Case Presentation
Theory Behind the Treatment
Political and Social Influences Make High Dose Chemotherapy Standard of Care
Early Phase I/II Trials
Randomized Control Trials
Clinical Case Reviewed
Conclusion

David T. Martin, MD
Wake Forest University School of Medicine
February 6, 2001

C.S. is a 27 year old white female with no significant past medical history who presented in June 1999 with a breast mass. The patient stated that six weeks prior to this presentation she had a normal physical exam, including a breast exam. Because of painful intercourse, her birth control pill was switched to a higher estrogen-containing pill. Soon after starting this medication she noticed the mass and states that it grew rapidly. She underwent fine needle aspiration of the mass that was non-diagnostic. She subsequently had lumpectomy with revealed a 7.5 x 5.5 x 5.5-cm mass that was positive for ductal carcinoma. The patient was treated with a mastectomy and axillary node dissection. She was found to have 15/15 positive lymph nodes (ER positive). She underwent CT scan of the chest and abdomen that were negative for metastatic disease. She also had negative bone scan, chest x-ray, CMP, and bone marrow biopsies. The patient was referred to North Carolina Baptist Hospital for evaluation for high dose chemotherapy and autologous bone marrow transplant.

Past Medical History: None

Past Surgical History: None

Medications: None

Family History: She denied any history of breast cancer, ovarian cancer, or colon cancer.

GYN History: Menarche at age 12. She has never been pregnant. She had taken birth control pills for past five years. She never had any breast disease or breast biopsies prior to recent cancer diagnosis. She never had any mammograms.

Review of Systems: Negative

VS 99.1 Pulse 85 BP 123/62

Gen: Young white female in no acute distress

HEENT: PERRLA, EOMI, oropharynx clear

Chest: Right mastectomy site clear without nodules/discharge

Left Breast: No masses

CV: RRR no M/G/R

Lungs: CTAB

Ab: Soft NTND No hepatosplenomegaly

Nodal Exam: No cervical, supraclavicular, axillary, inguinal lymphadenopathy

Extremities: No c/c/e

Neuro: Non-focal

Pathology:

Tumor Size 7.5 x 5.5 x 5.5 cm. 15/15 positive lymph nodes. ER positive in more than 90%. PR positive in more than 20%. Her-2/neu negative. DNA index 2.0 Tetraploid S-Phase 19%.

The patient received four cycles of conventional dose chemotherapy with Cytoxan/Adriamycin followed by high dose chemotherapy with Cytoxan (6000 mg/m2), Thiopeta (500mg/m2), and Carboplatin (800mg/m2) followed by peripheral blood stem cell rescue. She was subsequently treated with radiotherapy and tamoxifen. She is currently 12 months post bone marrow transplant and is disease free.

The patient received the high dose chemotherapy on January 20, 2000. On the day before she was to have her peripheral blood stem cells reinfused, the patient was found to be tearful. She stated that she spoke to a friend of hers who read on the Internet that Bone Marrow Transplants don’t work for breast cancer and that in a month, insurance companies are going to stop covering this procedure. The patient asked, "Does high dose chemotherapy and autologous bone marrow transplants help women with breast cancer?"

Despite a recent decrease in the incidence and mortality, breast cancer currently develops in one of eight American women who live to the age of 85, and remains the leading cause of death in American women ages 15 to 54. Virtually all patients who initially present with or later develop metastatic breast cancer will ultimately die of their disease.

Adjuvant therapy has consistently demonstrated a modest improvement in long-term disease-free and overall survival in breast cancer patients. The prognosis of patients with primary breast cancer is inversely related to the number of involved axillary lymph nodes at surgery. Analysis of treatment outcomes in patients with four to nine positive lymph nodes indicates that 50-60% will relapse by 10 years. The outcome of patients with 10 or more positive lymph nodes is even worse: at 5 years 55-87% and at 10 years 70-90% have relapsed, respectively. Twenty-year follow-up data suggests that even at that time, no plateau has been reached (1). Only complete responders to therapy have a chance at prolonged disease-free and overall survival. Thus curative therapy for this group is desperately needed.

The most easily understood rationale for the use of high-dose chemotherapy is "more is better." The scientific basis for this hypothesis assumes that for some drugs, doses above certain levels will successfully overcome drug resistance. The demonstration that increased drug exposure increases cell kill is termed "dose-response" and high-dose chemotherapy is the translation of this laboratory observation to the clinical setting. Clinically relevant drugs for which a steep dose-response relationship has been seen in the laboratory include most alkylating agents and anthracyclines which, given their proven efficacy, makes them excellent candidates for study (2).

The method of applying high-dose therapy is also based on laboratory studies. Some experiments suggest that the application of high-dose alkylating agents following optimal cytoreduction can eradicate viable tumor, even when the same treatment is not curative if applied earlier (i.e. prior to an initial cytoreductive therapy). This concept is also supported by the Gompertzian model of tumor growth which predicts that a smaller volume of tumor cells will have relatively increased growth fraction and therefore greater sensitivity to cell-cycle specific agents (3). These studies provide the basis for the most common regimens used in high dose chemotherapy in which patients are first treated with multiple (usually two to six) rounds of "induction" chemotherapy prior to the administration of a single or multiple rounds of high-dose chemotherapy.

Political and Social Influences make High-Dose Chemotherapy Standard of Care

By 1990, patients with advanced breast cancer, with the support of some clinicians, began to seek coverage for the experimental use of autologous bone marrow transplant from managed care organizations. Analogues to this treatment had proven effective for some lymphatic cancers, and there was some scientific rationale for extending the treatment to solid tumors. Despite the enthusiasm of the clinicians and the desperate belief of the breast cancer patients, there was no hard clinical evidence to support this therapy. Specifically, there were no randomized trials that showed a benefit from this expensive and risky treatment over standard treatments. (It should be remembered that at this time the mortality associated with bone marrow transplant was reported to be from 10-25%.) Because of the lack of data, many insurance companies refused to cover these treatments. When some managed care organizations insisted the therapy was still "investigational" and "unproven" and might even prove worse than standard therapies, patients pursued both litigation and legislation, and the media "exposed" the denials. In 1991, 60 Minutes featured a story about Aetna declining coverage for ABMT in breast cancer. In California in 1993, the estate of Neline Fox won $89 million suit against Healthnet, which had originally denied coverage, then provided it. The suit charged that the delay cost Fox her life (4).

Throughout the 1990’s many insurers were providing coverage for patients participating in approved clinical trials. Unfortunately, according to a study in the New England Journal of Medicine, this coverage did not correlate with pretreatment clinical characteristics, or the response to induction therapy. This study showed that as many as three out of four patients seeking coverage for participation in a trial were granted it, and another half of those who threatened legal action when initially denied also received coverage (5).

In addition, many state legislatures mandated coverage as early as 1994 and 1995 despite protests that these mandates would make it virtually impossible to continue proper clinical trials aimed at assessing efficacy. Thus through legislative mandates and lawsuits, high-dose chemotherapy soon became the standard of care for women with metastatic and "high-risk" breast cancer patients. As a result, the number of bone marrow transplants for breast cancer dramatically increased from 310 in 1989 to over 3000 in 1996 (6). Also, because bone marrow transplant was seen as standard of care, most the early data regarding high-dose chemotherapy for breast cancer consisted of small, non-randomized phase I/II studies.

As mentioned, most of the early data consisted of Phase I/II trials. A few of these trials are shown in Table 1.

One of the most sited trials in the literature is from Duke University (Peters et al. Table 1). In this study, 85 patients with 10 or more axillary lymph nodes were treated with high-dose cyclophosphamide, cisplatin and camustine (CPB) and ABMT after CAF adjuvant chemotherapy. The median age was 38 years, and the median number of lymph nodes was 14. Therapy related mortality was 12%. At the time the abstract was published, the median follow up was 5 years. The data (shown in Table 2) was compared to historical CALGB series selected for age <56, involvement of >10 lymph axillary lymph nodes.

The author concluded that this evidence showed high-dose chemotherapy to be feasible. He states that the results must be confirmed with a randomized trial.

Although these data seem to be impressive, many factors must be taken into account. First, this was not a randomized controlled trial. The historical controls used do not necessarily correlate with those selected for this study. For example, eligibility for this study included normal contrast-enhanced computed tomography (CT) scan of the head, chest, abdomen and pelvis along with normal bilateral bone marrow biopsies. The eligibility for the other studies only indicated normal blood work, chest x-ray and bone scan. A prospective trial conducted in Toronto showed that intensive screening using CT scans and bone marrow aspirates and biopsies uncovered distant metastatic disease in an additional 23% of patients (12).

Selection bias is one of the most frequently used criticisms of these early trials. Garcia-Carbonero et al. performed a retrospective study to determine the disease-free survival and overall survival in-patients who met the selection criteria for high dose chemotherapy but were treated with conventional chemotherapy (13). They found 171 breast cancer patients with >10 lymph nodes positive from 1975 through 1995. One-hundred twenty-eight patients met criteria for high dose chemotherapy (> 10 more positive lymph nodes, age < 60, no significant concomitant disease, and no progression during adjuvant treatment) but received conventional chemotherapy. Although patients in this study received many different forms of chemotherapy, authors state that each patient received what was considered the standard of care at the time of treatment. Progression of disease was determined by normal serum tests, chest x-ray and bone scan. CT scans and bone marrow biopsies were not used. The disease-free and overall survival were then compared between those patients who did and did not meet criteria for high-dose chemotherapy. A comparison was also made between these two groups and 39 patients who met criteria and underwent high dose chemotherapy. The mean follow-up for high-dose chemotherapy group was 2.5 years. The results are shown in Tables 3 and 4.

As shown in Table 3, this study indicates that those patients who meet criteria for high dose chemotherapy seem to have a significantly increased disease-free survival and overall survival. Furthermore, when comparing patients who met criteria for high dose chemotherapy, there was no significant difference in disease-free survival and overall survival between those treated with high dose chemotherapy than those who were treated with conventional therapy. This study also tried to determine what factors would predict prolonged DFS and OS. The study included the following variables: age (<50 vs. >50), menopausal status (premenopausal vs. postmenopausal), T stage (T1/T2 vs. T3/T4), radiotherapy (yes vs. no) chemotherapy (CMF vs. anthracycline- type) number of lymph nodes (10-15 vs. >15) and HDCT criteria (yes vs. no). Of all of these variables, the only significant differences were found in those who met HDCT criteria and those who received radiotherapy (as shown in Table 4). Thus meeting HDCT criteria was found to be an independent risk factor for prolonged DFS and OS. The data was also presented in graphical form as shown below in Figures 1-3.

In addition to selection bias, another criticism of the Duke University study is that the patients were treated with mastectomy plus local radiotherapy for local control. In contrast, patients in the historical controls were not routinely treated with chest radiotherapy. Two randomized trials recently demonstrated that the addition of chest wall radiotherapy improves not only local control, but also distant disease-free survival and overall survival (14, 15).

Finally, there were no conventional standards used in these trials. As seen in Table 1, different stages of disease, different eligibility requirements, different chemotherapies and different follow up times were used making any conclusions or comparisons of these studies almost impossible. The great diversity in the outcomes was also very troubling. Thus randomized controlled trials to determine the effect (if any) of high dose chemotherapy were desperately needed.

One of the first randomized controlled studies was the M.D. Anderson study by Hortobagyi et al. in February 1998 and is available only in abstract form (16). This study addressed the question of high dose chemotherapy versus standard chemotherapy. All patients received six cycles of 5-Fluorouracil, Adriamycin and cyclophosphamide. Half of the patients were then randomized to receive either two additional cycles of high dose chemotherapy with cyclophosphamide, etoposide, and cisplatin (5250/1200/165 mg/m2) followed by autologous bone marrow/stem cell support or two additional cycles of standard chemotherapy. All patients subsequently received radiotherapy and tamoxifen if estrogen receptor positive. The eligibility criteria were: resectable tumor with >10 lymph nodes (LN) after primary surgery or >4 positive LN after four cycles of neoadjuvant chemotherapy. The two groups were matched for age, race, stage, estrogen receptor status, # of nodes and histology. Seventy-eight patients were registered and randomized. Three patients in the standard dose group received high dose chemotherapy off protocol elsewhere. Six of the patients in the high dose chemotherapy group did not receive treatment (Refused: 3, Insurance denial 1, Other illness: 2). Median follow up was 53 months. The 4 year disease free survival rates for conventional chemotherapy and high dose chemotherapy were 55% and 48% respectively with intention-to-treat analysis (P=0.45) and 52% and 51% by actual treatment (P=0.84). The overall survival figures were 68% and 60% for the standard dose and high-dose chemotherapy groups, respectively, by intention-to-treat (P=0.27) or 64% and 63% by actual treatment. Six treatment related deaths (2 patients developed congestive heart failure, 1 developed acute leukemia and 1 sepsis) occurred in the high dose treatment group while none occurred in the conventional group. The author concluded that while this study had limited statistical power because of the small size, high dose chemotherapy is unlikely to produce major improvements over conventional chemotherapy. Interestingly, both the control and treatment groups had much longer disease-free survival and overall survival when compared to the previously used "historical" controls.

The next study published was the Netherlands trial by Rodenhuis et al in 1998 (17). This trial compared high dose versus conventional chemotherapy. In this study, all patients received three cycles of conventional chemotherapy with and 5-Fluorouracil, epirubricin and cyclophosphamide, (FEC) (500/120/500mg/m2). The patients were then randomized to receive either a forth cycle of chemotherapy or a high dose regimen of cyclophosphamide, thiotepa and carboplatin (6000/480/1600mg/m2). Both groups then received radiation therapy followed by two years of tamoxifen. This again was a small study involving only 96 patients. The eligibility criteria was age <60, "extensive axillary node involvement" confirmed by infraclavicular lymph node biopsy, an operable tumor and no distant metastasis. Patients were screened for metastatic disease by normal serology, chest x-ray, liver ultrasound and bone scan. Neither CT scans or bone marrow biopsies were used in the study. The two groups were matched for mastectomy, breast-conserving surgery, estrogen receptor status, progesterone receptor status T and N stage at diagnosis, p53 status and Neu status. Forty patients were randomized to the conventional chemotherapy group and forty-one to the high-dose chemotherapy group. After a median follow up of 49 months, the overall survival and disease-free survival to be 75% and 54%. There were no significant differences between the high-dose and conventional chemotherapy groups. Although more reversible toxicity was found in the high-dose group, no fatal toxicity occurred in either group. Once again, both the control and treatment groups had substantial overall survival when compared to those used previously for historical controls. Also, these overall and disease free rates appear to be consistent with the previously discussed study of patients who meet HDCT criteria.

The next two trials were published in abstract form in the Proceedings of the American Society of Clinical Oncology (18,19). Unfortunately, these studies do not provide additional information comparing conventional chemotherapy versus high dose chemotherapy.

Initially, the South African Trial appeared to be the first larger randomized controlled trial to demonstrate a significant difference between the HDCT and conventional chemotherapy with CAF. However, an onsite review of this study showed much disparity between the reviewed records and the data presented. In addition, the reviewers were unable to find neither any signed informed consent nor any record of approval for the investigational therapy (20). Therefore, this study should not be used as basis for determining the efficacy of high dose chemotherapy in high–risk breast cancer patients.

The final trial is the CALGB study by Peters et al which compared high- Vs intermediate-dose cyclophosphamide, platinol, and BCNU (CPB) after induction therapy with cyclophosphamide, Adriamycin, and 5-Fluorouracil (CAF) in women with 10 or more lymph nodes and no evidence of metastasis. Once again, patients were screened for metastatic disease with CT Scans and Bone Marrow Biopsies. Between 1/91 and 5/98, 874 women with stage II or IIIA breast cancers received four cycles of CAF (600/60/1200 mg/m2 q28 days). Patients were then randomized to either high dose CPB (5625/165/600 mg/m2) followed by autologous bone marrow transplant or to intermediate dose of CPB (900/90/90 mg/m2) with GCSF support. All patients were planned for local XRT and hormone receptor positive patients received tamoxifen for five years.

Of the 874 women admitted to the trial, 783 were randomized (394 to the HDCT, 389 to the IDCT). Ninety-one patients were not randomized for the following reasons: 22 had recurrent disease, 2 death from CAF toxicity, 26 denied insurance for ABMT, 20 withdrew, and 21 ineligible (reason not given). This study found at 5 years the overall EFS was 58% (95%CI 49%-67%) and OS was 70% (95% CI 61%-78%). At the median follow-up of 37 months, the intent-to-treat EFS HDCT vs. IDCT were 68% and 64% respectively (P = 0.7) and the OS HDCT vs. IDC were 78% vs. 80% respectively (P=0.1). Thus no significant difference between these two groups was noted. Also, while there were fewer relapses in the HDCT group (22% Vs 32%), the HDCT group was also noted to have 29 therapy-related deaths compared to none in the IDCT group. The author notes that this is preliminary data and that further follow up is necessary before final conclusions can be reached.

A summary of the data obtained from the randomized trials is shown in Table 5.

As mentioned previously, the rationale for high-dose chemotherapy followed by bone marrow transplant can be summarized in three words: "more is better." The CALGB study seems to contradict this hypothesis. The theory behind high dose chemotherapy relies on a continuous dose-response relationship existing with certain chemotherapy drugs. Thus increasing the dose should result in better clinical outcomes. The CALGB study failed to show any difference between the intermediate and high-dose groups. These data may indicate that the dose-response curve plateaus at a certain dosages, above which no further benefit occurs. Three clinical studies have looked at this issue (20-22).

The first study by Wood et al. examined CAF at low dosages (300/30/300 mg/m2) every 28 days for six cycles, intermediate-dosages (400/40/400 mg/m2) for six cycles or high-doses (600/60/600 mg/m2) for four cycles. This was a large trial consisting of 1572 women with stage II breast cancer. The disease free survival at three years was 74%, 70% and 63% in the high-, intermediate- and low-dose groups (P=<0.001). The overall survival at five years was 92%, 90% and 84% in the high-, intermediate- and low-dose groups respectively (P=0.004). In summary, the low dose group had significantly worse outcomes when compared to either the intermediate or high dose groups. Futhermore, no significant difference was found between the intermediate and high dose groups.

The National Surgical Adjuvant Breast and Bowel Project B-22 evaluated dose and dose intensity. In this trial, 2305 women with stage II breast cancer to either four courses of cyclophosphamide at standard (600mg/m2 X 4), or at increased dose intensity (1200mg/m2 X 2) or increased dose and dose intensity (1200mg/m2 X4). Note all patients also received doxorubicin 60mg/m2 with each treatment. . The disease free survival at five years was 62%, 60% and 64% in the high-, intermediate- and low-dose groups (P=0.59). The overall survival at five years was 78%, 77% and 77% in the high-, intermediate- and low-dose groups respectively (P=0.82). With more than four years of follow up B-22 failed to show any significant difference between any of the groups. These studies strongly suggest 600mg/m2 is an appropriate dose for cyclophosphamide and that there is no obvious benefit to the use of higher doses for the majority of node-positive patients.

For doxorubicin, a similar story is unfolding. The CALGB 9344 evaluated doxorubicin 60mg/m2 compared to 75 mg/m2 and 90 mg/m2. With 18 months of follow-up, no significant disease-free and overall survival were found between any group.

These studies seem to indicate that there is a maximum dosage above which no further clinical benefit is found. If this is found to be true, this would disprove the idea that more (higher dose) is better and eliminate the rationale for even attempting high-dose chemotherapy.

The patient described in the case is a young, healthy women with Stage IIIB breast cancer with 15 positive node and no evidence of further metastasis. The fact that she has greater than 10 positive nodes put her at high risk for recurrence. Thus this patient should receive adjuvant therapy of some type. This should include radiation and tamoxifen (Patient is ER +). The question becomes should this patient receive high-dose chemotherapy, conventional chemotherapy or become part of a clinical study involving a new chemotherapy regimen.

Proponents for high-dose chemotherapy will say this is the perfect patient. She is young with no comorbidities so she should tolerate the bone marrow transplant well. She is at high risk for recurrence (>10 lymph nodes positive) and has a minimal tumor burden making her tumor more sensitive to the chemotherapy (theoretically). Finally, because she is young the most aggressive therapy should be used in the event that a benefit may be discovered in these patients at longer follow-up times.

If this were my patient, I would advise her to try to get in a clinical trial using new chemotherapy for the following reasons. High-dose chemotherapy has not yielded any significant benefits over conventional therapy. Since this patient has minimal amount of tumor burden, she probably has about 40-50 month disease-free survival and 60-70 month overall survival. The 4-10% mortality rate associated with the high-dose chemotherapy is too high to justify its use. Also, studies appear to be showing that many of the chemotherapy agents do not continue to maintain their dose-response curves above levels much lower than those used in high-dose treatments. Thus the risk of significant morbitity and mortality would outweigh the possible benefit that has yet to be shown.

Patients have been treated for over a decade with high dose chemotherapy followed by autologous bone marrow transplant. For political and social reasons, this became standard of care for patients viewed at high risk for recurrence or with metastatic disease. Recently, a number of randomized controlled trails have been published questioning the efficacy of this treatment. Many of these studies are preliminary with three to five years of follow-up and most authors of these studies indicate that further follow-up is necessary before any conclusions can be drawn. While this is true, the fact that no benefit is seen in patients after this amount of time makes the likelihood of any significant long term benefit low as the disease-free survival appears to be 40 to 50 months. Finally, recent studies have been published which question whether a continuous dose-response relationship exists with the chemotherapy agents used. Thus high doses may only add significant toxicity without any clinical benefit. In conclusion, high-dose chemotherapy with bone marrow transplant should only be performed as part of randomized controlled trials until studies revealing benefits are performed.

1. Lalisang RI, Hupperets PSGJ et al. "High-dose chemotherapy with autologous bone marrow support as consolidation after standard-dose adjuvant therapy in primary breast cancer patients with seven or more involved axillary lymph nodes." Bone Marrow Transplant 1998; 21: 243-247.

2. Hudis Clifford, Munster Pamela, "High-dose chemotherapy for breast cancer." Seminars in Oncology 1999; 26: 35-47.

3. Norton L, Simon R et al. "Predicting the course of Gompertzian growth." Nature 1976; 264: 542-545.

4. Daniels Norman, Sabin James, "Last Chance Therapies and Managed Care: Pluralism, Fair Procedures, and Legitimacy." Hastings Center Report 1998; 28: 27-41.

5. Peters W. and Rogers M., "Variations in Approval by Insurance Companies for Coverage of Autologous Bone Marrow Transplantation for Breast Cancer." New England Journal of Medicine 1994; 330: 473-477.

6. Gluck S. and Stewart D., "High-dose therapy in breast cancer: out of favor but not out of promise." Bone Marrow Transplant 2000; 25: 1017-1019.

7. Peters W. Berry D. et al. "Five year follow-up of high-dose combination alkylating agents with ABMT as consolidation after standard-dose CAF for primary breast cancer involving greater than or equal to 10 axillary lymph nodes." Proceedings from the American Society of Clinical Oncology. 1995 14: A933 (abstract).

8. Bearman S., Overmoyer B. et al. "High-dose chemotherapy with autologous peripheral blood progenitor cell support for primary breast cancer in patients with 4-9 involved axillary nodes." Bone Marrow Transplant 1997 20: 931-937.

9. Somlo G., Doroshow J. et al. "High-dose chemotherapy and stem-cell rescue in the treatment of high risk breast cancer: Prognostic indicators of progression-free and overall survival." Journal of Clinical Oncology 1997 15: 2882-2893.

10. Ayash L., Elias A. et al. "High-dose multimodality therapy with autologous stem-cell support for stage IIIB breast carcinoma." Journal of Clinical Oncology 1998 16: 1000-1007.

11. Viens P., Penault-Llorca F. et al. "High-dose chemotherapy and haematopoietic stem cell transplantation for inflammatory breast cancer: Pathologic response and outcome." Bone Marrow Transplant 1998 21: 243-247.

12. Crump M. Goss PE. et al. "Outcome of extensive evaluation before adjuvant therapy in women with breast cancer and 10 or more positive axillary nodes." Journal of Clinical Oncology 1996 14: 66-69.

13. Garcia-Carbonero R., Hidalgo M. et al. "Patient Selection in High-dose Chemotherapy Trials: Relevance in High-Risk Breast Cancer." Journal of Clinical Oncology 1997 15: 3178-3184.

14. Ragaz J. Jackson S. et al. "Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer." New England Journal of Medicine 1997; 337: 956-962.

15. Overgaard M., Hansen P. et al. "Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy." New England Journal of Medicine 1997 337: 949-955.

16. Hortobagyi GN, Buzdar AU. et al. "Lack of efficacy of adjuvant high-dose tandem combination therapy for high-risk primary breast cancer: A randomized trial." Proceedings of the American Society of Clinical Oncology 1998 17:A12 (abstract)

17. Rodenhuis S., Richel KJ. et al. "Randomized trial of high-dose chemotherapy and hematopoietic progenitor-cell support in operable breast cancer with extensive axillary lymph node involvement." Lancet 1998 352: 515-521.

18. Peters W., Rosner G. et al. "A prospective, randomized comparison of two doses of combination alkylating agents as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes." Proceedings of the American Society of Clinical Oncology 1999 18:1a (abstract).

19. Bezwoda WR "Randomized, controlled trial of high-dose chemotherapy vs. standard dose chemotherapy for high-risk, surgically treated, primary breast cancer." Proceedings of the American Society of Clinical Oncology 1999 18:2a (abstract).

20. Weiss R., Rifkin R, et al. "High-dose chemotherapy for high-risk primary breast cancer: an on-site review of the Bezwoda study." Lancet 2000 355: 999-1003.

21. Wood W, Budman D., et al. "Dose and dose intensity trial of adjuvant chemotherapy for stage II, node-poisitive breast carcinoma." New England Journal of Medicine 1994 330: 1253-1259.

22. Fisher B., Anderson S. et al. "Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer. Findings from National Surgical Adjuvant Breast and Bowel Project B-22." Journal of Clinical Oncology 1997 15:1858-1869.

23. Henderson I., Berry D. et al. "Improved disease-free survival and overall survival from the addition of sequential paclitaxel but not from escalation of doxorubicin dose level in the adjuvant chemotherapy of patients with node-positive primary breast cancer." Proceedings of the American Society of Clinical Oncology 1998 17:390a (abstract).