Anthracycline-containing regimens can further reduce the odds of relapse and death compared with CMF. However, the findings observed in our trials emphasize that the relative merits of anthracycline adjuvant programs also can depend on the modality of administration and must be assessed in properly designed trials in which the magnitude of the benefits can be weighed against potential risks.

In a randomized trial of adjuvant chemotherapy, immunotherapy, or immunochemotherapy, 761 evaluable patients with pathological Stage II cutaneous melanoma anywhere on the body or with pathological Stage I melanoma of the trunk (Clark's level 3 to 5) were studied by the World Health Organization International Melanoma Group. Wide local excision and excisional regional lymphadenectomy alone were performed in 185 patients and the results were compared with those of surgery plus chemotherapy with dacarbazine (in 192 patients), surgery plus immunotherapy with bacille Calmette-Guérin vaccine (in 203), and surgery plus chemotherapy combined with immunotherapy (in 181). The rates of disease-free survival and overall survival at 36 months were 30.4 +/- 8.3 per cent (mean +/- S.E.) and 41.6 +/- 10.0 per cent, respectively, after surgical treatment alone; 37.2 +/- 7.9 per cent and 46.5 +/- 8.3 per cent after surgery plus chemotherapy; 34.8 +/- 7.9 per cent and 48.7 +/- 8.7 per cent after surgery plus immunotherapy; and 33.6 +/- 7.9 per cent and 50.0 +/- 8.8 per cent after surgery plus a combination of chemotherapy and immunotherapy. None of the differences between groups was significant, and thus no effect of adjuvant therapy could be demonstrated in this study.

We have reviewed the current status of primary chemotherapy for resectable breast cancer in view of the possibility that it may improve on results of present adjuvant drug therapies. The observed kinetic acceleration of micrometastases following noncurative surgical excision in animal studies represents strong biologic evidence supporting primary chemotherapy. From a clinical perspective, primary chemotherapy has consistently reduced the frequency of mastectomy in women with tumors initially considered too large for breast-conserving surgery. From studies of various drug combinations, it appears that the incidence of pathologic complete remission usually remains less than 10 percent. Based on results from the Milan study, it appears that the degree of tumor response is a marker of treatment outcome, at least for the first five years. A higher complete-remission rate could be expected by combining doxorubicin with paclitaxel, as has already been observed in the treatment of clinically disseminated breast cancer. In spite of the logical and scientific rationale, the available data do not as yet provide sufficient evidence to indicate a clear superiority of primary chemotherapy over adjuvant chemotherapy. The real question to answer through prospective, randomized trials is not whether the shift from adjuvant to neoadjuvant chemotherapy will result in a superior outcome, but rather how to properly integrate effective primary and adjuvant drug regimens to maximize tumor cell kill. This strategy should be further tested in patients at high risk for occult axillary adenopathy and/or distant micrometastases (i.e., tumor size larger than 2 to 3 cm). However, a more-refined risk assessment approach (e.g., using tumor grade or proliferative index) will clearly be needed. The new treatment approach may also allow for a wider use of fine-needle aspiration biopsy to obtain the primary diagnosis of cancer, a more uniform adoption of breast-conserving surgery, and use of response to chemotherapy as a marker of treatment outcome.

No abstract

Hematopoietic progenitor cells circulate in the peripheral blood (PB) of cancer patients during the recovery phase that follows treatment with high-dose cyclophosphamide followed by hematopoietic growth factor infusion. We report that when PB progenitors were exposed in vitro to filtered supernatant from cell line PA317-N2, producing amphotropic helper-free N2 vector at conventional titers, successful retroviral- mediated transfer of neomycin resistance gene was documented by polymerase chain reaction in 93% of day 14 myelomonocytic colonies. Under the same conditions, gene transfer was achieved in 22% of steady- state bone marrow-derived myelomonocytic colonies. Neo-resistance gene transfer was documented also in a CD34+/cyclophosphamide-resistant precursor to granulocyte-macrophage colonies, an undifferentiated progenitor close to the hematopoietic stem cell. Neither cocultivation with vector-producing cells nor high vector titer were stringent requisites for efficient gene transfer. The large-scale availability of PB hematopoietic progenitors in cancer patients, together with the high gene transfer rate achieved under safe and clinically feasible conditions, support an optimal approach for gene transfer procedures into the human hematopoietic system.