Autologous Stem Cell Transplant for Solid Tumors

1. Autologous Stem Cell Transplant for Solid Tumors David Kuperman, M.D. Fellow in Hematology/Oncology April 27, 2007

3. Introduction SCT has been reported in the treatment of breast cancer, germ cell tumors, ovarian cancers, renal cell cancer, and other solid malignancies with varying degrees of success. Both autologous and allogenic transplants have been used but most of the experience has been with autologous transplants

4. Introduction The rational for autologous stem cell transplants is that most solid tumors are at least moderately responsive to cytotoxic chemotherapy. In vivo and in vitro experiments have shown that as the dose of a chemotherapeutic is increased, more cancer cells are killed. Unfortunately, there is a limit to how much the dose of chemotherapy medication may be increased due to the toxicity of the treatment.

5. Introduction There is a class of chemotherapeutics (i.e. alkylating agents) whose primary dose limiting toxicity is marrow suppression. Autologous stem cell transplants allow patients to receive much higher doses of these chemotherapies by giving an autologous stem cell �rescue� to prevent prolonged pancytopenia.

6. Breast Cancer Autologous SCT for breast cancer is the most extensively studied. The initial phase I and II studies were very encouraging that high dose chemotherapy with autologous stem cell transplant was superior to standard dose chemotherapy for metastatic breast cancer. This exciting preliminary data led to the frequent use of autologous stem cell transplants for the treatment of metastatic breast cancer.

7. Breast Cancer Over 41,000 women underwent the procedure with the vast majority being treated off IRB-approved clinical trial.

8. Bezwoda, et al. The first randomized trial was published by Bezwoda et al. in 1995. 90 patients were randomized to either 6-8 cycles of conventional dose cyclophosphamide, mitoxantrone, and etoposide or 2 cycles of the same drugs at much higher doses together with autologous stem cell rescue given after each cycle of high dose therapy.

9. Bezwoda, et al. At 3 years following treatment, 18% of patients in the high dose arm were alive compared to only 4% with the conventional dose.

10. Stadtmeier, et al.

14. Meta-analysis Recently a meta-analysis of the available randomized trials was published by Farquhar et al. There was no statistically significant difference in overall survival. At five years there was a significant difference in progression free survival favoring the high dose group.

15. Meta-analysis There was a prolongation in progression free survival at five years but it was barely statically significant. Per the investigator, one more relapse would have made the results not significantly different.

16. Autologous Stem Cell Transplant for non-metastatic breast cancer There are a number of reasons to consider that the addition of high dose therapy with autologous stem cell rescue would be beneficial for breast cancer patients receiving adjuvant therapy. The first is that these patients have a minimal disease burden. These patients had received minimal prior chemotherapy; therefore, there would be less opportunity to develop chemotherapy resistance and the patient would be in better overall condition to tolerate the therapy.

17. Autologous Stem Cell Transplant for non-metastatic breast cancer Peters et al. treated 102 patients with stage II/III breast cancer with at least 10 positive lymph nodes. The patients received 4 cycles of standard dose adjuvant chemotherapy followed by high dose cyclophosphamide, cisplatin, and BCNU (Stamp V) and then SCT. The five year event free survival was 72% versus 25% for historical controls.

18. Tallman, et al. Tallman et al. randomly assigned 540 woman with resected stage II/III breast cancer who had at least 10 positive axillary lymph nodes to either six cycles of standard dose adjuvant chemotherapy high dose chemotherapy with autologous SCT. Patients also received radiation and tamoxifen if indicated following completion of their chemotherapy (standard dose or high dose).

20. Tallman, et al. In the 417 patients who strictly met treatment criteria, there was a prolongation in disease free survival at five years (55% versus 45%) (p=0.045). Thus prolongation in disease free survival did not translate into a benefit in overall survival.

21. Rodenhuis, et al. Rodenhuis et al. randomized 885 women with stage II/III breast cancer with at least 4 positive lymph nodes positive to standard adjuvant therapy or high dose chemotherapy. The standard dose arm received FEC for five cycles. The treatment arm received by high dose cyclophosphamide, thiopeta, and carboplatin and autologous stem cell rescue following FEC.

22. Rodenhuis, et al. Patients received radiation and tamoxifen if indicated following completion of their chemotherapy

24. Rodenhuis, et al. At five years, the event free survival was not significantly different. When only the patients with more than 10 positive lymph nodes were examined, the event free survival was higher in the high dose arm (61% versus 51%) (p=0.05). Overall survival was not different between the two groups.

25. Germ Cell tumors Given the chemosensitivity of this cancer, it has been thought that the opportunity for cure could be improved with more intense chemotherapy. It has been tested as both salvage therapy and as upfront therapy.

26. Salvage therapy for Germ Cell Tumors Nichols et al. reported a phase I/II trial of high dose carboplatin and etoposide followed by autologous stem cell rescue in 33 patients with heavily pretreated testicular cancer. 44% of patients had a response to therapy with 24% achieving a complete response. Four of the patients maintained a complete response for more than 1 year.

27. Salvage therapy for Germ Cell Tumors Bhatia et al. published the University of Indiana�s experience with salvage high dose chemotherapy and autologous stem cell rescue for testicular cancer. Between 1992 and 1998, 65 patients with either relapsed or primary refractory testicular cancer were given 2 cycles of high dose carboplatin and etoposide followed each time by autologous stem cell rescue. Some of the patients received one to three cycles of standard dose salvage chemotherapy prior to high dose therapy and many also received maintenance oral etoposide following the therapy.

28. Salvage therapy for Germ Cell Tumors Complete responses were achieved in 43% of patients and an additional 20% were rendered NED by salvage surgery. At a median follow-up of 39 months 57% of patients had no evidence of disease. The median survival had not been reached when the results were published in 2000.

29. Salvage therapy for Germ Cell Tumors Beyer et al. performed a matched pair analysis of high dose chemotherapy with autologous SCT compared to conventional dose chemotherapy. The analysis suggested an overall survival benefit of 9-11% over standard chemotherapy.

30. Rosti, et al. Rosti et al. randomized 280 patients with relapsed or primary refractory testicular or extragonadal germ cell tumors to either 4 courses of standard dose VIP or VIEP or 3 cycles of these regimens followed by autologous stem cell rescue.

31. Rosti, et al. The complete response rate was 41% in the standard dose arm and 44% in the high dose arm. The three year survival rate was 53% in both arms.

32. Salvage therapy for Germ Cell Tumors The role of autologous transplant as salvage in germ cell cancer remains unclear. Currently, the National Comprehensive Cancer Network recommends high dose chemotherapy with autologous stem rescue as salvage for patients with poor risk disease. We await the results of the other phase III trials comparing tandem transplants to standard salvage.

33. Initial therapy for Germ Cell Tumors A phase III trial was recently presented using high dose chemotherapy as first line therapy for patients with intermediate or poor risk germ cell tumors. Bajorin et al. randomized 219 previously untreated patients with International Germ Cell Cancer Collaborative group intermediate or poor risk germ cell tumors to 4 cycles of standard dose bleomycin, etoposide, and cisplatin (BEP) or 2 cycles of BEP and tandem autologous stem cell rescue.

34. Initial therapy for Germ Cell Tumors There was no significant difference in complete response or survival between the high dose and the standard dose arm. High dose chemotherapy, therefore, is not recommended as initial treatment of patients with germ cell cancer.

35. Neuroblastoma Neuroblastoma is one of the most common solid tumors in children. It is a chemosensitive tumor. A number of phase II trials have been performed using high dose chemotherapy to treat metastatic neuroblastoma. Most have shown a long term survival of 28 to 33%. This is superior to historical control of 10-15%.

36. Matthay, et al.

38. Matthay, et al. The patients who did not progress on this therapy were randomly assigned to another three courses of the above chemotherapy or to high dose therapy. The three year event free survival was significantly higher with the high dose arm (34% versus 22%; p=0.034)

40. Conclusion The results of hematopoietic stem cell transplants for solid tumors have been disappointing. The initial phase II trials were very encouraging Unfortunately, with the exception of neuroblastoma, SCT have not been shown to prolong survival in randomized clinical trials. These results illustrate the necessity for randomized trials comparing new therapies to the standard of care.

41. References Antman K, Gale P. Advanced breast cancer: High-dose chemotherapy and bone marrow autotransplants. Ann Intern Med 1988; 108:570-574. Bajorin DF, Nichols CR, Margolin KA, et al. Phase III trial of conventional-dose chemotherapy alone or with high-dose chemotherapy for metastatic germ cell tumors (GCT) patients (PTS): A cooperative group trial by Memorial Sloan-Kettering Cancer Center, ECOG, SWOG, and CALGB. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 4510 Bezwoda WR, Seymore L, Dansey R. High-dose chemotherapy with hematopoietic rescue as a primary treatment for metastatic breast cancer: a randomized trial. J Clin Oncol 1995; 13: 2483-2489. Beyer J, Stenning S, Gerl A, et al. High-dose versus conventional-dose chemotherapy as first-salvage treatment in patients with non-seminomatous germ-cell tumors: a matched-pair analysis. Ann Oncol 2002; 13: 599-605.

42. References Bhatia S, Abonour R, Porcu P, et alia. High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer. J Clin Oncol 2000; 18: 3346-3351. Biron P, Durand M, Roche H, et al. High dose thiotepa (TTP) cyclophosphamide (CPM) and stem cell transplantation after 4 FEC 100 compared with 4 FEC alone allowed a better disease free survival but the same overall survival in first line chemotherapy for metastatic breast cancer. Results of the PEGASE 03 French Protocole. Proc Am Soc Clin Oncol 2002; 21: abstract 167. Crown J, Pey L, Lind M, et al. Superiority of tandem high-dose chemotherapy (HDC) versus optimized conventionally-dosed chemotherapy (CDC) in patients with metastatic breast cancer (MBC): the International Randomized Breast Cancer Dose Intensity Study (IBDIS 1). Proc Am Soc Clin Oncol 2003; 22: 23a. Crump M, Gluck S, Stewart D, et alia. A randomized trial of high-dose chemotherapy (HDCT) with autologous peripheral blood stem cell support (AHPCT) compared to standard chemotherapy in women with metastatic breast cancer: a National Cancer Institute of Canada (NCIC) Clinical Trials Group study. Proc Am Soc Clin Oncol 2001; 20: 21a.

43. References Farquhar C, Marjoribanks J, Basser R, et al. High dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with metastatic breast cancer. Cochrane Database of Systemic Reviews 2005; 3: Art. No. CD003142. Hale GA. Autologous stem cell transplantation for pediatric solid tumors. Expert Rev Anticancer Ther 2005; 5: 835-846. Harmann O, Valteau-Couanet D, Vassal G, et al. Prognostic factors in metastatic neuroblastoma over 1 year of age treated with high-dose chemotherapy and stem cell transplantation: a multivariate analysis in 218 patients treated in a single institution. Bone Marrow Transplant 1999; 23: 789-795. Lotz JP, Cure H, Janvier M, et al. High-dose chemotherapy with haematopoietic stem cell transplantation for metastatic breast cancer patients: final results of the French multicentric randomized CMA/PEGASE 04 Protocol. Eur J Cancer 2005; 41: 71-80.

44. References Mathay KK, Villablanca JG, Seeger RC, et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group. N Engl J Med 1999; 341: 1165-1173. Nichols CR, Anderson J, Lazarus HM, et al. High-dose carboplatin and etoposide with autologous bone marrow transplantation in refractory germ cell cancer: an Eastern Cooperative Oncology Group protocol. J Clin Oncol 1992; 10: 558-563. Peters WP, Ross M, Vredenburgh JJ, et al. High dose chemotherapy and autologous bone marrow support as consolidation after standard-dose adjuvant therapy for high-risk breast cancer. Pro Am Soc Clin Oncol 1995; 14:90a. Rodhenhuis S, Bontebal M, Beex LVAM, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. N Engl J Med 2003; 349: 7-16.

45. References Rosti G, Pico JL, Wandt H, et al. High-dose chemotherapy (HDC) in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumors (GCT); first results of a prospective randomized trial of the European Group for Blood and Marrow Transplantation (EBMT): IT-94 study. Proc Am Soc Clin Onc 2002; 21:716. Stadtmeir EA, O�Neill A, Goldstein LJ, et al. Conventional-dose chemotherapy compared with high-dose chemotherapy with autologous hematopoietic stem-cell transplantation for metastatic breast cancer. N Engl J Med 2000; 342: 1069-1076. Schmid P, Schippinger W, Nitsch T, et alia. Up-front tandem high-dose chemotherapy compared with doxorubicin and paclitaxel in metastatic breast cancer: Results of a randomized trial. J Clin Oncol 2005; 23: 432-440. Tallman MS, Gray R, Robert NJ, et al. Conventional adjuvant chemotherapy with or without high-dose chemotherapy with autologous stem-cell transplantation in high-risk breast cancer. N Engl J Med 2003; 349: 17-26.