Multimodal therapy with CMF in resectable breast cancer with positive axillary nodes: the Milan Institute experience.
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Publications and source records attributed to G Tancini.
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The pertinent radiographs of 151 patients treated with radical mastectomy who showed relapse in the chest and/or in the skeleton as first site were reevaluated. Diagnostic accuracy was calculated by comparing the first examination considered as positive with the previous ones reported as negative. For chest lesions the accuracy was 80% (70% for parenchymal nodular densities), with no difference between symptomatic and asymptomatic patients. For bone metastases retrospective evaluation confirmed the radiological report (i.e., the time of relapse), in 73.8%, with a value of 89.7% in symptomatic and 53.4% in asymptomatic patients. The site of involvement and morphological characteristics of the lesions did not influence the diagnostic accuracy. Therefore chest examination and, for symptomatic patients, radiographic bone survey still represent a useful modality to assess the diffusion of breast cancer. For asymptomatic patients other modalities, such as bone scan and biochemical tests, should be utilized.
From June 1973 to May 1978 a total of 845 patients with operable breast cancer were entered into different adjuvant programs. The medical records of the 278 patients showing relapse were carefully re-evaluated to assess the pattern(s) of first recurrence and the consistency of follow-up modulation. Ninety-one of 179 patients treated with surgery alone, 130 of 414 given 12 cycles of adjuvant CMF and 57 of 252 treated with 6 cycles of CMF showed treatment failure within 5 years from radical mastectomy. The frequency of new disease manifestations was significantly affected by primary treatment, since patients given adjuvant CMF showed a lower tendency to recur in local-regional area(s) and in bone(s). However, in relapsed patients, patterns of new lesions were not substantially altered by type of primary treatment. The most frequently involved sites were soft tissues (37.8%) and bones (37%) followed by viscera (34.2%). Retrospective evaluation of X-rays revealed that in 26.2% of osseous metastases, diagnosis could have been assessed earlier, with a median delay of 4 months (range 1-8). Present analysis also revealed that short-term repeated X-ray examinations yielded findings more controversial than reliable for assessing the exact time of relapse, thus preventing firm conclusions in the presence of suspicious recurrence. A new follow-up schedule after completion of adjuvant chemotherapy is proposed, since on the basis of our experience, in asymptomatic patients frequently repeated examinations are not necessary and some can safely be omitted.
Adjuvant trials ongoing at the Istituto Nazionale Tumori of Milan for operable breast cancer with nodal involvement are reviewed in this paper. In the first trial (cyclophosphamide, methotrexate, 5-fluorouracil [CMF] versus control), the early 5-year results confirm the usefulness of combination chemotherapy in significantly affecting the relapse-free survival (RFS) and total survival rates. The degree of axillary node involvement remains the most important prognostic indicator also in patients receiving adjuvant chemotherapy. The contention concerning the therapeutic effect of CMF in pre- versus postmenopausal women is overcome by the observation that about 80% of patients receiving greater than 85% of the planned dose are surviving relapse free at 5 years regardless of their menopausal status. The 3-year results of the second CMF trial indicate that both RFS and total survival are comparable between the groups receiving 12 or 6 cycles of adjuvant CMF. The results were not affected by drug-induced amenorrhea nor by estrogen receptor status. Provided the percent of dose administered is high, there is probably no real advantage in prolonging CMF chemotherapy beyond the sixth month. However, the results are still preliminary.
The medical records of 84 postmenopausal women treated with oral norethisterone acetate (NTA) for advanced breast cancer have been analyzed retrospectively. Treatment was devoid of significant toxicity. 21 patients were not evaluable for treatment response, either due to insufficient data or inadequate tratment trial. Among the 63 evaluable patients, complete plus partial response was obtained in 21 (33.3%) with a median duration of 10 months. Disease stabilization was observed in 16 patients (25.4%) for a median duration of 5 months, while 26 patients (41.3%) showed progressive disease while on treatment. The best response was observed in women with predominantly soft tissue metastases (CR + PR: 34.9%) and aged over 70 (CR + PR: 48%). The literature on norethisterone acetate is reviewed and compared with the present results. The role of progestational agents in the treatment of advanced mammary carcinoma is discussed.
The value of estrogen receptor (ER) status in the prediction of tumor response to combination chemotherapy was retrospectively analyzed in breast cancer patients selected for prospective controlled trials of chemotherapy (85 with advanced disease and 256 with operable tumors). All patients were previously untreated with either chemotherapy or endocrine therapy, and in all instances drug therapy was applied at the time of primary treatment. The ER status was considered positive in 54% of women with advanced disease and in 70% of women with operable breast tumor and positive axillary nodes, respectively. About 12% of patients were considered to have borderline ER. The response to drug therapy (complete plus partial remission in advanced breast cancer and 3-year relapse-free survival after mastectomy, respectively) was not significantly different between ER+ and ER- tumors. The comparative results of ER+ vs ER- patients were similar whether the cutoff point for ER+ t-mors was greater than 5 or greater than 10 fmol/mg cytosol protein. The present results indicate that in advanced and early breast cancer combination chemotherapy is effective regardless of ER status. Therefore, in the presence of ER+ tumors there is no reason to delay the early administration of effective chemotherapy. This is particularly true both in the presence of rapidly progressing metastatic disease and in the adjuvant setting.
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The medical records of 84 postmenopausal women treated with oral norethisterone acetate (NTA) for advanced breast cancer were retrospectively analyzed. Treatment was devoid of significant toxicity. Twenty-one patients were not evaluable for treatment response either because of insufficient data or inadequate treatment trial. Complete plus partial response was obtained in 21 (33.3%) of the 63 evaluable patients, with a median duration of 10 months. Disease stabilization was observed in 16 (25.4%) patients for a median duration of 5 months, while 26 patients (41.3%) showed progressive disease while on treatment. The best response was observed in women with dominant soft part disease and an age over 70 (CR+PR 48%). The literature on norethisterone acetate is reviewed and compared with present results. The role of progestational agents in the treatment of advanced mammary carcinoma is discussed.
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In hope of reducing the duration of adjuvant treatment in premenopausal patients with operable breast cancer and histologically positive axillary lymph nodes, a prospective controlled study was started in September 1975. A total of 160 patients were randomized to receive 12 cycles of adjuvant CMF, while 165 were allocated to receive 6 cycles. At 3 years from radical mastectomy, the relapse-free survival was 85.4% in the 12-cycle group compared to 82.6% for the 6-cycle subset (P = 0.29). In both treatment groups, the incidence of treatment failure was directly proportional to the number of involved axillary nodes and to the clinical tumor size. Drug-induced amenorrhea as well as estrogen receptor status failed to significantly affect the results obtained. Treatment failures were more often documented in distant sites, while only 4--5% relapse was observed in local-regional areas. Overall survival was also similar for both treatment arms (86.2% vs. 85.1%, P = 0.49). Toxicity was moderate and reversible and no drug-induced neoplasms were so far observed. Present results achieved with 6 cycles of adjuvant CMF appear encouraging. However, they are still too preliminary to recommend the routine use of 6 cycles instead of the classical 12 cycles.
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The updated results are reported of a prospective controlled clinical trial employing combined chemotherapy with cyclophosphamide, methotrexate and fluorouracil (CMF) as adjuvant treatment in patients with operable breast cancer and positive homolateral axillary lymph nodes (N+). At 36 months from surgery, actuarial analysis shows that there is a significant difference in the relapse rate in favor of adjuvant chemotherapy (45.7% in the control group vs. 26.3% in the CMF group). Distant recurrences were the most frequent site of treatment failure and occurred particularly in the skeleton. The therapy was fairly well tolerated. Both the influence of adjunctive therapy on overall survival after mastectomy and the incidence of long-term side effects are still unknown.
In stage IV non-Hodgkin's lymphomas, CVP (cyclophosphamide, vincristine, and prednisone) was randomly compared to ABP (adriamycin, bleomycin, and prednisone). Of 62 patients entered into the study, 57 (CVP 27, ABP 30) were considered evaluable for comparison. In patients with liver and/or marrow involvement a second biopsy was performed to define complete remission (CR). CR occurred in 48% of patients treated with CVP and in 50% of those given ABP. The median duration of CR was 10.5 and 20.5 months, respectively. The difference is not statistically significant. Also, the survival of complete responders was not significantly different between the two treatment groups. After cross-over, secondary treatment with CVP produced an overall response rate of 40% (six of 15), compared to 50% (six of 12) obtained with ABP. In the ABP group, four patients developed a reversible interstitial penumonia. In two other patients, cardiomyopathy (fatal in one) was observed. In conclusion, although complete remission was similar in both groups, cumulative toxicity occurred in few patients given ABP. However, this combination could represent an effective alternative treatment to be used either in CVP failures or sequence with CVP.
Prolonged cyclic combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil was evaluated as adjuvant treatment to radical mastectomy in primary breast cancer with positive axillary lymph nodes. After 27 months of study, treatment occurred in 24 per cent of 179 control patients and in 5.3 per cent of 207 women given combination chemotherapy (P less than 10(-6)), the advantage appearing statistically significant in all subgroups of patients. Patients with four or more positive axillary nodes had a higher per cent of relapses than those with fewer nodes. The initial new clinical manifestations occurred in distant sites in 81.5 per cent of relapsed patients. Long-term chemotherapy produced an acceptable toxicity, thus allowing the administration of a high percentage of drug dosage. These results should be considered with caution, since, at present, the effect of this therapy on survival and possible long-term side effects remain unknown.
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In a series of 121 unselected, previously untreated patients with Hodgkin's disease staging laparoscopy combined with needle bone marrow biopsy detected the presence of extranodal disease in the liver or marrow or both in 9% of the patients. A spleen biopsy yielded positive findings in 13%. Subsequent laparotomy with open marrow biopsy performed in 110 patients with negative liver and marrow findings from the first combined procedure revealed the presence of extranodal hepatic lymphoma in two additional spleens. Surgical marrow biopsy was always interpretey. Although devoid of major complications, biopsy of the spleen is not recommended as a routine procedure in staging laparoscopy. This prospective sequential study confirms that laparoscopy plus needle marrow biopsy is a useful, rapid, safe, and economic procedure to establish stage IV disease in the large majority of patients with nodal involvement. Considering the recent more extensive use of chemotherapy for intermediate stages of Hodgkin's disease, our findings suggest that laparotomy with splenectomy needs a critical re-evaluation as a routine staging procedure for patients with no overt extranodal lymphoma.