8/22/2018

Desmoplastic Small Round Cell Tumor: A Pediatric Oncology Rarity

September 15, 2018 Paulette Kelly CFNP Kleoniki Diamantis CFNP Rachel Glincher, CPNP-AC

Conflicts of Interest • We have no conflicts of interest

Outline:

• Desmoplastic Small Cell Tumor (DSRCT) demographics • Case Study Presentation • MSK Standards of Care and new approaches • What’s on the Horizon • Conclusions

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Desmoplastic Small Round Cell Tumor (DSRCT)

• Rare, highly aggressive tumor of mesenchymal origin with a dismal prognosis. • Presumed to originate from the chromosomal translocation t(11,22)(p13:q12), leading to the fusion of the N-terminal domain of Ewing’s sarcoma gene EWS to the c-terminal domain of Wilm’s tumor suppressor gene, WT1 [1,2] • Presence of EWS-WT1 present in most but not all DSRCT patients • VEGFR-2 and VEGFA are overexpressed in DSRCT • >90% express B7H3 • Tends to grow along serosal lining, most commonly the peritoneal surface, but other primary sites have been identified.

DSRCT: Gender and Age Characteristics

DSRCT: Gender Distribution

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DSRCT: Disease Distribution

Desmoplastic Small Round Cell Tumor

• More common in males than females (4:1) • More common in blacks than whites – In whites peak age 20-24 – In blacks peak ages 25-29 40% of patients present with metastasis at presentation to liver, lung, bones and lymph nodes Commonly reported symptoms at presentation • Pain • Constipation • Nausea • Vomiting • Difficulty passing stool or gas • Palpable mass • Abdominal swelling

Desmoplastic Small Round Cell Tumor

• Histology includes variably sized clusters of small round or spindle cells lying with in desmoplastic, collagenous stroma. Microscopic (histologic) description:

Clusters of small round Effusion fluid. Present are Tumor cells in effusion tumor cells showing tridimensional clusters of showing nuclear positive rosette‐like features in neoplastic cells. Nuclei were reaction to WT1. smear of fine needle round to oval, some of them aspiration. with small nucleoli and the cytoplasm is scanty.

(Granja, 2005)

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Desmoplastic Small Round Cell Tumor

Current treatment – NO STANDARD OF CARE – Multimodal therapy with chemotherapy, surgery, and radiation therapy – Prognosis continues to be poor – Evidence supports that radiation therapy following surgical resection improves outcome

Case Presentation

DT was diagnosed at 21 years of age. He had no significant medical history. DT was active with school, work and sports.

• He went to his primary care physician complaining of lower abdominal pain while exercising. • Over the next two months symptoms progressed to include nausea vomiting and frequent urination every 1-2 hours. • He had increased pain and abdominal distension • Primary care physician evaluated and ultrasound obtained revealing an abdominal mass with bilateral hydronephrosis. • He was admitted to local hospital where a CT of the abdomen and pelvis was obtained.

CT Findings

• 12cm x 6cm mass in its largest dimension • serosal implants and retroperitoneal lymphadenopathy

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Case Presentation • Percutaneous nephrostomy tubes placed urgently • CT guided biopsy was performed • Pathology revealed DSRCT • Care then transferred to MSKCC

Initial work-up and preparation

• Scans – CT chest – MR abdomen pelvis – PET • Pathology confirmed by MSKCC pathologist • EKG and ECHO • Complete history and physical exam • Lab studies – CBC, clinical chemistries, liver function test, renal function, coagulation studies, urine – to test for proteinuria • Fertility consult - sperm banking completed • Double lumen MediPort placed • Enrolled on MSKCC protocol 10-091 • 6/8/15 – chemotherapy initiated

A Pilot Trial of Irinotecan, Temozolomide and Bevacizumab for Treatment of Newly Diagnosed Patients with Desmoplastic Small Round Cell Tumor

Heather Magnan, Emily K. Slotkin, , Anita Price, Alexander J. Chou, Elyn Riedel, Leonard H. Wexler, Srikanth R. Ambati, Gary Ulaner, Shakeel Modak, Michael P. LaQuaglia, Paul A. Meyers Memorial Sloan‐Kettering Cancer Center, New York, New York 10065

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Background:

• Desmoplastic small round cell tumor (DSRCT) is a are tumor with a dismal prognosis. • VEGFR-2 and VEGFA are overexpressed in DSRCT. • Marked, sustained responses were seen in DSRCT xenografts treated with bevacizumab and irinotecan . This response was superior to that seen in xenografts treated with irinotecan alone. • This study was designed to explore the safety and feasibility of adding irinotecan, temozolomide and bevacizumab (ITB) to the existing alkylator based chemotherapy regimen used to treat newly diagnosed DSRCT.

Method:

•Primary objective • Eligibility: Newly diagnosed, -To define the tolerability previously untreated patients with and adverse event DSRCT, 30 years or younger with profile of ITB in patients with normal organ function and no known newly diagnosed DSRCT bleeding disorders • Treatment Regimen: •Secondary objectives • -8 cycles of chemotherapy + 4 doses -To estimate the response of bevacizumab rate of 2 cycles of ITB • -First dose of bevacizumab -To estimate survival and scheduled based on type and date of TTP with the addition of ITB initial biopsy to modified P6 therapy • -Surgeries planned after cycles 5 and 8

DSRCT: MSK Protocol IRB 10-091 Roadmap

Bevacizumab Treatment Cycles 1-2 Irinotecan 20 mg/m2 x 10 days 10 mg/kg q 2weeks Temozolomide 100 mg/m2 x 5 days 4 total doses prior to resection Treatment Cycles 3-5 Cyclophosphamide 2,100 mg/m2 on days 1 & 2 Doxorubicin 37.5 mg/m2 on days 1 & 2 Vincristine 2 mg/m2 on day 1

Surgical Control

Treatment Cycles 6-8 Ifosfamide 1,800 mg/m2 days 1-5 Etoposide 100 mg/m2 days 1-5

Second Look surgery

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Chemo Agents - Bevacizumab

• VEGF (vascular endothelial growth factor) has been identified as a regulator of normal and pathologic angiogenesis and is thought to also be critical to tumor angiogenesis.

• Microarray demonstrates that DSRCT has a 10 fold over expression of VEGFR-2 RNA, and over expression of VEGF-A suggesting that this may be an appropriate target for therapy.

• Bevacizumab is a humanized monoclonal antibody that binds to all five isoforms of VEGF.

• Approved for use in non-squamous cell lung, HER2 negative breast, metastatic colorectal carcinoma

Chemo Agents – Bevacizumab in Peds

• Pre-clinical testing with anti-VEGF monoclonal antibody in models of rhabdomyosarcoma, neuroblastoma and hepatoblastoma showed inhibition of angiogenesis.

• COG study conducted to adding of Bevacizumab to chemotherapy in patients with solid tumors. Toxicity profile was found to be acceptable with no adverse events causing discontinuation of therapy.

• Observed side effects – hypertension, proteinuria, thromboembolic events, GI perforation, wound healing complications, hemorrhage reversible posterior leukoencephalopathy syndrome, CHF, neutropenia

Chemotherapy agents - Irinotecan

• Irinotecan is a semi-synthetic camptothecin analog which inhibits topoisomerase I activity

• Has been well studies for side effects and dosing in pediatric patients

• Two case reports documented the use of irinotecan in DSRCT. One with rapid response with CR after 7 cycles, and the other resulting in disease free period of 18 months.

• Side effects – diarrhea and abdominal cramping – can range from mild to severe

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Chemotherapy Agents - Temozolomide

• Temozolomide is an imidazotetrazine prodrug that methylates DNA. • Modifications in DNA leads to the recruitment of toposisomerase I, increasing the probability of a camptothecin drug stabalizing the DNA-enzyme covalent complex. • Temozolomide can potentiate Irinotecan cytotoxicity • Use of temozolomide and irinotecan has been studied in children with recurrent tumors and has been shown to be well tolerated in patients have been heavily pre treated. • Side effects – nausea, myelosuppression • Considerations: oral temozolomide must be taken on empty stomach

Why Bevacizumab, irinotecan and temozolomide all together?

• In Colorectal CA, the addition of bevacizumab to an irinotecan containing regimen for previously untreated patients improved overall survival and led to the FDA approving bevacizumab

• Several studies of bevacizumab and irinotecan in brain tumors have suggested promising results.

• Xenografts in DSRCT patients demonstrated a marked and sustained response when treated with irinotecan and bevacizumab together instead of each agent alone

DSRCT xenograft growth after no treatment, treatment with bevacizumab, irinotecan, or irinotecan and bevacizumab

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Chemotherapy Agents - Cyclophosphamide

• Alkylating agent related to nitrogen mustard • Only active once metabolized • Is cell cycle non-specific • Is used to treat many cancers and has a wide range in dose depending on disease being treated • In high doses is given with Mesna for bladder protection • Nursing Considerations/Side effects – hemorrhagic cystitis, SIADH, sterility

Chemotherapy Agents - Doxorubicin • An anthracycline antibiotic isolated from cultures of Streptomyces peucetius. • Binds to DNA and inhibits nucleic acid synthesis • Mainly effects the S phase of the cell cycle • Given with dexrozoxane due to cardio-toxic profile • Used in the treatment of many cancers

• Nursing Considerations/Side effects – cardiomyopathy, mucositis, severe tissue damage if extravasated, secondary malignancy

Chemotherapy Agents - Vincristine • An alkaloid that is isolated from Vinca rosacea (periwinkle) • Binds to tubulin disrupting microtubules and inducing metaphase arrest • Used in the treatment of many cancers

• Nursing considerations/side effects – vesicant (if extravasated administer hyaluronidase and apply warmth) neuropathy, constipation

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Chemotherapy Agents - Etoposide • Is an epipodophyllotoxin that forms a complex with topoisomerase II and DNA which results in DNA breaks. • Most effects appear to be in the S and G2 phase of the cell cycle • Used in the treatment of many cancers

• Nursing considerations/side effects – hypotension, anaphylaxis

Chemotherapy Agents - Ifosfamide

• An alkylating agent related to nitrogen mustard and and is a synthetic analog of cyclophosphamide • Is cell cycle non-specific • Used in the treatment of many cancers • MUST be administered with Mesna

• Nursing consideration/side effects – hemorrhagic cystitis, neurotoxicity, neuropathy, sterility,

Case Presentation • 6/29/15 - Re-imaging per protocol following first 2 cycles consisting of Irinotecan and Temoozlomide showed little response • 7/20/18 – Cycle 3 with cyclophosphamide, doxorubicin, vincristine (CAV) • 8/3/15 – stem cell harvest for future need • 8/10/15 – cycle 4 with CAV • 8/26/18 -Nephrostomy tube exchange • Admitted following with uncomplicated sepsis for cycles 3 and 4 only • Echocardiogram prior to cycle 5 normal • 8/31/15 – cycle 5 CAV • Scans performed following cycle 5 to assess response to chemo and for surgical planning

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• 9/24/18 – surgical resection • 10/2/15 – nephrostomy removal

Timing of Surgery • DSRCT generally responsive to systemic therapy • 4-6 months post initiating chemotherapy • Size of tumors may not change with chemotherapy

Pre- Operative • H+ P • Scans • Bloodwork • Surgical Consent • PACT team consult • Special considerations • Pain management with epidural • Nutritional status • Bowel prep

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Pre operative- Special Considerations • Preoperatively patients should be educated on the possibility of having: • Temporary ileostomy • Splenectomy (for which vaccines are given , Haemophilus influenzae, meningococcal and pneumococcal ) • Possibility of hysterectomy in females and erectile dysfunction in males due to retrovesical masses

Debulking Surgery • Staged surgeries • Goal for complete resection – Midline laparotomy • Omentectomy • Excision of peritoneal nodes • Splenectomy • Limited bowel resection • Ureteral re‐implantation may be necessary • Resection of pelvic mass with rectal and bladder preservation

• 1) Exploratory laparotomy and resection of multiple areas of desmoplastic small round cell tumor • 2) Excision of the right Gerota’s fascia anteriorly and nodules over the right anterior diaphragm • 3) Excision of lesions from the spleen and hilus of the spleen • 4) Excision of multiple lesions over peritoneum • 5) Removal of large pelvic mass with serosal closure of the rectum • 6) Intraoperative flexible sigmoidoscopy to check for colon integrity • 7) Lysis of both ureters with freeing of both ureters • 8) Partial resection of segment 6 and 7 • 9) Partial omenectomy

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Postoperative • Infection • Atelectasis • Fluid Shifts • Pain

Risks vs. BENEFITS • 3 year overall survival • 58% with complete resection • 0% with chemotherapy and radiation alone • (Lai, 2005) – Need Intraperitoneal treatment

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HIPEC • Hyperthermic intraperitoneal chemotherapy • Cisplatin • Transient leukopenia or thrombocytopenia • Should only be used on protocol • Not for all patients

8H9 • antibody or protein which binds to B7H3 found on >90% DSCRT • antibody 8H9 injected into the lining of the abdomen or • radioactive iodine bound to this antibody to deliver radiation to the tumor

Case Presentation

• Resumed chemotherapy following surgery with cycle 6-8 with Etoposide and Ifosfamide – 10/12/15 – 11/2/15 – 11/30/15 • No admission for neutropenia with fever following these cycles • 12/14/15 – PET/CT CAP performed prior to second look surgery. • 12/28/15 - Second look surgery including exploratory laparotomy with lysis of adhesions and insertion of IP catheter – Biopsies obtained and negative

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IP Catheter • Intraperitoneal catheters are inserted in the OR by pediatric surgery team at the time of the last planned major abdominal resection. Catheter is placed through rectus muscle and guided into the pelvic cavity or intraperitoneal space. • No imaging is required to confirm catheter placement. • Secured to the skin with suture and covered with a transparent dressing. • The catheter will be removed at the end of therapy by a NP/PA

Preparing for Treatment

The maximum volume target for normal saline instillations through the IP catheter is 1200mL/m2 BSA and rounded down to nearest multiple of 500mL The first Normal Saline instillation through the catheter is performed in the operating room by the surgeon. 8 hours post-operatively, the RN begins the instillations following

Guidelines for Increasing Normal Saline Instillation (Max Volume 1200ml/m2 BSA)

Postoperative Day 0.9% Normal Saline Volume POD #0, 1, 2 50ml every 8hours POD # 3, 4 250 ml twice per day POD # 5, 6 500 ml twice per day POD # 7, 8 1000 ml twice per day POD # 9 and as dictated by LIP/PA 1500 ml twice per day

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Case Presentation

• 2/8/16 –CT CAP and PET scans post 8H9 imaging, prior to planned whole abdomen pelvic (WAP) radiation therapy (RT) • PET showed 7mm RLQ nodule with SUV of 1.6 • Determined to proceed with WAP RT in IMRT (intensity- modulated RT) • IMRT for a dose of 30 Gy in 20 daily fractions: started 2/22/16 ending 3/18/16 • Re imaging post RT on 3/25/16 demonstrated resolution of the RLQ module. Mildly FDG avid areas have previously been biopsied. No viable tumor was demonstrated. Visualized was his serosal hepatic implant - necrotic tissue on biopsy/ laparotomy suture line and chronic inflammation.

Case Presentation

• 3/31/16 – re-infused stem cells because of prolonged pancytopenia • 5/31/16 – recommendation was made to continue with a “maintenance” regimen of chemotherapy with irinotecan, temozolomide and bevacizumab and started same day • 6/1/16 baseline studies obtained and showed a new 1.7cm x1cm abdominal implant. Thought to be related to post-surgical changes with combined RT changes.

Case Presentation • Decision to proceed with two cycles of maintenance regimen and re-image. • Bevacizumab was not initiated until July due to difficulty obtaining insurance approval. • Imaging following first two cycles • Continue regimen consisting of irinotecan and temozolomide x 12 cycles completing February 2017

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MSK STUDY RESULTS:

•15 patients were enrolled •Median age 20 years (12-30 years) •13 males, 2 females •14 patients completed treatment •Median follow-up for survivors = 27 months (9-59) •Stopping rules for unacceptable toxicity were not met •No patient experienced toxicity attributed to bevacizumab •Surgical morbidity was no greater than expected

Toxicities attributed to the investigational combination (CTCAE v. 4.0) by # of cycles:

Toxicity Grade 2Grade 3Grade 4 Diarrhea 7 2 0 ALT increase 2 0 1 AST increase 1 1 0

The objective response rate go the 2 investigational cycles was 27% (95% CI, 8 – 55% The objective response rate to the 5 pre resection cycles was 73% 5 patients were in clinical remission prior to second look surgery

Results:

Progression Free Survival Overall Survival

IRB 10-091 Study Conclusions:

• The combination of irinotecan, temozolomide and bevacizumab is active in DSRCT • It is feasible to combine these agents with standard chemotherapy without greater than expected toxicity

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Case Presentation - Salvage regimens for disease progression

• Treatments – 7/2017-10/2017 – Cyclophosphamide, Vinorelbine and Temsirolimus – 11/20/18 - Enrolled on study with adult medicine with agent GSK- 3326895 (immunotherapy) – 1/8/18 - Imaging showed possible pseudo progression – continued on protocol – 2/17/18 showed clear progression including bony lesion to his right humerus • 2/20/18 - Ipilumimab and Nivolumab • 3/27/18 - following 2 cycles showed progression • 4/3/18 - Olaratumab and Doxorubicin – scans post 2 cycles show a decreased size in tumor with less avidity on PET. • Admission post one cycle for uncomplicated fever and neutropenia • Echocardiogram post each Doxorubicin cycle for close monitoring

Conclusions

‐ DSRCT is highly malignant tumors with poor prognosis ‐ Induction chemotherapy with a dose‐intensive regimen seems to reduce tumor vascularity and may in rare instances result in complete tumor necrosis. The addition of Bevacizumab, Temozolomide and Irinotecan have extended life with controlled side effects. ‐ Complete response without surgical resection is extremely rare ‐ Complete resection requires a staged approach and may require stomas ‐ > 90% debulking surgery with induction chemotherapy is associated with better outcomes ‐ Total abdominal radiation seems to augment the effect of gross total resection ‐ HIPEC and 8H9 have shown the need for intraperitoneal treatment ‐ Studies including 8H9 therapy continue in order to improve outcomes ‐ NEW THERAPIES ARE NEEDED

Continue the FIGHT with IMPACT Testing. Learn the specifics about the GENOME!

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References

Granja NM, Begnami MD, Bortoian J, Filho AL, et al: Desmoplastic Small Round Cell Tumor: Cytological and Immunocytochemical Features. CytoJournal.http//www.ncbi.nlm.nih.gov/pmc/articles/PMC555739/, March 18,2005

Gerald WL, Miller HK, Battifora H, et al: Intra‐abdominal desmoplastic small round‐cell tumor. Report of 19 cases of a distinctive type of high‐grade polyphenotypic malignancy affecting young individuals. Am J Surg Pathol 15(6): 499‐513, 1991

Hayes‐Jordan A, LaQuaglia M, Modak S: Management of Desmoplastic Small Round Cell Tumor. Sem Pediatr Surg. 25(5): 299‐304, 2016

Kushner BH, LaQuaglia MP, Wollner N, et al: Desmoplastic Small Round Blue Cell Tumor: Prolonged Progression‐ Free Survival With Aggressive Multimodality Therapy. J Clin Oncol 14:1526‐1531, 1996

Lal DR, Su WT, Wolden Sl, et al. Results of multimodal treatment for desmoplastic small round cell tumors. J Pediatr Surg 2005 :40(1):251‐255

Lettieri CK, Garcia‐Filion P, Hingorani P: Incidence and Outcomes of Desmoplastic Small Round Cell Tumor: Results from the Surveillance, Epidemiology, and End Results Database. Journal of Cancer Epidemiology 14: Article ID 680126, 5 pages, 2014

La Quaglia MP: State of the Art in Oncology: High Risk Neuroblastoma, Alveolar Rhabdomyosarcoma, Desmoplastic Small Cell Tumor and POST TEXT 3 and 4 Hepatoblastoma. Journal of Pediatric Surgery 49(2): 233‐ 240, 2014

References

• Magnan H CT, LaQuaglia M, Gerald W, Ladanyi M, Merchant M. Elevated expression of VEGF R‐2 and VEGF A in desmoplastic small round cell tumor and activity of bevacizumab and irinotecan in a xenograft model of DSRCT. J Clin Oncol 2009:27(15s):Abstract 10016.

• Magnan H, Slotkin EK, Price A, et al: A Pilot Trial of Irinotecan, Temozolomide, and Bevacizumab for Treatment of Newly Diagnosed Patients with Desmoplastic Small Round Cell Tumor, Poster Presentation, 2018 • Stiles Z, Dickson P, Glazer E, et al: Desmoplastic small round cell tumor: A nationwide study of a rare sarcoma. Journal of Surgical Oncology, 1‐9, 2018.

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Thank you to members of the Pediatric Sarcoma Service and Pediatric Surgery Department at Memorial Sloan Kettering Cancer Center

Heather Magnan, MD Marrano, Mariel, APRN, CPNP Emily K. Slotkin, MD La Quaglia, Michael P., MD Chou, Alexander J., MD Heaton, Todd, MD Wexler, Leonard, MD Price, Anita MD Modak, Shakeel MD Ambati, Srikanth, MD Meyers, Paul A., MD Hillsberg, J., APRN, CPNP Maire, S., APRN, CPNP Voccola, J., APRN, CPNP Swanson, K., ARPN, CPNP

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