Breast cancer recurrence dynamics following adjuvant CMF is consistent with tumor dormancy and mastectomy-driven acceleration of the metastatic process.

PURPOSE: The aim of this study was to better understand human breast cancer biology by studying how the timing of metastasis following primary resection is affected by adjuvant CMF (cyclophoshamide, methotrexate, 5-fluorouracil) chemotherapy. PATIENTS AND METHODS: Discrete hazards of recurrence and recurrence risk reductions for treated patients relative to controls were analyzed for all patients enrolled in two separate randomized clinical trials [study 1 (386 women): no further treatment versus 12 cycles of CMF; study 2 (459 women): six versus 12 cycles of CMF] and a historical group (396 women: surgery alone) of axillary node-positive patients undergoing mastectomy. RESULTS: (i) Nearly all CMF benefit occurs during the first 4 years following resection/chemotherapy. (ii) The CMF recurrence rate reduction is largely restricted to two specific spans. These temporally separate recurrence clusters occur during the first and third year of follow-up, while the second-year recurrences are weakly affected. (iii) Prolonging adjuvant treatment from 6 to 12 months partially alters this recurrence timing, without appreciably affecting the overall recurrence rate. (iv) These effects upon the dynamics of post-resection occurrence are menopausal status-independent. CONCLUSIONS: At least two different therapeutically vulnerable proliferative events, resulting in clinical appearance of two metastasis temporally distinct clusters of post-resection cancer recurrence, apparently occur during the administration of adjuvant chemotherapy. Metastases that transpire outside of these temporal windows are refractory to adjuvant therapy. The dynamics of both post-treatment recurrence risk and CMF effectiveness are similar for both pre- and postmenopausal women, suggesting that post-resection mechanisms by which chemotherapy prevents metastases are similar, but of different magnitude in pre- and postmenopausal women. These findings are consistent with a metastasis model that includes tumor dormancy in specific micrometastatic phases (single cells and avascular foci) and with the acceleration of the metastatic process by the surgical resection of the primary breast cancer.

Response to cyclophosphamide, methotrexate, and fluorouracil in lymph node-positive breast cancer according to HER2 overexpression and other tumor biologic variables.

PURPOSE: There is considerable interest in biologic markers able to predict the response of cancer patients to therapy. HER2 overexpression is a potential indicator of responsiveness to doxorubicin and paclitaxel and of unresponsiveness to tamoxifen in breast carcinoma patients. However, the significance of HER2 overexpression in responsiveness to cyclophosphamide, methotrexate, and fluorouracil (CMF) has remained unclear. In this study, we investigated this issue in the 386 breast cancer patients in the first CMF controlled clinical trial with a 20-year follow-up. PATIENTS AND METHODS: Node-positive breast carcinoma patients were randomly assigned to receive either no further treatment after radical mastectomy (179 women) or 12 monthly cycles of adjuvant CMF chemotherapy (207 women). Overexpression of HER2 and the status of other tumor variables was assessed by immunohistochemistry in at least 324 (84%) of the 386 patients. Statistical analyses were performed to assess the efficacy of CMF treatment for the subgroups defined by HER2 and the status of other variables using a Bayesian approach. The end points considered were relapse-free survival (RFS) and cause-specific survival (CSS). RESULTS: Bayesian analysis of the treatment effect for HER2 and other variables indicated a clinical benefit from CMF treatment in all subgroups defined according to variables status. In particular regarding HER2 status, Bayesian estimates of RFS hazard ratios were equal to 0.484 and 0.641 and estimates of CSS hazard ratios were equal to 0.495 and 0.730 for HER2-positive and -negative tumors, respectively. CONCLUSION: CMF treatment showed a clinical benefit in the considered subgroups, defined according to HER2 and other tumor variables status. Patients with HER2-positive or HER2-negative tumors benefit from CMF treatment, and the poor prognosis associated with the HER2 overexpression in the untreated group could be completely overcome by the chemotherapy treatment.

Cell proliferation and outcome following doxorubicin plus CMF regimens in node-positive breast cancer.

At the Istituto Nazionale Tumori of Milan, a randomised adjuvant chemotherapy trial was carried out from 1982 to 1990 to compare alternating with sequential regimens of doxorubicin and CMF in 403 patients with more than 3 positive axillary nodes. Tumour proliferative activity was determined in 71% (285 cases) of women entering the clinical study. We investigated the relation between proliferative rate, determined as the [(3)H]thymidine labelling index (TLI) on tumour specimens obtained at diagnostic surgery, and clinical outcome following the 2 regimens, in which the same drugs were administered at the same dose intensity but with a different schedule. A high TLI was significantly associated with 12-year overall relapse (P = 0.009), distant metastasis (P = 0.001), and death (P = 0.002), even in the presence of information provided by tumour size, lymph node involvement, oestrogen receptors, and treatment regimen. The highest relapse-free survival (RFS) probability (45%, 95% CI 34-55%) was observed for patients with tumour TLI <5% and subjected to the sequential treatment. The lowest RFS probability (11%, 95% CI 0-26%) was observed for patients with tumour TLI >9% following the alternating regimen. Intermediate RFS probabilities, ranging from 23% to 34%, were observed for the other kinetic subgroups following the 2 treatment regimens. The benefit of sequential administration of doxorubicin and CMF was evident mainly in patients with tumours at low to intermediate proliferation.

Diffuse large-cell lymphoma of the testis.

PURPOSE: To evaluate clinical outcome of patients with testicular diffuse large-cell lymphoma treated with conventional-dose systemic chemotherapy. PATIENTS AND METHODS: This study is a retrospective analysis of adult patients with testicular diffuse large-cell lymphoma who were treated with a doxorubicin-based chemotherapy regimen at our institution, the Istituto Nazionale Tumori of Milan. Twenty-nine assessable patients, with a median age of 61 years, were identified. Sixteen patients had limited stage (Ann Arbor stage I/II) disease, whereas 13 patients had a testicular mass and distant organ involvement (Ann Arbor stage IV). Patients were retrospectively classified according to the International Prognostic Index. RESULTS: After a median follow-up of 82 months, 22 patients presented disease progression and 22 patients had died. Actuarial median time to treatment failure and overall survival were 44 and 41 months for patients with limited stage and 9 and 16 months for patients with advanced stage, respectively. Eight patients failed initial treatment, and 14 patients relapsed from clinical remission after a median disease-free time of 17 months (range, 6 to 98 months). Median survival time after progression of lymphoma was 5 months (range, 0 to 22 months). In nine (41%) of the 22 failing patients, the initial site of relapse was either the CNS or the contralateral testis; the remaining patients experienced relapse in multiple extranodal sites. CONCLUSION: Poor prognosis of patients with diffuse large-cell lymphoma calls for more effective treatment strategies, such as high-dose chemotherapy programs for younger patients or specifically designed chemotherapy regimens for patients not suitable for high-dose treatment, with the purpose to provide control of both systemic disease and disease of the CNS and contralateral testis. The potential benefit of contralateral testicular irradiation has to be taken into account in the treatment planning.

Comparative analysis of breast cancer recurrence risk for patients receiving or not receiving adjuvant cyclophosphamide, methotrexate, fluorouracil (CMF). Data supporting the occurrence of 'cures'.

PURPOSE: To comparatively analyse the risk of recurrence at given times after surgery for breast cancer patients receiving or not receiving adjuvant CMF. PATIENTS AND METHODS: A total of 1452 node positive patients, who entered controlled clinical trials carried out at the Milan Cancer Institute and underwent radical or modified radical mastectomy for operable breast cancer, were examined. In 575 cases no further treatment was performed, whereas 877 pts were given 6 or 12 courses of adjuvant Cyclophosphamide, Methotrexate, Fluorouracil (CMF). The recurrence risk was estimated by the event-specific hazard rate for first failure and distant metastases, and, following Efron, hazard rates were fitted by logistic regression models. RESULTS: The hazard rate for first failure and distant metastases showed a double peaked pattern for both treated patients and controls, with a first major peak at about 18-24 months from surgery (early metastases), a second minor peak at the 5th-6th year, and a tapered plateau-like tail extending over 10 years from surgery (late metastases). As expected, the recurrence risk of CMF treated patients was lower than the corresponding risk of patients undergoing surgery only. However, the difference was highly evident for early recurrences, while it declined and disappeared afterwards. CONCLUSION: Our findings confirm previous reports on patients not receiving adjuvant chemotherapy, suggesting that the recurrence risk for operable breast cancer has a multipeak pattern. As far as CMF treated patients are concerned, the unchanged peak timing together with the early recurrence risk reduction in comparison to controls are much more consistent with the real nonappearance of some early recurrences (putatively 'cured' patients) than with the delay in their manifestation. As late relapsing patients seem to have at most marginal benefits from adjuvant CMF, ways to recognize patients doomed to have late recurrence and new ways for treating micrometastases resulting in late recurrences are required.

Pilot study of primary chemotherapy with doxorubicin plus paclitaxel in women with locally advanced or operable breast cancer.

A pilot study of primary chemotherapy with bolus doxorubicin plus paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) infused over 3 hours was performed in 38 women with locally advanced and 41 with stage II/III breast cancer. Patients received four cycles of primary chemotherapy followed by surgery and treatment with cyclophosphamide/methotrexate/5-fluorouracil for six cycles. Preliminary data are available on 73 patients. Doxorubicin plus paclitaxel was well tolerated. Primary toxicity consisted of grade 1 or 2 reversible peripheral neuropathy and grade 3 alopecia. After a median follow-up of 13 months, none of the patients have developed cardiac toxicity or any significant alteration of the left ventricular ejection fraction, which was measured before treatment, at each cycle of doxorubicin plus paclitaxel, and every 3 months thereafter. Major clinical response of the breast tumor was observed in 88% of patients. At pathologic examination of the surgical specimen, 40% were pT1, 15% had no macroscopic tumor residue, and 7% had complete disappearance of invasive neoplastic cells. After a median follow-up of 17 months for patients with locally advanced breast cancer, freedom from progression was 67%, disease-free survival was 71%, and overall survival was 74%. The same end points were 100% for patients with stage II/III disease, with a shorter median follow-up of 10 months. In conclusion, doxorubicin plus paclitaxel is safe, feasible, and effective, and can be used as primary or adjuvant chemotherapy to assess its actual therapeutic role in women with early breast cancer.

Adjuvant cyclophosphamide, methotrexate and fluorouracil in node-negative and estrogen receptor-negative breast cancer. Updated results.

BACKGROUND: Node-negative breast cancers are considered to comprise a subgroup which is amenable to cure with local-regional therapy alone. However, approximately 30% of affected patients present new disease manifestations within 10 years after surgery. To test the hypothesis that node-negative and estrogen receptor-negative breast cancer patients can benefit from adjuvant chemotherapy, a prospective randomized study was activated at the Istituto Nazionale Tumori of Milan in 1980. PATIENTS AND METHODS: The study was conducted in 90 patients operated on for unilateral breast cancer who were then assigned to receive either 12 intravenous cycles of cyclophosphamide, methotrexate and fluorouracil (CMF) every three weeks, or no further treatment. Adjuvant chemotherapy was administered in the outpatient clinic of the Division of Medical Oncology. Patient characteristics were fairly well balanced between the two treatment groups except for primary tumor size: 58% of those with a primary tumor measuring > 2 cm in its largest diameter were randomized in the control group compared with 38% in the CMF regimen (P = 0.06). RESULTS: At 12 years after surgery treatment outcome was significantly superior for patients given adjuvant CMF. The relapse-free survival rate was 71% (95% confidence limits (CL): 56-86) versus 43% (95% CL: 28-58), and total survival was 80% (95% CL: 68-92) versus 50% (95% CL: 34-66), respectively. The benefit from the administration of CMF was evident in all patient subsets and was not influenced by menopausal status. CONCLUSIONS: The long-term results of this trial of adjuvant combination chemotherapy confirm our previous observations on the efficacy of adjuvant chemotherapy in node-negative breast cancer patients at high risk of early disease relapse.

Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up.

BACKGROUND: Adjuvant combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil was administered after radical mastectomy for primary breast cancer with histologically positive axillary lymph nodes to assess whether it would improve treatment outcome as compared with surgery alone. Here we report a 20-year follow-up of this investigation. METHODS: In 1973 we began a trial involving 386 women who were randomly assigned to receive either no further treatment after radical mastectomy (179 women) or 12 monthly cycles of adjuvant combination chemotherapy (207 women). All patients were admitted to the Istituto Nazionale Tumori in Milan, Italy. Adjuvant chemotherapy was delivered in the outpatient clinic of the Division of Medical Oncology. RESULTS: After a median follow-up of 19.4 years, the patients given adjuvant combination chemotherapy had significantly better rates of relapse-free survival (unadjusted relative risk of relapse, 0.71; 95 percent confidence interval, 0.56 to 0.90; P = 0.004; adjusted relative risk, 0.65, 95 percent confidence interval, 0.51 to 0.83; P < 0.001) and total survival (unadjusted relative risk of death, 0.78; 95 percent confidence interval, 0.62 to 0.99; P = 0.04; adjusted relative risk, 0.76; 95 percent confidence interval, 0.60 to 0.97; P = 0.03). With the exception of postmenopausal women, a benefit from adjuvant chemotherapy was evident in all subgroups of patients. CONCLUSIONS: The long-term results of this trial of adjuvant combination chemotherapy confirm our preliminary observations of the effectiveness of the treatment in women with node-positive breast cancer.

Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes. Ten-year results.

OBJECTIVE: To improve current adjuvant results in patients with resectable mammary carcinoma and more than three positive axillary lymph nodes. DESIGN: A prospective randomized study was carried out to compare the effectiveness of four courses of doxorubicin hydrochloride followed by eight courses of cyclophosphamide, methotrexate, and fluorouracil (CMF) (sequential regimen) vs two courses of CMF alternated with one course of doxorubicin for a total of 12 courses (alternating regimen). All drug courses were recycled every 3 weeks. The median duration of follow-up at the time of current analysis was 9 years. SETTING: The study was conducted on patients operated on for primary unilateral breast cancer at the Istituto Nazionale Tumori of Milan, Italy. Adjuvant chemotherapy was delivered in the outpatient clinic of the Division of Medical Oncology. PATIENTS: A total of 405 women were entered into the study, 403 of whom met the protocol criteria. Patient characteristics were fairly well balanced between the two treatment groups, with the exception of extent of nodal involvement: 38% with more than 10 positive nodes were randomized to the alternating regimen compared with 29% in the sequential regimen (P = .08). MAIN OUTCOME MEASURE: Relapse-free and total survival at 10 years after surgery estimated according to the Kaplan-Meier product limit method. RESULTS: Treatment outcome was significantly superior for patients who received the sequential regimen compared with those given the alternating chemotherapy. The relapse-free survival was 42% vs 28% (P = .002) and total survival was 58% vs 44% (P = .002), respectively. The benefit of the sequential regimen was evident in all patient subsets. Treatment was fairly well tolerated, but we documented four cases of congestive heart failure, which was fatal in two patients. CONCLUSIONS: Current findings indicate that in women with extensive nodal involvement, sequential chemotherapy with doxorubicin followed by CMF yields superior results compared with the alternating administration of the same regimens or with classical CMF.

Second malignancies following CMF-based adjuvant chemotherapy in resectable breast cancer.

BACKGROUND: Only a few studies have evaluated the long-term effects of adjuvant chemotherapy for breast cancer. Furthermore, neither the relation between the risk of second malignancies and type of adjuvant regimen utilized nor the interaction between chemotherapy and breast irradiation or age of the patients have been described in detail. METHODS: A total of 2,465 patients entered into prospective studies of CMF-based adjuvant chemotherapy carried out at the Milan Cancer Institute between June 1973 and July 1990 were evaluated. The median follow-up was 12.0 years and detailed information about therapy was available for all patients. RESULTS: At 15 years, the cumulative actuarial risk of second malignancies (excluding contralateral breast cancer and basal skin cancer) was 6.7% +/- 0.8% for the total series. The figures were 8.4% +/- 2.9% after local-regional treatment alone, 6.4% +/- 0.9% following CMF, and 5.1% +/- 1.0% following CMF plus Adriamycin (doxorubicin; Farmitalia-Carlo Erba, Milan, Italy). Compared to the general female population, the relative risk following CMF-based adjuvant chemotherapy was 1.29. Three patients, all of whom had received CMF-based chemotherapy, developed acute non-lymphocytic leukemia (cumulative risk 0.23% +/- 0.15%; relative risk 2.3). No differences were evident when breast irradiation was considered, but the cumulative risk of second tumors was slightly higher in women aged > or = 50 years at surgery (7.7% +/- 1.3%) than in younger patients (6.0% +/- 1.0%). CONCLUSIONS: At present, there is no evidence of a significantly increased risk of second malignancies following adjuvant CMF-based chemotherapy such as the one given in this case series. A low risk of acute leukemia was associated with the cumulative total dose of cyclophosphamide administered, and breast irradiation did not enhance this risk. IMPLICATIONS: Our findings suggest that there is no reason to omit alkylating agents from short-term effective adjuvant chemotherapy.

Adjuvant CMF for node-negative and estrogen receptor-negative breast cancer patients.

From December 1980 to September 1985, a total of 90 eligible patients with stage T1-3a, node-negative, and estrogen receptor-negative (less than or equal to 10 fmol/mg of cytosol protein) tumors were entered into a randomized study to assess the effectiveness of adjuvant intravenous (IV) cyclophosphamide, methotrexate, and fluorouracil (CMF) in a subset of patients at high risk of early disease relapse. High values of [3H]thymidine labeling index were documented in two thirds of 62 assessed specimens from the patient population, and one half of the patients had histologically undifferentiated tumors. Patients were allocated to either local-regional modality alone (control group, 45 women) or to CMF (45 patients) after surgery. A full dose of CMF (600 mg/m2 each of cyclophosphamide and fluorouracil, and 40 mg/m2 of methotrexate) was administered IV on day 1, and then repeated every 3 weeks for a total of 12 treatments. After a median follow-up of 80 months, the 7-year results confirmed the superiority of adjuvant CMF compared to local-regional modality alone (relapse-free survival 85% vs 42%, P = .0001; total survival 86% vs 58%, P = .006). A benefit from adjuvant CMF was observed in all subgroups, and the rates of both local-regional and distant failure were decreased. Treatment was fairly well tolerated and devoid of life-threatening toxicity. Present results confirm our previous observation concerning the dismal prognosis of node-negative and estrogen receptor-negative breast cancer patients as well as the beneficial effect of adjuvant chemotherapy in this selected subset.

Adjuvant chemotherapy with doxorubicin plus cyclophosphamide, methotrexate, and fluorouracil in the treatment of resectable breast cancer with more than three positive axillary nodes.

To improve current adjuvant results in high-risk breast cancer, in February 1982 we activated a prospective randomized trial using both intravenous cyclophosphamide, methotrexate, and fluorouracil (CMF) and Adriamycin (doxorubicin; Farmitalia-Carlo Erba, Milan, Italy) involving patients with resectable mammary carcinoma and more than three positive axillary lymph nodes. The objective of the study was to assess the effectiveness of four courses of Adriamycin followed by eight courses of CMF versus two courses of CMF alternated with one course of Adriamycin for a total of 12 courses. All drug courses were recycled every 3 weeks. Rather than temporarily reducing doses in the event of myelosuppression on the planned day of treatment, drug administration was delayed for 1 to 2 weeks. At a median follow-up of 59 months, treatment outcome was significantly superior for patients who received Adriamycin followed by CMF (Adriamycin----CMF) than for those given alternating regimens (CMF/Adriamycin). The 5-year relapse-free survival was superior post-Adriamycin----CMF (61%) compared with post-CMF/Adriamycin administration (38%; P = .001). The corresponding figures for the 5-year total survival were 78% and 62%, respectively (P = .005). The benefit of Adriamycin----CMF was observed in all patient subsets. Treatment was fairly well tolerated, and we documented only one case of fatal congestive heart failure in a patient who received postoperative irradiation to the left breast in addition to Adriamycin. Present findings indicate that in women with extensive nodal involvement, Adriamycin----CMF yielded superior results compared with CMF/Adriamycin.

Cyclophosphamide, methotrexate, and fluorouracil with and without doxorubicin in the adjuvant treatment of resectable breast cancer with one to three positive axillary nodes.

In the attempt to improve current adjuvant results in patients with one to three positive axillary lymph nodes, in November 1981 we activated a prospective randomized study to assess the effectiveness of intravenous (IV) cyclophosphamide, methotrexate, and fluorouracil (CMF) for 12 courses versus CMF for eight courses followed by Adriamycin (doxorubicin; Farmitalia Carlo Erba, Milan, Italy) for four courses. The 5-year results were evaluated in a total of 486 patients entered into the study up to December 1987. CMF chemotherapy was delivered IV for a total of 12 courses when given alone and for eight courses when followed by four courses of Adriamycin. All drugs were recycled every 3 weeks. Rather than temporarily reducing doses, drug administration was delayed for 1 to 2 weeks in the face of myelosuppression on the planned day of treatment. After a median follow-up of 61 months, no significant differences were evident between the treatment groups in terms of relapse-free (CMF 74% v CMF followed by Adriamycin 72%) and total survival (CMF 89% v CMF followed by Adriamycin 86%). Drug treatments were fairly well tolerated and devoid of life-threatening toxicity. Present results, which were not influenced by menopausal status, indicate that Adriamycin given after CMF failed to improve treatment outcome over CMF alone. However, the role of Adriamycin in an adjuvant setting remains to be further clarified. Considering the good 5-year results achieved in this study at the expense of minimal toxicity, full-dose CMF remains, at present, the adjuvant chemotherapy of choice for patients with one to three positive nodes.

Comparison of different trials of adjuvant chemotherapy in stage II breast cancer using a natural history data base.

Prognostic factors and treatment were analyzed for 2,578 patients to assess the impact of various forms of adjuvant chemotherapy on the natural history of operable stage II (node-positive) breast cancer. The outcome after surgery alone (or with radiotherapy) was determined in 1,014 patients in the natural history data base (NHDB). Adjuvant chemotherapy consisted of L-phenylalanine mustard (L-PAM; 130 patients); cyclophosphamide, methotrexate, and 5-fluorouracil (CMF; 645 patients); doxorubicin and cyclophosphamide (AC; 241 patients); CMF plus vincristine and prednisone (CMFVP; 263 patients); and 5-fluorouracil plus AC (FAC; 285 patients). L-PAM had minimal effect on relapse-free survival (RFS) compared to the NHDB, but all combination chemotherapy programs significantly improved RFS and survival compared to the NHDB. In women with 1-3 positive nodes, all combination chemotherapy programs produced similar results. In women with 4-9 positive nodes, the FAC regimen appeared to be associated with superior RFS compared to other programs, but all were superior to the NHDB. In women with 10 or more positive nodes, FAC was the only regimen associated with improved RFS. The use of a NHDB and known pretreatment characteristics, such as nodal status and tumor size, permits comparison of patients at similar risk of recurrence of breast cancer who have received adjuvant chemotherapy and provides leads for evaluation in future prospective clinical trials.

Development and use of a natural history data base of breast cancer studies.

Pretreatment information, type of treatment, and longitudinal follow-up on 1,971 patients with operable breast cancer were used to establish a breast cancer natural history data base (NHDB). Data were available for 957 patients with stage I (node-negative) breast cancer and 1,014 stage II (node-positive) patients. In women with negative nodes, information was available on 759 patients treated at the Milan National Cancer Institute and 188 patients treated at the Royal Marsden Hospital. After adjustment for differences in the distribution of patient prognostic factors, relapse-free survival and overall survival were not significantly different. Of the 1,014 node-positive patients, 540 were treated at the Milan National Cancer Institute, 258 at the Royal Marsden, and 216 at the M. D. Anderson Hospital. Relapse-free survival and overall survival did not significantly differ between Milan patients and those treated at the Royal Marsden Hospital. However, M. D. Anderson Hospital patients did have significantly better relapse-free and overall survival. In each institution, outcome was consistently most dependent on the number of involved axillary lymph nodes and tumor size. Also, similar patterns of survival were observed for each of the institutions. The development of an NHDB can be of value in the identification and evaluation of consistency of prognostic factors, permitting improved comparisons between clinical trials. The development of such a natural history data base (NHDB) provides a reference for assessing the impact of different adjuvant chemotherapy programs, and aids in the design of new protocols.