the increasing age, number of drugs and immunocompromised status(4).

REVIEW OF COMMON DRUGS IMPLICATED IN ADVERSE

CUTANEOUS DRUG REACTIONS

1. ALKYLATING AGENTS:

Mechanism of action:

They form the highly reactive carbonium ion intermediates. These reactive intermediates covalently link to sites of phosphates, amines, sulfhydryl, and hydroxyl groups and causes alkylation of reactive amines, or phosphates on DNA. Alkylating agents covalently bind with N7 atom of guanine residue on DNA and result in abnormal base pairing and DNA strand breakage leading to arrest of cellular proliferation(5).

Side effects of alkylating agents:

A. MECHLORETHEMINE:

Mechlorethamine is the first clinically used nitrogen mustard and used topically for cutaneous T cell lymphoma (CTCL). It has highly irritant effect. It has been replaced by other alkylating agents.

B. CYCLOPHOSPHAMIDE and IFOSFAMIDE:

Cyclophosphamide is highly toxic to mucosal cells and hair follicles.

Most common side effects are permanent alopecia (Anagen effluvium)(5) followed by oral mucositis, hyperpigmentation of palms, soles, nails(6,7).

Pigmentation is reversible after discontinuation of therapy.

C.CHLORAMBUCIL:

It is exclusively used in long term maintenance therapy for chronic lymphocytic leukemia (CLL). Allergic reactions in the form of urticated plaques has been reported with chlorambucil(8).Morbilliform drug eruption and Drug Rash with Eosinophilia and Systemic

Symptoms(DRESS) have also been reported in literature.

D.MELPHALAN:

Melphalan is primarily used for multiple myeloma. It has less irritant effect and causes less alopecia when compared to other alkylating agents.

E. BENDAMUSTINE:

It is used in the treatment of CLL and Non Hodgkin’sLymphoma

(NHL). Most common adverse effects are mucositis, SJS and infusion reaction which are reversible on withdrawing the drug. Papulopruritic eruption occurring with Bendamustine has been reported in literature(9).

1a. ALKYL SULFONATES:

A. BUSULFAN:

Busulfan is the standard agent to treat chronic myelocytic leukemia.

Adverse drug events are hyperpigmentation of skin and nails followed by permanent alopecia.

1b. TRIAZENES:

A. DACARBAZINE:

Photosensitivity and alopecia are the most commonly reported side effects.

2. ANTIMETABOLITES:

2.1 FOLATE ANTAGONIST:

A. METHOTREXATE:

Methotrexate is a synthetic folic acid analogue and it has both antiproliferative and anti-inflammatory properties. The drug is cell cycle specific and is active only in the Synthetic phase of the cell cycle. It is used in the treatment of malignancy due to its antiproliferative effect. Its primary metabolite polyglutamate competitively inhibits dihydrofolate reductase (DHFR), and thereby preventing the reduction of folate cofactors leads to inhibition of thymidylate synthesis, that causes inhibition of pyrimidine synthesis. Other folate-dependent enzymes inhibited by polyglutamate include aminoimidazole-carboxamide-ribonucleotide

(AICAR) transformylase. The inhibition of AICAR impairs purine

9 synthesis. The methylation of homocysteine to methionine is also inhibited, thereby affecting the synthesis of polyamines such as spermidine and spermine.

Mucositis can occur in patients without adequate folate supplementation and in the setting of concomitant haematopoietic and gastrointestinal toxicities. Two types of cutaneous ulceration induced by methotrexate have been described in patients with psoriasis. Type 1 includes the painful erosion of psoriatic plaques which can take place shortly after initiation of the treatment or in the setting of dose alteration and drug interaction. This can be mistaken as an exacerbation of the condition itself. Type 2 describes ulceration in diseased skin, which has a variable correlation with treatment duration and thus may be overlooked as evidence of methotrexate toxicity. Alopecia, hyperpigmentation, ultraviolet burn recall and toxic epidermal necrolysis also have been reported.

B. PEMETREXED:

Pemetrexed is a multi-targeted antifolate that is used to treat Non-

Small cell lung cancer and mesothelioma. In addition to inhibiting DHFR, it also inhibits thymidine synthase and glycinamide ribonucleotide formyltransferase, decreasing the risk of the development of drug resistance. The approved labelling of pemetrexed requires administration of folic acid and vitamin B12 prior to initiating pemetrexed therapy and throughout the duration of treatment. Pemetrexed-related cutaneous

10 adverse reactions are commonly referred to as ‘cutaneous rash’, symptomatic diffuse hyperpigmentation of the upper body that resolves on cessation of treatment. Other side effects include stomatitis, oral erosion, alopecia , acral pigmentation, acute generalized exanthematous pustulosis (AGEP) (10).

2.2 PURINE ANALOGUES:

A. AZATHIOPRINE:

Azathioprine, a prodrug for 6-mercaptopurine (6-MP), inhibits DNA synthesis and prevents immune cell proliferation.

Pharmacology/Mechanism of Action:

Azathioprine is an inactive compound that is converted rapidly to 6-

MP in the blood and is subsequently metabolized by three different enzymes. Xanthine oxidase which is found in the liver and gastrointestinal

(GI) tract, converts 6-MP to the inactive final end product, 6-thiouric acid.

Thiopurine S-methyltransferase (TPMT), found in hematopoietic tissues and red blood cells, methylates 6-MP to an inactive metabolite, 6- methylmercaptopurine. Finally, hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is the first step responsible for converting 6-MP to 6-thioguanine nucleotides (6-TGNs), the active metabolites, which are incorporated into nucleic acids, ultimately disrupting both the salvage and de novo pathways of DNA, RNA, and protein synthesis(3). This process is toxic to the cell and renders the cell

11 unable to proliferate. Eventually, 6-TGNs are catabolized by xanthine oxidase and thiopurine S-methyltransferase to inactive products.

Adverse drug reaction:

Common skin lesions include alopecia, zoster, verruca vulgaris, hyperpigmentation and rarely malignant neoplasms. Allergic contact dermatitis has also been reported in persons who come into physical contact with azathioprine tablets. More severe systemic hypersensitivity reactions have been reported in patients taking azathioprine. Azathioprine hypersensitivity syndrome (AHS), which commonly occurs within the first

4 weeks of therapy, can present clinically and histopathologically like

Sweet syndrome(11). Shared clinical features include fever, constitutional symptoms and prompt response to systemic corticosteroid therapy, neutrophilia, and abrupt onset of erythematous cutaneous lesions.

Microscopically, both Azathioprine hypersensitivity syndrome and Sweet syndrome have rich neutrophils.

Bidinger JJ et al reviewed 67 cases of Azathioprine hypersensitivity syndrome.49% (33/67) had cutaneous manifestations. Of those 33 cases with cutaneous findings, 76% (25/33) had Histopathological results or clinical features of neutrophilic dermatosis; 8 out of 33 cases were reported as nonspecific cutaneous eruption.

2.3 PYRIMIDINE ANALOGUES:

A.5- FLUOURACIL:

Fluorouracil (FU or 5-FU) is a fluorinated uracil analogue and is widely used for in the treatment of malignant neoplasms of the gastrointestinal(GI) tract, breast, and pancreas(12). It can be used alone or combination with other cytotoxic drugs. It acts as a false pyrimidine and undergoes sequential phosphorylation to a mono-, di-, and triphosphate. In the presence of folates, the monophosphate tightly binds and interferes with the function of thymidylate synthase. The triphosphate metabolite is incorporated into ribonucleic acid (RNA) as a false base and interferes with its function. The cutaneous adverse effects include mucositis, hand foot syndrome, photosensitivity(13), supravenous pigmentation, acral pigmentation, diffuse or nail restricted hyperpigmentation(14).The dosage and route of administration influences both the mechanism of action and toxicity(15). With continuous-infusion regimens, thymidylate synthesis inhibition plays important role. Dose limiting toxicity is hand – foot syndrome. Dihydropyrimidine dehydrogenase (DPD) is a pyrimidine catabolic enzyme that is responsible for the catabolism of FU. Reduced level of this enzyme has been associated with drug accumulation and serious adverse events(16).

B. CAPECITABINE:

Capecitabine is an orally administered pyrimidine uracil analogue and is indicated in breast and colon cancers. It is a prodrug of 5’- deoxy- 5- fluorouridine, and it is converted into 5 – FU. Hand –foot syndrome is most commonly associated with capecitabine, reported in 71% of patients.

It starts 24 hours to 3 weeks after the initiation of chemotherapy. Patients initially complain of a tingling or burning sensation that precedes the eruption(17). Capecitabine -induced nail changes are due to accumulation of the drug into nail bed, change and disruption of the nail plate, subungual edema with loss of adhesion between nail bed and nail plate. Inflammatory process leads to the development of nail and periungual abnormalities. Nail changes include onycholysis, pyogenic granuloma-like lesions, onychomadesis, subungual hyperkeratosis, and paronychia(18). It may cause stomatitis, pyogenic granuloma and hyperpigmentation. Toxic epidermal necrolysis is an idiosyncratic reaction and rarely reported. Matos

– Fernandez et al reported one case of TEN to capecitabine in which the drug was stopped(19).

C.GEMCITABINE:

Gemcitabine is an antimetabolite nucleoside and fluorine-substituted deoxycytidine analogue that is related structurally to cytarabine. It is incorporated into deoxyribonucleic acid (DNA), and inhibits DNA polymerase activity. It also inhibits ribonucleotide reductase, which is

14 required to convert ribonucleotides into the deoxyribonucleotides that are needed for both DNA synthesis and repair(3). It is indicated in pancreatic, non-small cell lung, breast, and bladder cancers. 25% of individuals with gemcitabine were reported with cutaneous toxicity including alopecia, hand foot syndrome, urticaria, maculopapular eruption, and rarely vasculitis. Gemcitabine induced vasculitis is due to endothelial damage, increased adherence of platelets and deposition of immune complex(20).

D.CYTARABINE:

Morbilliform rashes, Hand – foot syndrome, generalized urticaria are the adverse events reported with Cytarabine. The incidence is about

53%(21). Both Neutrophilic eccrine hidradenitis and eccrine syringo squamous metaplasia are reported with cytarabine.

3. PLATINUM COMPOUNDS:

Mechanism of action:

They form DNA addicts by the intrastand and interstand DNA cross link and inhibit the replication and lead to apoptosis(5).Hypersensitivity reactions are most commonly reported in platinum compounds. It is due to type1 IgE mediated or type 4 T – cell mediated hypersensitivity.

A.CISPLATIN:

It is a first generation platinum compound and is associated with more adverse drug reactions. The most frequent cutaneous side effects patchy or localised hyperpigmentation, reported in 70% of patients.

Hypersensitivity reaction reported in 5 to 20% of individuals with cisplatin. It occurs after few minutes of infusion and reported in 4th to 8th cycles of chemotherapy(22). Maculopapular eruptions are reported with cisplatin and incidence is found to be 5% when used alone and increased to

20% when used with combination therapy(23). It may also cause oral hyperpigmentation, melanonychia, exfoliative dermatitis.

B. CARBOPLATIN:

Carboplatin is categorized under second generation platinum compound. Efficacy of both cisplatin and carboplatin is equal but toxicity is more commonly associated with cisplatin. So cisplatin is replaced by carboplatin. Most common side effect of carboplatin is alopecia. Next one is hypersensitivity reaction. The Overall incidence of carboplatin induced hypersensitivity is 1-44%. Hypersensitivity reaction occurs within minutes or days from infusion. Severity increases with subsequent exposure of carboplatin(22).

C. OXALIPLATIN:

It is the third generation platinum compound and is used in the treatment of metastatic colorectal cancer. Hypersensitivity with oxaliplatin is less commonly reported and found to be 10 to 18%. It occurs within minutes and hours of infusion and reported after 6thpulse of treatment.

4. MICROTUBULES DAMAGING AGENTS:

4.1. TAXANES:

Taxanes are microtubule damaging agents. They bind to microtubular protein and inhibit polymerisation and assembly leading to mitotic spindle arrest and metaphase arrest(24). Paclitaxel (PC) and

Docetaxel are the 2 types of taxanes. They are structurally and functionally similar in nature but dissolved in different vehicles. Signs of dermatological toxicity are observed in around 65% of cases which include alopecia, hand and foot syndrome, hypersensitivity reactions, extravasation injury and ungual alterations(25).

A. DOCETAXEL:

Docetaxel is a semisynthetic chemotherapeutic agent, polysorbate

80 in ethanol solvent system. It is derived from Taxus baccata and has been successfully used for the treatment for ovarian, breast, and lung cancer(26). The common side effects include PalmoPlantar

Erythrodysesthesia (PPES), alopecia, mucositis, maculopapular eruption, photolichenoid reaction, hyperpigmentation, extravasation injury and rarely urticaria. Taxane associated PPES has been identified with acronym of PATEO (Periarticular Thenar Erythema with Onycholysis). It has been reported with docetaxel and occurs in approximately about 40% of patients. Mechanism of PPES is due to direct cytotoxic effect of drug on acral epidermis. Incidence of nail changes is about 0 to 44% and they

17 include paronychia, onycholysis, subungual hemorrhage and pyogenic granuloma(26).

B. PACLITAXEL:

Paclitaxel is polysorbate 80 in polyoxyethylated caster oil and dehydrated alcohol and derived from bark of the Pacific yew tree Taxus brevifolia. Paclitaxel is most commonly associated with alopecia, extravasation injury than docetaxel and reported in 2% of patients(27). It has activity against breast and ovarian carcinoma. Other adverse events include mucositis, onycholysis, erythema multiforme, pustular eruptions,

HFS, and scleroderma- like changes(28).

4.2 VINCA ALKALOIDES:

Vincristine, vinblastine, and vinorelbine come under vinca alkaloids and are effective in lymphoproliferative malignancies and solid tumours.They are derived from periwinkle plant and inhibit the microtubule polymerization causing microtubule destabilization leading to cell death(29).

A. VINCRISTINE:

Vincristine is used in the treatment of Acute Lymphoblastic

Lymphoma (ALL), Hodgkins lymphoma, lymphosarcoma, Wilms tumor,

Ewings sarcoma. It acts as a vesicant, and is known to produce extravasation injury followed by ulceration. Other reported side effects are

18 alopecia, xerosis, HFS, photosensitvity and Beau’s lines(4). It causes peripheral neuropathy on long term therapy.

B. VINBLASTINE:

This is another compound of vinca alkaloids and approved in the treatment of Hodgkins disease & other lymphomas, breast cancer, testicular cancer. The reported side effects are alopecia, photosensitivity,

HFS and nail changes(30).

C.VINORELBINE:

It is new semisynthetic vinca alkaloids, approved for unresectable

Non Small Cell Lung Carcinoma (NSCLC). Vinorelbine is known to cause mild to moderate peripheral neuropathy, and alopecia. Less common side effects include acral erythema and extravasation injury(31).

5. TOPOISOMERASE INHIBITORS:

Topoisomerases I and II are essential enzymes involved in maintaining DNA structure during replication. These enzymes cleave DNA strands and form intermediates with the strands, producing a gap through which DNA strands can pass, and then reseal the strand breaks.

Topoisomerase I produces single-strand breaks and topoisomerase II produces double-strand breaks.

E.g. : Anthracyclines, Camptothecins, Podophyllotoxins.

5.1 CAMPTOTHECIN ANALOGUES:

Topotecan and irinotecan inhibit topoisomerase I enzyme activity.Topoisomerase I enzymes stabilize DNA single-strand breaks and inhibit strand resealing(32). They are indicated in colorectal and ovarian cancer. Cutaneous side effects include diffuse pigmentation, mucosal and nail bed pigmentation(33)

5.2 ETOPOSIDE:

Etoposide is Topoisomerase 2 inhibitor. It can cause erythema multiforme, exanthema, hypersensitivity, SJS, urticaria, and alopecia.

6. ANTHRACYCLINES:

A. DOXORUBICIN:

It is an Anthracycline topoisomerase inhibitor indicated for ovarian cancer, AIDS-related Kaposi sarcoma, and multiple myeloma. It is incorporated within DNA between adjoining nucleotide pairs and thereby inhibits DNA & RNA synthesis. Generation of oxygen radicals mediate single strand scission of DNA and also inhibits Topoisomerase II enzyme(24). The most common CADRs is hand-and-foot syndrome, which is followed by desquamation of the palms and soles, reported in approximately 50% of patients(34). Next common side effect includes mucositis, reported in 3 to 21% of patients. Ten percent of patients reported a diffuse follicular rash with mild, diffuse, scaly erythema and follicular accentuation that occurs over the lateral limbs but also may occur

20 over the trunk. UV light recall, intertrigo like eruption, melanotic macules are less commonly reported side effects with doxorubicin(35).

B. DAUNORUBICIN:

It is the hydrochloride salt of an anthracycline cytotoxic antibiotic agent that is produced by a strain of Streptomyces coeruleorubidus.

Cutaneous pigmentation, mucosal pigmentation and nail pigmentation are the CARs with daunorubicin. Angioedema with generalized urticaria have been reported. Alopecia, stomatitis, extravasation injury and infusion reactions are other associated conditions. Hand – foot syndrome associated with high dose of Daunorubicin(36).

C. BLEOMYCIN:

Bleomycin is antitumour antibiotic, and is derived from

Streptomyces verticillus. It is found to be effective in Hodgkin’s lymphoma, and germ cell tumour. It has effect on cell cycle of G2 and M phase(3). It has cytotoxic effect due to oxygen free radicals that cause single and double strand DNA breaks and lead to cell death. The common cutaneous adverse effects are pigmentation that is reported in approximately 50% of individuals, followed by alopecia. Other dermatological side effects include anaphylaxis, hypersensitivity reactions, mucositis, HFS, nail bed changes, and flagellate erythema. Flagellate erythema is due to micro trauma, increased melanogenesis, reduced epidermal turn over allowing prolonged melanocytes(37). Aminohydrolase

21 enzyme is a cytosolic cysteine proteins that inactivates the bleomycin. This enzyme is distributed in normal tissues, but is present in only low concentrations in the skin and the lungs. This is the reason for cutaneous toxicity and pulmonary toxicity(38).

SIGNAL TRANSDUCTION INHIBITORS:

EGFR is distributed over basal keratinocytes, sebocytes, hair and endothelial cells. Adverse drug reactions are Papulo pruritic eruptions, xerosis,telangiectasia, infusion reaction, hypertrichosis, alopecia and paronychia.

CLASSIFICATION:

Multikinase inhibitors: Imatinib, Nilotinib, Dasatinib, Sunitinib and

Sorafenib.

EGFR INHIBITORS - Erlotinib, Gefitinib

Monoclonal antibodies to EGFR – Cetuximab, Panitumumab

1. EPIDERMAL GROWTH FACTOR RECEPTOR INHIBITORS

(EGFR):

A.ERLOTINIB:

Erlotinib consists of small molecules that inhibit EGFR tyrosine kinase activity. It is indicated in treatment of locally advanced or metastatic Non Small Cell Lung Carcinoma (NSCLC) and can be combined with gemcitabine for metastatic pancreatic carcinoma. Most common CADRs include papulo pruritic eruption/ acneiform eruption,

HFS, xerosis and splinter haemorrhage. Kerato acanthoma, actinic keratosis, verruca vulgaris are other rare reported side effects(39).

B.GEFITINIB:

It is used as monotherapy for locally advanced or metastatic

NSCLC.

PAPULOPRURITIC ERUPTIONS:

Papulopruritic eruption is the most common side effect with EGFR inhibitors. It is seen in 48 to 67% of patients with erlotinib and 24 to 62% patients with gefitinib(31). It usually occurs after 7 to 10 days of initiation of chemotherapy and distributed over seborrheic areas. Histologically it is characterized by suppurative folliculitis with destruction of hair follicles and subsequent granuloma formation.

XEROSIS:

12 to 35 % of patients with EGFR inhibitors have been observed to develop xerosis. It is due to keratinocyte growth arrest and initiates the terminal differentiation.

TELANGIECTASIA:

It is defined as abnormal dilated tortuous capillaries and occurs following EGFR inhibitors. It occurs over face, on and behind ears, chest and back. It tends to fade over months and leave hyperpigmentation.

NAIL CHANGES:

Paronychia occurs in 10 to 15% of patients between 4 and 8 weeks.

It most commonly involves great toe and can be associated with painful fissures of the nail folds.

ALOPECIA:

EGFR has an important role in hair cycle. So, EGFR blockade leads to short wavy hairs and alopecia. Patchy or extensive non scarring alopecia occurs following gefitinib and erlotinib and recovers after discontinuation of therapy.Trichomegaly and increase in the length of eyebrows has also been reported with EGFR inhibitors.

These findings of papulo-pustular eruption, xerosis, hair and nail changes to EGFR inhibitors are collectively known as PRIDE syndrome

(Papulopustules, paronychia, Regulatory abnormality of hair growth,

Itching, Dryness)

2. MULTIKINASE INHIBITORS:

A.IMATINIB:

Imatinib is approved for the treatment of chronic myeloid leukemia

(CML), and Gastro Intestinal Stromal Tumours (GIST). It inhibits vascular endothelial growth factors(VEGFs), platelet derived growth factor(PDGF) and c-KIT, BCR-ABL(40)(41). 22% of patients with imatinib developed dermatitis in the form of maculopapules. Another study also reported few cases of exfoliative dermatitis(42),(43). Other adverse drug reactions

24 include hypopigmentation, Stevens - Johnson Syndrome (SJS)(44), Acute generalised exanthematous pustulosis (AGEP), lichenoid drug eruptions(45), nail pigmentation. 19% of individuals with imatinib reported with melasma pigmentation(46).These reactions occurred within 1 to 3 months following imatinib therapy. Hypopigmentation following imatinib present mainly over sun exposed areas and is due to inhibition of

C-KIT which is stem cell factor for melanogenesis, melanocyte homeostasis and is found to be reversible on withdrawal of the drug(31).

Cutaneous manifestations associated with Imatinib(42)

Dose dependant reactions Hypersensitivity reactions

Alopecia Maculopapular eruption

HFS SJS/TEN

Papulopustular eruption DRESS

Exfoliative dermatitis AGEP

Xerosis Urticaria/ angioedema

Stomatitis Exfoliative dermatitis

Pruritus Anaphylaxis

B.SUNITINIB:

It selectively inhibits VEGFR- 2, PDGFR β and is approved for

GIST, Renal cell carcinoma. Most common CARs are yellow discolouration of skin and urine (which occur after 3 to 4 weeks of

25 treatment), HFS, loss of pigmentation of hair. Other side effects include alopecia, xerosis, nail changes(47).

C.SORAFENIB:

It is classified as multikinase inhibitor that inhibits VEGFR -2,

PDGFR β and RAF kinase. It is used in treatment of hepatocellular carcinoma and renal cell carcinoma(3,47). Cutaneous toxicity includes erythema over face and scalp which simulate seborrheic dermatitis, usually occurs after 1 to 2 weeks of treatment with sorafenib. Acral erythema, subungual splinter haemorrhages are less frequent reported side effects.

Case reports of keratoacanthoma, eruptive melanocytic nevi have been reported in English literature.

ADVERSE CUTANEOUS DRUG REACTIONS (ACDRs):

ACDRs in chemotherapy can be discussed under

Adverse drug reaction in skin

Mucosal changes

Hair changes

Nail changes

CUTANEOUS ADVERSE DRUG REACTION:

1) Toxic erythema of chemotherapy

2) Papulopruritic eruptions/ papulopruritic eruptions

3) Pigmentary abnormalities

4) Extravasation injury

5)Xerosis and ichthyosis

6) Radiation recall

7) Photosensitivity

1) TOXIC ERYTHEMA:

Toxic erythema includes,

A) Palmoplamtarerythrodysesthesia

B) Intertriginous eruption associated with chemotherapy

C) Neutrophilic eccrine hidradenitis

Toxic erythema occurs due to direct toxicity of chemotherapy drug that is excreted through the acrosyringium of eccrine duct and the epidermis.

Other factors include microtrauma, friction, and temperature gradient(48).

It usually presents after 2 days to 3weeks of administration of drug. Patient presents with painful, itchy, erythematous plaques over acral skin and over the flexures.

Drugs implicated with toxic erythema are

Doxorubicin, Taxanes, 5 FU, capecitabine and methotrexate

Clinical variants:

HAND – FOOT SYNDROME (HFS):

Hand – foot syndrome is also called as chemotherapy induced acral erythema, palmar plantar erythrodysesthesia(18). It usually presents between 1day to 3 weeks after the administration of chemotherapeutic agents with pain, pruritus, paraesthesia and tenderness over the hands and

27 feet and/or intertriginous areas. Patients present with erythematous patches or oedematous plaques, typically distributed on the acral skin and at the major flexures(17). It is dose dependant and resolved with discontinuation of treatment(40),(39) Doxorubicin, cytarabine, docetaxel, fluorouracil and capecitabine, and EGFR inhibitors are the most commonly associated drugs with HFS(17),(47).HFS in kinase inhibitor is characterised by more localised and hyperkeratotic nature when compared to other cytotoxic chemotherapeutic agents(39).The combination of a Taxane with capecitabine is associated with an increased incidence of palmoplantar erythrodysaesthesia.

Mechanism of reaction:

Hand – foot syndrome is due to increased levels of the enzyme thymidine phosphorylase in keratinocytes, which can cause drug accumulation. Another theory suggested that increased number of eccrine glands on hands and feet resulting in the elimination of drug by sweat secretion. It causes direct stimulation of melanogenesis in melanocytes leads to hyperpigmentation.

Treatment:

Treatment of HFS is usually symptomatic and spontaneously resolves with desquamation. Symptomatic measures include regional cooling(49), oral pyridoxine with methylprednisolone(50), and topical dimethylsulfoxide.

INTERTRIGINOUS ERUPTIONS:

Patient presents with dusky red papules coalescing into patches and plaques over flexures. It resolves spontaneously by post inflammatory hyperpigmentation.

NEUTROPHILIC ECCRINE HIDRADENITIS:

It is usually characterised by erythematous papules, plaques, nodules over the extremities, trunk. Patient may have constitutional symptoms. It is associated with cytarabine and resolves spontaneously with hyperpigmentation.

Management of toxic erythema:

Treatment is based on symptoms because reactions resolve spontaneously with desquamation. If skin reaction is severe, discontinuation of treatment is needed(17)

2. ACNEIFORM ERUPTION OR PAPULOPUSTULAR

ERUPTIONS

It is an inflammatory follicular reaction which simulates the acne vulgaris. It present as monomorphic papules and pustules which usually lacks comedones. It occurs in 90% of individuals with EGFR inhibitors.

Other drugs with acneiform eruptions are anticancer antibiotics(51).

Pathophysiology:

EGFR inhibition of normal keratinocytes results in impaired migration and growth of keratinocytes, apoptosis of keratinocytes that

29 leads to inflammatory chemokine expression by keratinocytes. These events cause inflammatory cells adhesion and cutaneous injury that is responsible for the tenderness and pustules(52).

Clinically patient presents with erythema followed by papules and pustules. It occurs after 1 to 2 weeks after starting EGFR inhibitors and seen over seborrheic areas with sparring of palms and soles. It is exaggerated by sun exposure. Acneiform eruption associated with EGFR inhibitors is more pruritic when compared to other drugs like steroids, anticonvulsants(53).Early histopathological finding shows T-cell infiltrate around the follicular infundibulum followed by a suppurative folliculitis(54). Culture for microbial is quite negative but occasional growth of Propionibacterium acnes and secondary infection with staphylococcus has been documented. It usually resolves with post inflammatory hyperpigmentation(47).

Treatment:

Topical treatment includes clindamycin gel, retinoids and 5% metronidazole gel. For severe reactions, topical metronidazole with systemic retinoids or oral antibiotics may be required.

3. PIGMENTATION ABNORMALITIES:

It may be due to hyper or hypopigmentation. Cutaneous hyperpigmentation occurs due to cytotoxic chemotherapeutic agents and commonly affects skin, mucous membrane, hair, nails. It may be localised,

30 diffuse or some may have characteristic pattern.The common pigmentary pattern include palmoplantar pigmentation, nail and mucous membrane pigmentation. Characteristic patterns are flagellate and melasma like pigmentation.

Cancer chemotherapy agents associated with hyperpigmentation:

Types of hyperpigmentation Chemotherapeutic agents

Generalised, transverse bands in Cyclophosphamide

nails

Generalised and melanonychia Methotrexate

Generalised, nails, mucous 5- FU

membrane and supravenous

pigmentation

Serpentine supravenous 5 FU, Taxanes, Vincristine,

pigmentation Vinorelbine

Acral pigmentation Capecitabine and 5 FU

Generalised, acral, nail Doxorubicin, Daunorubicin

pigmentation

Flagellate erythema Bleomycin

Patchy hyperpigmentation 5- FU

MECHANISM FOR HYPERPIGMENTATION:

1) Chemotherapeutic agents have a direct toxic effect on epidermal

melanocytes stimulating increased melanin production;

2) It causes direct toxicity to adrenal gland leading to increased

adrenocorticotrophic hormone(ACTH) and melanocyte‐stimulating

hormone(MSH)

3) Pigmentary effect of deposited drug in the skin

4) Reduced tyrosinase inhibitors resulting in increased pigmentation.

5) Formation of drug and melanin complex.

Bleomycin‐induced flagellate hyperpigmentation due to minor trauma

to the skin that causes increased blood flow and produce local

accumulation of the drug(4).Incidence of flagellate erythema was found

to be 8 to 22%(55).

Treatment:

There is no specific treatment for hyperpigmentation. It usually resolves spontaneously after discontinuation of treatment.

Chemotherapy induced hypopigmentation:

Hypopigmentation can occur as early as 2nd day or as long as 6 months after initiating chemotherapy. Pathogenesis of hypopigmentation is unknown. But the proposed pathogenesis includes genetic factors, toxic metabolites and lack of melanocyte growth factors. With the use of tyrosine kinase inhibitors, the proto‐oncogene c‐Kit mutations, leads to

32 inhibition of signal transduction pathway of melanocytes and causes hypopigmentation(56).

Chemotherapeutic agents causing hypopigmentation:

Doxorubicin, Imatinib, Dasatinib, Gefitinib

Treatment:

It may get spontaneously resolved or may persist after stoppage of chemotherapy. Patients are advised to use sunscreen properly.

4. PHOTOSENSITIVITY:

It is defined as abnormal sensitivity following ultraviolet rays due to chemotherapeutic agents. It may be phototoxic or photoallergic reaction.

But phototoxic is more common than photoallergic. UV recall reactions can occur with certain chemotherapeutic agents. Patients present with burning sensation over sun‐exposed sites and occurring within 12 to 24 hours after drug intake. Skin lesions resolve with hyperpigmentation.

Drugs with phototoxicity:

5‐Fluorouracil, Methotrexate, Dacarbazine,Thioguanine,

Mitomycin C Vinblastine and Doxorubicin(55).

Treatment:

Treatment measures include topical steroids, broad spectrum sunscreens and UV light‐protective clothing.

5. EXTRAVASTION INJURY:

It is defined as the leakage of drug from vessels into surrounding tissues. The frequency of extravasation is reported to be 0.1 to 6 % of intravenous infusion. Vesicant and irritant chemotherapeutic agents are responsible for the extravasation injury. Vesicant drugs cause severe tissue injury and ulceration. In this, patient presents with swelling, erythema, pain and blistering that progressively leads to tissue destruction. Irritants drugs produce inflammatory reaction and resolve with hyperpigmentation.

These are less severe when compared to vesicant(29,57). Anthracyclines, vinca alkaloids, mitomycin C are the most chemotherapeutic drugs causing extravasation(58,59). Complete recovery is possible with taxanes induced extravasation injury.

Grades of Infusion site extravasation(59)

Grading Cutaneous manifestations Grade 1 - Grade 2 Erythema with associated symptoms (edema, pain, induration, phlebitis) Grade 3 Ulceration or necrosis; soft tissue damage, operative intervention is needed Grade4 Life-threatening consequences; urgent intervention indicated Grade 5 Death

Eg of vesicants and irritants(57)

Vesicants Irritants

Doxorubicin, daunorubicin Cisplatin, Carboplatin

Mechlorethamine Taxanes

Mitomycin c 5 FU

Vincristine Etoposide

Vinblastine Cyclophosphamide

Vinorelbine Irinotecan

Dactinomycin Melphalan

Treatment:

Therapeutic measures include cold application that causes vasoconstriction and thereby prevents the systemic absorption of the drugs.

Flush out technique is useful to prevent severe injury, where we use an infiltration canula into subcutaneous tissue and flush out the extravasated drug. Antidotes are useful in vesicant chemotherapeutic agents or large volume extravasations.

Eg : Hyaluronidase for vinca alkaloids

Dimethysulfoxide for anthracyclines

Sodium thiosulphate for nitrosoureas

6. XEROSIS:

Chemotherapy induced xerosis is mainly due to direct toxicity of chemotherapeutic agents to eccrine glands. It is characterised by dryness, may or may not be associated with scaling. Scales are flaky or greasy scales, resembles seborrheic dermatitis. EGFR inhibitors are the mostly encountered drug associated with xerosis. Xerophthalmia, vaginal dryness, and perineal dryness has also reported in literature(31).

7. CHEMOTHERAPY INDUCED HAIR CHANGES:

ALOPECIA:

Effluvium is defined as hair loss of more than 100 hairs per day over a period of 2-4 weeks, whereas alopecia is a visible reduction in the hair density of about 30%. Anagen efﬂuvium is mainly due to chemotherapy- induced alopecia and other causes are rarely considered. Anagen effluvium is described as abrupt loss of hairs in growing phase (anagen phase) due to direct toxicity that affects the metabolic activity of hair follicles. The most common site of hair loss is scalp.The hair loss starts from the crown and sides of the head, which may be due to t increased friction. It usually starts

1 to 3 months of starting chemotherapy.In anagen effluvium, only the

“proliferating cells in the bulb” are affected ,while the quiescent stem cells of the bulge that are responsible for reinitiating follicle growth are spared, so hair loss is usually completely reversible. Incidence of chemotherapy- induced anagen effluvium is reported to be 65%(60).

Cytotoxic agents that cause Anagen effluvium commonly associated:

Doxorubicin, Daunorubicin, Paclitaxel, Docetaxel,

Cyclophosphamide, Ifosfamide, Etoposide, Mechlorethamine,

Methotrexate, Bleomycin.

Uncommonly associated with anagen effluvium:

Vincristine, Vinblastine, 5-Fluorouracil, Hydroxyurea, Thiotepa

Treatment:

The aim is to reduce the hair loss by reducing the drug delivery to the growing hair follicle by temporarily obstructing blood flow with a tourniquet or by inducing scalp hypothermia by a scalp tourniquet.

Tourniquet consists of a pneumatic device placed around the hairline during chemotherapy infusion and inflated to a pressure greater than the systolic blood pressure. Several studies have found scalp tourniquets to be effective for preventing hair loss(61,62). Scalp hypothermia (scalp temperature of less than 24°C) is induced by cooling agents applied through a cooling cap or by continuous cooling of the scalp with cold air or liquid .Multiple cooling systems like ice turban, gel packs, cool caps, thermocirculator, and room air conditioner can be used. Psychological support is necessary because hair loss is psychologically affecting the patient. Patient education is very important in anagen effluvium. Patients should also be reassured that the hair loss is temporary and that normal hair growth will occur a few weeks after completion of treatment.

Recommendations for hair care include: Avoiding physical or chemical trauma to the hair (e.g. bleaching, colouring, perming, using curling irons, or hot rollers). Using a soft brush, washing hair only as often as necessary, and using a gentle shampoo.

Chemotherapy induced nail changes:

Drug induced nail alterations are due to drug toxicity to nail matrix, nail bed, periungual tissues and melanocyte stimulation.

Nail matrix and nail plate changes:

Abnormal colour changes of nail plate or surface of nail plate or subungual tissues known as chromonychia. 3 types of chromonychia are melanonychia, leukonychia and erythronychia. Melanonychia is most common type of nail changes due to antineoplastic drugs such as doxorubicin, bleomycin, capecitabine(63), paclitaxel, cyclophosphamide, docetaxel(6,64). Mechanism of melanonychia is due to photosensitivity or abnormal nail matrix melanocyte stimulation and deposition of melanin in nail matrix(65,66). Antineoplastic drugs such as vincristine, doxorubicin,and cyclophosphamide are associated with mee’s lines(66).

Nail bed changes:

Splinter hemorrhages are associated with Sunitinib, Sorafenib due to inhibition of physiological repair process(64). Docetaxel and

Paclitaxel produce hemorrhagic onycholysis resulting in suppuration and hemorrhage of nail bed which leads to nail plate loss(66).

Nail fold changes:

Paranychia and pyogenic granuloma are commonly reported with

EGFR inhibitors, taxanes(66). Early lesions of periungual and nail fold are not infected and are also negative for bacterial and fungal cultures. But superinfection may occur with bacterial or fungal infections(64).

Digit tip xerosis:

Xerosis or erythema or fissuring of the fingertips are associated with EGFR Inhibitors.

Treatment:

Nail changes are asymptomatic and usually require no treatment.

They usually resolve after discontinuation of treatment.

Chemotherapy induced mucosal changes:

The common adverse events following chemotherapy which involve the mucosa include mucositis, mucosal pigmentation, Xerostomia, nutritional deficiencies and infections. The onset of mucositis is usually 2 to 5 days after initiation of chemotherapy and ulcerations occur usually after 7 days though it may vary depending upon the regimen used. Non keratinized buccal and labial mucosa is more commonly affected than the dorso lateral surface of tongue. Commonly implicated chemotherapeutic agents include alkylating agents such as Busulfan and Cyclophosphamide;

Anthracyclines such as Daunorubicin, Doxorubicin; antimetabolites such as Hydroxyurea, 5- FU and Methotrexate; Antibiotics such as Actinomycin

D and Bleomycin; Vinca alkaloids such as Vinblastine and Vincristine; and Taxanes.

New drugs and new therapeutic schedules have prolonged survival and hence brought better prognosis to many malignancies. But most of the chemotherapeutic agents have a narrow therapeutic index and hence dosage monitoring needed. Hence cautious and detailed evaluation of associated toxicities with a sequential series of skin tests will greatly help in determining the culprit drug and finding a safer replacement molecule which permits the continuation of effective chemotherapy.

CHEMOTHERAPEUTIC AGENTS AND ITS SIDE EFFECTS

Alkylating agents Mechanism of action Side effects

Mechlorethamine They form the highly reactive Topical vesicant, extravasation injury carbonium ion intermediates. These Alopecia Cyclophosphamide reactive intermediates covalently ( anagen effluvium), link to sites of phosphates, amines, Oral mucositis sulfhydryl, and hydroxyl groups Hyperpigmentation of palms, soles, nails. Chlorambucil and cause alkylation of reactive Urticated plaques, amines, or phosphates on DNA Morbilliform drug eruption, produce abnormal base pairing, And drug rash with eosinophilia and systemic DNA strand breakage, Alkylation symptoms(dress) Melphalan also damages RNA and proteins. Less irritant effect and less alopecia Bendamustine Mucositis, sjs ,infusion reaction, papulopruritic eruption

Busulfan Hyperpigmentation of skin and nails, Permanent alopecia Dacarbazine Photosensitivity,alopecia

Antimetabolites Mechanism of action Side effects Methotrexate -DNA synthesis inhibition – ‘S’ phase Mucositis, alopecia, hyperpigmentation, ultraviolet burn recall specific and toxic epidermal necrolysis -Inhibitis DHFRimpairs thymidylate synthesisimpairs pyrimidine synthesis -Inhibits AICAR transformylase impairs purine synthesis Pemetrexate Inhibits DHFR, thymidine synthase Cutaneous rash ,stomatitis, oral erosion, alopecia , acral and glycinamide ribonucleotide pigmentation formyltransferase AGEP Purine antagonist 6-thioguanine nucleotides (6-TGNs), Alopecia, zoster, verruca vulgaris, hyperpigmentation ,rarely 6 TG , 6MP (active metabolite), which are malignant neoplasms, allergic contact dermatitis, azathioprine incorporated into nucleic acids, hypersensitivity syndrome ultimately disrupting both the salvage and de novo pathways of DNA, RNA, and protein synthesis Pyrimidine Inhibits thymidylate synthase  Mucositis, hand foot syndrome, photosensitivity, supravenous antagonist failure of DNA synthesis pigmentation, acral pigmentation, diffuse or nail restricted 5 FU hyperpigmentation Capecitabine -Prodrug of 5FU -hand and foot syndrome -Metabolised to 5 – FU -nail changes – onycholysis, pyogenic granuloma-like lesions, -Inhibit thymidylate synthase onychomadesis, subungual hyperkeratosis, and paronychia -stomatitis, pyogenic granuloma,hyperpigmentation Gemcitabine -inhibits DNA polymerase Alopecia, hand foot syndrome, urticaria, maculopapular -inhibits ribonucleotide reductase eruption, and rarely vasculitis Cytarabine -inhibits DNA polymerase -Morbilliform rashes, hand foot syndrome, generalized urticaria -blocks DNA synthesis. -Neutrophilic eccrine hidradenitis and eccrine syringo squamous metaplasia

Platinum Mechanism of action Side effects

compounds

Cisplatin Inter and intra strand Patchy or localised hyperpigmentation, hypersensitivity reaction,

crosslinking  abnormal maculopapular eruptions, oral hyperpigmentation, melanonychia,

base pairing  DNA exfoliative dermatitis.

damage inhibits cell

Carboplatin proliferation. Alopecia, hypersensitivity

Oxaliplatin Hypersensitivity is less

Microtubule Mechanism of action Side effects damaging agents Taxanes Bind to microtubular Alopecia, hand and foot syndrome, hypersensitivity reactions,

protein and inhibit extravasation injury and ungual alterations

1.Docetaxel polymerisation and Palmoplantar erythrodysesthesia(PPED), alopecia, mucositis,

assembly mitotic maculopapular eruption, photolichenoid reaction,

spindle arrest and hyperpigmentation, extravasation injury and rarely urticaria,

metaphase arrest PATEO

Nail changes- paronychia, onycholysis, subungual hemorrhage

and pyogenic granuloma

2.Paclitaxel Mucositis, onycholysis, erythema multiforme, pustular eruptions,

HFS and scleroderma- like changes

Vinca Alkaloids Mechanism Of Action Side Effects

1. Vincristine Inhibit the microtubule Vesicant- extravasation injury followed by ulceration

polymerization causing Alopecia, xerosis, hfs, photosensitivity ,beau’s lines, peripheral

microtubule neuropathy

2.vinblastine destabilization Alopecia, photosensitivity, HFS and nail changes

3.vinorelbine Peripheral neuropathy, alopecia, acral erythema and extravasation

injury

Topoisomerase Mechanism of action Side effects

inhibitors

Topotecan and irinotecan Topoisomerase 1 inhibitor Diffuse pigmentation, mucosal and nail bed pigmentation

Stabilize DNA single-strand

breaks and inhibit strand

resealing

Etoposide Topoisomerase 2 inhibitor Erythema multiforme, exanthema, hypersensitivity, SJS,

urticaria, and alopecia

Antibiotics Mechanism of action Side effects Doxorubicin Directly binds with DNA and HFS, mucositis, diffuse follicular rash, UV light recall, inhibits its synthesis. intertrigo like eruption, melanotic macules Daunorubicin Cutaneous pigmentation, mucosal pigmentation and nail pigmentation, Angioedema with generalized urticaria, alopecia, stomatitis, extravasation injury and infusion reactions,HFS Bleomycin - effect on cell cycle of g2 and m Pigmentation,alopecia, anaphylaxis, hypersensitivity reactions, phase mucositis, HFS, nail bed changes, and flagellate erythema -produces superoxide ions -interfere with DNA strands -chain scission -inhibits repair mechanism

AIMS AND OBJECTIVES

AIM:

To estimate and describe the mucocutaneous adverse effects of cancer chemotherapeutics agents.

OBJECTIVES:

. To describe the various morphological pattern and frequency of side

effects.

. To study about the specific or peculiar reaction to particular class of

chemotherapeutic agents.

. To identify the correlation between morpology of reaction with

types of tumour if any.

MATERIALS AND METHODOLOGY

STUDY DESIGN:

Observational Prospective study.

STUDY POPULATION AND STUDY PERIOD:

Study was conducted in Dermatology and Medical oncology department in Tirunelveli Medical College, Tirunelveli. All confirmed cases on cancer chemotherapy were enrolled in the study over a period of

18 months after obtaining clearance from institutional ethical committee.

MATERIALS:

All diagnosed cancer patients on chemotherapy attending oncology

OPD irrespective of age and sex were included in the study. Both written and informed consent were obtained from patients or guardian to carry out necessary investigations and to take clinical photographs.

Detailed history regarding residence, occupation, nature of chemotherapy drugs administered, number of cycles completed, and other treatment modalities were recorded. History pertaining to any drug reaction, if so, the reaction time, duration of reaction, previous allergic history, type of skin lesions was noted. Coexisting dermatological conditions and other medical ailments were obtained. A thorough drug history was recorded related to all prescriptions and over the counter drugs during last month with date and dosages.

A detailed physical examination was performed and dermatological examination regarding morphological patterns, site of skin lesions were recorded in predesigned profoma. Relavant investigations were carried out.

Patients were managed with appropriate treatment.

STATISTICAL ANALYSIS:

CADRs were described according to their demographical and clinical variables in terms of percentages and averages in respect of categorical variables and continous variables respectively. The relationship between morphology of reaction with types of tumour was studied by χ2 test. The P values less than or 0.05 (P≤0.05) were considered as statistically significant

INCLUSION CRITERIA:

. Patients with mucocutaneous adverse effects following cancer

chemotherapy irrespective of their age and sex.

EXCLUSION CRITERIA:

. Patients with Mucocutaneous symptoms present before starting of

chemotherapy.

. Patient developing skin lesions due to internal malignancies.

. Patients receiving chemotherapeutic drugs for other indications

. Patients receiving radiotherapy with chemotherapy.

. Patients receiving chemotherapy concurrent with radiotherapy.

OBSERVATION AND RESULTS

In this study, titled “Mucocutaneos manifestations in patients

receiving cancer chemotherapy in regional cancer centre of Tirunelveli

Medical College”, we collected and analysed data regarding CADRs in

patients receiving cancer chemotherapy alone, without Radiotherapy over a

period of 18 months.

Table-1: Description of cancer subjects according to their Age and

Gender.

Age group Males Females Total (years) Frequency % Frequency % Frequency % 0-20 1 0.95 1 0.95 2 1.88 21-40 4 3.77 10 9.43 14 13.20 41-60 13 12.26 59 55.66 72 67.92 61-80 4 3.81 14 13.20 18 16.98 Total 22 20.75 84 79.24 106 100.00 Mean± SD 50.7±12.0 51.2±10.7 51.1±10.9, Range= 16 to 74 Significance t=0.208, df=103, P=0.836 years

The table-1 describes the cancer subjects according to their age and

sex. Among the total subjects ( n-106), the males were 20.75% (22) and

females were 79.24% (84). The mean ages of the males and females were

50.7±12.0 years and 51.2±10.7 years. The difference between the ages of

males and females was statistically not significant (P>0.05).

Figure 1 : Description of cancer subjects according to Gender

MALE-20.75%

FEMALE-79.24%

INCIDENCE OF CADRs:

Out of 302 cancer patients who received cancer chemotherapy without Radiotherapy were studied, 106 patients had CADRs in that females were 79.24% and males were 20.75%. The total incidence of

CADRs is about 35% (106 Patients among 302 cancer patients receiving

Chemotherapy.

Table 2 : Description of cancer subjects according to their age group

AGE OF THE PATIENTS Total TYPES OF CANCER 0 TO 20 21 TO 40 41 TO 60 61 TO 80 % YEARS YEARS YEARS YEARS M F T M F T M F T M F T M F T Breast carcinoma - - - - 5 5 - 36 36 - 8 8 - 49 49 46.7 Lung carcinoma - - - - - 5 4 9 2 1 3 7 5 12 11.4 Carcinoma colon 1 1 2 2 1 3 2 2 4 - - - 5 4 9 8.6 Carcinoma of ovary - - - - 1 1 - 7 7 - 1 1 - 9 9 8.6 Carcinoma of stomach - - - - 1 1 - 4 4 1 - 1 1 5 6 5.7 Chronic myelocytic leukemia - - - 1 - 1 2 2 4 - - - 3 2 5 4.8 Hodgkin’s lymphoma - - 1 1 2 1 1 2 - - - 2 2 4 3.8 Carcinoma of rectum - - - - - 2 - 2 1 1 2 1 3 2.9 Carcinoma of gall bladder ------1 - 1 - 1 1 1 1 2 1.9 Carcinoma of endometrium ------1 1 - 1 1 1.0 Carcinoma of vulva ------1 1 - - - - 1 1 1.0 Non hodgkins lymphoma ------1 1 - 1 1 1.0 Chronic lymphocytic leukemia ------1 1 - - - - 1 1 1.0 Renal cell carcinoma ------1 1 - - - - 1 1 1.0 Unknown primary with ------1 - 1 1 - 1 1.0 secondary metastases Castleman’s disease - - - - 1 1 ------1 1 1.0 Total 1 1 2 4 10 14 13 59 72 4 14 18 22 84 106 100

Out of 106 patients, majority belonged to the age group 41 to 60 years

(67.92%) with most common malignancy being carcinoma of breast.The second most common age group affected was 61 to 80 years (16.98%). Youngest age affected was 16 years in males, a case of carcinoma colon and 17 years in females, a case of carcinoma colon.

Figure 2: Classification of subjects according to the type of malignancy

49 50

Male 20 Female

9 10 7 5 5 4 5 3 2 2 2 2 0 0 1 1 1 1 0 1 0 1 0 1 0 1 1 0 0 1 0 0

In our study, most common malignancy was carcinoma of breast (46.7%) followed by carcinoma of lung (11.4%), carcinoma of ovary and colon (8.6%).

Most common malignancy in female was carcinoma of breast (58.3%) and in male was carcinoma of lung (31.8%).

Table 3 : Genderwise incidence of cutaneous manifestations

Total patients - 106

S.No Cutaneous features Male Female Total Percentage % 1 Alopecia 2 52 54 50.9 2 Melanonychia 9 39 48 45.2

3 Acral pigmentation 9 30 39 36.7 4 Tongue pigmentation 6 17 23 21.6 5 Xerosis 4 11 15 14.1 6 Extravasation injury 2 14 16 15.0 7 Supravenous 2 13 15 14.1 pigmentation 9 Mucositis 0 4 4 3.7 10 Hand and foot 1 7 8 7.5 syndrome 12 Melasma like 3 1 4 3.7 pigmentation 13 seborrheic dermatitis 1 0 1 0.9

Specific Specific cutaneous changes due to drugs like picture 14 Stevens - Johnson 1 0 1 0.9 syndrome 15 Urticaria 0 2 2 1.8

1 Dermatophytosis 2 5 7 6.6 2 Herpes zoster 1 3 4 3.7 3 Oral candidiasis 0 3 3 2.8

4 Folliculitis 0 1 1 0.9

Non specific changes

Incidence of cutaneous manifestations:

CADRs were divided into specific and non specific manifestations. Most common specific cutaneous manifestation in our study was alopecia (50.9%) followed by melanonychia i.e. diffuse hyperpigmentation of nails (45.2%), acral pigmentation (36.7%), patchy tongue pigmentation (21.6%), extravasation injury

(15%), supravenous pigmentation (14.1%), and xerosis (14.1%). Among, the non specific changes most commonly reported was dermatophytosis (6.6%) followed by herpes zoster (3.7%), oral candidiasis (2.8%). Mostly females outnumbered males in the frequency of various cutaneous manifestations.

REGIMENS USED IN VARIOUS MALIGNANCIES:

Breast carcinoma:

In our institute various regimens were given according to malignancy types.

In early breast carcinoma, Taxanes/Doxorubicin and Cyclophosphamide combination were given as adjuvant therapy. In advanced breast carcinoma

Taxanes alone or if HER2 neu positive, Taxanes with Trastuzumab were given.

Neoadjuvant chemotherapy was given before surgery for early breast carcinoma and locally advanced carcinoma which includes 5FU / Doxorubicin and

Cyclophosphamide or Doxorubicin / Cyclophosphamide or

Docetaxel/Cyclophosphamide. After surgical procedures, biopsy samples were sent for receptor status and patient continued on 4 cycles of the above regimen.

According to the receptor status, chemotherapy was fixed. If receptor positive, they will start on Trastuzumab or hormonal therapy. Docetaxel, Paclitaxel,

Gemcitabine alone can be used for locally advanced metastatic breast cancer after chemotherapy failure, HER2 neu negative and metastatic carcinoma.

Carcinoma of lung:

CARCINOMA REGIMEN

Small cell lung carcinoma Cisplatin plus Etoposide; or Cisplatin,

Etoposide plus Irinotecan (topotecan).

Non small cell lung carcinoma Cisplatin plus Etoposide or

Cisplatin plus Pemetrexed

Carboplatin plus Paclitaxel

Non squamous cell carcinoma Pemetrexed plus Carboplatin or

Carboplatin, Paclitaxel plus

Bevacizumab.

Squamous cell carcinoma Gemcitabine plus Cisplatin

EGFR mutation positive Non small Erlotinib , Gefitinib

cell lung carcinoma

Colon carcinoma:

For carcinoma colon most frequently used regimen was Leucovorin/

Oxaliplatin and 5-FU every 2 weeks for 12 cycles.

Ovarian carcinoma:

For epithelial ovarian cancer Taxanes and Plantinum combination,

Cisplatin plus Cyclophosphamide regimens were used.

Recurent and refractory ovarian cancer:

Single agent:

Docetaxel / Paclitaxel, or Cisplatin/Carboplatin, or Doxorubicin,

Gemcitabine or Capecitabine.

Combination agents:

Gemcitabine plus Carboplatin/Cisplatin

Doxorubicin plus Carboplatin.

6. Incidence of CADRs with various Regimens

reaction

S. Regimen No

/ ichthyosis

pigmentation

Diffuse hyperpigmentation

Alopecia Melanonychia Supravenous pigmentation Acral Extravasation injury Hand foot syndrome tonguePigmentation of Xerosis Urticarial Flagellate erythema Beau’lines

M F M F M F M F M F M F M F M F M F M F M F M F

1 Taxanes/Adriamycin/Cyclophosphamide(13) CA Breast - 9 - 7 3 - 4 - 4 - 1 - 2 - - - 1 - - - 1 - -

2 Adriamycin /Cyclophosphamide(10) CA Breast - 9 - 7 - - - 6 - - - 1 - 2 - 2 ------Leucovorin/5FU/Oxaliplatin(10)CA Colon,1 CA Stomach, 1 3 1 - 3 4 - 2 3 7 - - - - 1 3 1 ------1 1 - CA Rectum 4 Docetaxel/Cyclophosphamide (5) CA Breast, 1 CA Stomach - 5 - - - 2 - - - 2 ------5 Paclitaxel/Carboplatin(5)3 CA Ovary,1 Lung, 1EM - 3 - 1 - 2 - 1 ------1 ------6 Adriamycin/5FU/Cyp( 2) CA Breast - 2 - 1 - - - 1 - - - - - 1 ------7 Pemetrexed/Carboplatin(4) CALung - - 1 - 1 - 1 - - - 1 ------8 Cisplatin / Etoposide (4) CA Lung - 1 1 1 - - 1 - - - - 1 - 1 1 ------1 - 9 Capecitabine/Cyclophosphamide(3) CA Breast - 3 - 2 - - - 3 - - - - - 2 ------1 - - 10 ABVD Regimen(4) HL - 2 - 2 ------1 - - - 1 - - - 1 - - - - 11 Capecitabine /Irinotecan(1) CA Breast - - 1 - - - - 1 - - - - 1 ------12 Carboplatin/Gemcitabine(4) CA Ovary(3), CA GB(1) - 1 - - - - 1 1 - 1 - - 1 1 - 1 - - - - - 1 - - 13 Docetaxel/Carboplatin/5FU(1) CA Stomach) - - - 1 - 1 ------1 ------

6. Incidence of CADs with various Regimens

S.No Regimen

pigmentation

Alopecia Melanonychia Supravenous pigmentation Acral Extravasation injury Hand foot syndrome Pigmentation tongue of /ichthyosis Xerosis Urticarial reaction reaction Beau’lines Diffuse hyperpigmentation M F M F M F M F M F M F M F M F M F M F M F

14 Epirubicin/Oxaliplatin/Capecitabine(1) CA Stomach - 1 - - - - - 1 - - - - - 1 ------

15 Docetaxel/Carboplatin/Capecitabine(1) CA Stomach - - 1 - 1 1 - 1 - - - - - 1 ------

16 Epirubicin /Oxaliplatin /5FU(F 1) CA Stomach - - 1 - 1 ------1 ------

17 Capecitabine (2) CA GB, Ca Breast - - - 1 - - - 1 - - - 1 - 1 ------18 Docetaxel (8) CA Breast - 6 - 3 - 2 - 1 - 3 - 1 - 2 - 2 ------19 Taxanes/ Trastuzumab(4) CA Breast - 3 - 2 - - - - - 1 - 1 - 1 ------20 Docetaxel/Carboplatin/Trastuzumab (2 CA Breast) - 2 ------2 ------21 Trastuzumab/Capecitabine/Cyp (1) (CA Breast) - - - 1 ------1 ------Bevacizumab/Capecitabine/Irinotecan(2) CA Rectum, 22 1 - 2 - - - 2 - - - - - 2 ------Colon 23 Bevacizumab/Doxorubicin(2) (CA Ovary) - 1 - 1 - - - 2 - - - - - 1 ------24 Rituximab, etoposide,prednisolone (F 1)(Castleman’s dis) - 1 - - - - 1 ------

25 R- CHOP regimen (F 1)(NHL) - 1 - 1 - - - - - 1 ------60

6. Incidence of CADs with various Regimens

tongue

Regimen Xerosis

Alopecia

No dermatitis

Seborrheic Seborrheic

Supravenous Supravenous

pigmentation pigmentation

Pigmentation

palmoplantar

Melanonychia

Melasma Melasma Like

Pigmentation of

Urticarial Urticarial reaction

Flagellate Erythema

Hand foot syndrome

Extravasation Extravasation injury

M F M F M F M F M F M F M F M F M F M F M F M F

26 Gefitinib (2)( CA Lung) - 1 ------1 1 - - 1 - - - - - Imatinib (5) (CML) ------1 - - 3 1 - - 27 28 Bendamustine/Rituximab (CLL) Papulopruritic eruption Cyclophosphamide ( CA Ovary) 29 Phototoxic dermatitis and alopecia Female-1

30 Erlotinib male-1 ( CA Lung) Stevens – Johnson syndrome

31 Sunitinib female-1 (RCC) HFS with hypopigmentation over face

7. MUCOSAL CHANGES WITH CHEMOTHERAPY:

Mucosal changes Regimen Carcinoma Atrophic tongue (7) 3 cases with Docetaxel alone Breast carcinoma FOLFOX regimen Colon carcinoma Carboplatin plus Gemcitabine Carcinoma ovary Paclitaxel and carboplatin Carcinoma ovary Sunitinib Renal cell carcinoma Lip pigmentation(3) Rituximab ,Etoposide, Prednisolone Castleman’s disease Bevacizumab and Doxorubicin Carcinoma ovary FOLFOX Carcinoma colon Mucositis (3) Methotrexate Unknown primary Erlotinib Carcinoma lung Imatinib CML

Patchy pigmentation of tongue most commonly was seen in regimens containing 5 FU, Adriamycin, Taxanes

A) INCIDENCE OF REGIMEN WISE CADRs

1. Taxanes/ Adriamycin/ Cyclophosphamide: (13 breast carcinoma):

Total of 13 patients of breast carcinoma received Taxanes (11

Paclitaxel and 2 Docetaxel)/Adriamycin/Cyclophosphamide regimen, 9 patients had alopecia, melanonychia each (69.2%), 4 patients had extravasation injury, acral pigmentation (30.7%), 3 patients had supravenous pigmentation (23.0%), and 2 patient had tongue pigmentation;

Each patient had HFS (Paclitaxel) (Pic 1), urticarial reaction (Docetaxel) and Beau’s lines(67).

2. Adriamycin/ Cyclophosphamide ( 10 - Carcinoma breast):

Total of 10 patients received Adriamycin/Cyclophosphamide regimen, 9 patients had alopecia, 7 patients had melanonychia, 6 patients had acral pigmentation, 2 patients had xerosis and pigmentation of tongue, and 1 patient had HFS. Another one patient had dermatophytosis alone.

3. Leucovorin/5FU/Oxaliplatin(10)( 8- CA colon, 1 CA stomach and

1 CA rectum):

Out of 10 patients with this regimen, 10 patients had acral pigmentation (100%), 7 patients (70%) showed melanonychia, 4 patients

(40%) had pigmentation of tongue, 2 patients had supravenous pigmentation, 1 had diffuse pigmentation and alopecia and another patient had generalised ichthyosis and atrophic tongue.

4. Docetaxel/Cyclophosphamide (4 CA breast and 1 CA stomach):

Total of 5 patients received Docetaxel and Cyclophosphamide, all 5

patients (100%) had alopecia, 2 patients had supravenous pigmentation, 2

patients had extravasation injury.

5. Paclitaxel/ Carboplatin (5): (3 – CA ovary, 1- CA lung, CA

endometrium):

5 patients developed CADRs in that 2 patients had supravenous pigmentation. Alopecia was found in 3 patients in that 1 patient also had atrophic tongue and xerosis. One patient presented with both acral pigmentation and melanonychia.

6. Adriamycin/ 5FU/ Cyclophosphamide(2): (CA breast)

Two of the carcinoma breast patients, those who received

Adriamycin/ 5FU/ Cyclophosphamide presented with CADRs, in that one patient had alopecia and herpes zoster, another patient was found to have alopecia, melanonychia, pigmentation of tongue and acral pigmentation.

7. Pemetrexed/Carboplatin (4):( 4 CA lung):

With this regimen, total of 4 patients, 2 patients had dermatophytosis.1 patient had HFS, supravenous pigmentation and another one patient presented with acral pigmentation, supravenous pigmentation, melanonychia.

8. Cisplatin/Etoposide(4): CA lung:

Out of 4 patients, 3 patients had melanonychia, acral pigmentation and alopecia, in that one patient associated with ichthyosis; one patient had dermatophytosis.

9. Capecitabine/ Cyclophosphamide: 3 CA breast

Total of 3 carcinoma breast patients were received Capecitabine/

Cyclophosphamide regimen, 3 patients had acral pigmentation and alopecia in that 2 patients had melanonychia, pigmentation of tongue, and

1 patient had Beau’s lines.

10. ABVD regimen:4 Hodgkin’s lymphoma :

Four patients with ABVD regimen for Hodgkin’s lymphoma were

found to have CADRs. Alopecia and melanonychia were found in 2

patients and one patient also had HFS and generalised xerosis. One

patient presented with HZ and another patient had flagellate erythema.

11. Capecitabine/ Irinotecan: 1 – CA breast:

One carcinoma of breast patient with this regimen had a feature of melanonychia and pigmentation of tongue and acral pigmentation.

12. Carboplatin/Gemcitabine(4): 3 – Ca ovary; 1 Ca GB:

A total of 4 patients with Carboplatin and Gemcitabine regimen were evaluated for CADRs. Acral pigmentation and tongue pigmentation were found in 2 patients in that one patient had alopecia. One patient had xerosis, and dystrophy of nails. Another one had dermatophytosis.

Four patients with carcinoma stomach received

Docetaxel/Carboplatin/5FU, Epirubicin /Oxaliplatin /5FU,

Epirubicin/Oxaliplatin/Capecitabine, Docetaxel/Carboplatin/Capecitabine patients had pigmentary abnormalities (melanonychia, acral pigmentation, supravenous pigmentation) and alopecia.

13. Docetaxel (8): CA breast

Total 8 patients 6 patients received Docetaxel. Another 2 patient paclitxael alone was used. Among 2 patients of Paclitaxel, one patient presented with pigmentation of tongue, alopecia, melanonychia, xerosis;

Another one had side effects of extravasation injury and alopecia.

Among 6 patients with Docetaxel, 1st patient had extravasation injury with contracture, supravenous pigmentation and melanonychia.

Second patient had a feature of acral pigmentation, pigmentation of tongue, melanonychia, supravenous pigmentation and alopecia

Third patient presented with xerosis, atrophic tongue, melanonychia

Two patients had extravasation injury and alopecia.

One case with docetaxel presented with HFS and phototoxic dermatitis

(pic 3). Phototherapy recall reaction with docetaxel and cyclophosphamide was observed in one study of Ludlow et at, USA(68).

14. Capecitabine(2): 1 CA breast and 1 CA GB:

Capecitabine alone used in carcinoma gall bladder and breast. One patient had HFS, another one had pigmentation of tongue and acral pigmentation and melanonychia.

Trastuzumab was given 3 different combination regimens like Taxanes,

Docetaxel and Carboplatin; Capecitabine and Cyclophosphamide.

15. Taxanes and Trastuzumab: 4 CA breast:

Among 2 patients with Paclitaxel plus Trastuzumab, one patient had

HFS, atrophic tongue, tongue pigmentation and melanonychia, another one had dermatophytosis. Total of 2 patients with Docetaxel and Trastuzumab,

2 patients found to have alopecia, another one presented with extravasation injury, melanonychia, xerosis and atrophic tongue.

16. Docetaxel/Carboplatin/Trastuzumab: 2 CA breast

Extravasation injury and alopecia was seen in both patients.

17. Trastuzumab/ Capecitabine/ Cyclophosphamide : 1 CA breast:

One patient with carcinoma breast with this regimen, presented with

HFS and melanonychia.

18. Bevacizumab/ Capecitabine/ Irinotecan(2):CA rectum and CA

colon:

This regimen used in case of carcinoma of rectum and colon, they had feature of acral pigmentation, pigmentation of tongue and melanonychia, one patient additionally had alopecia.

19. Bevacizumab / Doxorubicin(2): CA ovary

With this regimen, one patient had acral pigmentation, and another one had combination of acral pigmentation, pigmentation of tongue and alopecia.

20. R-CHOP regimen 1 -NHL

This regimen was used in a case of NHL; patient had side effect of extravasation injury, alopecia and melanonychia.

21. Rituximab / Etoposide/ Prednisolone: (Castleman’s disease)

Acral pigmentation and melanonychia were seen with this regimen

 Imatinib :

Total 5 patients with Imatinib, 4 cases showed melasma like pigmentation, 1 case was found to have urticarial reaction with mucositis.

 One patient with Sunitib presented with HFS and

hypopigmentation. (pic5)

 SJS has occurred in our study with Erlotinib.

 One female with carcinoma of ovary received Cyclophosphamide

alone presented with photosensitivity and alopecia.(pic 6)

 One female patient with CLL received combination of

Bendamustine and Rituximab presented with papulopruritic

eruption.(pic -7)

 2 patients with Gefitinib, one had seborrheic dermatitis, another one

had ichthyosis and alopecia.

Non specific cutaneous manifestations:

 Seven cases (6.6%) with dermatophytosis seen in our study with

following regimen Adriamycin and Cyclophosphamide;

Trastuzumab and Paclitaxel; Leucovorin , Oxaliplatin and 5

Fluouracil(5FU); Carboplatin, Gemcitabine; 2 cases with

Pemetrexed and Carboplatin; Cisplatin and Etoposide.

 Herpes zoster seen in 4 patients (3.7%) 1 male and 3 female with

following regimen, Tratuzumab and Capecitabine; Cisplatin and 5 –

FU; ABVD regimen; and Adriamycin, Cyclophosphamide and 5FU.

 Single case of folliculitis seen with Methotrexate in a case of

unknown primary with neck secondaries.

 Oral candidiasis seen with Rituximab and CHOP Regimen;

Adriamycin and Cyclophosphamide; Taxanes, Adriamycin and

Cyclophosphamide regimen.

8. RECEPTOR POSITIVE BREAST CARCINOMA:

Receptor status Regimen CADRs Trastuzumab plus 1.HFS, Paclitaxel (2 cases) melanonychia,patchy tongue pigmentation, Her 2 neu positive atrophic tongue

2.dermatophytosis Total 8 patients Docetaxel plus 1. Alopecia Trastuzumab (2) 2. Extravasation injury, melanonychia, alopecia, atrophic tongue. Paclitaxel, Carboplatin Both had extravasation plus Trastuzumab (2) injury and alopecia Trastuzumab, HFS and melanonychia Capecitabine plus cyclophosphamide(1) Trastuzumab plus Herpes zoster capecitabine (1)

When compared to biological therapies with cytotoxic drugs, CADRs were less reported.

DISCUSSION

Chemotherapeutic agents frequently cause Cutaneous Adverse Drug

Reactions (CADRs), but they are not well known. They range from mild to severe reactions that worsen the quality of life and produce life threatening complications. In most of the cases withdrawal of causative chemotherapeutic agents is not necessary, because they are essential life saving drugs and adverse reactions depend on the mechanism of action of the drugs. But in few cases with life threatening conditions, cessation of drug is essential. To improve the survival rate of cancer patients, a wide variety of newer drugs are introduced in recent years. Many of the newer chemotherapeutic agents are associated with some specific adverse reactions. Incidence of drug induced cutaneous reaction to cancer chemotherapy is about 2 to 5% of hospitalised patients. There are so many case reports with individual drugs available in literature. But there are few studies only available with cutaneous manifestations of various chemotherapeutic agents in Indian and foreign literature.

INCIDENCE OF CADRs:

In our study, a total of 106 patients out of 302 patients with malignancies attending Dermatology and Oncology Department in

Tirunelveli Medical College, Hospital were included according to the inclusion criteria after excluding radiotherapy, during the period of one and half years (March 2017 to Sep 2018). Total incidence of CADRs with

71 chemotherapy was 35%. The incidence was similar, when compared to

Biswal et al, Buvaneswar(38.4%) and lower when compared to, Menon et al study where it was about, 84% (69) (70). Out of 106 patients, 19 patients were on single chemotherapy drugs like Docetaxel, Cyclophosphamide,

Capecitabine, Imatinib, Gefitinib, Erlotinib, or Sunitinib. 87 patients were received combined chemotherapy. Drugs used in combination chemotherapeutic agents were Taxanes, Cyclophosphamide, Doxorubicin,

Platinum compounds, 5-FU and Capecitabine.

Out of 106 patients, Females -84 patients (79%) and Males- 22 patients (21%) which is comparable with the most of the Indian studies particularly Biswal et al, Bhuvaneswar where F – 70.5%; M – 29.5%

(70)(Figure 1).

Among the 106 patients, Carcinoma breast (49 patients) was most frequently observed (46.7%) followed by carcinoma of lung (11.4%), carcinoma of ovary and colon (each 8.6%) (Figure 2). Similar to our study, Pavey et al Karnataka and Fabbrocini et al Italy, have reported that the most common malignancy was carcinoma breast with incidence of

22.6% and 45% respectively.(19,52).

Demographical characteristics of CADRs:

In our study according to gender, most common malignancy in females was carcinoma breast (58.3%) followed by carcinoma ovary whereas in males, it was carcinoma lung (31.8%) followed by carcinoma colon (Figure 2).

Age of the patients with malignancy ranges from 16 to 74 years in which most common age group was 41 to 60 years. The mean age of the male and female was 50.7±12.0 years and 51.2±10.7 years respectively

(Table 1). This similar age pattern with malignancy was observed by

Menon et al from Karnataka (69). Among the patients between 41 and 60 years age group (67.92%), carcinoma of breast (50%) was most commonly encountered followed by carcinoma lung (12.5%), ovary (9.7%) and colon

(5.5%) (in decreasing order of frequency) (Table 2). The second most common age group affected was 61 to 80 years (16.98%), with similar pattern of malignancies viz. carcinoma breast (44%), lung (16.6%) and ovary (5.5%).

MORPHOLOGICAL PATTERNS OF CADRs:

In our study we included all patients who had at least one cutaneous drug reaction and most of the paients had more than one CADR. The morphological patterns were classified as specific and non specific cutaneous changes. Specific changes are due to drugs, mechanism of action of drugs and its metabolites. Non specific changes are related to

73 immunosuppression, nutritional deficits and following the effects of drugs in the body. Specific changes were alopecia, melanonychia, pigmentary abnormalities, extravasation injury, HFS, xerosis and ichthyosis. Non specific changes were dermatophytosis, herpes zoster, oral candidiasis and folliculitis (Table 3). Severe cutaneous side effects were reported in 6 patients receiving Erlotinib, Imatinib, or Sunitinib and 2 cases with

Taxanes. Others were of milder variants. Specific changes can be divided into allergic or non allergic cutaneous side effects. Allegic CADRs are mediated by immune system. Eg: Urticaria, Angioedema, flushing, maculopapular rash and SJS/TEN. Non allergic side effects are related to drug, its metabolism or mechanism of action. Eg: Alopecia, HFS, pigmentary abnormalities, xerosis and ichthyosis.

The frequent cutaneous reaction following chemotherapy was alopecia, which was seen in 50.9%, which is similar but lower than Biswal et al (78.6%) Alley et al (70,71) and Trueb et al studies (65%) (72).

Second most common CADR was nail pigmentation (45.2%) followed by acral pigmentation (36.7%) and tongue pigmentation (21.6%). Among the non specific changes most commonly reported was dermatophytosis

(6.6%) followed by herpes zoster (3.7%), and oral candidiasis (2.8%)

(Table 3) .

The most common type of alopecia was anagen effluvium (Pic 1) and it was proved by hair examination, seen in patients who received

74 combination regimens with Cyclophosphamide, Taxanes, Doxorubicin and

Platinum compounds. These results are comparable to the study done by

Amrinder et al, Chandigarh, India where alopecia was commonly reported with Daunorubicin, Taxanes and Alkylating agents. It was most frequently observed in 38 cases of carcinoma breast (77.5%) followed by carcinoma of ovary. It usually occurred after 1st cycle of chemotherapy and duration of alopecia was seen between 3 weeks to 3 months , which was similarly reported in Trueb et al study, Switzerland (73).

Chemotherapeutic agents directly affect the mitotic activity of hair matrix cells, that will in turn affect the proliferative activity of hair. It was severe, when combination chemotherapy is used than with single drug and also severity depends on the dosage of the drug (72). Treatment is usually not required; it is reversible after stopping the causative chemotherapy.

Second most common CADRs observed was nail pigmentation i.e. melanonychia(48 patients) which was diffuse pigmentation of nails

(Pic 2), seen in 45.2% which usually occurred after 2nd cycle of chemotherapy and encountered in patients with the regimens like Taxanes,

Doxorubicin, Capecitabine, 5-FU and Etoposide which was observed similarly in Jefferson et al, USA and Gilbar et al study, Australia(74,75).

Pigmentation is due to stimulation and hyperplasia of nail matrix melanocytes. It was most commonly seen in patients with carcinoma of colon (77.7%) followed by breast carcinoma (52%) and carcinoma lung.

Diffuse acral pigmentation (Pic 3) was 3rd frequent cause of chemotherapy induced side effects followed by tongue pigmentation,

36.7% and 21.6% respectively and usually started after 3rd to 4th cycle of chemotherapy. Among 39 cases of acral pigmentation, melanonychia was seen in 20 cases. The common pigmentary abnormality was acral pigmentation, nail and tongue pigmentation and was seen with regimens like Doxorubicin, 5FU(76), Capecitabine, Etoposide (18,77) which is similar to Criado et al study (78).

Extravasation injury was seen in 16 patients (15%) and observed exclusively in patients who received docetaxel (3/8 patients) (Pic 4,5) or regimens like Taxanes and Doxorubicin or Taxanes and Platinum compounds in breast carcinoma. They come under the vesicant and irritant drugs which are responsible for extravasation injury. Extravasation injury usually occurred within 1 day or less than 1 week. Patients presented with erythema and swelling followed by hyperpigmentation. The frequency of extravasation injury was reported to be 0.1 to 6%(79,80). The frequency of this side effect observed in our study is higher than that by Schrijvers et al and Lemmers et al.

Fifteen patients (14.1%) developed supravenous pigmentation

(Pic 8) with regimens of Taxanes, 5FU (81), Platinum compounds and

Doxorubicin following 1st cycle of chemotherapy and it occurred due to thrombophlebhitis or due to direct deposition of the drug. Supravenous

76 pigmentation most commonly occurred following 5FU, which is comparable to our study (82).

HFS was seen in 8 patients (7.5%) with regimens containing

Taxanes, Capecitabine (Pic 7,9) and Sunitinib (Pic 6A) and Doxorubicin.

In our study incidence was lower when compared to Martin et al study where Capecitabine, 5 FU, and Doxorubicin were responsible for HFS and incidence was reported to be 19.6%(83). Only one case of HFS with

Sunitinib (Pic 5) has occurred in our study. Because of the unavailability of

Sunitinib, it is not used frequently. It was suggested that increased number of eccrine glands on hands and feet resulting in the elimination of drug by sweat secretion. It causes direct stimulation of melanogenesis in melanocytes leads to hyperpigmentation

Melasma like pigmentation occurred in 4 cases of CML who received Imatinib out of total 5 patients (Pic 11). It presented as patchy and diffuse hyperpigmentation of face and usually started after 4 to 5 months of chemotherapy. Another patient with Imatinib developed urticarial lesions and mucositis (Pic 12) involving oral and nasal mucosa. Incidence of melasma like pigmentation is lower when compared to Mohammed et al study where incidence is about (19.2%) (46). Mucositis is one of the common side effects with cancer chemotherapy. It was reported with alkylating agents such as Busulfan and Cyclophosphamide;

Anthracyclines, Antimetabolites, Antibiotics such as Actinomycin D and

Bleomycin; Vinca alkaloids and Targeted therapies. With Imatinib one patient had mucositis and urticarial reaction. After 7 days of Imatinib, patient developed urticated plaques all over the body with mucositis of oral and nasal mucosa. In this patient urticaria occurred due to immune mediated hypersensitivity reaction and mucositis occurred due to inhibition physiological function of protein kinases that is responsible for mechanism of action of Imatinib(42). So treatment was withheld for few weeks and then restarted with close monitoring and supported with blood transfusion.

After few months patient died due to severity of disease.

Herpes simples, herpes zoster, verruca vulgaris, dermatophytosis and tinea versicolor are frequently encountered with chemotherapy. It occurs due to immunosuppression secondary to cancer chemotherapy. In our study non specific cutaneous side effects were dermatophytosis (6.6%), herpes zoster 3.7%), oral candidiasis (2.8%) and folliculitis (0.9%).

Interesting cases:

 One case of Sunitinib induced HFS (Pic 10B) and

hypopigmentation (Pic 10 A):

One patient with Sunitinib showed HFS and hypopigmentation. She

was presented with thick sheets of exfoliation with erythema after 10

days of treatment with Sunitinib. HFS due to kinase inhibitor is

more hyperkeratotic and localised. When compared the incidence

was lower than the Motzer et al study (84), because less frequently

used due to unavailability of drug. The common pigmentary

abnormality with Sunitinib is Yellow discolouration of the skin due

to yellow colour of the active metabolite and incidence is about 30%

of patients which is reversible on withdrawal of therapy. In addition

to skin manifestations, hair depigmentation also can occur(85).

Hypopigmentation to Sunitinib was not reported previously. But hypopigmentation to Imatinib occurred frequently with incidence of 41% in Indian study(86). It is due to inhibition of c-Kit by Imatinib there by it inhibiting the signal transduction pathway of melanocytes. Sunitinib also has similar mechanism of action that may be the reason for hypopigmentation in Sunitinib (83,87).

 Erlotinib induced SJS (Pic 14):

A case of carcinoma of lung with brain metastases received

Erlotinib for 18 days. After 2 weeks of treatment, patient developed

SJS with features of extensive erythema, crusted plaque over the

face, multiple dusky erythematous papules, conjunctival and scrotal

erosion with phimosis. After withdrawal of drug and treatment with

steroids, skin lesions resolved well. Then drug was switched over to

Gefitinib. After that patient had no complaints with Gefitinib. In

literature Erlotinib induced SJS has not been reported previously.

 One female with carcinoma of ovary received Cyclophosphamide

alone, who presented with photosensitivity (Pic 15) and alopecia.

Patient presented with lichenification over face and extensor aspect

of forearms after 6 months of starting chemotherapy. Alopecia was

noticed after 1st cycle of chemotherapy. Skin biopsy was taken from

lichenified skin over extensor aspect of forearm, and histopathology

showed hyperkeratosis, acanthosis and increased basal melanin

pigmentation.

Alopecia was frequently reported with alkylating agents.

Phototherapy recall can occur in treatment with commonly used

medications and chemotherapy. These reactions are rare. It is an

inflammatory reaction following certain chemotherapeutic agents.

Cyclophosphamide and Docetaxel induced phototherapy recall was

reported in Steven et al study(68).

 One female patient with CLL who received combination of

Bendamustine and Rituximab presented with papulopruritic eruption

(Pic 18).

Patient presented with erythematous to hyperpigmented multiple

papules with excoriations all over the body with few papules

showing ulceration over legs and back of trunk, after 3 months of

initiating chemotherapy. Histopathology showed eroded epidermis

with collection of inflammatory infiltrate in the dermis which was

suggestive of inflammatory pathology. Similarly papulopruritic rash

with Bendamustine reported in Malipatil et al study, Chennai (9).

They reported 9 cases with similar features with Bendamustine and

pathogenesis regarding papulopruritic eruption was not clear.

 Two patients with Gefitinib (Pic 16), one had seborrheic dermatitis

like feature, and another one had ichthyosis and alopecia.

Seventy two years old male patient a case of carcinoma lung

received Gefitinib had feature of seborrheic dermatitis like feature

progressing to erythroderma with itching and generalised xerosis.

Riahi and Cohen et al, Texas described seborrheic dermatitis like

picture in one case with dasatinib for Imatinib resistant CML (88).

Regimen wise morphological pattern of CADRs:

1. Taxanes/ Adriamycin/ Cyclophosphamide:

This is the most common regimen used in carcinoma breast. Total of

13 patients received Taxanes/Adriamycin/Cyclophosphamide regimen, 9 patients had alopecia (69.2%), 9 patients had melanonychia (69.2%), 4 patients each had extravasation injury and acral pigmentation respectively

(30.7%), 3 patients had supravenous pigmentation (23.0%), 2 patients had patchy tongue pigmentation; Each patient had HFS (Paclitaxel) (Pic 6), urticarial reaction (Docetaxel) and Beau’s lines. So most common side effects with this regimen are alopecia and melanonychia. Interestingly

Docetaxel induced urticarial reaction was observed in our study; it may

81 have occurred due to hypersensitivity reaction to solvent used for

Docetaxel(67).

2. Adriamycin/ Cyclophosphamide: (10 cases breast carcinoma)

Total of 10 patients received Adriamycin/Cyclophosphamide

regimen, 9 patients had alopecia, 7 patients had melanonychia, 6 patients

had acral pigmentation, 2 patients had xerosis and pigmentation of

tongue, 1 patient had HFS. Another one patient had dermatophytosis

alone. The frequently observed cutaneous toxicity with this regimen

was alopecia followed by pigmentary abnormalities. So alopecia was

most commonly seen in carcinoma breast cases with Taxane,

Adriamycin, and Cyclophosphamide regimen. Pigmentary abnormalities

were observed with Doxorubicin or Adriamycin.

3. Leucovorin/5 -FU/Oxaliplatin(10)( 8- CA colon, 1 CA stomch and

1 CA rectum):

Out of 10 patients with this regimen, 10 patients had acral pigmentation

(100%), 7 patients (70%) showed melanonychia, 4 patients (40%) had pigmentation of tongue, 2 patients had supravenous pigmentation, 1 had diffuse pigmentation and alopecia and another patient had generalised ichthyosis and atrophic tongue. With this regimen pigmentary abnormalities were most common CADRs followed by alopecia.

4. Docetaxel/ cyclophosphamide (4 CA breast and 1 CA stomach):

Total of 5 patients received Docetaxel/Cyclophosphamide, all 5

patients (100%) had alopecia, 2 patients had supravenous pigmentation

and 2 patients had extravasation injury.

5. Paclitaxel/ Carboplatin(5): (3 – CA ovary, 1- CA lung, CA

endometrium):

All 5 patients with this regimen, 2 patients had supravenous

pigmentation. Alopecia was found in 3 patients in that 1 patient also

had atrophic tongue and xerosis. One patient presented with both

acral pigmentation and melanonychia. This combination was

associated with alopecia and pigmentary abnormality.

6. Adriamycin/ 5FU/ cyclophosphamide(2):- (CA breast and CA

stomach):

Two of the carcinoma breast patients, who received Adriamycin/

5FU/ Cyclophosphamide presented with CADRs. In that one patient had

alopecia and herpes zoster, another patient was found to have alopecia,

melanonychia, pigmentation of tongue and acral pigmentation.

7. Pemetrexed/Carboplatin (4):- ( 4 CA lung):

With this regimen, out of 4 patients, 2 patients had dermatophytosis,

1 patient had HFS, supravenous pigmentation and another one patient presented with acral pigmentation, supravenous pigmentation, melanonychia.

8. Cisplatin/Etoposide(4):- CA lung:

Out of 4 patients, 3 patients (75%) had melanonychia, acral pigmentation and alopecia, in that one patient associated with ichthyosis; one patient had dermatophytosis.

9. Capecitabine/ Cyclophosphamide: 3 CA breast

Three carcinoma breast patients received Capecitabine/

Cyclophosphamide regimen, 3 patients had acral pigmentation and

alopecia in that 2 patients had melanonychia, pigmentation of tongue,

and 1 patient had Beau’s lines. Regimen containing Capecitabine

usually found to have pigmentary abnormalities.

10. ABVD regimen:4 HL :

Four patients with ABVD regimen for hodgkin’s lymphoma were found to have CADRs. Alopecia and melanonychia were found in 2 patients

(50%) and one patient also had HFS and generalised xerosis. One patient presented with HZ and another patient had flagellate erythema (25%) (Pic

13)

11. Capecitabine/ Irinotecan: 1 – CA breast:

One patient with this regimen had a feature of melanonychia and pigmentation of tongue and palmoplantar pigmentation.

12. Carboplatin/Gemcitabine(4): 3 – CA ovary; 1 CA GB:

Four patients with carcinoma stomach received

Docetaxel/Carboplatin/5FU, Epirubicin /Oxaliplatin /5FU,

Epirubicin/Oxaliplatin/Capecitabine, Docetaxel/Carboplatin/Capecitabine patients had pigmentary abnormalities and alopecia.

13. Docetaxel (8): CA breast

Out of total 8 patients, 6 patients received Docetaxel. In another 2 patient Daclitaxael alone was used. Among 2 patients of Paclitaxel, one patient presented with pigmentation of tongue, alopecia, melanonychia, and xerosis; Another one had side effects of extravasation injury and alopecia.

Among 6 patients with docetaxel, 1st patient had extravasation injury with contracture, supravenous pigmentation and melanonychia.

Second patient presented with acral pigmentation, pigmentation of tongue, melanonychia, supravenous pigmentation and alopecia

Third patient had xerosis, atrophic tongue, melanonychia

Two patients had extravasation injury and alopecia.

One case with docetaxel presented with HFS and phototoxic dermatitis

(Pic 17). Phototherapy recall reaction with Docetaxel and

Cyclophosphamide was observed in one study of Ludlow et at, USA(68).

14. Capecitabine (2): 1 CA breast and 1 CA GB:

Capecitabine alone used in carcinoma gall bladder and breast. One patient had HFS, (Pic 9) another one had pigmentation of tongue and acral pigmentation and melanonychia

Trastuzumab is combined with regimens like Taxanes, Docetaxel and

Carboplatin, Capecitabine and Cyclophosphamide.

15. Taxanes (2 Docetaxel/2 Paclitaxel) and Trastuzumab: 4 CA

breast:

Among 2 patients with Paclitaxel plus Trastuzumab, one patient had

HFS, atrophic tongue, tongue pigmentation and melanonychia, another one had dermatophytosis. 2 patients with Docetaxel plus Trastuzumab, 2 patients found to have alopecia, another one presented with extravasation injury, melanonychia, xerosis and atrophic tongue.

16. Docetaxel/Carboplatin/Trastuzumab: 2 CA breast

Extravasation injury (100%) and alopecia (100%) was seen in both

patients.

17. Trastuzumab/ Capecitabine/ Cyclophosphamide : 1 CA breast:

One patient with carcinoma breast with this regimen, presented with

HFS.

18. Bevacizumab/ Capecitabine/ Irinotecan(2):CA rectum and CA

colon:

This regimen was used in case of carcinoma of rectum and colon, both had features of acral pigmentation, pigmentation of tongue and melanonychia (100%), one patient also had alopecia.

19. Bevacizumab / Doxorubicin(2): CA ovary

With this regimen, one patient had acral pigmentation, another one had acral pigmentation, pigmentation of tongue and alopecia.

20. R-CHOP regimen

This regimen was used in a case of NHL, and patient had side effects of extravasation injury, alopecia and melanonychia.

21. Rituximab / Etoposide/ Prednisolone:

Acral pigmentation and melanonychia seen with this regimen

Most frequently used regimen in our study was

Taxanes/Adriamycin/Cyclophosphamide (breast carcinoma) (12.3%) followed by Adriamycin/Cyclophosphamide (breast carcinoma) (10%),

FOLFOX regimen (carcinoma colon) (10%) and Docetaxel (breast carcinoma) ( 7.5%).

Biological agents were combined with cytotoxic drugs to improve the clinical outcome. It was used in 14 patients (13.2%) with carcinoma breast, CA ovary, CA rectum and CLL. CADRs were minimal when

87 cytotoxic drugs combined with biological agents, than when they were used alone.

Total number of patients who received targeted therapies was 9

(8.4%); the observed side effects and severity was proportionately more.

SUMMARY

 Patients who had at least one cutaneous drug reaction were included

in this study.

 Total number of cancer patients who received chemotherapy with

CADRs – 106 patients.

 Females were 84 patients (79.24%) and males were 22 patients

(20.75%).

 Total incidence of CADRs found in this study was 35%.

 The most common age group of patients with chemotherapy was 41

to 60 years.

 CADRs were more commonly reported in the age group of 40 to 60

years.

 Most common malignancy observed in our study was carcinoma

breast (46.7%) followed by carcinoma of lung (11.4%), carcinoma

of ovary and colon each (8.6%).

 Most common malignancy in females was carcinoma of breast

(58.3%) and in males was carcinoma of lung (31.8%).

 Breast carcinoma was more frequently encountered with CADRs

followed by carcinoma of colon and ovary.

 Alopecia was the most frequent specific CADRs occurring in 50.9%

and seen with Taxanes, Anticancer antiobiotics and Alkylating

agents in patients with carcinoma breast. Alopecia was the most

commonly observed CADR in 38 cases of carcinoma breast (77.5%)

followed by carcinoma of ovary.

 Second most common cutaneous toxicity was Nail pigmentation

(45.2%), followed by diffuse acral pigmentation (36.7%) and patchy

tongue pigmentation (21.6%) with regimen of Doxorubin, 5 FU and

Capecitabine. It was most commonly seen in patients with

carcinoma of colon (77.7%) followed by breast carcinoma (52%)

and carcinoma.

 Three cases with specific allergic mediated CADRs were reported

(2 cases with urticarial reaction in patients who received Docetaxel

and Imatinib. Another one patient had SJS to Erlotinib) lung.

 Most frequently used regimen in our study was

Taxanes/Doxorubicin/ Cyclophosphamide and Doxorubicin/

Cyclophosphamide, used in breast carcinoma followed by FOLFOX

regimen in carcinoma colon.

 Among non specific CADRs, dermatophytosis (6.6%) was most

commonly observed followed by herpes zoster (3.7%) and oral

candidiasis (2.8%).

 Combination of Taxanes, Vinca alkaloids and Platinum compounds

were used in carcinoma ovary and lung. Extravasation injury was

most commonly seen in this combination therapy (15%).

 Incidence of Alopecia, supravenous pigmentation (14.1%) was seen

among patients with combination of Platinum compounds and

Taxanes.

 HFS (7.5%) was most commonly observed in patients treated with

regimens of Taxanes, Doxorubicin and Capecitabine combination

therapy.

 Mucositis (3.7%) was commonly seen in patients with Imatinib, and

Taxanes.

 Bleomycin associated flagellate erythema (25%) was observed in

patient who received ABVD regimen.

 Papulopruritic eruption was observed in a single patient treated with

Bendamustine.

 With the regimen of Irinotecan, Topotecan, Gemcitabine acral

pigmentation was most frequently encountered.

 Extravasation injury with Rituximab was seen in patient with NHL.

 Among regimen with monoclonal antibodies, CADRs were less

reported in our study.

 Incidence of cutaneous adverse reaction with targeted

chemotherapy was more and severity of CADRs was also high.

 Melasma like pigmentation (80%) was observed in 4 patients out of

5 receiving Imatinib for CML. Mucositis with urticarial reaction was

seen in patient with Imatinib.

 One HFS was seen with Sunitinib. Multi kinase inhibitor like

Sunitinib and Sorafenib were less frequently used due to

unavailability of the drug.

 SJS was observed in one and only case treated with Erlotinib for

carcinoma lung (EGFR positive non small cell lung CA)

 One patient with Gefitinib, seborrheic dermatitis was observed.

CONCLUSION

 In this study, various cutaneous manifestations in cancer patients

associated with cytotoxic drugs, biological and targeted therapies

were observed.

 Total incidence of CADRs observed was 35%.

 Alopecia was the most frequent specific non immunological CADRs

occurring in 50.9% and seen with Taxanes, Anticancer antiobiotics

and Alkylating agents and it was seen in 38 cases of carcinoma

breast (77.5%) followed by carcinoma of ovary (55.5%).

 Second most common cutaneous toxicity was Nail pigmentation

(45.2%), followed by diffuse acral pigmentation (36.7%) and patchy

tongue pigmentation (21.6%) observed with regimen containing

Doxorubin, 5-FU and Capecitabine. It was most commonly seen in

patients with carcinoma of colon (77.7%) followed by breast

carcinoma (52%) and carcinoma lung.

 Three cases with specific allergic mediated CADRs were reported in

our study. (2 cases with urticarial reaction in patients who received

Docetaxel and Imatinib. Another one patient had SJS to erlotinib)

 Among non specific CADRs, as a sequelae to the

immunosuppression, dermatophytosis (6.6%) was most commonly

observed followed by herpes zoster (3.7%) and oral candidiasis

(2.8%).

 Most frequently used regimen in our study was

Taxanes/Doxorubicin/ Cyclophosphamide and Doxorubicin/

Cyclophosphamide, used in breast carcinoma followed by FOLFOX

regimen in carcinoma colon and they were most commonly

associated with CADRs.

 Among regimen with monoclonal antibodies, CADRs were less

reported in our study.

 Incidence of cutaneous adverse reaction with targeted

chemotherapy was proportionately more and severity was also

high.

Patient compliance is necessary to achieve the best clinical outcome. So before initiating therapy, counselling the patient regarding cutaneous adverse effects can improve the clinical outcome and compliance of the patient. Better awareness about the incidence of CADRs and early recognition will improve the treatment outcome. Some mucocutaneous reactions are serious enough to cause fatal outcome. Hence early diagnosis and appropriate management are necessary to reduce mortality associated with CADRs.

LIMITATIONS

 Newer targeted therapies were used less in this study due to scarcity

of drugs; hence entire gamut of CADRs related to these could not be

studied.

 Long term follow up will be needed.

 Patients with carcinoma cervix, thyroid carcinoma and few

haematological malignancies like AML, ALL were treated in

concerned speciality and not by medical oncologist, so those patients

were not included in this study.

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PIC 2 – DIFFUSE PIGMENTATION OF BOTH HANDS AND BEAU’S LINES IN A CASE OF CARCINOMA COLON RECEIVED FOLFOX REGIMEN. A) DIFFUSE B) DIFFUSE HYPERPIGMENTATION HYPERPIGMENTATION OF OF HANDS AND FEET HANDS

PIC 3 –DIFFUSE ACRAL PIGMENTATION FOLLOWING PACLITAXEL IN A CASE OF RECURRENT BREAST CARCINOMA (3 WEEKS AFTER 1ST CYCLE) A)DIFFUSE HYPERPIGMENTATION OF FEET PIC 4 –DOCETAXEL INDUCED EXTRAVASATION INJURY IN A CASE OF RECURRENT BREAST CARCINOMA ( 1 DAY AFTER 1ST CYCLE OF CHEMOTHERAPY) A) HEALED ULCER WITH CONTRACTURE AND MELANONYCHIA

PIC 5– EXTRAVASATION INJURY DUE TO DOCETAXEL IN A CASE OF CA BREAST (IMMEDIATELY AFTER INFUSION) PIC TAKEN ON 10TH DAY OF CYCLE A) MINIMAL ERYTHEMA WITH HYPERPIGMENTATION PIC 6 – HFS IN BREAST CARCINOMA (MULTIPLE METASTASES) PATIENT RECEIVED PACLITAXEL AND ADRIAMYCIN AND CYCLOPHOSPHAMIDE REGIMEN – AFTER 3 DAYS OF 1ST CYCLE

A)THICK SHEETS OF EXFOLIATION B)ALOPECIA

PIC 7– HFS TO CAPECITABINE AFTER 1 MONTH OF THERAPY IN A CASE OF CA BREAST A)HYPERPIGMENTATION AND SCALING B)HYPERPIGMENTATION AND INVOLVING ENTIRE SOLES SCALING OVER PALMS AND SOLES:

PIC 8 – SUPRAVENOUS PIGMENTATION FOLLOWING DOCETAXEL A)HYPERPIGMENTATION ALONG THE VEINS PIC 9 - PATCHY TONGUE PIGMENTATION OVER TONGUE DUE TO CAPECITABINE: A)PATCHY HYPERPIGMENTATION B)HFS

C)HPE -4X INCREASED BASAL D)PIC – HPE 10X – INCREASED MELANIN: BASAL MELANIN: PIC 10 - SUNITINIB INDUCED HYPOPIGMENTATION IN A CASE OF RCC AFTER 10 DAYS OF THERAPY A)HYPOPIGMENTED MACULES OVER B)SUNITINIB INDUCED HFS – THICK BOTH CHEEKS SHEET OF EXFOLIATION OF BOTH SOLES

PIC 11– MELASMA LIKE PIGMENTATION WITH IMATINIB: 2 YEARS DURATION

A)DIFFUSE HYPERPIGMENTATION OF B) PATCHY HYPERPIGMENTATION FACE OVER BOTH CHEEKS AND NOSE PIC 12 – IMATINIB INDUCED MUCOSITIS (AFTER 11 DAYS OF IMATINIB TREATMENT IN A CASE OF CML) A)MINIMAL CRUSTING OF NASAL B)ATROPHIC TONGUE AND LIP MUCOSA PIGMENTATION AND SCALING

PIC -13 FLAGELLATE ERYTHEMA DUE TO BLEOMYCIN IN A CASE OF HODGKIN’S LYMPHOMA PIC 14 – ERLOTINIB INDUCED SJS: (2 WEEKS AFTER INTAKE OF ERLOTINIB)

A)CRUSTED PLAQUES OVER B)SCROTAL EROSION FOREHEAD AND CHEEKS WITH CONJUNCTIVAL EROSION

C)THICK CRUSTED PLAQUE OVER D)DUSKY ERYTHEMATOUS PAPULES FOREHEAD AND CHEEKS OVER BACK OF TRUNK PIC – 15 – PHOTOSENSITIVITY AND LICHENIFICATION OVER EXTENSOR ASPECT OF FOREARMS IN A CASE OF CA OVARY WITH CYCLOPHOSPHAMIDE A)LICHENIFACTION OVER B)SPARING OF FLEXOR ASPECT EXTENSOR OF BOTH FOREARMS

C)DIFFUSE PIGMENTATION AND D) HPE 4X – HYPERKERATOSIS LLICHENIFICATION OVER FOREHEAD AND CHEEKS

E)HPE 10X HYPERKERATOSIS, F)HPE 40X: INCREASED BASAL INCREASED BASAL MELANIN MELANIN AND INCREASED MELANOCYTES PIC 16 – GEFITINIB INDUCED SEBORRHEIC DERMATITIS LIKE PICTURE IN A CASE OF CA LUNG (AFTER 2WEEKS) A)POWDERY SCALING WITH B) XEROSIS HYPERPIGMENTATION

C)DIFFUSE POWDERY SCALING OVER D) GREASY SCALES OVER POST SCALP AURICULAR AREA

E)HPE 10 X-IRREGULAR F) HPE 40 X-SPONGIOSIS ACANTHOSIS WITH INFLAMMATORY INFILTRATE IN PAPILLARY DERMIS PIC 17- DOCETAXEL INDUCED PHOTOSENSITIVITY AND HFS IN A CASE OF METASTATIC BREAST CARCINOMA (AFTER 10DAYS OF 3RD CYCLE) A)HYPERPIGMENTATION WITH B)EXFOLIATION OF SKIN OVER EXFOLIATION V NECK AREA

C)EXFOLIATION PRESENT OVER D)HFS SUN EXPOSED PART OF BACK OF TRUNK

E)HPE 10X HYPERKERATOSIS, F)40X - INCREASED BASAL BASAL MELANIN MELANIN AND MELANIN INCONTINENCE PIC -18 PAPULOPRURITIC ERUPTION FOLLOWING BENDAMUSTINE IN A CASE OF CLL (AFTER 2ND CYCLE OF CHEMOTHERAPY)

A)MULTIPLE ERYTHEMATOUS B) MULTIPLE ERYTHEMATOUS PAPULES AND PUSTULES PAPULES AND PUSTULES

C)HPE – 4 X ERODED EPIDERMIS D)HPE – 10 X - COLLECTION OF INFLAMMATORY INFILTRATE:

E) HPE 40X – COLLECTION OF INFLAMMATORY CELLS g';F bgWnthupd; xg;g[jy; gotk;

g';nfw;nghupd; bgah; : tpyhrk; :

Muha;r;rpapd; jiyg;g[ :

“தி ெந ேவ ம வ க ாி ம வமைனயி ேநா ைமய தி ேநா ம வ சிகி ைச ெப ேநாயாளிக ஏ ப ேதா ம சீத ச ப கவிைள கைள ப றி ஆரா த ”

,e;j Muha;r;rp gw;wpa KG midj;J tpgu';fSk; vGj;J kw;Wk; tha;tHpahf vd;Dila jha;bkhHpapy; KGikahf tpsf;fg;gl;Ls;sJ/ ,t;thuha;r;rpia KGikahf g[hpe;Jbfhz;nld; vd;Wk; ,t;thuha;r;rpia gw;wpa nfs;tpfis vGg;g[tjw;F vdf;F jFe;j tha;g;gspf;fg;gl;lJ vd;Wk; cWjpaspf;fpnwd;/ ,t;thuha;r;rpapy; g';F bgWtJ vd;Dila brhe;j tpUg;gj;ij bghWj;jJ vd;Wk;. ,t;thuha;r;rpapd; nghJ vg;nghJ ntz;LkhdhYk; tpyfpf;bfhs;syhk; vd;Wk;. ,jdhy; vdf;F mspf;fg;gLk; rpfpr;iriaa[k; kw;Wk; chpikfisa[k; vt;tpjj;jpYk; ghjpf;fhJ vd;W g[hpe;Jbfhz;nld;/ ,t;thuha;r;rpapy; tUk; Kot[k; kw;Wk; mstpfis mwptpaypd; Kd;ndw;wj;jpw;fhf gad;gLj;Jtjw;F ve;jtpj jila[k; Vw;gLj;jkhl;nld; vd;Wk; cWjp TWfpnwd;/ ehd; ,t;thuha;r;rpapy; g';Fbfhs;tjw;F KGikahf rk;kjpf;fpnwd;/

g';FbgWnthupd; bgw;nwhu; ifbahg;gk; : njjp :

rhl;rpahsu; ifbahg;gk; : njjp :

rhl;rpahsu; bgah; kw;Wk; Kfthp : njjp :

Muha;r;rpahshpd; ifbahg;gk; : njjp : MUCOCUTANEOUS MANIFESTATIONS IN PATIENTS RECEIVING CANCER CHEMOTHERAPY IN REGIONAL CANCER CENTRE OF TIRUNELVELI MEDICAL COLLEGE

NAME: AGE/SEX: OCCUPATION: ADDRESS: OP/IP NUMBER: PHONE NUMBER: DIAGNOSIS: TREATMENT DETAILS: TIME OF OCCURENCE OF DRUG REACTION: DURATION OF REACTION: COMPLAINTS: H/O PRESENT ILLNESS:

H/o itching – H/o dry skin – H/o hair loss – H/o oral ulcer – painful/painless H/o dyspigmentation – H/o nail changes – H/o any blistering lesion of skin – H/o peeling of skin – H/o erythema over palms and soles – H/o erythema of skin over body – H/o giddiness during infusion – H/o chest pain – H/o cough and cold – H/o abdominal pain/ vomiting – H/s/o hypersensitivity reaction – H/o coexisting dermatological conditions – PAST HISTORY: H/o previous episodes – H/o other comorbid conditions – PERSONAL HISTORY: Diet : Alcohol : Smoking : Betalnut chewer: MENSTRUAL HISTORY: MARITAL HISTORY: TREATMENT HISTORY: GENERAL EXAMINATION Conscious /oriented General condition Built and nourishment Pallor Cyanosis /clubbing /icteric Pedal edema / lymphadenopathy BP: PR: RR: TEMPERATURE: CVS: RS: P/A : CNS: DERMATOLOGICAL EXAMINATION:

Oral mucousa/ genital mucosa : Scalp / hair : Palms / soles : Nail : DIAGNOSIS OF CUTANEOUS REACTION: DRUG TIME OF MORPHOLOGY DIAGNOSIS HPE OCCURENCE OF OF REACTION CUTANEOUS REACTION

INVESTIGATIONS:

URINE – ALB

SUG

DEP

RBS:

UREA

CREATININE

RBC

PCV

PLATELET COUNT

T.BILLIRUBIN

D.BILLIRUBIN

ID.BILLIRUBIN

SGOT SGPT

ALP

T.PROTEIN

SR.ALBUMIN

SR.GLOBULIN

HPE:

Biosy site

Date

HPE number

DIAGNOSIS OF SKIN REACTION: C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C15 C17

Sex

Age

Name

reaction

Regimen

Serial no Serial

Diagnosis

Complaints

examination

nailchanges

hair changeshair

dermatological

mucosalchanges

Diagnosisskinof

cutaneous reaction cutaneousreaction

Durationreaction of

to onset of symptomsof onset to

drugs responsible for for drugsresponsible

inition of chemotherapyof inition 1 Lakshmi 45 2 1 1 16 w 12w 1,2,3 1,4,5g,21 1 Bendamustine 2 Chendu 65 2 2 2 20w less than 1 w 3,5b,5f 13,5b,7 3 1 2 2 docetaxel 3 shanthi 52 2 2 3 6w 8w 1,2,3,5f 1 1 2 3 cyclophosphamide 4 muthulakshmi 55 2 3 4 4w 14w 2,5f 1,5b 1 4 docetaxel 5 manju usha 31 2 2 2 4w 3w 5c,3,5f 5c,5b,5a 1 2 5 Acral pigmentation, pigmentation of tongue, Melanonychia supravenous pigmentation alopecia - docetaxel 6 rajeshwari 58 2 4 5 1w 3w 10 19 6 related to immunosuppression 7 velammal 60 2 2 6 2w 14w 8,1,2,3,4a,5f,5c 23,2,5a,1b 1 2 7 paclitaxel 8 mookammal 54 2 2 10 12w 9w 5a,3,5f 1,5a 1 2 8 paclitaxel 9 gurulakshmi 61 2 2 11 6w 6w 2,3,5f,5b 5b 1 2 14 alopecia - cyclophosphamide supravenous pigmentation and alopecia - paclitaxel 10 chidambaraammal 70 2 7 9 6w 6w 1,2,3,5c,5f 5c, 1 2 15 paclitaxeland carboplatin 11 chidambaranayagi 62 2 8 12 3w 5w 5c,5a 5c,5a 16 capecitabine 12 revathi 44 2 2 2 2w 1w 11, 5h 9,3,5a 2 37,26 docetaxel 13 arundhathi 67 2 2 14 6w less than 1w 1,3,6 7 2 18 docetaxel 14 gnanamani 54 2 9 13 2years 6m 5d 6 13 imatinib 15 Arunachalavadivu 68 2 2 12 8w 4w 8,5c,7,2 23,5c,3 26 capecitabine 16 mary 55 2 3 15 6w 6w 5b,2,3,5f 1,5b 1 2 19 supravenous pigmentation - 5fu alopecia - epirubicin melanonychia, xerosis - oxaliplatin 17 muthaiah 56 1 10 16 6w 4w 5c,1,8 5c,3 26 pemetrexed 18 chithiraikani 43 2 2 3 12w 4w 5c,3, 5c 1 2 15 acral pigmentation, melanonychia - adriamycin alopecia- cyclophosphamide

19 50 2 2 3 2 20 alagumuthu 8w 4w 5c,3,5a 5a,5c acral pigmentation and hyperpigmentation of tongue- adriyamycin alopecia -cyclophosphamide 20 thangamani 60 2 9 13 1w 1w 1,2,4b,12 1 1b,4 27 imatinib 21 petchiammal 62 2 11 17 1w 8w 6,3,4b,5f 12 1d 1 2 21 extravastion injury rituximab alopecia and melanonychia- cyclophosphamide 22 madasamy 55 1 10 18 36w 3w 5c,5f,5a 5a,5c 1 22 etoposide 23 inbarubi 62 2 12 7 12w 16w 5c,5a,3 5c,5b,5a 1 2 23 5fluouracil 24 rajima beevi 50 2 2 19 4w 4w 5c,3 5c, 2 24 Acral pigmentation - capecitabine alopecia and nail dystrophy - cyclophosphamide 25 muthukarupan 62 1 3 20 24w 6w 5c,5f 5c 1 25 capecitabine 26 sornam 57 2 2 2 20w 3w 1,2,4b,5f,8 1,5f,23 1b 1 28 docetaxel 27 backyasheela 42 2 2 10 14w 6w 5b,6,5f,3,5a 5b,7,5a 1 2 29 paclitaxel 28 arumugam 60 2 6 21 1w 4w 1,2 1 30 carboplatin 29 sudalaimodi 35 2 6 22 8w 1w 5c 5b,5c 5 31 doxorubicin 30 lakshmi 55 2 2 3 14w 6w 2,3,13,5f,5c 1,5c 1d 1 2 32 alopecia and HFS - cyclophosphamide melanonychia, xerosis - adriamycin 31 guruvathai 42 2 13 23 3w 8w 5c,8,2,3,5f,13 5c,3 1 2 32 ABVD Regimen 32 mohamed natchi 54 2 2 8 8w 6w 6,3 7 2 33 docetaxel 33 45 2 2 24 1 2 34 valli 14w 3w 3,5c,5a,5f, 5c,5a acral pigmentation,melanonychia,tongue pigmentatio-adriamycin alopecia-cyclophosphamide 34 Ramathal 45 2 2 11 3w 3w 3,5f 1 2 12 alopecia - cyclophosphamide melanonychia - adriamycin 35 kadarkarai 65 1 10 16 8w 4w 5c,5f 5c,5d 1 25 pemetrexed 36 pappathi 37 2 5 7 3w 3w 5c,5a,5f 5c,5a 1 22 5 fluorouracil 37 pitchaiah 52 1 12 25 3w 4w 3,5c,5a,5f 5a,5c 1 2 34 capecitabine 38 Gurulakshmi 42 2 2 26 less than12w 1w 6,5b,3 8,5b 2 18 docetaxel 39 35 2 2 3 1 2 34 vijayalakshmi 5w 3w 3,5c,5a,5f 5a,5c acral pigmentation,melanonychia,tongue pigmentatio-adriamycin alopecia-cyclophosphamide 40 shenbagavalli 74 2 2 26 3w less than 1 wk 1,2,3,4a,5g 1,7, 1b 1 2 35 extravasation injury - docetaxel melanonychia, atophic tongue, xerosis- trastuzumab 41 palanivel 53 1 5 25 3w 1w 5c,5a,5f 5c,5a 1 22 capecitabine

42 nagajothi 46 2 6 9 3wk less than 1wk 5b 5b 9 paclitaxel

43 muniyammal 65 2 2 11 8wk 6wk 5b,3, 5c 5b 2 14 supra venous pigmentation - docetaxel melanonychia - adriamycin alopecia - cyclophosphamide 44 valarmaathi 67 2 2 14 2wk less than 1wk 6 7 10 docetaxel 45 radhakrishnan 54 1 13 23 less than4wk 1wk 10 19 6 related to immunosuppression

46 subramani 49 1 5 7 20wk 12wk 5c,5f,5a 5c,5a 1 22 5fu

47 prema 55 2 2 11 3wk 3wk 3,5f, 5c 1 2 15 alopecia - cyclophosphamide melanonychia - adriamycin 48 avudaithai 42 2 2 35 8wk 3wk 5c,3,5f 5c 1 2 15 alopecia - cyclophosphamide acral pigmentation and melanonychia - adriamycin 49 guruvammal 48 2 2 11 3wk 3wk 5g, 5c 7 10 paclitaxel

50 shanthakumari 42 2 2 28 12w 4w 13,5c,5h,5d 6,5c,5g 26 capecetabine 13 trastuzumab 37 cyclophosphamide 51 veeralakshmi 39 2 2 3 4w 4w 1,5f 18 1 38 related to immunosuppressio 39 cyclophosphamide 52 poolammal 45 2 10 16 1w 8w 1 18 38 related to immunosuppressio 53 vanuvamalai 62 1 14 29 3w 7w 12 22 1b 40 related to immunosuppressio 54 perambuammal 58 2 2 2 4w less than 1w 6,5g,3 7 2 33 docetaxel 55 selvanayagi 32 2 13 23 12w less than 1w 5i,3 10 2 41 flagellate erythema-bleomycin alopecia-vinblastin 56 Murugaiah 60 1 10 30 1w 2w 14,12,1 16 6,7 42 Erlotinib 57 Daisy 75 2 10 31 24w 4w 1,2,3,5d 2,5d 2 43 Geftinib 58 Bharat 16 1 5 7 24w 4w 1,2,4a 2,5c 1b 44 acral pigmentation,atrophic tongue-5 fluorouracil generalised acquired ichthyosis-oxaliplatin 59 Thangam 35 2 15 32 3w 3w 5c 5c 5 1 2 15 etoposide 60 Vellaiammal 55 2 2 2 6w less than 1w 5g,3 7 2 33 docetaxel 61 Rajalakshmi 50 2 2 33 less than8w 1 w 12,15 45 docetaxel 62 Mariammal 52 2 2 6 3w 8w 1 18 38 related to immunosuppressio 63 esakiammal 60 2 6 21 4w 14w 1 18 38 related to immunosuppressio 64 yesudas 60 2 5 7 6w 8w 5e,3, 5c 5e 1,3,4 1 46 5 fluorouracil,platinum compound 65 Vellathai 54 2 3 7 10w 3w 5b, 5c 5b 9 5 fluorourcil 66 Murugan 55 1 10 16 3w 6w 1,3 18 2 38 related to immunosuppressio 11 platinum compounds 67 Chellammal 48 2 2 34 2w 20w 10 19 6 related to immunosuppressio 68 Parvathy 64 2 2 8 2w 8w 6,5g 7 10 docetaxel 69 Noorjahan 50 2 6 9 4w 6w 3 2 11 paclitaxel 70 Muniyasamy 48 1 10 18 4w 1w 1 18 38 related to immunosuppressio 71 Mallika 45 2 2 11 3w 3w 5f, 5c 1 25 adriamycin acral pigmentation,melanonychia,pigmentation of tongue- 72 38 2 2 35 1 2 34 Meena devi 12w 2w 5c,3,5a,5f 5c,5a adriamycin alopecia-ifosfamide 73 Shanthi 54 2 2 11 3w less than 1w 6,14 7 2 33 extravasation injury-docetaxel alopecia-cyclophosphamide 74 Petchiammal 52 2 6 9 8w 3w 1,2,3 1,2 1b 2 47 paclitaxel,carboplatin 75 Ramaiah 40 1 5 7 6w 12w 5c 5c 1 25 5 fluorouracil 76 ponnammal 36 2 2 3 14w 6w 3,5f 1 2 39,11 cyclophosphamide 77 Swaminathan 72 1 10 31 8w 8w 1,9 9,24 17 gefitinib 78 murugalakshmi 45 2 2 24 less than14w 1w 10 19 48 related to immunosuppression supravenous pigmentation - docetaxel: alopecia - 79 46 2 2 11 1 2 14 Esakiammal 3w 3w 5g,3 5b cyclophosphamide : melanonychia - adriamycin 80 Paapammal 61 2 2 11 2w less than 1w 14,3 22 2 40,11 folliculitis-related to immunosuppession alopecia-cyclophosphamide 81 Subbammal 54 2 2 11 5w 6w 5g,3,5f 7,5g,5c 1,3 2 29,11,49 Extravasation injury-paclitqxel

anagen effluvium,melanonychia,beau's line-cyclophosphamide 82 Deivanai 51 2 5 7 12w 3w 5c 5c 5 1 25,50 5 fluorouracil 83 chitra 17 2 5 7 12w 1w 5c 5c 1 25 5 fluorouracil 84 jeeva 48 2 2 21 36w 6w 6,5b,3 7 2 33 carboplatin and gemcitabine 85 mariya pushpam 54 2 2 14 6w 3w 5b,3 5b 2 9,11 supravenous pigmentation - docetaxel anagen effluvium - cyclophosphamide 86 esakkiyammal 55 2 10 18 8w 6w 5c,1,2,3 5c,2 1 2 15,51 platin and etoposide 87 susaiammal 49 2 2 33 2w 3w 5g, 7 10 docetaxel 88 ponnammal 57 2 6 22 8w 8w 5c,3 5c,5a 1 34 doxorubicin 89 Murugesan 47 1 12 36 8w 14w 5c 5c,5a 1 22 capacetabine 90 Vedhamani 65 2 6 37 12w 6month 1,3,5h 5g,5d 2 37,11 cyclophosphamide 91 shanmugam 36 1 9 13 24w 2years 5d 6 13 imatinib Acral pigmentation, pigmentation of tongue, 92 60 2 2 19 1 34 vasanthi 20w 8w 5c,2, 5c,5d,2,5a Melanonychia,alopecia - capecitabine alopecia - cyclophosphamide 93 rajakumari 31 2 3 27 2w less than 1wk 5c,3 5c 2 20 capecitabine 94 balasundary 42 2 2 11 3w less than 1wk 8,13,3 23,3 2 36 paclitaxel 95 rukmani 50 2 2 19 4wk less than 1wk 5c,3 5c,5a 3,1 2 22 capecitabine 24 cyclophosphamide 96 devanesam 56 2 6 21 12wk 3wk 5c,3 5c 1b 2 20 gemcitabine 97 soundarraj 47 1 9 13 32wk 36wk 5d 6 13 imatinib 98 ponnupandi 59 1 8 21 12w 3wk 5c 5c,5a 16 gemcitabine 99 ramalakshmi 42 2 10 9 3wk less than 1wk 5g 5b 9 paclitaxel 100 muniyasamy 35 1 5 7 3wk 4wk 1 18 38 related to immunosuppression 101 chinnadurai 34 1 10 23 6wk 3wk 3 1 2 12 melanonychia - adriamycin alopecia - vinblastine 102 thangamani 39 2 2 3 7wk 2wk 3,5f 1 2 12 melanonychia - adriamycin alopecia - cyclophosphamide 103 muthumari 58 2 9 18 6w 3w 5c 5c 1 25 etoposide 104 nagaraj 45 1 8 13 16w 20w 5d 6 13 imatinib 105 sundari 55 2 2 14 6w 6w 5g,3 7 2 33 extravastion injury - docetaxel alpecia - cyclophosphamide 106 mallika 45 2 16 38 6w 2w 7,8 3,25, 1b - 26,52 hypopigmentation and HFS sunitinib KEY TO MASTER SHEET

C1 - Serial number

C2 - Name

C3 – Age

C4 – Sex M = Male F = Female

C5 –Diagnosis

1-Chronic lymphocytic leukemia

2-Carcinoma breast

3-Carcinoma of stomach

4-Carcinoma of vulva

5-Carcinoma of colon

6-Carcinoma of ovary

7-Carcinoma of endometrium stage 4

8-Carcinoma gall bladder stage 4

9-Chronic myelocytic leukemia

10-Carcinoma of lung

11-Non-hodgkins lymphoma

12-Carcinoma of rectum

13-Hodgkin's lymphoma

14-Unknown primary with secondary’s neck

15-Castle man's disease

16-Renal cell carcinoma

C6 – Regimen

1 Bendamustine and rituximab

2 Docetaxel

3 Adriamycin and cyclophosphamide

4 Docetaxel, carboplatin and 5fluouracil

5 Cisplatin and 5 fluouracil 6 Trastuzumab and paclitaxel

7 Leucovorin , oxaliplatin and 5 fluouracil(5fu)

8 Docetaxel, carboplatin and trastuzumab

9 Paclitaxel and carboplatin

10 Paclitaxel

11 Paclitaxel, adriamycin, cyclophosphamide

12 Capecitabine

13 Imatinib

14 Docetaxel and cyclophosphamide

15 Epirubicin, oxaliplatin and 5 fu

16 Pemetrexed and carboplatin

17 Rituximab , CHOP Regimen

18 Cisplatin and etoposide

19 Capecitabine, cyclophosphamide

20 Docetaxel, carboplatin, capecitabine

21 Carboplatine,gemcitabine

22 Bevacizumab and doxorubicin

23 Adriamycin, bleomycin, vinblastine, dacarbazine

24 Adriamycin,cyclophosphamide,5 fluorouracil

25 Bevacizumab,capecitabine,irinotecan

26 Docetaxel,trastuzumab

27 Epirubicin, oxaliplatin and capecitabine

28 Trastuzumab,capecitabine and cyclophosphamide

29 Methotrexate

30 Erlotinib

31 Geftinib

32 Rituximab,etoposide,prednisolone

33 Docetaxel,adriamycin,cyclophosphamide 34 Trastuzumab,capecitabine

35 Adriamyin,ifosfamide

36 Capecitabine,irinotecan

37 Cyclophosphamide

38 Sunitinib

C7 - Duration of reaction

C8 - initiation of treatment to onset of symptoms

C9 - Complaints

1 itching

2 dry skin

3 hair loss

4 oral ulcer 4a - painless

4b - painful

5 pigmentation

5a - tongue pigmentation

5b - pigmentation along veins

5c - pigmentation of palms and soles

5d - pigmentation of face

5e - generalised pigmentation

5f - pigmentation of nails

5g- pigmentation at the site of injection

5h-pigmentation of photo exposed area

5i-pigmentation of back of trunk

6 erythema at the site of infusion

7 erythema of palms and soles

8 scaling of palms and soles 9 generalised scaling

10 fluid filled skin lesions

11 peeling of skin

12 red raised skin lesions

13 numbness of hands and feet

14 ulcerated skin lesion

15 facial puffiness

16 hypopigmentation

C10 - dermatological examination

1 xerosis

2 ichthyosis

3 hand foot syndrome

4 papulopruritic eruption

5 pigmentation

5a- tongue pigmentation

5b - supravenous pigmentation

5c - acral pigmentation

5d - pigmentation of face

5e - generalised pigmentation

5f -post inflammatory hyperpigmentation

5g-pigmentation of photo exposed area

6 melasma like pigmentation

7 extravastion injury

8 thrombophlebitis

9 exfoliative dermatitis

10 flagellate erythema

11 acneiform eruption

12 ulceration at the site of infusion 13 ulceration and contracture

14 infusion reaction

15 urticaria

16 SJS - Steven johnson syndrome

17 TEN - toxic epidermal necrolysis

18 dermatophytosis

19 grouped vesicles in a dermatomal pattern

20 scabies

21 abscess

22 folliculitis

23 superficial exfoliation of hands and feet

24 palmar erythema

25 hypopigmentation

C11 - mucosal changes

1 mucositis

1a - angular cheilitis

1b - atrophic tongue

1c - fissured tongue

1d - candidiasis

3 coated tongue

4 hemorrhagic crusting and fissuring of both lips

5 pigmentation of lips

6 erosion of genital mucosa

7 conjunctival congestion

C12 – nail changes

1 melanonychia

2 mee's lines

3 beau's lines 4 dystrophy of nails

C13 - hair changes

1 diffuse hair loss

2 anagen effluvium

C14 - Diagnosis of skin reaction

1 xerosis with secondary infection and papulopruritic eruption 2 extravastion injury with contracture, supravenous pigmentation, melanonychia 3 xerosis,melanonychia , alopecia 4 melanonychia, xerosis, supravenous pigmentation 5 Acral pigmentation, pigmentation of tongue, Melanonychia, Supravenous pigmentation, alopecia 6 herpes zoster 7 HFS,Atrophic tongue, tongue pigmentation, melanonychia, diffuse hair loss 8 Hyperpigmentation of tongue, alopecia,melanonychia, xerosis

9 supravenous pigmentation 1 0 extravastion injury 1 1 alopecia 1 2 alopecia and melanonychia 1 3 melasma like pigmentation 1 4 supravenous pigmentation, alopecia, melanonychia 1 5 Acral pigmentation, melanonychia, alopecia 1 6 Acral pigmentation, pigmentation of tongue 1 7 Exfoliative dermatitis 1 8 Thrombophlebitis and alopecia 1 9 supravenous pigmentation, alopecia, melanonychia, Xerosis 2 0 Acral pigmentation, pigmentation of tongue, Alopecia 2 rituxima 1 extravastion injury b alopecia and melanonychia- cyclophosphamide 2 2 Acral pigmentation, pigmentation of tongue, Melanonychia

2 3 Acral pigmentation, pigmentation of tongue, Melanonychia, Supravenous pigmentation 2 4 Acral pigmentation - capecitabine alopecia and nail dystrophy - cyclophosphamide 2 5 Acral pigmentation, melanonychia 2 6 hand foot syndrome 2 7 infusion reaction with mucositis 2 8 HFS, Generalised xerosis, atropic tongue, melanonychia 2 9 extravastion injury and melanonychia 3 0 xerosis , dystrophy of nails 3 1 supravenous pigmentation and acral pigmentation 3 2 HFS, Generalised xerosis, alopecia, melanonychia 3 3 extravasation injury,alopecia 3 4 Acral pigmentation, pigmentation of tongue, Melanonychia,alopecia 3 5 extravastion injury, melanonychia,alopecia,atrophic tongue,generalised xerosis 3 6 HFS, alopecia 3 7 Photosensitivity 3 8 Dermatophytosis 3 9 melanonychia 4 0 Folliculitis 4 1 Flagellate erythema,alopecia 4 2 Steven Johnson Syndrome 4 3 acquired icthyosis,diffuse pigmentation of face,alopecia 4 4 acquired icthyosis,acral pigmentatio,atrophic tongue 4 5 infusion reaction

4 6 diffuse hyperpigmentation,diffuse hair loss,melanonychia 4 7 generalised xerosis,alopecia 4 8 Herpes simplex labialis 4 9 Beau's line 5 0 lip pigmentation 5 1 ichthyosis 5 2 hypopigmentation

C16 – Drugs responsible for skin reaction