Seminal Articles
High-Dose Chemotherapy for Solid Tumors

The third article by Arun, et al., which appeared in the 1 January 1999 issue of Cancer, reports on inflammatory breast cancer patients at Georgetown University's Lombardi Cancer Center and at the Massachusetts General Hospital.   We greatly appreciate permission from the American Cancer Society to put the abstract on our Web site.  For the complete article referenced by this abstract, please see the appropriate issue of Cancer.

Peters, WP; Ross, M; Vredenburgh, JJ; Meisenberg, B; Marks, LB; Winer, E; Kurtzberg, J; Bast, RC Jr; Jones, R; Shpall, E; et al. (1993) High-dose chemotherapy and autologous bone marrow support as consolidation after standard-dose adjuvant therapy for high-risk primary breast cancer. Journal of Clinical Oncology, 11(6):1132-43.

PURPOSE:  We studied high-dose cyclophosphamide, cisplatin, and carmustine (CPA/cDDP/BCNU) with autologous bone marrow support (ABMS) as consolidation after standard-dose adjuvant chemotherapy treatment of primary breast cancer involving 10 or more axillary lymph nodes.

PATIENTS AND METHODS:  One hundred two women with stage IIA, IIB, IIIA, or IIIB breast cancer involving 10 or more lymph nodes at surgery were registered; 85 were eligible, treated, and assessable.
Patients were treated with four cycles of standard-dose cyclophosphamide, doxorubicin, and fluorouracil (CAF), followed by high-dose CPA/cDDP/BCNU with ABMS.

RESULTS:  Actuarial event-free survival for the study patients at a median follow-up of 2.5 years is
72% (95% confidence interval, 56% to 82%).  Comparison to three historical or concurrent Cancer and Leukemia Group B (CALGB) adjuvant chemotherapy trials selected for similar patients showed event-free survival at 2.5 years to be between 38% and 52%.  Therapy-related mortality was 12%; pulmonary toxicity of variable severity occurred in 31% of patients.  Quality-of-life evaluations indicate that patients are functioning well without major impairments.

CONCLUSION:  High-dose consolidation with CPA/cDDP/BCNU and ABMS after standard-dose CAF results in a decreased frequency of relapse in patients with high-risk primary breast cancer compared with historical series at the median follow-up of 2.5 years.  Evaluation in a prospective, randomized trial is warranted and currently underway.

Somlo, G.; Doroshow, J.H.; Forman, S.J.; Odom-Maryon, T.; Lee, J.; Chow, W.; Hamasaki, V.; Leong, L; Morgan, R., Jr; Margolin, K.; Raschko, J.; Shibata, S.; Tetef, M.; Yen, Y.; Simpson, J.; Molina, A.  (1997)     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, 15(8):2882-2893

PURPOSE:  To examine the predictive value of tumor- and treatment-specific prognostic indicators of relapse-free survival (RFS) and overall survival (OS) in patients with high-risk breast cancer (HRBC) treated with high-dose chemotherapy (HDCT) and stem-cell rescue.

PATIENTS AND METHODS:  Between June 1989 and September 1994, 114 patients with HRBC (stage II with > or = 10 axillary lymph nodes involved, stage IIIA, and stage IIIB inflammatory carcinoma) received adjuvant chemotherapy followed by HDCT with etoposide, cyclophosphamide, and either doxorubicin (CAVP) or cisplatin (CCVP).  Variables analyzed included stage, tumor size, number of axillary nodes involved, grade and receptor status, and types of adjuvant chemotherapy and radiation therapy and HDCT.

RESULTS:  With a median follow-up time of 46 months (range, 23 to 93), Kaplan-Meier estimates of 3.5-year OS for stage II, IIIA, and IIIB HRBC are 82% (95% confidence interval [CI], 67% to 97%), 79% (95% CI, 67% to 91%), and 72% (95% CI, 53% to 91%); RFS estimates are 71% (95% CI, 56% to 85%), 57% (95% CI, 43% to 72%), and 50% (95% CI, 29% to 71%) irrespective of the HDCT regimen.  In univariate analysis, the risk of relapse was lower for patients with progesterone receptor (PR)-positive tumors (risk ratio [RR], 0.43; 95% CI, 0.22 to 0.81; P = .01) and higher for patients with inflammatory carcinoma (RR, 2.20; 95% CI, 1.02 to 4.76; P = .05).  OS was better for patients with PR (RR, 0.16; 95% CI, 0.05 to 0.55; P = .003) and estrogen receptor (ER)-positive tumors (RR, 0.42; 95% CI, 0.17 to 1.02; P = .05); OS was worse for patients with high-grade primary tumors (RR, 4.08; 95% CI, 1.21-13.7; P = .02).  In multivariate analysis, PR positivity was associated with improved RFS (P = .01) and OS (P = .001).

CONCLUSION:  HDCT in selected patients with HRBC is safe and warrants further evaluation.  Patients with receptor-negative, high-grade, or inflammatory tumors require improvement in their therapeutic options. Better assessment of the role of HDCT awaits completion of ongoing randomized trials.

Note:  This study was updated at the 1999 meeting of the American Society of Clinical Oncology.

Arun, Banu; Slack, Rebecca; Gehan, Edmund; Spitzer, Thomas; Meehan, Kenneth R. (1999) Survival after Autologous Hematopoietic Stem Cell Transplantation for Patients with Inflammatory Breast Carcinoma. Cancer, 85:1(1 January 1999), 93-99.

BACKGROUND.  The authors retrospectively determined the clinical outcome of patients with inflammatory breast carcinoma (IBC) treated with high dose chemotherapy (HDC) and autologous bone marrow (ABM) or peripheral blood stem cell (PBSC) support.

METHODS.  Twenty-four consecutive patients with IBC received HDC, including escalating doses of carboplatin (range, 1.2-1.8 g/m²) and cyclophosphamide (range, 4.8-6.0 g/m²) over 3 days followed by ABM (n = 5) or PBSC infusion (n = 19).  Restaging evaluation we performed 100 days after transplant, every 6 months for two years, and then yearly thereafter.  After transplantation, fifteen patients received immunotherapy with interleukin-2 (IL-2) or IL-2 and interferon-a.

RESULTS.  The 2-year estimated disease survival (DFS) and overall survival (OS) for these patients were 71% (90% confidence interval [CI], 55-87%) and 73% (90% CI, 53-93%), respectively.  The median follow-up of surviving patients was 19 months (range, 8-68 months).  Six patients developed disease recurrence at a median of 10 months (range 4-16 months) after transplantation.  Four of these 6 patients died from metastatic disease at a median of 18 months (range, 14-21  months).  Using the generalized Wilcoxon test and the Cox proportional hazards regression model, patients with tumors that demonstrated estrogen receptors had an improved DFS (P=0.03).

CONCLUSIONS.  Combining HDC and ABM or PBSC for patients with IBC may yield an improved OS and DFS.

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