Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.

Description

Hematopoietic Stem Cell Transplantation
Hematopoietic stem-cell transplantation (SCT) refers to a procedure in which hematopoietic stem cells are infused to restore bone marrow function in cancer patients who receive bone marrow toxic doses of cytotoxic drugs with or without whole body radiation therapy. Bone marrow stem cells may be obtained from the transplant recipient (autologous SCT) or from a donor (allogeneic SCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood and placenta shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem cells in it are antigenically “naïve” and thus are associated with a lower incidence of rejection or graft vs. host disease. Cord blood is discussed in greater detail in policy No. 7.01.50.
Immunologic compatibility between infused stem cells and the recipient is not an issue in autologous SCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic SCT. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the HLA A, B, and DR loci on each arm of chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci (with the exception of umbilical cord blood).

Conventional Preparative Conditioning for Hematopoietic Stem Cell Transplantation
The conventional ('classical') practice of allogeneic SCT involves administration of myelotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to destroy endogenous hematopoietic capability in the recipient. The beneficial treatment effect in this procedure is due to a combination of initial eradication of malignant cells and subsequent graft-versus-malignancy (GVM) effect mediated by non-self immunologic effector cells that develop after engraftment of allogeneic stem cells within the patient’s bone marrow space. While the slower GVM effect is considered to be the potentially curative component, it may be overwhelmed by extant disease without the use of pretransplant conditioning. However, intense conditioning regimens are limited to patients who are sufficiently fit medically to tolerate substantial adverse effects that include pre-engraftment opportunistic infections secondary to loss of endogenous bone marrow function and organ damage and failure caused by the cytotoxic drugs. Furthermore, in any allogeneic HSCT, immune suppressant drugs are required to minimize graft rejection and GVHD, which also increases susceptibility of the patient to opportunistic infections.

The success of autologous HSCT is predicated on the ability of cytotoxic chemotherapy with or without radiation to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of bone marrow space with presumably normal hematopoietic stem cells obtained from the patient prior to undergoing bone marrow ablation. As a consequence, autologous HSCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HSCT are susceptible to chemotherapy-related toxicities and opportunistic infections prior to engraftment, but not GVHD.

Reduced-Intensity Conditioning for Allogeneic Stem Cell Transplantation
Reduced-intensity conditioning (RIC) refers to the pretransplant use of lower doses or less intense regimens of cytotoxic drugs or radiation than are used in traditional full-dose myeloablative conditioning treatments. The goal of RIC is to reduce disease burden, but also to minimize as much as possible associated treatment-related morbidity and non-relapse mortality (NRM) in the period during which the beneficial GVM effect of allogeneic transplantation develops. Although the definition of RIC remains arbitrary, with numerous versions employed, all seek to balance the competing effects of NRM and relapse due to residual disease. RIC regimens can be viewed as a continuum in effects, from nearly totally myeloablative, to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allogeneic HSCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism, which may be supplemented with donor lymphocyte infusions to eradicate residual malignant cells.

HSCT in Solid Tumors in Adults

HSCT is an established treatment for certain hematologic malignancies, however, its use in solid tumors in adults continues to be largely experimental. Initial enthusiasm for the use of autologous HSCT for solid tumors has waned with the realization that dose intensification often fails to improve survival, even in tumors with a linear-dose response to chemotherapy. (1) With the advent of nonmyeloablative allogeneic transplant, interest has shifted to exploring the generation of alloreactivity to metastatic solid tumors via a graft-versus-tumor effect of donor-derived T cells. (2)

Miscellaneous Solid Tumors in Adults

Hematopoietic stem-cell support as a treatment either of breast, ovarian or testicular cancer, ependymoma or malignant glioma is addressed in separate policies, No. 8.01.27, 8.01.23, 8.01.15, 8.01.28 or 8.01.31, respectively. This policy collectively addresses other solid tumors of adults for which SCT has been investigated, including lung cancer; malignant melanoma; tumors of the gastrointestinal tract (include colon, rectum, pancreas, stomach, esophagus, gallbladder, and bile duct); male and female genitourinary systems (e.g., renal cell carcinoma, cervical carcinoma, cancer of the uterus, fallopian tubes, and prostate gland); tumors of the head and neck; soft tissue sarcoma; thyroid tumors; tumors of the thymus; and tumors of unknown primary origin.

Policy

Policy Guidelines

Benefit Application

Rationale

This policy was initially based on a 1995 TEC Assessment that focused on the malignancies listed previously in the Policy section. (3) The Assessment offered the following conclusions:

A 1999 TEC Assessment evaluated the use of HDC with allogeneic stem-cell support as a salvage therapy after a failed prior course of HDC with autologous stem-cell support for solid tumors. (4) Data were inadequate to permit conclusions.

A review by Nieto and Shpall (5) and a report from the European Group for Bone Marrow Transplantation's Solid Tumors Working Party (6) agreed that evidence was still insufficient to establish a definite role for HDC and autologous transplantation in small-cell lung cancer. Nieto and Shpall (5) also concluded that evidence was inadequate to demonstrate a survival benefit from HDC for melanoma or sarcoma. Other malignancies listed in the Policy section of this document were not considered in either of these reviews. Uncontrolled pilot studies on HDC with hematopoietic stem-cell support for patients with refractory urothelial carcinoma (7) and recurrent or advanced nasopharyngeal carcinoma (8) also provide inadequate evidence of improved outcomes to alter previous conclusions.

2008 Update

Autologous SCT in solid tumors of adults

Data on the use of autologous transplant for the solid tumors of adults addressed in this policy consists mainly of anecdotal reports and small series, and the number of randomized trials is limited.

Adult soft tissue sarcomas

The prognosis of patients with unresectable or metastatic soft tissue sarcomas is poor, with a median survival of about 1 year, and less than 10% 5-year survival. (9) In general, dose-intensive doxorubicin and ifosfamide-based regimens have yielded higher response rates and prolonged disease-free survival, but not overall survival. (9) However, as it was shown that patients who achieved complete remission (CR) had longer survival, several Phase I and II trials were conducted in the 1990s in an attempt to improve outcomes. (9) These trials were composed of small numbers of patients (ranging from 2 –55), with autologous HSCT yielding overall response rates from 20 –65% with CR from 10 –43%. The longest reported 5-year progression-free survival (PFS) rate was 21%, and 5-year overall survival (OS) was 32%. (9) One study of 21 patients with soft-tissue sarcoma showed a PFS and OS benefit only in patients with no evidence of disease before receiving HDC. (10) The data from these small trials are insufficient to support the use of autologous SCT in adult patients with soft tissue sarcoma. In 1 additional Phase ll study, 21 of 55 (38%) patients responded to doxorubicin-based induction chemotherapy (14% vs. 3%; p =0.003), but estimated OS was not statistically different between those that received an autologous SCT and those that did not. The authors felt that their results warranted a Phase lll trial examining the role of HDC as consolidation therapy in these patients. (11) No phase lll trials involving SCT for first line therapy of advanced or metastatic adult soft tissue sarcoma compared to conventional standard-dose chemotherapy were found in a systematic review. (12)

Small cell lung carcinoma (SCLC)

The interest in treating SCLC with SCT stems from its extremely high chemosensitivity and poor prognosis. A phase III trial of 318 patients with SCLC randomly assigned patients to standard chemotherapy or HDC with stem-cell transplantation. (13) No statistically significant difference in response rates was seen between the two groups (80% response rate in the standard arm vs. 88% in the HDC group [difference =8%, 95% confidence interval of -1% to 17%; p =0.09]). There was no statistically significant difference in OS between the two groups, with a median OS of 13.9 months in the standard arm (95% confidence interval [CI] of 12.1 to 15.7 months) versus 14.4 months in the HDC arm (95% CI: 13.1 to 15.4); p =.76. One smaller, randomized study and several single-arm studies of HDC and autologous SCT for SCLC are summarized in a review article. (14) Overall, the majority of the data from these studies, including the randomized study, showed no increased OS with autologous SCT.

Review articles summarize the most recent data from studies of autologous SCT for solid tumors in adults. (5,15)

Allogeneic SCT in solid tumors of adults
Single-case reports and small series of patients with various types of solid tumors have been treated with allogeneic hematopoietic SCT, including some of the tumor types addressed in this policy. (1, 2, 16)

Renal cell carcinoma

Metastatic renal cell carcinoma (RCC) has an extremely poor prognosis, with a median survival of less than 1 year and a 5-year survival of less than 5%. (17) RCC is relatively resistant to chemotherapy, but is susceptible to immune therapy, and interleukin-2 (IL-2) and/or interferon alpha have induced responses and long-term progression-free survival in 4%–15% of patients. (16) Therefore, the immune-based strategy of a graft-versus-tumor effect possible with an allogeneic transplant has led to an interest in its use in RCC. In 2000, Childs and coworkers published the first series of patients with RCC treated with nonmyeloablative allogeneic SCT. (17) The investigators showed regression of the tumor in 10 of 19 (53%) patients with cytokine-refractory, metastatic RCC who received an HLA-identical sibling allogeneic SCT. Three patients had a complete response, and remained in remission 16, 25, and 27 months after transplant. Four of 7 patients with a partial response were alive without disease progression 9 to19 months after transplantation. Other pilot trials have demonstrated the graft-versus-tumor effect of allogeneic transplant in metastatic RCC, but most have not shown as high a response rate as the Childs’ study. Overall response rates in these pilot trials have been about 25%, with complete response rates of about 8%. (1) Prospective, randomized trials are needed to assess the net impact of this technique on the survival of patients with cytokine-refractory RCC. (1)

2009 Update

Autologous SCT in Solid Tumors of Adults

Jiang and colleagues performed a meta-analysis of the medical literature through October 2008 of English-language studies using intensified chemotherapy with autologous hematopoietic progenitors to treat small-cell lung cancer. (18) The meta-analysis consisted of 5 randomized, controlled trials (3 were Phase III trials and 2 were Phase II), for a total of 641 patients. They found no significant increase in the odds ratio for response rate with autologous transplant versus control chemotherapy (odds ratio, 1.29; 95% CI: 0.87–1.93; p =0.206). No statistically significant increase in overall survival was seen among the autologous transplant patients compared to control regimens (hazard ratio, 0.94; 95% CI: 0.80–1.10; p =0.432). The authors concluded that current evidence does not support the use of intensified chemotherapy and autologous HSCT for treating small-cell lung cancer.

Allogeneic SCT in Solid Tumors of Adults

Aglietta and colleagues reported their experience with 39 patients with metastatic colorectal cancer who underwent reduced-intensity conditioning (RIC) allogeneic HSCT between 1999 and 2004 at 9 European Group for Blood and Marrow Transplantation (EBMT) centers. (19) Patients were treated with one of five different RIC regimens. Endpoints that were assessed were achievement of mixed chimerism, incidence of graft versus host disease, treatment-related mortality and toxicities, overall survival and time to treatment failure (in patients who responded to the therapy). Patient population characteristics were heterogeneous; pretransplant disease status was partial response in 2 patients, stable disease in 6 patients and progressive disease in 31. Thirty-eight patients (97%) had been previously treated, some with only chemotherapy and others with surgery and/or chemotherapy. After transplant, tumor responses were complete in 2% of patients, partial in 18% and 26% of patients had stable disease, for overall disease control in 46% of patients. Transplant-related mortality was 10%. Median overall follow-up was 202 days (range 6 –1,020), after which time 33 patients had died and 6 were still alive. Tumor progression was the cause of death in 74% of patients. A comparison of overall survival of patients was performed after stratifying by some potential prognostic factors. Achievement of response after transplantation was associated with a difference in overall survival, with the 18 patients who had a response having a median overall survival of approximately 400 days versus approximately 120 days for those who had no response (p =.00018). The authors concluded that the HSCT approach should probably be reserved for patients with a partial response or stable disease after second-line therapy for metastatic colorectal cancer, and that second-generation clinical trials in these patients are warranted.

Bregni and colleagues assessed the long-term benefit of allografting in 25 patients with cytokine-refractory metastatic renal cell cancer who received an RIC allograft from an HLA-identical sibling. (20) All patients received the same conditioning regimens. Response to allograft was available in 24 patients, with a complete response in one patient and partial response in 4 patients. Twelve patients had minor response or stable disease, and 7 reported progressive disease. Overall response rate (complete plus partial) was 20%. Six patients died because of transplant-related mortality. Median survival was 336 days (12 –2,332 +). One-year overall survival was 48% (95% CI: 28 –68) and 5-year overall survival was 20% (95% CI: 4 –36). The authors concluded that allografting is able to induce long-term disease control in a small fraction of cytokine-resistant renal cell cancer patients, but that with the availability of novel targeted therapies for renal cell cancer, future treatment strategies should consider the incorporation of these therapies into the transplant regimen.

Kanda and colleagues reported on the efficacy of RIC allogeneic HSCT against advanced pancreatic cancer in 22 patients from 3 transplantation centers in Japan. (22) The RIC regimens differed among the centers, and the patient population was fairly heterogeneous, with 15 patients having metastatic disease and 7 locally advanced disease. All but one patient received chemotherapy of various combinations before transplant, and 10 patients received local radiation. After HSCT, one patient achieved complete response (defined as disappearance of all clinical evidence of tumor for a minimum of 4 weeks), partial response was seen in 2 patients, minor response in 2 and stable disease in 8, with an overall response rate of 23%. Median survival was 139 days and the major cause of death was tumor progression (median duration of survival in advanced pancreatic cancer in the nontransplant setting is less than 6 months, even in patients treated with gemcitabine). Only one patient survived longer than one year after transplantation. The authors concluded that a tumor response was observed in one-fourth of patients with advanced pancreatic cancer who underwent HSCT and that the response was not durable. However, they felt that their observation of a relationship between longer survival and the infusion of a higher number of CD34-positive cells or the development of chronic graft-versus-host disease, warrants future studies to enhance the immunologic effect against pancreatic cancer.

Clinical Trials and Guidelines

An August 2009 search of the National Cancer Institute (NCI) database of ongoing clinical trials (Physician Data Query [PDQ] database) shows a Phase III clinical trial of chemotherapy followed by peripheral stem-cell or bone marrow transplant compared with chemotherapy alone in treating patients with small-cell lung cancer (NCT00011921) is active but not recruiting. Also ongoing is a Phase II/III study of disease-specific high-dose conditioning regimens followed by autologous HSCT (single or tandem) in patients with hematologic malignancies or solid tumors (NCT00536601), with an estimated completion date in 2024. No additional ongoing Phase III clinical trials of chemotherapy followed by HSCT in treating adults with miscellaneous solid tumors listed in this policy were identified.

The 2009 National Comprehensive Cancer Network (NCCN) guidelines on the tumors addressed in this policy do not indicate HSCT as a treatment option. (22)

Summary
In summary, as of August 2009, no trials have been published that would alter the current policy statement; this is considered investigational.

References:

1. Imanguli MM, Childs RW. Hematopoietic stem cell transplantation for solid tumors. Update Cancer Ther 2006; 1(3):343-52.
2. Carnevale-Schianca F, Ricchiardi A, Capaldi A et al. Allogeneic hemopoietic stem cell transplantation in solid tumors. Transplant Proc 2005; 37(6):2664-6.
3. 1995 TEC Assessments; Tab 4.
4. 1999 TEC Assessments; Tab 11.
5. Nieto Y, Shpall EJ. Autologous stem-cell transplantation for solid tumors in adults. Hematol Oncol Clin North Am 1999; 13(5):939-68.
6. Rosti G, Ferrante P, Ledermann J et al. High-dose chemotherapy for solid tumors: results of the EBMT. Crit Rev Oncol Hematol 2002; 41(2):129-40.
7. Nishimura M, Nasu K, Ohta H et al. High dose chemotherapy for refractory urothelial carcinoma supported by peripheral blood stem cell transplantation. Cancer 1999; 86(9):1827-31.
8. Airoldi M, De Crescenzo A, Pedani F et al. Feasibility and long-term results of autologous PBSC transplantation in recurrent undifferentiated nasopharyngeal carcinoma. Head Neck 2001; 23(9):799-803.
9. Pedrazzoli P, Ledermann JA, Lotz JP et al. High dose chemotherapy with autologous hematopoietic stem cell support for solid tumors other than breast cancer in adults. Ann Oncol 2006; 17(10):1479-88.
10. Kasper B, Dietrich S, Mechtersheimer G et al. Large institutional experience with dose-intensive chemotherapy and stem cell support in the management of sarcoma patients. Oncology 2007; 73(1-2):58-64.
11. Schlemmer M, Wendtner CM, Falk M et al. Efficacy of consolidation high-dose chemotherapy with ifosfamide, carboplatin and etoposide (HD-ICE) followed by autologous peripheral blood stem cell rescue in chemosensitive patients with metastatic soft tissue sarcomas. Oncology 2006; 71(1-2):32-9.
12. Verma S, Younus J, Stys-Norman D et al. Dose-intensive chemotherapy with growth factor or autologous bone marrow/stem cell transplant support in first-line treatment of advanced or metastatic adult soft tissue sarcoma: a systematic review. Cancer 2008; 112(6):1197-205.
13. Lorigan P, Woll PJ, O’Brien ME et al. Randomized phase III trial of dose-dense chemotherapy supported by whole-blood hematopoietic progenitors in better-prognosis small-cell lung cancer. J Natl Cancer Inst 2005; 97(9):666-74.
14. Crivellari G, Monfardini S, Stragliotto S et al. Increasing chemotherapy in small-cell lung cancer: from dose intensity and density to megadoses. Oncologist 2007; 112(1):79-89.
15. Pedrazzoli P, Rosti G, Secondino S et al. High-dose chemotherapy with autologous hematopoietic stem cell support for solid tumors in adults. Semin Hematol 2007; 44(4):286-95.
16. Demirer T, Barkholt L, Blaise D et al. Transplantation of allogeneic hematopoietic stem cells: an emerging treatment modality for solid tumors. Nat Clin Pract Oncol 2008; 5(5):256-67.
17. Childs R, Chernoff A, Contentin N et al. Regression of metastatic renal cell carcinoma after nonmyeloablative allogeneic peripheral blood stem cell transplantation. N Engl J Med 2000; 343(11):750-8.
18. Jiang J, Shi HZ, Deng JM et al. Efficacy of intensified chemotherapy with hematopoietic progenitors in small-cell lung cancer: a meta-analysis of the published literature. Lung Cancer 2009; 65(2):214-8.
19. Aglietta M, Barkholt L, Schianca FC et al. Reduced-intensity allogeneic hematopoietic stem cell transplantation in metastatic colorectal cancer as a novel adaptive cell therapy approach. The European Group for Blood and Marrow Transplantation experience. Biol Blood Marrow Transplant 2009; 15(3):326-35.
20. Bregni M, Bernardi M, Servida P et al. Long-term follow-up of metastatic renal cancer patients undergoing reduced-intensity allografting. Bone Marrow Transplant Feb 23 2009; [Epub ahead of print].
21. Kanda Y, Omuro Y, Baba E et al. Allo-SCT using reduced-intensity conditioning against advanced pancreatic cancer: a Japanese survey. Bone Marrow Transplant 2008; 42(2):99-103.
22. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. 2009. Available online at http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Last accessed August 2009.

Index

Policy History