Phase III multicenter clinical trial of the sialyl-TN (STn)-keyhole limpet hemocyanin (KLH) vaccine for metastatic breast cancer

Purpose.

This double-blind, randomized, phase III clinical trial evaluated time to progression (TTP) and overall survival in women with metastatic breast cancer (MBC) who received sialyl-TN (STn) keyhole limpet hemocyanin (KLH) vaccine. Secondary endpoints included vaccine safety and immune response.

Experimental design.

The study population consisted of 1,028 women with MBC across 126 centers who had previously received chemotherapy and had had either a complete or a partial response or no disease progression. All women received one-time i.v. cyclophosphamide (300 mg/m²) 3 days before s.c. injection of 100 μg STn-KLH plus adjuvant (treatment group) or 100 μg KLH plus adjuvant (control group) at weeks 0, 2, 5, and 9. Subsequently, STn-KLH without adjuvant or KLH without adjuvant was then administered monthly for 4 months, and then quarterly until disease progression, without cyclophosphamide.

Results.

STn-KLH vaccine was well tolerated; patients had mild to moderate injection-site reactions and reversible flu-like symptoms. Week-12 antibody testing revealed high specific IgG titers and a high rate of IgM-to-IgG seroconversion; the median IgG titers in STn-KLH recipients were 320 (anti-ovine submaxillary mucin) and 20,480 (anti-STn), with no detectable antimucin antibodies in the control group. The TTP was 3.4 months in the treatment group and 3.0 months in the control group. The median survival times were 23.1 months and 22.3 months, respectively.

Conclusions.

Although STn-KLH was well tolerated in this largest to date metastatic breast cancer vaccine trial, no overall benefit in TTP or survival was observed. Lessons were learned for future vaccine study designs.     

A randomised phase II study of sialyl-Tn and DETOX-B adjuvant with or without cyclophosphamide pretreatment for the active specific immunotherapy of breast cancer.

Studies in animal models of mouse mammary carcinoma have shown that ovine submaxillary mucin, which carries multiple sialyl-Tn (STn) epitopes, is effective in stimulating an immune response and inhibiting tumour growth. In similar studies using carbohydrate antigens, pretreatment with low-dose cyclophosphamide has been shown to be important in modulating the immune response to antigen possibly by inhibiting suppresser T-cell activity. In a clinical trial assessing the efficacy and toxicity of synthetic STn, patients with metastatic breast cancer were randomised to receive 100 micrograms STn linked to keyhole limpet haemocyanin (KLH) with DETOX-B adjuvant given by subcutaneous injection at weeks 0, 2, 5 and 9 with or without low-dose cyclophosphamide (CTX, 300 mg m-2) pretreatment, 3 days before the start of immunotherapy. Patients with responding or stable disease after the first four injections were eligible to receive STn-KLH at 4 week intervals. The main toxicity noted was the development of subcutaneous granulomata at injection sites. Of 23 patients randomised, 18 received four injections, 5 patients having developed progressive disease during the initial 12 week period. Two minor responses were noted in the 18 patients who received four active specific immunotherapy (ASI) injections and a further five patients had stable disease. Six patients continued ASI at 4 week intervals and a partial response was noted in a patient who had previously had stable disease. All patients developed IgG and IgM responses to sialyl-Tn and levels of IgM antibodies were significantly higher in those patients who were pretreated with CTX. Measurable tumour responses have been recorded following ASI with STn-KLH plus DETOX and the immunomodulatory properties of low-dose CTX have been confirmed.     

The role of cancer vaccines following autologous stem cell rescue in breast and ovarian cancer patients: experience with the STn-KLH vaccine (Theratope)

The success of high-dose chemotherapy followed by autologous stem-cell rescue as treatment for breast and ovarian cancer is limited by a high incidence of relapse. After autologous transplantation, patients are likely to have a low tumor burden and thus would be more likely to respond immunologically to a cancer vaccine. Sialyl-Tn (STn) is a carbohydrate associated with the MUC1 mucin on breast and ovarian cancer and is an ideal candidate for vaccine immunotherapy. Sialyl-Tn-keyhole limpet hemocyanin (STn-KLH) vaccine (Theratope) incorporates a synthetic STn antigen that mimics the unique tumor-associated STn carbohydrate and is designed to stimulate tumor antigen-specific immune responses in patients with mucin-expressing tumors. Between 1995 and 2000, 70 patients (16 with stage II/III breast cancer, 17 with stage III/IV ovarian cancer, and 37 with stage IV breast cancer) were treated with 2 different formulations of STn-KLH. Toxicity, outcome, and immune response data are reported. STn-KLH was well-tolerated with minimal toxicity. The most common side effects were indurations and erythema at the sites of injections. Humoral and cellular responses were elicited in the majority of patients. Overall, these data indicate that post-autologous transplant patients are able to mount an effective immune response to vaccine immunotherapy with minimal side effects, and that vaccine immunotherapy may be a useful addition to high-dose chemotherapy regimens.     

The use of mitoxantrone plus cyclophosphamide as first-line treatment of metastatic breast cancer

Thirty-two patients with metastatic breast cancer who had not received prior chemotherapy for metastatic disease were entered into a trial of mitoxantrone 12 mg/m2 plus cyclophosphamide 600 mg/m2 given at three weekly intervals. Thirty-one patients are eligible for assessment. Response was seen in 65% (4/31 complete regression; 16/31 partial regression). Median duration of response was 6 months and median duration of survival was 10 months. Mitoxantrone + cyclophosphamide appears to be an active combination in treatment of metastatic breast cancer.     

Comparative trial of low-dose adriamycin plus cyclophosphamide with or without additive hormonal therapy in advanced breast cancer.

We treated 56 women with advanced metastatic breast cancer who had not received prior chemotherapy in a comparative trial of cytotoxic chemotherapy with low-dose adriamycin plus cyclophosphamide alone or in combination with the androgenic steroid calusterone. The response rate to chemohormonal therapy (65%) could not be shown to be statistically better than that for chemotherapy alone (53%) for this size patient population. However, the median remission duration (21.5 months) was significantly prolonged over the 11.5-month remission duration for chemotherapy alone (p = 0.03). The median survival of the chemohormonal therapy group was 23.5 months, whereas that for chemotherapy alone was 13.5 months (p = 0.05). These results indicate that the addition of a potent hormonal agent to effective cytotoxic chemotherapy improves the results of treatment of women with metastatic breast cancer.     

Clinical outcome of breast cancer patients with liver metastases alone in the anthracycline-taxane era: a retrospective analysis of two prospective, randomised metastatic breast cancer trials

Liver metastases have long been known to indicate an unfavourable disease course in breast cancer (BC). However, a small subset of patients with liver metastases alone who were treated with pre-taxane chemotherapy regimens was reported to have longer survival compared with patients with liver and metastases at other sites. In the present study, we examined the clinical outcome of breast cancer patients with liver metastases alone in the context of two phase III European Organisation for Research and Treatment of Cancer (EORTC) trials which compared the efficacy of doxorubicin (A) versus paclitaxel (T) (trial 10923) and of AC (cyclophosphamide) versus AT (trial 10961), given as first-line chemotherapy in metastatic BC patients. The median follow-up for the patients with liver metastases was 90.5 months in trial 10923 and 56.6 months in trial 10961. Patients with liver metastases alone comprised 18% of all patients with liver metastases, in both the 10923 and 10961 trials. The median survival of patients with liver metastases alone and liver plus other sites of metastases were 22.7 and 14.2 months (log rank test, P=0.002) in trial 10923 and 27.1 and 16.8 months (log rank test, P=0.19) in trial 10961. The median TTP (time to progression) for patients with liver metastases alone was also longer compared with the liver plus other sites of metastases group in both trials: 10.2 versus 8.8 months (log rank test, P=0.02) in trial 10923 and 8.3 versus 6.7 months (log rank test, P=0.37) in trial 10961. Most patients with liver metastases alone have progression of their disease in their liver again (96 and 60% of patients in trials 10923 and 10961, respectively). Given the high prevalence of breast cancer, improved detection of liver metastases, encouraging survival achieved with currently available cytotoxic agents and the fact that a significant portion of patients with liver metastases alone have progression of their tumour in the liver again, a more aggressive multimodality treatment approach through prospective clinical trials seems worth exploring in this specific subset of women.     

Combined antiestrogen and cytotoxic therapy with pseudomonas vaccine immunotherapy for metastatic breast cancer. A prospective, randomized trial

One hundred thirty-three consecutive, previously untreated patients who had metastatic breast cancer were treated with a combination of 5-fluorouracil, doxorubicin (Adriamycin), and cyclophosphamide (FAC). They were randomly assigned to receive nonspecific immunotherapy with a heptavalent pseudomonas vaccine. Sixty-five patients were treated with pseudomonas vaccine, whereas 68 did not receive immunotherapy. In addition, all patients with estrogen receptor-positive tumors or tumors with an estrogen receptor status were also treated with tamoxifen. To allow clinical assessment of hormone sensitivity in vivo, tamoxifen was started 6 weeks before chemotherapy except in patients who had life-threatening disease. After the initial 6 weeks of tamoxifen, 3% of patients had achieved a complete remission, 9% a partial remission, while 16% achieved a minor response. The maximum response after tamoxifen and chemotherapy included complete remissions in 20% of patients and partial remissions in 61% of patients for an overall remission rate of 81%. The median response duration was 15 months, and the median survival time, 27 months. There were no differences in remission rate, remission duration, or survival time between the groups treated with or without pseudomonas vaccine. Eleven patients with limited metastatic disease received radiotherapy consolidation to initially involved sites. In these patients the median time from radiotherapy to progression of disease was 33 months, and the median survival time was 46 months. We conclude that nonspecific immunotherapy with pseudomonas vaccine failed to increase remission rate or survival time. Furthermore, the addition of tamoxifen to FAC chemotherapy did not improve the remission rate or duration compared to a recent, historical control group of patients treated with only FAC chemotherapy.     

Combination of adriamycin and cyclophosphamide (alone or with other substances) in the treatment of breast cancer]

This paper reviews clinical trials at the University of Arizona Cancer Center which were designed to improve the outcome in breast cancer by utilizing the combination of adriamycin and cyclophosphamide (A--C) alone or with the addition of other agents or modalities. Our initial trial in advanced breast cancer with A--C produced an overall objective response rate of 78% in 51 patients with advanced breast cancer without prior chemotherapy. The median duration of disease control was 12 months. Subsequent studies showed that the addition of either vincristine or the androgen, calusterone, effectively doubled the remission duration and prolonged survival. In our surgical adjuvant trial with 6 months of treatment with A--C there has been only a 9% relapse rate in stage II patients thus far, with a median follow-up of close to 2 years. A subset of stage II patients who received regional radiotherapy along with A--C have not yet shown added benefit compared to the use of A--C alone. Since 1975, stage I patients have been treated with an abbreviated treatment schedule (3 courses of A--C over 9 weeks). While there have not yet been relapses in this category, much longer periods of follow-up will be required. The use of A--C (plus other drugs) has clearly provided excellent palliation and improved survival in patients with advanced or recurrent breast cancer; in our opinion it should be used as initial cytotoxic chemotherapy. The brief intensive program of A--C as a surgical adjuvant also shows considerable promise for erradicating occult micrometastases in both pre- and postmenopausal women.     

Five-year survival for cisplatin-based chemotherapy versus single-agent melphalan in patients with advanced ovarian cancer and optimal debulking surgery

The purpose of this study was to evaluate 5-year survival and 5-year progression-free survival in previously untreated patients with advanced ovarian cancer treated with single-agent melphalan in which very few patients underwent optimal debulking surgery (less than 2 cm residual) as compared with the patients treated with Cisplatin-based chemotherapy in which most patients underwent optimal debulking surgery. Significant increases in 5-year survival and 5-year progression-free survival were noted as we changed from the melphalan trial, in which only 14% underwent optimal debulking surgery, to PAC-H, in which 57% and the PAC trial in which 90%, respectively, underwent optimal debulking surgery. However, for those patients whose tumors were optimally debulked in the three trials, there were no statistically significant differences in median survival, median progression-free survival, 5-year survival, or 5-year progression-free survival in those patients treated with melphalan, PAC-H, or PAC. Without optimal debulking surgery, Cisplatin-based multiagent chemotherapy offered a small survival advantage. These results are similar to that reported by Gruppo Interregionale Cooperativo Oncologico Ginecologia, in which survival curves were identical for all the subgroups of chemotherapy regimens for those patients with residual disease less than 2 cm at the onset of chemotherapy whether they received (1) cyclophosphamide; (2) cyclophosphamide and Adriamycin; (3) cyclophosphamide, Adriamycin, and Cisplatin; (4) cyclophosphamide, Adriamycin, and hexamethylmelamine; (5) Cisplatin and cyclophosphamide; (6) low-dose Cisplatin; (7) high-dose Cisplatin; or (8) carboplatin.     

A phase II trial of continuous low-dose oral cyclophosphamide and celecoxib in patients with renal cell carcinoma

Purpose The lack of effective systemic therapies for patients with advanced renal cell carcinoma (RCC) has stimulated interest in evaluating novel treatment strategies for this disease. Methods This was a two-institution, two-stage, phase II trial of continuous low-dose oral cyclophosphamide (50 mg daily) in combination with celecoxib (400 mg twice daily) in patients with progressive, locally advanced or metastatic RCC. The primary endpoint was disease control rate (DCR) defined as the number of patients with complete (CR) or partial response (PR) or prolonged (≥6 months) stable disease (SD). Secondary endpoints included time to progression and toxicity. Results Between May 2001 and January 2003, 36 patients were enrolled onto the trial of which 32 were evaluable for response. One patient had a PR and three others had SD for longer than 6 months (DCR 12.5%, 95% CI 3.5–29.0%). The median progression free survival was 3.5 months (95% CI, 1.9–4.1 months) and the median overall survival was 14.5 months (95% CI, 8.4–20.8 months). One patient experienced grade five gastrointestinal bleeding. Otherwise, the treatment was well tolerated. Conclusions Although generally well tolerated, continuous therapy with low-dose cyclophosphamide and celecoxib had limited activity in RCC.     

羟基喜树碱、环磷酰胺抗血管生成热化疗治疗肝胆胰等难治性肿瘤

目的:观察小剂量羟基喜树碱、环磷酰胺抗血管生成热化疗治疗肝胆胰等难治性肿瘤的近期临床疗效和安全性。方法:27例肝癌、胆囊(管)癌、胰腺癌等难治性肿瘤患者采用低剂量羟基喜树碱(HCPT5mg静滴d1、5、9、13)及环磷酰胺(CTX50mg口服d1～13)联合热疗(2次/周)方案治疗3周期,比较两组治疗近期临床疗效、临床受益率、中位生存期及VEGF值的变化。结果:单用羟基喜树碱、环磷酰胺抗血管生成化疗组疾病控制率为58.33%(7/12例SD),临床受益率为58.33%,中位生存期11.2月,VEGF值下降者41.67%;联合热疗组疾病控制率为80%(2/15例PR,10/15例SD),临床受益率66.67%,中位生存期19.2月,VEGF值下降者60%。结论:小剂量羟基喜树碱、环磷酰胺化疗能提高肝胆胰等难治性肿瘤治疗的有效率,改善临床受益,延长其生存期,联合热疗可以有显著的协同作用,而无明显的毒副作用。小剂量羟基喜树碱、环磷酰胺可能具有抗血管生成作用。     

Long-term results of combined-modality therapy for inflammatory breast carcinoma

Sixty-eight patients with inflammatory breast carcinoma (IBC) received treatment in 2 prospective randomized trials of multimodality therapy for locally advanced breast cancer. The treatment plan consisted of 3 courses of neoadjuvant chemotherapy with CAF (cyclophosphamide/doxorubicin/5-fluorouracil [5-FU]) or CEF (cyclophosphamide/epirubicin/5-FU) followed by surgery and 6 adjuvant courses of CAF or CEF alternated with CMF (cyclophosphamide/methotrexate/5-FU). Radiation therapy was administered at the end of adjuvant treatment. All patients with estrogen receptor-positive tumors received tamoxifen 20 mg daily for 5 years. The response rate to induction chemotherapy was 73.6% (95% CI, 61.4%-83.5%): 4 of 68 patients (6%) exhibited a pathologic remission of primary breast tumor (persistent disease in the axilla), and 2 patients (3%) exhibited a pathologic complete response. Median follow-up was 10 years (range, 5 months to 14.7 years). Disease-free survival (DFS) rates at 5 and 10 years were 29% and 20%, respectively, and median DFS was 2.2 years (range, 3.8 months to 11.5 years). Overall survival (OS) rates at 5 and 10 years were 44% and 32%, respectively, and median OS was 4 years (range, 5 months to 14.7 years). Significant prognostic factors for DFS and OS were the number of axillary nodes and residual disease in the breast at surgery. This analysis confirmed that patients with IBC obtained significant long-term survival benefit from combined-modality therapy.     

Continuous Administration of Low-Dose Cyclophosphamide and Prednisone as a Salvage Treatment for Multiple Myeloma

Purpose:The purpose of this study was to evaluate the efficacy and tolerability of continuous low-dose cyclophosphamide and prednisone (CP) as a salvage therapy for multiple myeloma (MM).Patients and Methods:A total of 27 consecutive patients with MM received a treatment regimen that consisted of oral cyclophosphamide 50 mg and prednisone 15 mg daily. Nineteen patients had severe comorbid conditions; 8 were unwilling to continue conventional chemotherapy as a result of severe infection associated with the conventional chemotherapy. Patients had received 1 to 4 chemotherapeutic regimens before the enrollment.Results:The overall response rate (complete remission, very good partial response, and partial response) was 66.7%. The median time to response was 2 months. In the patients who responded to the treatment, the median progression-free survival (PFS) has not been reached. In the nonresponding patients, the median PFS was 4 months.Conclusion:Continuous low-dose CP is an effective and well-tolerated salvage therapy for MM.     

Results of adjuvant chemotherapy trials in breast cancer at M. D. Anderson Hospital and Tumor Institute

Between 1974 and 1982, 796 patients with operable breast cancer following local therapy were treated with 3 consecutive doxorubicin-containing adjuvant therapy trials. The median follow-up of patients entered on the first trial was 102 months; the second trial, 71 months; and for the third trial, 41 months. The treatment program consisted of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC). We altered the study designs to determine the role of nonspecific immunotherapy with BCG and postoperative irradiation in the second trial and the impact of additional chemotherapy with alternate drugs after completion of FAC in the third trial. In the first study, an overall 39% reduction in mortality was observed, and, in stage II disease, reductions of 54% and 37% in mortality were observed for patients less than 50 and greater than or equal to 50 years of age, respectively, in comparison to the historical control group. The data of the second trial illustrated that BCG and postoperative irradiation had no significant impact on the disease-free and overall survival. In the third trial, patients with estrogen receptor-positive tumor treated with additional chemotherapy with alternate drugs following completion of FAC had significantly superior disease-free survival compared with patients who did not receive additional chemotherapy. The results of 3 studies show that intensive combination chemotherapy significantly reduced the risk of recurrence and death in patients with breast cancer.     

Survival of premenopausal women with metastatic breast cancer. Long-term follow-up of Eastern Cooperative Group and Cancer and Leukemia Group B studies

In premenopausal women with metastatic breast cancer, differences in survival curves early during follow-up can be misleading. The authors therefore analyzed long-term survival in 378 patients, entered in three randomized trials, started between 1973 and 1978. Combined data from the three trials were used to increase the power for identifying prognostic variables. Cancer and Leukemia Group B (CALGB) trial 7382 randomized patients to oophorectomy plus either cyclophosphamide or combination chemotherapy or observation. Eastern Cooperative Oncology Group (ECOG) 2174 randomized patients who had not progressed 3 months after oophorectomy to combination chemotherapy or combination chemotherapy or observation. Trial ECOG 2177 randomized estrogen receptor (ER) positive or ER-unknown patients to oophorectomy plus combination chemotherapy or immediate combination chemotherapy, and ER-negative patients were directly assigned to combination chemotherapy. Hence ER-negative patients need not have been healthy enough to be randomized to oophorectomy. With only 14% of the patients still alive, median survival on the three studies was 30, 24, and 28 months. The median survival of individual treatments changed noticeably in ECOG 2174 and ECOG 2177 with long-term follow-up. At this time there are no differences in survival between randomized regimens in any of the three trials. In a multivariate model, factors associated with significantly poorer survival were visceral-dominant disease, nodal metastases, breast metastases, age younger than 45 years, ER negativity, and not receiving chemotherapy immediately after oophorectomy. This treatment difference was thus not due to imbalances in the prognostic variables used in the model, but it may be due to imbalances of unknown prognostic factors or differences in patient selection.     

Postoperative chemotherapy and chemohormonal therapy in women with node-positive breast cancer

Separate trials for premenopausal and postmenopausal (less than or equal to 65 yr of age) patients with node-positive breast carcinoma were initiated by the Eastern Cooperative Oncology Group in 1978 to evaluate adjuvant chemotherapy and chemohormonal therapy approaches. Postoperative patients were stratified by degree of axillary nodal involvement and estrogen receptor (ER) status prior to randomization. Premenopausal patients received 12 monthly cycles of intermittent cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), CMF plus prednisone (CMFP), or CMFP plus continuous tamoxifen (CMFPT). Postmenopausal patients received either observation or 12 monthly cycles of CMFPT or CMFP. The median follow-up for the analyzed patients is 54 months for the 553 premenopausal patients and 59 months for the 223 postmenopausal patients. The premenopausal trial has not demonstrated any significant differences between the regimens for either relapse-free or overall survival. The relapse-free survival in the postmenopausal trial has demonstrated a trend for CMFPT over observation (P = .07). Both CMFP and CMFPT are associated with an improved relapse-free survival over observation alone in ER-negative patients (P = .01) and in progesterone receptor-negative patients (P = .01). However, the relapse-free survival advantages have not translated to survival. Side effects were significantly increased with the addition of P to CMF in the premenopausal trial. The addition of T to CMFP was associated with an increased incidence of edema and hot flashes in premenopausal patients; however, the latter was decreased in postmenopausal patients relative to CMFP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Survival analysis after resection of metastatic disease followed by peptide vaccines in patients with Stage IV melanoma

BACKGROUND: Metastatic melanoma carries a poor prognosis, with a median survival of 7-9 months. Surgical resection of metastatic disease has been advocated to improve survival. Immunotherapy after metastasectomy may further improve the outcome for high-risk resected disease. METHODS: Charts from patients treated on institutional vaccine trials were analyzed. Patients with American Joint Committee on Cancer (AJCC) Stage IV melanoma who underwent surgical resection of metastatic sites followed by treatment on a peptide vaccine trial were eligible for this study. Survival was calculated from the date of enrollment on the clinical trial. RESULTS: Forty-one patients met inclusion criteria. The median age was 56.5 years, with approximately equal numbers of men and women. The ECOG performance status was 0 in all patients. Approximately 46% of patients underwent resection of visceral metastases before vaccine. The median follow-up was 5.6 years. The median overall survival was 3.8 years. CONCLUSIONS: In selected patients with AJCC Stage IV melanoma, resection of metastatic disease followed by vaccine therapy can result in long-term survival.     

Maintenance therapy with thalidomide improves overall survival after autologous hematopoietic progenitor cell transplantation for multiple myeloma

BACKGROUND: High-dose chemotherapy with autologous hematopoietic progenitor cell (HPC) transplantation improves survival for patients with multiple myeloma (MM); however, most patients develop recurrent disease after undergoing transplantation, and new treatment approaches are needed. The objective of this retrospective review of autologous HPC transplantation for patients with MM was to evaluate the impact of conditioning regimens and posttransplantation therapy on survival. METHODS: The authors reviewed 112 patients with MM who received autologous HPC grafts at their institution. Between June 1992 and August 2001, 54 patients received busulfan, cyclophosphamide, and etoposide (Bu/Cy/VP-16), and 58 patients received high-dose melphalan (MEL-200) followed by autologous HPC transplantation. After transplantation, 36 patients received thalidomide for maintenance or salvage therapy, and 76 patients received no posttransplantation thalidomide. RESULTS: At a median follow-up of 58 months, the median survival was 54 months. There was no statistically significant difference noted with regard to response to conditioning regimen, progression-free survival, or overall survival between the Bu/Cy/VP-16 and MEL-200 cohorts. Patients who received thalidomide after transplantation had improved median survival (65.5 months) compared with patients who did not receive thalidomide (44.5 months; P = .09). When they were separated according to reasons for thalidomide use, patients who received thalidomide as maintenance had improved overall survival compared with patients who received thalidomide as salvage (65 months vs. 54 months; P = .05). CONCLUSIONS: Combination chemotherapy provided no advantage over high-dose melphalan in patients with MM who underwent autologous HPC transplantation. The posttransplantation use of thalidomide seemed to improve the survival of patients compared with historical controls from the prethalidomide era. Further prospective trials are underway to confirm the benefit of thalidomide in the posttransplantation setting.     

Adjuvant chemotherapy of axillary node-negative carcinoma of the breast using doxorubicin and cyclophosphamide

One hundred fifty-six women with axillary node-negative breast cancer and primary tumors less than or equal to 5 cm in diameter (T1N0 or T2N0) were treated with a brief course of postoperative adjuvant chemotherapy consisting of doxorubicin and cyclophosphamide. Treatment was well tolerated and toxicity was minimal. With a median follow-up time of 58 months, there has been 1 relapse among 58 patients with T1 primary lesions and 15 relapses among 98 patients with T2 primary tumors. When compared with a matched historical control group receiving surgery alone, significant improvement was apparent in disease-free survival among the patients who received adjuvant chemotherapy. Prospective controlled trials are needed if we are to confirm this favorable experience with adjuvant chemotherapy in the treatment of women with node-negative breast cancer.     

Comparison of chemotherapy with chemohormonal therapy as first-line therapy for metastatic, hormone-sensitive breast cancer: An Eastern Cooperative Oncology Group study.

PURPOSE: Although hormonal therapy represents standard therapy for metastatic hormone-sensitive disease, many patients receive initial chemotherapy because of the location, bulk, or aggressiveness of their disease. It is uncertain whether simultaneous hormonal therapy provides additional benefit compared with chemotherapy alone. Eastern Cooperative Oncology Group trial E3186 was initiated to explore this question. PATIENTS AND METHODS: Between January 1988 and December 1992, 231 patients with estrogen receptor (ER)-positive or ER-unknown metastatic breast cancer were randomized to receive either chemotherapy (cyclophosphamide, doxorubicin, and fluorouracil ?CAF) or chemohormonal therapy (CAF plus tamoxifen and Halotestin ?fluoxymesterone; Pharmacia-Upjohn, Kalamazoo, MI ?CAFTH) as front-line therapy for metastatic breast cancer. Patients who experienced a complete response to induction therapy either received or did not receive maintenance cyclophosphamide, methotrexate, fluorouracil, prednisone, and TH as a secondary randomization. RESULTS: The response rates (complete response and partial response) of patients who received CAF and CAFTH were similar (69.2% v 68.9%, respectively; P =.99). Time to treatment failure (TTF) was slightly longer for patients who received chemohormonal therapy compared with chemotherapy alone patients (13.4 months v 10.3 months, respectively; P =.087), and TTF was significantly longer in ER-positive compared with ER-negative patients (17.4 months v 10.3 months, respectively; P =.048). However, ER status had no effect on overall survival (30.0 months for CAF v 29.3 months for CAFTH). CONCLUSION: In patients with potentially hormone-sensitive metastatic breast cancer, chemohormonal therapy prolongs TTF for ER-positive patients without improving overall survival.