Capecitabine Induces Rapid, Sustained Response in Two Patients with Extensive Oral Verrucous Carcinoma1

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580 Vol. 9, 580–585, February 2003 Clinical Cancer Research

Advances in Brief Capecitabine Induces Rapid, Sustained Response in Two Patients with Extensive Oral Verrucous Carcinoma1

Anastasios Salesiotis, Richie Soong, chemical evaluation of pretreatment biopsies from both pa- Robert B. Diasio, Andra Frost, and tients revealed a high level of expression of thymidine phos- Kevin J. Cullen2 phorylase, a key enzyme in the metabolism of capecitabine. Conclusions: Oral VC is a rare entity with a progressive Lombardi Cancer Center, Georgetown University, Washington DC course over years and limited options in terms of treatment. 20007 [A. S., K. C.], and University of Alabama Cancer Center, Birmingham, Alabama [R. D., R. S., A. F.] Preliminary observations in two elderly patients demon- strate that capecitabine, an oral fluoropyrimidine, is well tolerated and may induce rapid, clinically significant re- Abstract sponse. Although not curative, it may provide a cost-effec- Purpose: Oral verrucous carcinoma (VC) has been tra- tive alternative for elderly patients with a significant im- ditionally treated with surgery or radiation with frequent provement in their quality of life. recurrences and significant morbidity. We describe rapid and dramatic response to oral capecitabine in two patients Introduction with advanced refractory VC. Verrucous carcinomata are rare tumors of the oral cavity, Experimental Design: VC is a rare tumor of the oral representing anywhere from 1 to 10% of all oral squamous cavity. It does not metastasize but over time causes morbid- malignancies (1–5). Although oral presentations are most com- ity and mortality through local invasion. Radiation and mon, VC3 may also be present in the larynx or elsewhere in the surgery have been the main treatment modalities but are aerodigestive tract (6). Similar lesions may be present elsewhere plagued by mutilating effects, recurrences, and possibly main the body as well. The most common sites of involvement in lignant degeneration in some cases. To date, no effective the mouth are the buccal mucosa and gingiva, the alveolar ridge, chemotherapy regimens have been described in the interna- the palate, and the tongue. Compared with convential squamous tional literature. The clinical records of two elderly females cell tumors of the head and neck, they tend to present at an with extensive oral VC are described. Both patients were advanced age, with a higher proportion of female patients. prescribed one cycle of capecitabine, 1000 mg bid for 14 Although these tumors are classified as carcinomata, they are days. Response was documented by photography in one extremely well-differentiated rare variants of squamous carci- patient. Immunohistochemical evaluation of three 5-fluo- noma with little or no metastatic potential. However, they cause rouracil metabolizing enzymes on pretreatment biopsies significant morbidity because of their local invasiveness and from both patients was also performed. A review of the their pattern of stubborn recurrence with the currently accepta- literature with emphasis on treatment of oral VC is pre- ble modalities of radiation and surgery (7, 8). sented in view of our findings. We present two cases of VC of the oral cavity in elderly Results: Examination of the oral cavity before treat- females that have responded dramatically to Capecitabine (Xe- ment revealed extensive involvement with an evenly spread- loda), an oral fluoropyrimidine that has been shown to be very ing, exophytic, warty, whitish lesion in both patients. Micro- effective against advanced colorectal cancer (9). These rapid scopic examination of H&E-stained slides from biopsies of responses occurred with a reduced dose during the first cycle of these lesions confirmed the clinical suspicion of VC. Both administration in both cases. To date, there has been no system- patients underwent treatment with oral capecitabine for one atic published evaluation of the use or efficacy of chemotherapy cycle (2 weeks on/1 week off) at a reduced dose of 1000 mg, in VC with published retrospective series rarely mentioning this p.o., bid. Both had a dramatic response with near complete treatment modality. An exception to that is a Japanese study that resolution of their lesions within 3 weeks of initiating ther- mentions an elaborate chemoradiation scheme with combination apy. A durable partial response was documented at 1 year in chemotherapy that includes i.v. drugs (10). We also discuss all the first patient and 6 months in the second. Immunohisto- relevant literature. Case 1. A 71-year-old Argentinean female presented to her doctor with a 1 ϫ 1-cm erythematous plaque in the palate in June 1988. Posterior to that lesion, a 0.5-cm whitish raised Received 6/27/02; revised 8/29/02; accepted 9/5/02. circumscribed papule was also discovered that was subsequently The costs of publication of this article were defrayed in part by the biopsied and called squamous/keratinized papilloma. Up to that payment of page charges. This article must therefore be hereby marked point, she had an unremarkable medical history except for an advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported, in part, by National Cancer Institute Grants CA 82238, CA 76903, CA 13148, and a gift from Mr. Robert Edenbaum. 2 To whom requests for reprints should be addressed, at Lombardi Cancer Center, Georgetown University Hospital, 3800 Reservoir Road, 3 The abbreviations used are: VC, verrucous carcinoma; DPD, dihydro- Northwest, Washington, DC 20007. Phone: (202) 687-2110; Fax: pyrimidine dehydrogenase; TP, thymidine phosphorylase; TS, thymi- (202) 687-5185; E-mail: [email protected]. dine synthetase; SCC, squamous cell carcinoma; 5-FU, 5-fluorouracil. Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2003 American Association for Cancer Research. Clinical Cancer Research 581

appendectomy and a prolapsed uterus repair. She had never been was consistent with VC. Her head and neck surgeon felt that, a smoker or drinker, and her family history was significant for although resection with reconstruction in stages was technically gastric cancer in her brother. Within months, new exophytic feasible, it would be associated with marked morbidity and lesions appeared and were similar to the original papule under referred the patient to the medical oncology service for a con- both gross and microscopic examination. Three separate exci- sultation. sions were performed, but a recurrence was noted in the first These two patients represent the only cases of VC treated half of 1990. Histological examination again revealed papillo- at our center since 1998. matosis. In September 1990, she underwent electrocoagulation and then received IFN A, vitamin A, and vitamin C. Soon Patients and Methods afterward in 1991, a recurrence in the left buccal mucosa was These patients were seen at the Lombardi Cancer Center, again treated with electrocoagulation. An excisional biopsy in Georgetown University. A complete history was obtained, and a 1992 demonstrated the same histology. The lesions continued to physical was performed on the initial visit. Photographs of the spread in the mouth gradually. oral lesions were taken during the initial visit for the second In January 1993, the patient was evaluated in the United patient. Chemotherapy consent was obtained from both patients States, and a biopsy was taken and read as hyperkeratosis. She and routine chemistries were drawn. We reviewed all biopsy returned to Argentina where in April 1993, a surgical excision specimens with our staff pathologists and confirmed the diag- was performed followed by repair of the oral deficit with a skin nosis of oral VC. Capecitabine was prescribed at 1000 mg/day graft from the leg. The histology of the excised lesion was again for 2 weeks. The patients were instructed not to take the cape- read as papillomatosis. The patient was then treated with elec- citabine during the third week. They were seen at the end of the trocoagulations, vitamins, and IFN A intermittently with tem- third week. Again a brief history was taken with special em- porary remissions. phasis on side effects of capecitabine. A focused physical fol- In April 1996, chemotherapy was started with single agent lowed, and photographs of the oral cavity were taken and methotrexate given 50 mg i.v. and 0.05 mg intralesionally every compared with the pretreatment photographs. No pretreatment 20 days for a period of 12 months. An excellent response was photographs were available for the first patient. noted with almost total disappearance of all lesions. A residual Immunohistochemistry was performed in the laboratory of lesion together with the entire palate mucosa was excised, and Dr. Robert B. Diasio at the University of Alabama at Birmingham. again a skin graft was placed to close the gap in July 1997. Five-␮m paraffin sections were cut and stained immunohisto- Despite this treatment in March 1998, a recurrence was noted chemically to evaluate DPD, TP, and TS with commercially avail- and its biopsy was shown to be consistent with dysplasia. Soon able antibodies from Roche Diagnostics (Indianapolis, IN). Stain- afterward, a large verrucous lesion was excised and read as VC. ing reagents were obtained from Dako, Inc. (Glostrup, Denmark). The patient received i.v. methotrexate at a dose of 75 mg Antigen retrieval and immunohistochemical staining were per- intermittently until July 2000, with little response. The lesions formed according to protocols recommended by the manufacturer. continued to spread throughout the oral cavity. In August 2000, The biopsy from the first patient was from a previous procedure in a thrombocytopenia detected on routine blood analysis Argentina which was obtained previously. The biopsy from the prompted an extensive work-up, which led to the diagnosis of second patient was obtained a few weeks before initiation of hepatitis C. Liver biopsy in September 2000 revealed hepatic treatment at Georgetown University Hospital. cirrhosis. The patient presented to our institution in January 2001. At that time, examination revealed extensive involvement of the Results oral cavity with ϳ50% of the mucosa replaced by tumor, pri- The first patient presented to us in January 2001 for treat- marily involving buccal mucosa, palate, and floor of mouth. The ment options. We reviewed her slides from Argentina and patient complained of significant pain and was confined to a confirmed the diagnosis of VC. Her main complaint was burn- liquid diet. Review of her previous biopsy specimens confirmed ing on swallowing and mouth sores. Her physical exam was the diagnosis of VC. remarkable in her oral cavity for a whitish, exophytic, fungating, Case 2. The second patient is a 75-year-old Caucasian and irregular mucosal lesion extending from the left side of the female with multiple medical problems who presented with tongue to the anterior portion of the hard palate and into the similar complaints especially on the right side of her oral cavity. internal surface of the upper lip. The lesion covered Ͼ50% of The patient was diagnosed with an in situ carcinoma of unspec- her oral mucosa. There was no cervical or supraclavicular or ified histology in the left lateral mandibular ridge (third molar) infraclavicular lymphadenopathy. The patient was given cape- in 1999 for which she underwent a wide excision. Afterward, citabine at a dose of 1000 mg bid for 14 days. This dose was she had what was felt to be recurrent leukoplakia on the right selected because of her history of hepatitis C and cirrhosis. She mandible and soft palate which necessitated four additional developed grade III mucositis from day 10 to day 20 of treat- laser-assisted excisions. The lesions continued to recur and get ment but denied other symptoms, including diarrhea or hand/ worse with time. She, too, however, had an unremarkable med- foot syndrome. After resolution of her mucositis, Ͼ90% of her ical history. She had never been a smoker or drinker, and her disease had resolved with several small (Ͻ1 cm) patches of family history was noncontributory. She presented to our insti- disease remaining on the buccal mucosa. Her pain had resolved, tution in January 2002. Evaluation by an otolaryngologist re- and she was able to eat more solid foods. More than 90% of the vealed extensive tumor involving the floor of mouth, lateral previously involved buccal mucosa remained disease free on tongue, buccal mucosa, and palate. A biopsy was performed that visual inspection 6 months later.

Fig. 1 Clinical response to capecitabine in case 2. Top panels: pretreatment appearance February 13, 2002. Extensive whitish, exophytic, papillary lesions are present on the buccal mucosa, tongue, floor of mouth, and palate. Middle panels: same patient March 6, 2002. All lesions have resolved, but there are areas of denuded mucosa. Bottom panels: same patient August 14, 2002. There is a small area of tumor visible at the floor of the mouth, but other areas of previous involvement on the tongue, buccal mucosa, and palate remain clear.

The patient subsequently returned to Argentina and did on swallowing and mouth sores. Her physical exam was remark- well with much improved symptoms for 18 months after her able in her oral cavity for a whitish, exophytic, fungating, and initial therapy. She then developed gradually worsening dys- irregular mucosal lesion extending from the right side of the phagia and returned for to our clinic for an evaluation. Work-up tongue and adjacent buccal mucosa and floor of mouth into the at that time revealed that an extensive tumor recurrence involv- soft and hard palate crossing the midline (Fig. 1). There was no ing the floor of the mouth, tonsil pillar, and lateral pharyngeal cervical or supraclavicular or infraclavicular lymphadenopathy. wall. Two 2-cm left level II cervical lymph nodes were also This patient too was given capecitabine at a dose of 1000 mg bid observed. Because the clinical appearance at that time was more for 14 days starting on February 14, 2002. She also had a rapid consistent with invasive squamous carcinoma, repeat biopsies and complete response after the first cycle of administration as were performed. A biopsy of the floor of the mouth was char- evidenced on March 6, 2002 (Fig. 1). Unlike the first patient, acteristic of her previous verrucous cancer, whereas deeper she did not complain of significant mucositis but stated that the biopsies of the pharyngeal wall mass revealed verrucous cancer verrucous lesions began to slough off the basal mucosa at with areas of invasive squamous carcinoma. She is currently approximately day 7 of treatment. Her pain was significantly undergoing combined chemotherapy and radiation. improved after her treatment but did not entirely resolve. Al- The second patient presented with a complaint of burning though Ͼ90% of the previously involved buccal mucosa re-

Fig. 2 Immunohistochemistry on biopsies from both patients with commercial antibodies against DPD (left panels), TP (middle panels), and TS (right panels). Note the low staining intensity for DPD and high staining intensity for TP in both biopsies. The high staining intensity for TP is present in the cytoplasm of cells belonging to the basal and squamous cell layer. In addition, intense nuclear staining for TP is seen in cells belonging to the squamous cell layer. DPD staining was low to moderate throughout these two layers and predominantly cytoplasmic. TS was similar to TP for the first patient but very weak for the second patient.

mained disease free on visual inspection, evidence of early The pathogenesis of VC is poorly understood, and its recurrence was obvious at the floor of the mouth 1 month later. origin, classification, and response to treatment are controver- Immunohistochemical evaluation of pretreatment biopsies sial. It is a distinct neoplastic entity of squamous origin that of both patients (Fig. 2) revealed low staining of DPD (Fig. 2, occurs in the oral cavity (14), larynx (15), penis (15), cervix left panels) as compared with high staining for TP (Fig. 2, (15), perianal area (15), esophagus (16), nose (17), and more middle panels) in both patients. DPD staining was low to mod- rarely in any epithelium of squamous morphology (18). Larynx erate throughout both the basal and squamous cell layers and (35.2%) and oral cavity (55.9%) are the most common sites for mostly cytoplasmic. More specifically, in both patients the basal head and neck cases (6). It has been associated with smoking but and squamous cell layers showed intense cytoplasmic staining not drinking. Tobacco chewing has been implicated in verrucous for TP. In addition, both patients had high nuclear TP staining in lesions. About 30% of patients in Ackerman’s original report the squamous cell layer but not in the basal cell layer. There was were tobacco chewers (13). Verrucous hyperplasia and verru- a similar pattern for TS staining in the first patient’s biopsy (Fig. cous leukoplakia have been shown to be likely precursor lesions 2, right panels), whereas the second patient’s biopsy showed a (11). Controversy surrounds the etiologic role of human papil- weaker intensity and a reduction in nuclear expression. loma virus. DNA of noncarcinogenic strains 6 and 11 was frequently detected in archival tissue biopsies of cases of oral Discussion VC (19) both by PCR and in situ hybridization. Verrucous hyperplasia (11) is a verrucous lesion that in- Tumors originally thought to be VC with features of SCC variably leads to VC, which represents a distinct extremely are a source of potential confusion. Recent reports classify these well-differentiated and slow-growing variant of SCC. It is most mixed cases separately as low-grade papillary SCC rather than common in the oral cavity and presents in patients who are older VC (20). The formal definition (13) refers to a warty and and more likely to be female than those with routine head and densely keratinized surface. The lesion is contained within a neck SCC. The first case report was published in 1941 by sharply circumscribed deep margin. Close inspection reveals Friedell and Rosenthal (12) who described it as papillary ver- bulbous well-oriented rete ridges with well-keratinized squa- rucoid carcinoma. In 1949, Ackerman (13) reported a series of mous epithelium with no anaplasia. One of the most distinguish- 31 similar oral cases and coined the term VC with characteristic ing features is a pushing rather than infiltrating type of advanc- clinical and histological findings. This type of SCC is fairly rare ing margin. There is associated inflammation in the adjacent compared with the conventional form and, although it does not stroma. metastasize, is very difficult to eradicate because of its stubborn VCs neither fulfill the classical histological and cytological tendency to recur locally. The major treatment modalities have criteria of malignancy nor possess the capability to metastasize. been surgery and radiation but their effectiveness has been a The diagnosis is largely a clinical one and is most effectively matter of debate over the years (14). achieved by persistent communication between the pathologist

and the surgeon but usually only after multiple biopsies have conversion in the liver, and reaches both healthy and malignant been taken. Adjacent cervical lymph nodes are often enlarged, cells through circulating blood. However, it is the last two but this is generally secondary to inflammatory changes and not metabolic steps, which occur primarily within cancer cells, tumor spread (1, 2, 15). Ackerman pointed out that the lymph- which allow for selective activation and cytotoxicity. More adenopathy was attributable to poor oral hygiene and coexistent specifically, capecitabine is converted to 5-FU via a three-step infections (13). Imaging and cytopathological techniques can enzymatic process (31). It is absorbed intact in the gastrointes- easily distinguish between these possibilities. tinal mucosa. It is converted to 5-deoxyfluorocytidine through Surgery has been thought to be by far the preferred mo- the action of carboxylesterase in the liver. Then, intratumoral dality of treatment especially for smaller lesions, which are easy cytidine deaminase and TP are required for activation. It is to localize (2, 3, 15). Excision aims at eradication and preser- exactly this requirement for TP that is thought to contribute to vation of function. Radiation has reemerged recently as an its increased efficacy and reduced toxicity as compared with acceptable alternative to surgery, especially for lesions that are 5-FU because many types of cancer cells are believed to have more extensive (21). VC was initially thought to be somewhat higher levels of TP than normal tissues. Indeed, whereas 5-FU radioresistant in the mouth or the larynx (22, 23). Local recur- response has been associated with low levels of its metabolic rence rate was reported as high as 57% in early studies. In addition, early studies suggested that radiation-induced dedif- enzymes, TP, TS, and DPD (32), response to capecitabine has ferentiation into anaplastic cancer in irradiated lesions. This been associated with a high TP:DPD ratio (33). transformation seems to occur in Ͼ10% of VC cases (24). In a The immunohistochemical profile obtained in these pa- series (2) of 104 patients treated from 1946 to 1980 with a tients agrees with the above observations and supports our minimum follow-up of 2 years, 20% of cases had SCC within hypothesis that VC selectively activates capecitabine and makes VC lesions. A high incidence of multiple primaries with a higher this new p.o. bioavailable drug a suitable option in the treatment tendency for local recurrence was noted. Surgery was consid- of VC. Obviously a larger series of patients with oral VC is ered as the primary treatment modality with 82% control after needed to assess the response rate of this cancer to capecitabine primary lesion excision and 94% after surgical salvage of re- as well as duration of response, dosage, and number of cycles to currence. Radiation was deemed less effective but an acceptable achieve complete remission. In addition, an immunohistochem- alternative. A retrospective analysis of 2350 cases of VC of the ical evaluation similar to ours may establish predictive markers head and neck between 1985 and 1996 (6) found an overall to help clinicians if this drug is suitable for a specific patient. 5-year survival rate of 77.9%. For localized disease, survival Capecitabine has an acceptable toxicity profile. Diarrhea after surgery was 88.9%, compared with 57.6% after irradiation, and hand/foot syndrome are the dose-limiting toxicities (9). a modality generally applied to more advanced lesions. Most reported adverse effects are of gastrointestinal nature We have found limited literature information on chemo- (diarrhea, stomatitis, and nausea) and are less common than with therapy schemata applicable to this rare malignancy. A Japanese bolus 5-FU/leukovorin. The same conclusion applies to myelo- study reports a case of VC of the tongue that was treated with a suppression. Because capecitabine has such an acceptable tox- concurrent chemoradiation regimen before surgery (10). A triple icity profile, convenient dosing, and excellent activity in other drug combination was used, including tegafur/uracil, an oral major cancers, we hypothesized that contrary to conventional fluorinated pyrimidine. No evidence of tumor cells was found in thinking it may show activity in VC. We used capecitabine at a the surgical specimen. No clinical evidence of recurrence was reduced dose for a single cycle and obtained a rapid and dra- noted ϳ2 years after excision. Tegafur/uracil has been exten- matic response in two elderly patients with extensive oral VC. sively studied in head and neck cancer (25). Its dose-limiting This response was associated with excellent palliation of symp- toxicities have been reported as diarrhea and stomatitis. It was toms with low morbidity. The role of capecitabine in the initial shown to produce a partial response rate of 19% when used management of VC is not clear but given the morbidity and lack alone in a Phase II study involving 43 patients with previously of long-term efficacy of existing therapies, this highly active treated head and neck cancer (26). In combination with cispla- drug may be an acceptable alternative to those treatments in tin, it has comparable response rates to infusional 5-FU in selected patients. combination with cisplatin as demonstrated in a small randomized trial involving 67 patients in the neoadjuvant setting (27). 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Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2003 American Association for Cancer Research. Capecitabine Induces Rapid, Sustained Response in Two Patients with Extensive Oral Verrucous Carcinoma

Anastasios Salesiotis, Richie Soong, Robert B. Diasio, et al.

Clin Cancer Res 2003;9:580-585.

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