Dose-intensive epirubicin-based chemotherapy is superior to an intensive intravenous cyclophosphamide, methotrexate, and fluorouracil regimen in metastatic breast cancer: a randomized multinational study.

PURPOSE: To determine the relative efficacy of a cyclophosphamide epirubicin and fluorouracil (CEF) regimen compared with an intravenous (IV) cyclophosphamide, methotrexate, and fluorouracil (CMF) combination in metastatic breast cancer. PATIENTS AND METHODS: Patients were randomized to receive either CEF (cyclophosphamide 400 mg/m(2) IV, epirubicin 50 mg/m(2) IV, and fluorouracil 500 mg/m(2) IV on days 1 and 8), or CMF (cyclophosphamide 500 mg/m(2) IV, methotrexate 40 mg/m(2) IV, and fluorouracil 600 mg/m(2) IV on days 1 and 8). Treatment was given in 3- to 4-week cycles for a total of six to nine cycles. RESULTS: A total of 460 patients (223 CEF and 237 CMF) were randomized. Overall response rate was superior for CEF than CMF in all randomized patients (57% v 46%, respectively; P =.01) and in the assessable subset (66% v 52%, respectively; P =.005). With a median follow-up of more than 20 months, time to progression (TTP) was significantly longer with CEF than CMF (median 8.9 v 6.3 months, respectively; P =.0064), as was time to treatment failure (TTF) (median 6.2 v 5.0 months, respectively; P =.01). Significant survival differences were not observed between CEF and CMF (median 20.1 v 18.2 months, respectively; P =.23). Granulocytopenia and infections were similar in both arms. Grade 3/4 nausea/vomiting and alopecia were more frequent with CEF, whereas diarrhea was more frequent with CMF. Cardiac toxicity, primarily asymptomatic, required withdrawal from study of 15 patients on CEF (7%) and one patient on CMF. CONCLUSION: This CEF regimen safely provides significantly better tumor control than CMF, manifest as a higher response rate, and longer TTP and TTF, but not survival, when used as first-line chemotherapy for metastatic breast cancer.     

Vincristine, doxorubicin and cyclophosphamide with and without etoposide in limited small cell lung cancer

A total of 80 patients with limited disease of small cell lung cancer were randomized to receive either vincristine 1 mg/m2 (max. 2 mg), doxorubicin 50 mg/m2 and cyclophosphamide 750 mg/m2 (VAC) i.v. on day 1, or the same drugs and etoposide 80 mg/m2 i.v. daily for 3 days (VACE) every 3 weeks for nine courses. Chest irradiation was given in both regimens after the second course. The response rate was 84% for VAC (41% complete responses) and 75% for VACE (46% complete responses). The median survival time was 10 months with VAC regimen, and 14 months with VACE (difference statistically not significant). The median duration of remission was 8 months with VAC and 14 months with VACE (p = 0.03), and the median survival for complete or partial responders was 12 months and 20 months respectively (p = 0.006). Myelosuppression was significantly greater in the VACE group, and there was one treatment related death in the group receiving VACE. In this study the addition of etoposide to VAC improved the duration of response, but did not lead to longer survival of patients with limited disease of small cell lung cancer.     

High-dose cyclophosphamide and 5-fluorouracil versus vincristine, doxorubicin, and cyclophosphamide in advanced carcinoma of the breast. A phase III study of the Piedmont Oncology Association (POA)

Forty-nine patients with advanced carcinoma of the breast who had received no prior chemotherapy were randomized to receive either high-dose cyclophosphamide (C) 1250 mg/M2 intravenously on day 1 and 5-fluorouracil (F) 600 mg/M2 intravenously on days 1 through 5 (CF), or vincristine (V) 1.5 mg/M2, doxorubicin (A) 50 mg/M2 and cyclophosphamide (C) 500 mg/M2 (VAC), all intravenously on day 1. Both regimens were repeated at 3-week intervals. Nine of 25 patients (36%) treated with CF and ten of 21 patients (48%) treated with VAC showed a complete or partial response as defined by the (UICC) guidelines. The estimated median time to progression for all patients was 3.5 months for CF and 6.0 months for VAC, with the median time to progression for responding patients being 8.5 months on CF and 6.3 months on VAC. Estimated survival is also similar for the two regimens. Ten of the patients treated with high-dose CF experienced septic episodes and four died. Toxicity on the CF arm necessitated premature closure of the study, and thus full statistical comparison of the efficacy of the two regimens cannot be made.     

High-dose, continuous-infusion cyclophosphamide, cytarabine, vincristine, and prednisone for remission induction in refractory adult acute leukemia

Fifteen consecutive patients with refractory adult acute leukemia (RAAL) were treated with a combination of high-dose, continuous-infusion cyclophosphamide, cytarabine, vincristine, and prednisone (Hi-COAP). The initial nine patients received cyclophosphamide 350 mg/m2 as a 24-hour intravenous (IV) infusion over 5 days; cytarabine, 100 mg/m2 IV bolus every 12 hours for ten doses; vincristine, 2.0 mg IV bolus on day 1; and prednisone, 100 mg orally for 7 days. The last six patients had the cyclophosphamide infusion lengthened to 7 days, and the cytarabine increased to 14 doses. All patients were evaluable for toxicity and response. Seven patients (47%) obtained a complete remission and six patients (40%) a partial remission. Median duration of all remissions has been 7.0 months with a range of 1 to 32 months. Toxicity has been limited to primarily myelosuppression with no hemorrhagic cystitis, central nervous system (CNS), hepatic, or pulmonary toxicity noted. Gastrointestinal toxicity was mild, with no effect on nutritional status noted. Median duration of complete responders was 8.5 months. Thus, Hi-COAP demonstrates promising efficacy with minimal toxicity in RAAL and warrants further exploration in multiinstitutional trials.     

Neoadjuvant chemotherapy with cyclophosphamide, mitoxantrone, and 5-fluorouracil in locally advanced breast cancer

OBJECTIVES: Our primary objective was to determine the response rate; secondary objectives were to assess the toxicity rate, and disease-free and overall survival rates in patients with locally advanced breast cancer (LABC) receiving a cyclophosphamide (500 mg/m2), mitoxantrone (12 mg/m2) and 5-fluorouracil (500 mg/m2) (CMF) chemotherapy regimen. PATIENTS AND METHODS: The data from 74 patients with LABC with neoadjuvant CMF chemotherapy were analyzed retrospectively. Preoperatively, all patients received 3 cycles of CMF on day 1, repeated every 21 days. In 3 (4.1%) patients, breast-conserving surgery was given and in 71 (95.9%) modified radical mastectomy. All patients received radiotherapy and 3 additional cycles of CMF chemotherapy after surgery. RESULTS: Median age of the patients was 47 years (range: 17-74). 43 patients were premenopausal, whereas 31 were postmenopausal. 54 patients were in stage IIIA, and 20 were in stage IIIB. The overall clinical response rate was 88%; 11 (14.9%) had a complete response, 54 (73%) had a partial response, and 2 (2.8%) had progression. 14 (18.9%) had a pathological complete response. The median follow-up was 62 months. The median disease-free survival was 64.9 months, and the median overall survival was 97.5 months. The 5-year disease-free and overall survival rates were 52% and 79.9%, respectively. Most frequent side-effects were nausea/vomiting, mucositis, alopecia and leukopenia. CONCLUSION: The CMF regimen has a high overall response rate and an acceptable side effect profile in the treatment of locally advanced breast cancer. Further studies are needed to evaluate its effectiveness in breast-conserving strategies.     

A randomised trial comparing combination chemotherapy using mitomycin C, mitozantrone and methotrexate (3M) with vincristine, anthracycline and cyclophosphamide (VAC) in advanced breast cancer

This paper describes a randomised clinical trial in patients with advanced breast cancer, comparing the regimen 3M, mitomycin C 7-8 mg m-2 (day 1), mitozantrone 7-8 mg m-2 (day 1 and 21), methotrexate 35 mg m-2 (day 1 and 21) given on a 42 day cycle with a standard anthracycline containing regimen, VAC, vincristine 1.4 mg m-2 (day 1), anthracycline (adriamycin or epirubicin) 30 mg m-2 (day 1), cyclophosphamide 400 mg m-2 (day 1) given on a 21 day cycle. Of a total of 217 patients, 107 were randomised to 3M and 110 to VAC and a mean of 5.5 courses was given per patient. The overall response rate (complete and partial) was 53% (95% Confidence Limits (CL): 43-62%) for 3M and 49% (CL; 39-58%) for VAC. The response according to sites of metastases was the same for both treatment groups. Symptomatic toxicity including alopecia, neuropathy, vomiting (P less than 0.001) and nausea (P less than 0.01) were significantly less for 3M. Myelosuppression including leucopenia (P less than 0.001) and thrombocytopenia (P less than 0.001) was significantly greater with 3M at day 21, although there was no difference in nadir counts in patients at special risk of myelosuppression and there was no evidence of an increase in infective or bleeding complications. There was no significant difference in the duration of response to 3M (10 months, CL 6-15) and VAC (11 months, CL 7-12), nor in survival (3M, 8 months, CL 6-12; VAC, 10 months, CL 8-12). These results indicate that 3M is as effective as, but has significantly less symptomatic toxicity than, an anthracycline containing regimen for the treatment of advanced breast cancer.     

Low-dose mitomycin and weekly low-dose doxorubicin combination chemotherapy for patients with metastatic breast carcinoma previously treated with cyclophosphamide, methotrexate, and 5-fluorouracil

Forty-four evaluable patients with breast carcinoma previously treated with combination chemotherapy consisting of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) were treated with a combination chemotherapy regimen consisting of doxorubicin (A) (20 mg/m2 on days 1, 8, 15, and 22, repeated every 28 days) and mitomycin (MIT) (10 mg/m2 on day 1, repeated every 28 days). Five patients (11%) achieved a complete remission (CR) and 14 patients (32%) had a partial response (PR). The median duration of survival was 11.5 months and the median duration of response was 8 months for responders (CR and PR). Toxicity was moderate and consisted of neutropenia (74%), thrombocytopenia (25%), pneumonitis (11%), and cardiomyopathy (2%). The combination chemotherapy regimen A and MIT is an effective regimen for treating previously treated with CMF.     

Adjuvant doxorubicin and cyclophosphamide versus cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy in premenopausal women with axillary lymph node positive breast carcinoma

BACKGROUND: This randomized controlled trial was to determine whether a combination chemotherapy regimen that contains anthracycline (doxorubicin and cyclophosphamide [AC]) is superior to the conventional cyclophosphamide, methotrexate, and 5-fluorouracil [CMF] combination in premenopausal women with axillary lymph node positive Stage II breast carcinoma. METHODS: Premenopausal women with lymph node positive breast carcinoma were stratified according to age (younger than 35 or 35 years or older) and the number of positive axillary lymph nodes (1-3, 4-9, or >/= 10) and then randomly assigned to receive either doxorubicin 40 mg/m(2) and cyclophosphamide 600 mg/m(2) intravenously (i.v.) every 3 weeks or cyclophosphamide 100 mg/m(2) orally on Days 1 through 14, methotrexate 40 mg/m(2) and 5-fluorouracil 500 mg/m(2) i.v. on Days 1 and 8 every 4 weeks. Both arms were scheduled for six cycles. RESULTS: The median follow-up was 57 months. Eighteen of the 55 AC patients developed recurrence compared with 16 of the 69 CMF patients. The corresponding 5-year recurrence free survival rates were 64% and 78%, respectively (P = 0.12). The site of the first recurrence for AC patients was locoregional in 7%, distant in 22%, and combined in 4%. The corresponding data for the CMF arm were 4%, 16%, and 3%, respectively. Six AC patients died compared with 9 CMF patients. The corresponding 5-year survival rates were 90% and 86%, respectively (P = 0.96). More leukopenia (52%, mostly Grade 1-2) occurred in the CMF arm than in the AC arm (33%, P = 0.001), but no febrile episode was accompanied with leukopenia. CONCLUSIONS: This study showed no difference between AC and CMF with respect to both disease free and overall survival rates in premenopausal women with axillary lymph node positive breast carcinoma.     

Adriamycin, cyclophosphamide, vincristine and methotrexate combination chemotherapy of small cell lung cancer

Twenty-two patients who had not received previous chemotherapy for small cell lung cancer were treated with a combination of adriamycin (30 mg/m2, i.v., on day 1), cyclophosphamide (500 mg/m2, i.v., on day 1, and 350 mg/m2, i.v., on day 8), vincristine (1 mg/m2, i.v., on day 1) and methotrexate (20 mg/m2, i.v., on days 1 and 8). This chemotherapy regimen was repeated at 3- or 4-week intervals. Among 20 evaluable patients, none showed complete response but 14 (70%) showed a partial response, with a median response duration of 8 weeks (range, 4-20 weeks). The median survival time for the 20 evaluable patients was 28 weeks. Toxicity included mild to moderate hematologic toxicity, alopecia and nausea and vomiting. This combination chemotherapy appears to be suboptimal for the treatment of small cell lung cancer, with no complete responses and a relatively short median survival time.     

Randomized trial to compare the efficacy and toxicity of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) with methotrexate mitoxantrone (MM) in advanced carcinoma of the breast.

One hundred and sixteen patients with locally advanced or metastatic breast cancer were randomized to receive CMF (cyclophosphamide 600 mg m(-2) day 1 and 8 i.v., 5-fluorouracil 600 mg m(-2) day 1 and 8 i.v., methotrexate 40 mg m(-2) day 1 and 8 i.v., monthly for 6 cycles) or MM (methotrexate 30 mg m(-2), mitoxantrone 6.5 mg m(-2), both i.v. day 1 3-weekly for 8 cycles) as first line treatment with chemotherapy. Objective responses occurred in 17 patients out of 58 (29%) who received CMF and nine out of 58 (15%) who received MM; 95% confidence interval for difference in response rates (-1%-29%), P = 0.07. No statistically significant differences were seen in overall survival or time to progression between the two regimes although a tendency towards a shorter progression time on the MM regime must be acknowledged. There was, however, significantly reduced haematological toxicity (P < 0.001) and alopecia (P < 0.001) and fewer dose reductions and delays in patients randomized to MM. No statistically significant differences were seen between the two regimes in terms of quality of life (QOL). However, some association between QOL and toxicity was apparent overall with pooled QOL estimates tending to indicate a worsening in psychological state with increasing maximum toxicity over treatment. Despite the fact that results surrounding response rates and time to progression did not reach statistical significance, their possible compatibility with an improved outcome on CMF treatment must be borne in mind. However, MM is a well-tolerated regimen with fewer side-effects than CMF, which with careful patient management and follow-up, therefore, may merit consideration as a first-line treatment to palliate patients with metastatic breast cancer who are infirm or elderly.     

Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5.

PURPOSE: Certain anthracycline-containing adjuvant chemotherapy regimens are associated with improved relapse-free survival (RFS) and overall survival (OS) compared with the classic regimen of cyclophosphamide, methotrexate, and fluorouracil in women with early-stage breast cancer. PATIENTS AND METHODS: Between 1989 and 1993, 710 pre- and perimenopausal women with axillary node-positive breast cancer were randomly assigned to either cyclophosphamide 75 mg/m(2) orally days 1 through 14, epirubicin 60 mg/m(2) intravenously days 1 and 8, and fluorouracil 500 mg/m(2) intravenously days 1 and 8 (CEF) or CMF (cyclophosphamide 100 mg/m(2) orally days 1 through 14, methotrexate 40 mg/m(2) intravenously days 1 and 8, and fluorouracil 600 mg/m(2) intravenously days 1 and 8). On the basis of follow-up to May 1997 (median follow-up time, 59 months), there was a statistically significant improvement in RFS and OS for CEF compared with CMF. RESULTS: The trial results are now updated, with a median follow-up of 10 years for live patients. The 10-year RFS is 52% for patients who received CEF compared with 45% for CMF patients (hazard ratio [HR] for CMF v CEF = 1.31; stratified log-rank, P = .007). The 10-year OS for patients who received CEF and CMF are 62% and 58%, respectively (HR for CMF v CEF = 1.18; stratified log-rank, P = .085). The rates of acute leukemia have not changed since the original report, whereas the rates of congestive heart failure are slightly higher but acceptable (four patients [1.1%] in the CEF group v one patient [0.3%] in the CMF group). CONCLUSION: The previously demonstrated benefit of CEF compared with CMF adjuvant chemotherapy is maintained with longer follow-up in the MA5 trial.     

Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer.

PURPOSE: To compare a full-dose epirubicin-cyclophosphamide (HEC) regimen with classical cyclophosphamide, methotrexate, and fluorouracil (CMF) therapy and with a moderate-dose epirubicin-cyclophosphamide regimen (EC) in the adjuvant therapy of node-positive breast cancer. PATIENTS AND METHODS: Node-positive breast cancer patients who were aged 70 years or younger were randomly allocated to one of the following treatments: CMF for six cycles (oral cyclophosphamide); EC for eight cycles (epirubicin 60 mg/m(2), cyclophosphamide 500 mg/m(2); day 1 every 3 weeks); and HEC for eight cycles (epirubicin 100 mg/m(2), cyclophosphamide 830 mg/m(2); day 1 every 3 weeks). RESULTS: Two hundred fifty-five, 267, and 255 eligible patients were treated with CMF, EC, and HEC, respectively. Patient characteristics were well balanced among the three arms. One and three cases of congestive heart failure were reported in the EC and HEC arms, respectively. Three cases of acute myeloid leukemia were reported in the HEC arm. After 4 years of median follow-up, no statistically significant differences were observed between HEC and CMF (event-free survival [EFS]: hazards ratio [HR] = 0.96, 95% confidence interval [CI], 0.70 to 1.31, P =.80; distant-EFS: HR = 0.97, 95% CI, 0.70 to 1.34, P =.87; overall survival [OS]: HR = 0.97, 95% CI, 0.65 to 1.44, P =.87). HEC is more effective than EC (EFS: HR = 0.73, 95% CI, 0.54 to 0.99, P =.04; distant-EFS: HR = 0.75, 95% CI, 0.55 to 1.02, P =.06; OS HR = 0.69, 95% CI, 0.47 to 1.00, P =.05). CONCLUSION: This three-arm study does not show an advantage in favor of an adequately dosed epirubicin-based regimen over classical CMF in the adjuvant therapy of node-positive pre- and postmenopausal women with breast cancer. Moreover, this study confirms that there is a dose-response curve for epirubicin in breast cancer adjuvant therapy.     

Low dose chemotherapy of metastatic breast cancer with cyclophosphamide, adriamycin, methotrexate, 5-fluorouracil (CAMF) versus sequential cyclophosphamide, methotrexate, 5-fluorouracil (CMF) and adriamycin.

Seventy-eight advanced breast cancer patients with hormone-resistant disease or visceral metastases were randomized to receive either of two low dose regimens consisting of cyclophosphamide (C), methotrexate (M), 5-fluorouracil (F), and Adriamycin (A) as their initial chemotherapy. One group was treated with CAMF, and the other with CMF until progression, followed by A (CMF leads to A). C was given at 50 mg/m2, po, days 1-14; M at 20 mg/m2, F at 300 mg/m2, and A at 20 mg/m2, iv, days 1 and 8 of each 28-day cycle. The response rates for CAMF vs. CMF did not differ significantly (complete and partial responses-62% vs. 49%; stabilizations-23% vs. 31%). Responses by site of metasis, median times to progression and median survivals were similar for both groups. Poor and good risk partial responders had similar survivals. Twelve percent of CMF patients treated with Adriamycin at the time of progression had partial responses with an associated improved survival. Since CMF is as effective as CAMF, but has less toxicity, low dose therapy with CMF is more acceptable than CAMF as an initial chemotherapy regimen for metastatic breast cancer. Adriamycin may be reserved for subsequent regression induction.     

Carboplatin and Etoposide (Care) Combined with Radiotherapy and Vincristine, Doxorubicin and Cyclophosphamide (Vac) In Limited Small Cell Lung Cancer a Phase Ii Study

Sixty-eight patients with limited small cell lung cancer were treated between April 1988 and October 1990 with combination carboplatin 450 mg/m² i.v. on day 1 and etoposide 100 mg/m² i.v. on days 1-3 (CarE) for two courses, followed by thoracic radiotherapy (TRT) 50 Gy, and then vincristine 1 mg/m², doxorubicin 50 mg/m² and cyclophosphamide 750 mg/m² on day one (VAC) for four courses. Prophylactic cranial irradiation (30 Gy) was given to patients with CR after completion of chemotherapy. Sixty patients (89%) achieved an objective response (40% complete responses). The median time to progression was 8.5 months and median survival time 12.1 months. Predicted one- and two-year survival was 50% and 12% respectively. Myelosuppression was the main toxicity, with WHO grade 3 and 4 leukopenia occurring in 32% of VAC courses. There were 5 (7%) treatment-related deaths, all of them during VAC. We conclude that the present combination is active in terms of response rate, but it did not demonstrate any superiority in survival. The frequency of haematological toxicity was substantial during VAC courses.     

cis-platinum,adriamycin, and hexamethylmelamine versus cyclophosphamide in advanced ovarian carcinoma

Fifty-three evaluable patients with disseminated ovarian carcinoma (FIGO III or IV) not treated with prior chemotherapy were randomized to receive either combination chemotherapy consisting of cis-platinum 40 mg/m2 IV on day 1, adriamycin 40 mg/m2 IV on day 1, and hexamethylmelamine 150 mg/m2 PO on days 2-10 up to a maximum of 200 mg on a 4-weekly cycle, or moderate-dose cyclophosphamide alone 40 mg/kg given IV intermittently every 3 weeks. Entry was from 1. 11. 1978 until 30. 4. 1981 (last follow-up 31. 10. 1981). Pretreatment characteristics in both groups of patients, regarding median age at diagnosis, median time from diagnosis to chemotherapy, FIGO stage, histology, differentiation grade, type of surgery, residual disease, previous radiotherapy, and median performance status, were comparable. Objective responses were seen in 18 of 27 (66%) of patients receiving cyclophosphamide alone (range 5--32+ months) and in 10 of 26 (38%) of patients treated with the combination (range 3--30+ months), this difference being statistically significant (chi 2 = 4.228; P less than 0.05). The median duration of objective response (11 vs 10 months) and the median survival (12 vs 11 months) were greater in the cyclophosphamide group, but these differences were not statistically significant. The toxicity of the combination was more severe. It is concluded that there is no therapeutic advantage for this combination schedule over the alkylating agent used alone.     

Cisplatin, epirubicin and cyclophosphamide (PEC) in the treatment of advanced ovarian cancer

We report the long-term results of a series of patients affected by advanced epithelial ovarian cancer treated with the PEC combination (cisplatin 60 mg/m2, epirubicin 60 mg/m2 and cyclophosphamide 750 mg/m2, all at day 1, every 21 days). Response was evaluated after three cycles, and treatment continued in responsive patients. A total of 80 patients with a median follow-up of 55 months were studied. Fifty-eight patients with stage III ovarian cancer and 22 patients with stage IV received PEC as primary treatment (41 patients), or for residual disease after surgery (37 patients), or for relapsed disease after primary surgery (2 patients). The overall response rate was 67.5% (20.0% complete response, 47.5% partial response), with 22.5% stable disease and 3.7% progressive disease. Median progression free survival was 13.0 months, and median survival was 25 months. Grade III-IV toxicity was moderate: leukopenia 20.0% of patients, thrombocytopenia 5.0%, anemia 16.2%. No cardiac toxicity was observed. In conclusion, the PEC combination, an anthracycline-containing platinum-based regimen, proved to be effective in advanced ovarian cancer, in terms of response rate and overall survival. The regimen was devoid of significant toxicity and in particular of cardiac toxicity.     

Combination chemotherapy with cyclophosphamide, doxorubicin and vincristine in the treatment of stage III-IV small-cell lung cancer

Twenty patients with histologically confirmed small-cell lung cancer were treated with cyclophosphamide 1000 mg/m2 i.v. on day 1, vincristine 1.4 mg/m2 i.v. day 1, and adriamycin 50 mg/m2 i.v. on day 1. This protocol was repeated every 21 days. Out of 17 evaluable patients 2 obtained a complete response (12%) with a mean duration of 11 months, 4 patients achieved a partial response with a mean duration of 6.3+ months, and 1 had a minimal response of 7.2 months. Two patients had a stabilization which lasted a mean of 4+ months, while 8 patients progressed. Although the mean survival was higher in responders than in non-responders, the difference in survival time was not statistically significant. The treatment was quite well tolerated with hematological toxicity in 78% of cases, oral and gastrointestinal toxicity in 83%, alopecia in 78%, and neurotoxicity in 16% of cases.     

Efficacy of topotecan and cyclophosphamide given in a phase II window trial in children with newly diagnosed metastatic rhabdomyosarcoma: a Children's Oncology Group study.

PURPOSE: To determine the antitumor activity and toxicity of topotecan given immediately after cyclophosphamide as window therapy, then in combination with conventional agents in pediatric patients with newly diagnosed metastatic rhabdomyosarcoma (RMS). PATIENTS AND METHODS: Sixty-one patients younger than 21 years with newly diagnosed metastatic RMS or undifferentiated sarcoma were assigned window therapy (weeks 0 to 6) with topotecan (0.75 mg/m(2) daily x 5 every 21 days) immediately after cyclophosphamide (250 mg/m(2) daily x 5 every 21 days; TC). We continued to give these agents in combination with vincristine (VTC) to patients who showed objective improvement, partial response (PR), or complete response (CR) to TC and alternated courses of VTC with vincristine, dactinomycin and cyclophosphamide (VAC) during weeks 6 to 41 (VTC/VAC). Those who showed no response or progressive disease after TC received only VAC. All patients received radiotherapy to sites of unresected disease (weeks 15 to 21). RESULTS: The overall response rate (CR + PR) to TC was 47% (95% CI, 35% to 60%). Tumor size < or = 5 cm was associated with early response. Myelosuppression was the primary toxicity to TC. Overall 3-year disease-free survival and survival were estimated to be 10% (95% CI, 2% to 19%) and 20% (95% CI, 8% to 32%), respectively. Toxicity profiles for patients who received VTC/VAC or VAC alone were comparable. CONCLUSION: Topotecan after cyclophosphamide is a combination that is active against newly diagnosed RMS, with an acceptable toxicity profile. Disease-free survival and overall survival, however, remain disappointing for children with metastatic RMS at diagnosis.     

Sequential administration of cyclophosphamide, methotrexate, 5-fluorouracil, and folinic acid as salvage treatment in metastatic breast cancer

Experimental data show that sequencing methotrexate (MTX) and 5-fluorouracil (5-FU) may result in synergistic antitumor activity. Moreover, the effect of 5-FU is increased by folinic acid (FA), and finally, cyclophosphamide (CPA) produces an expansion of tumor growth fraction, suggesting an increased cytotoxic effect of cycle-specific drugs subsequently administered. Based on these premises, we have performed a Phase II study with CPA (600 mg/m2 i.v., day 1), MTX (200 mg/m2 1-h i.v. infusion, day 7), 5-FU (600 mg/m2 i.v., day 8), and FA (500 mg/m2 2-h i.v. infusion, day 8 plus 15 mg p.o. every 6 h on days 8 and 9) administered every 3 weeks. Thirty-six patients with metastatic breast cancer were admitted into the study. Median age was 52 years, and all but two patients were postmenopausal. Dominant sites of metastases were soft tissues in 10 patients, bones in 7 patients, and viscera in 19 patients. All patients were pretreated with chemo- and/or hormone therapy. Sixteen patients achieved an objective response (44.5%: 1 complete response and 15 partial responses), 8 had stable disease (SD) (22.2%), and 12 progressed (33.3%). Twenty-one patients had previously received conventional CMF in an adjuvant setting (15 patients) or for metastases (6 patients): 1 complete response (CR) and 7 partial responses (PR) were obtained in the first group and 1 in the second. Major toxic effects were hair loss (56.4%), nausea and vomiting (72%), mucositis (52.5%), and leukopenia (61%). A randomized study could be useful to assess the role of sequential CMF versus conventional CMF in metastatic breast cancer patients.     

Fec (Fluorouracil, epirubicin, cyclophosphamide) plus granulocyte macrophage-colony-stimulating factor (gm-csf) in advanced or inflammatory breast-cancer - a dose-finding study

Seven patients with inflammatory and 11 with metastatic breast cancer were treated with high dose FEC chemotherapy plus GM-CSF; 5-fluorouracil and cyclophosphamide were administered at 500 mg/m2/iv/day 1, epirubicin at three dose levels: 100 mg, 120 mg and 140 mg/m2/iv/day 1 every three weeks (six patients per level). GM-CSF was administered at a dosage of 5 mg/kg/sc from day 5 to 12 of each cycle. The overall response rate was 83% (95% CI: 66%-100%) with 22% complete response. The median response duration for patients with metastatic disease was 7 months (range: 4-10). The hematological toxicity was moderate but reversible due to GM-CSF rescue; mucositis represented the dose limiting toxicity. In conclusion, the increase of dose intensity resulted in a higher response rate but not longer response duration, which must be taken into account when administering high-dose chemotherapy with growth factor rescue.