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Minnesota Health Technology Advisory Committee. Minnesota Health Technology Assessments [Internet]. St. Paul (MN): Minnesota Department of Health; 1995-2001.

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Minnesota Health Technology Assessments [Internet].

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High-Dose Chemotherapy with Autologous Bone Marrow Transplantation and/or Peripheral Blood Stem Cell Transplantation for Breast Cancer

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High-Dose Chemotherapy With Autologous Bone Marrow Transplantation and/or Peripheral Blood Stem Cell Transplantation for Breast Cancer

Introduction

Breast cancer affects 1 in 9 American women during their lifetimes and is the second leading cause of cancer death among women. The incidence rate (the number of new cases per 100,000 population per year) of breast cancer has increased over the past 50 years. However, there has been little change in the rate of deaths (the number of deaths per 100,000 population per year) due to the disease.

Breast cancer is potentially curable when diagnosed in its early stages. When initially diagnosed, most breast cancer patients have local disease (about half) or regional disease (about one-third), without distant metastases. Some cases of breast cancer (10% to 15%) have already metastasized beyond the breast and adjacent lymph nodes, to other areas of the body, when the patient is first diagnosed.

Background

The National Cancer Institute (NCI) developed and published five common categories, known as stages, for the diagnosis of breast cancer in 1995. Each category is labeled as stage 0,1,2,3,or 4 and provides a means to classify the degree to which the carcinoma has progressed. Table 1 provides a summary of the criteria for each stage developed by the NCI, as well as overall statistics of diagnosis and five year survival rates by stage.

Table 1. NCI Breast Cancer Staging, Diagnosis and Overall Survival Rates.

Table 1

NCI Breast Cancer Staging, Diagnosis and Overall Survival Rates.

Up to 30% of patients whose lymph nodes do not show the presence of tumor (lymph node-negative) may have occult metastatic disease. That is, the cancer has spread but the lesions are not large enough to be detected with the best current diagnostic technology. Up to 90% of patients whose lymph nodes contain tumor cells (lymph node-positive) may have undetected metastatic disease. Even when diagnosed with early stage disease, as many as 21% of patients may ultimately experience a recurrence or relapse of their disease despite apparently successful surgery. Additional tumors may be either the same breast cancer, or from another source of cancer.

In addition to surgery and radiotherapy, chemotherapy is used to treat breast cancer. This involves the administration of drugs that kill the cancer cells, and as a side effect kill some normal cells. After breast cancer chemotherapy, most patients will enter complete or partial remission. Complete remission means that there is no evidence of cancer while partial remission means that the tumor size is reduced by 50% to 99%. A challenge in cancer treatment is that although most patients achieve a complete or partial remission with chemotherapy, in some patients the cancer cells are not all killed by the drugs, develop resistance, and reoccur.

Metastatic and recurrent cancers are presently considered incurable by standard chemotherapy. For these patients, the purpose for treating these tumors is to relieve symptoms and prolong life.

Description of High Dose Chemotherapy (HDC) with Autologous Bone Marrow Transplant (ABMT) or Peripheral Blood Stem Cell Transplantation (PBSCT)

The fact that some breast cancers become resistant to standard-dose treatment led researchers to investigate whether higher doses of drugs would kill greater numbers of cancer cells. But while increasing the dosages of the chemotherapeutic drugs, that is, high-dose chemotherapy (HDC), enhances the ability of the drugs to kill more breast cancer cells, the incidence of drug-related side effects also increases. HDC is highly toxic to the bone marrow and causes a profound suppression of normal function with resultant decrease in the numbers of white and red blood cells and platelets, which leads to potentially serious complications such as infection and bleeding.

To offset the bone marrow toxicity from HDC, the transplantation of stem cells (cells that develop into red and white blood cells and platelets) has been investigated. During the process of stem cell transplantation, called autologous bone marrow transplantation (ABMT) or peripheral blood stem cell transplantation (PBSCT), stem cells are collected from the patient before HDC, and are returned to the patient after HDC to restore bone marrow function.

Issues of HDC with ABMT and/or PBSCT

There are unanswered questions regarding the safety and effectiveness of HDC followed by ABMT and/or PBSCT for the treatment of high-risk (locally advanced or with 10+ lymph nodes positive) stage II and III breast cancers and stage IV metastatic cancers (with distant spread). Among these are:

  • Does HDC with ABMT and/or PBSCT improve survival rates in these breast cancer patients compared with standard-dose breast cancer treatment?
  • Do the potential benefits of high-dose treatment outweigh the risks of serious treatment-related complications and death, compared to standard-dose treatment?
  • For what subset of patients (considering age, type of cancer, estrogen response, etc.) does HDC have greater promise for long-term survival in women with earlier stages of breast cancer?
  • The issues surrounding costs of HDC with ABMT and/or PBSCT are an important consideration, but the clinical effectiveness of the treatment should be addressed first.

Summary of the Literature

  1. The prognosis for stage II and III breast cancer patients with extensive axillary lymph node involvement at the time of diagnosis is poor, despite surgery, radiotherapy and standard-dose chemotherapy. The recurrence rate among these patients is very high, with a majority having a recurrence of cancer by 10 years.
  2. In the nonrandomized studies examining HDC with ABMT and/or PBSCT in patients with high-risk stages II and III breast cancer and stage IV metastatic breast cancer (published from 1992-1994 and reviewed in Tables II and III in the body of this report), HDC with stem cell transplant produced higher rates of complete and partial remission, compared with standard-dose chemotherapy. However, the patients within these studies may not be comparable because the studies were not randomized. It is presently unknown whether these remissions are sustained. Studies so far have not shown whether initially superior response rates with HDC imply better long-term (five years or more) survival.
  3. Current data on the short- and long-term costs of HDC with ABMT and/or PBSCT, compared to standard-dose treatment, are not yet available. Though substantially higher than standard-dose chemotherapy, the cost of HDC has been falling as improvements in supportive care have been introduced and inpatient hospital stays have been shortened.
  4. While treatment-related morbidity and mortality has decreased somewhat with improved use of supportive measures to facilitate the restoration of bone marrow function post-HDC and ABMT/PBSCT, the mortality and morbidity associated with HDC is still higher than with standard chemotherapy.
  5. In the only randomized controlled clinical trial comparing HDC to standard-dose chemotherapy for patients with stage IV metastatic breast cancer, Bezwoda et al. (Journal of Clinical Oncology, October, 1995) found a statistically significant longer median duration2 of response and survival for HDC patients versus standard-dose patients. There were 90 patients in the study. There were no deaths due to the use of HDC. The standard-dose chemotherapy protocol used in the South African study was different from those commonly used in the United States, so there is disagreement about whether the results are applicable to treatment using United States standard-dose chemotherapy.

Conclusions

  1. HDC with ABMT and/or PBSCT is a promising treatment for breast cancer. However, there is controversy as to whether the improved response rates observed after HDC translate into significant health benefits (i.e., improved disease-free status, longer survival, increased likelihood of cure, enhanced quality of life) that justify the increased morbidity and mortality.
  2. For some patients, high costs are associated with this treatment, compared to standard-dose chemotherapy.
  3. Well-designed randomized clinical trials comparing state-of-the-art standard-dose chemotherapy to HDC with ABMT and/or PBSCT, controlling for cancer stage, treatment history, and other relevant patient factors such as age and estrogen receptor status, are necessary to answer the above questions. Except for a small South African study recently presented in the Journal of Clinical Oncology (Bezwoda et al., October, 1995), results from these studies are not yet available.
  4. The National Cancer Institute is sponsoring randomized, controlled clinical studies with adequate patient populations, strict patient inclusion criteria, and well-defined outcome parameters. Because there is not yet sufficient patient enrollment in these crucial studies, the data needed to determine the long-term effectiveness and safety of HDC with ABMT and/or PBSCT for breast cancer treatment compared with standard therapies for the disease, are not yet available.
  5. Whether HDC with ABMT and/or PBSCT can improve patient survival at acceptable levels of morbidity, mortality and costs to the health care system cannot be answered without data from randomized controlled trials.

Other Issues and Considerations

Because of the lack of critical data needed to evaluate this technology, the formal research trials must be completed. Eligible patients should be strongly encouraged to participate in clinical trials.

For patients who cannot or will not enter randomized trials, comprehensive data gathering, tracking and data analysis in conjunction with the national registry must be supported. These data must include all of the following: breast cancer patient characteristics (disease stage, cell type, lymph node involvement, hormone receptivity, patient age, etc.), treatment (surgery, radiotherapy, transplants, drug type, combinations, dosage and duration, etc.) and treatment outcomes (treatment response, survival duration, quality of life, treatment complications, etc.). These retrospective data will contribute to our understanding of treatment outcomes.

In 1995, the Minnesota Legislature required health plans in Minnesota to pay for HDC with ABMT. Minnesota Statues 62A.309 reads in pertinent part “Every health plan included in subdivision 1) must provide to each covered person who is a resident of Minnesota coverage for the treatment of breast cancer by high-dose chemotherapy with autologous bone marrow transplantation and for expenses arising from the treatment.”

Many ethical and policy issues on this and other health care interventions remain to be discussed. Until data are available to assist with this discussion, patients, physicians, and payers must use their best judgement on an individual basis, for treatment of the disease.

Approved by the Minnesota Health Care Commission August 21, 1996

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