Chemotherapy for stage III-IV ovarian cancer: the CAP-regimen in previously untreated patients

Twenty-nine patients with advanced previously untreated epithelial ovarian cancer (FIGO stage III + IV) received induction chemotherapy with CAP (cyclophosphamide 500 mg/m2, adriamycin 50 mg/m2 and cis-platinum 50 mg/m2). Of twenty patients whose post-surgical tumor size was greater than 2 cm, fifteen (75%) achieved objective response. The median duration of complete response is greater than 20 months and the median duration of partial response is greater than 11 months. Among the 75% responders (15 of 20) overall, eleven were determined by surgical evaluation and four by clinical evaluation. The response rate in the present study compares favorably with previously reported studies. Toxicity from the CAP regimen was frequent and often severe but no irreversible side effects or treatment related deaths were observed. It is concluded that the CAP regimen appears to be an effective drug combination against advanced ovarian cancer that may improve overall response and ultimate survival of previously untreated patients.     

Long term results of cyclophosphamide, adriamycin and platinum chemotherapy in advanced epithelial ovarian cancer

Between January 1980 and December 1983, 57 consecutive patients with advanced epithelial ovarian cancer (FIGO Stage IIc n = 5; III n = 45; IV n = 7) were treated with 6 cycles of cyclophosphamide 600 mg/m2, adriamycin 30-45 mg/m2 and platinum 50 mg/m2 (CAP) at 3 weekly intervals. Pathological complete remission (CR) was documented in 10 (18%) and 4 with no residual disease after primary cytoreductive surgery were free from progression (FFP). There were 19 partial remissions (PR) giving a 51% overall response rate. The median duration of CR was 33 months from second look surgery. Median survival (MS) for all patients was 22 months. Multivariate analysis indicated that response to chemotherapy was the most important prognostic factor, with MS for CR of 53 months, PR 23 months and stable or progressive disease 11 months (p = 0.001). Most CR (8 of 10) occurred in patients with minimal residual disease (no single lesion greater than 2.0 cm), but extent of disease, though significant in univariate analysis of prognostic factors was not an independent predictor of survival. Six patients (11%) are alive and tumour free with a minimum follow-up of 7 years. All had FIGO Stage III disease at presentation and four had no residual tumour after primary surgery.     

Chemotherapy of invasive thymoma

Thirty-two patients with stage III or IV invasive thymoma (14 women and 18 men; median age, 40 years) were treated at the Padua Medical Oncology Department from 1977 to 1988. All patients received the following chemotherapy in 4-day courses: 50 mg/m2 of cisplatin intravenously (IV) and 40 mg/m2 of doxorubicin IV on day 1; 0.6 mg/m2 of vincristine IV on day 3; and 700 mg/m2 of cyclophosphamide IV on day 4 (ADOC). The courses were repeated every 3 weeks, and toxic effects were tolerable. The radiologically defined overall clinical response rate (complete plus partial response) was 91% with 47% clinical complete remissions; median time to progression was 11 months (range, 0 to 96) and the median estimated (Kaplan-Meier) progression-free interval was 22 months. Five of the 15 clinical complete remissions were pathologically confirmed at thoracotomy. We believe the ADOC regimen qualifies for adjuvant and preoperative treatment of invasive thymoma due to the high complete response and overall response rates.     

Treatment of advanced and recurrent ovarian carcinoma with cyclophosphamide, doxorubicin, and cisplatin

Forty-seven patients with primary advanced (N = 37) or recurrent ovarian carcinoma (N = 10) completed a 12-month course of CAP chemotherapy or developed progressive disease while on therapy and were evaluated. All patients were treated between August 1, 1977 and August 1, 1982. Cyclophosphamide 400 mg/m2, Adriamycin (doxorubicin) 40 mg/m2, and cisplatin 60 mg/m2, were administered every 4 weeks intravenously. After 8 courses the cisplatin was stopped. The patients then received 500 mg/m2 of cyclophosphamide and 50 mg/m2 of Adriamycin. At the cumulative dose of 450 mg/m2, the Adriamycin was stopped and cyclophosphamide was given at 1 g/m2 alone until the patient had received a total of 12-13 courses from the initiation of the chemotherapy protocol. The cardiac, renal, and hematopoetic toxicity of the regimen was mild to moderate. The median survival of the entire study population was 32 months. The median survival of the patients with primary disease was 36 months. The median survival of patients with recurrent disease was 20 months. There was a significant difference in median survival based on size of the largest lesion prior to initiation of chemotherapy. There was no difference in median survival based on tumor grade or comparing Stage III to Stage IV tumors. The most important aspects of the study appeared to be the length of the median survival of the patients, the fact that all patients who were complete responders and who were considered to have no evidence of disease, have been documented by second look, and the success of secondary treatment after second-look procedures revealed persistent tumor. The authors additionally report the use of weight change as an indicator of tumor response, and the importance of the pelvic examination complimented by fine-needle aspiration in following the course of these patients.     

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.     

Treatment of advanced ovarian cancer with sequential combination chemotherapy

Fifty previously untreated patients with advanced or recurrent ovarian cancer (FIGO Stages III and IV) were treated with alternating combination chemotherapy. This consisted of high-dose doxorubicin (70 mg/m2) and cisplatin (100 mg/m2) alternated with CHF (cyclophosphamide, hexamethylmelamine, and 5-fluorouracil). Toxicity (myelosuppression, nephropathy, and neuropathy) was infrequent and mild. Clinical response rates were high (94% response, 62% complete clinical response), but the majority of patients had residual intraabdominal disease at second-look surgery (75%). Thirteen patients (26%) are alive after 4 years of observation (minimum follow-up). Survival was adversely influenced in patients who were older than 70, had Stage IV disease, residual tumor bulk greater than 2 cm, and who failed to achieve complete clinical remission. The median duration of survival (28 months) and percentage of long-term survivors appear similar to that in other platinum-based chemotherapy studies. Although the role of alternating combination chemotherapy in epithelial ovarian cancer remains undefined, it is likely that an alternate approach will be necessary to markedly improve survival rates for patients with this disease.     

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.     

三药联合化疗和单药拓扑替康二线治疗小细胞肺癌的疗效和安全性比较

  目的  比较顺铂、依托泊苷、伊立替康联合化疗方案和单药拓扑替康二线治疗敏感复发型小细胞肺癌(smalll cell lung cancer, SCLC)的疗效和安全性。  方法  收集2014年9月至2017年9月吉林省肿瘤医院就诊78例患者资料, 筛选敏感复发型小细胞肺癌患者, 其中36例患者给予顺铂、依托泊苷、伊立替康联合化疗方案, 42例患者给予单药拓扑替康化疗。联合化疗组药物用法:顺铂25 mg/m2, 第1天、第8天静脉滴注; 依托泊苷60 mg/m2, 第1、2、3天静脉滴注; 伊立替康90 mg/m2, 第8天静脉滴注, 连续给予5个2周方案的化疗。单药拓扑替康组药物用法:拓扑替康1.5 mg/m2, 第1~5天静脉滴注, 每3周1个周期。评价两组治疗方案的无进展生存时间(progressionfree survival, PFS)、总生存时间(overall survival, OS)及安全性。  结果  联合化疗组中位无进展生存时间(mPFS)5.3个月(95% CI:4.3~ 5.8), 拓扑替康组mPFS 3.2个月(95% CI:2.7~4.0), 差异具有统计学意义(P=0.003 0);联合化疗组中位总生存时间(mOS)16.3个月(95% CI:13.8~19.1), 拓扑替康组mOS 13.1个月, 差异具有统计学意义(P=0.009 7)。联合化疗组和单药拓扑替康组常见的3/4级不良事件主要有中性粒细胞下降[31例(86.1%) vs.28例(66.7%)]、白细胞下降[29例(80.6%) vs.21例(50.0%)]、贫血[26例(72.2%) vs.10例(23.8%)]、血小板下降[13(36.1%) vs.11(26.2%)]。联合化疗组发生1例治疗相关死亡(发热性中性粒细胞下降合并肺部感染), 拓扑替康组无治疗相关的死亡发生。  结论  顺铂、依托泊苷、伊立替康联合化疗方案比单药拓扑替康疗效更好, 可考虑作为敏感复发型SCLC患者二线化疗的备选方案之一。两种化疗方案毒性均可耐受, 但联合化疗组不良事件发生率更高, 应进一步探索更为合适的化疗剂量。      

Human immunodeficiency virus-related non-Hodgkin lymphoma: activity of infusional cyclophosphamide, doxorubicin, and etoposide as second-line chemotherapy in 40 patients.

BACKGROUND: The prognosis of patients with human immunodeficiency virus (HIV)-related non-Hodgkin lymphoma (NHL) is poor. In fact, despite a high complete response (CR) rate, approximately 50% of these patients die from progressive lymphoma. METHODS: From November 1994 to April 2000, the authors treated 40 patients with resistant or recurrent HIV-related NHL with a 96-hour continuous intravenous infusion of cyclophosphamide (187.5 mg/m(2) per day), doxorubicin (12.5 mg/m(2) per day), and etoposide (60 mg/m(2) per day). RESULTS: The median number of cycles administered was two (range, one to six cycles). A CR was documented in 4 of 40 patients (10%), and a partial remission (PR) was documented in 7 of 40 patients (18%). The CR median duration was 6 months (range, 4--30+ months), whereas PRs lasted for 5 months (range, 2--8 months). The overall median survival was 4 months (range, < 1--33 months), and the median survival for responding patients was 10 months. CONCLUSIONS: The current data confirm that infusional cyclophosphamide, doxorubicin, and etoposide is active in patients with refractory or recurrent HIV-related NHL. However, the median survival of these patients remains poor, and the other innovative approaches should be used.     

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.     

Treatment of advanced colon cancer with 5-fluorouracil (NSC19893) versus cyclophosphamide (NSC26271) plus 5-fluorouracil: prognostic aspects of the differential white blood cell count

One hundred twenty-one patients with advanced measurable adenocarcinoma of the colon were randomized for treatment with intravenous 5-fluorouracil (IV 5-FU) alone, 15 mg/kg/week vs. cytoxan, 15 mg/kg/week IV, on day 1 and 5-FU, 15 mg/kg/week IV during weeks 2--5, repeated in a six-week cycle. Age, sex, performance status, and disease free intervals, were comparable in both arms. Response frequency was 11% for treatment with 5-FU alone and 10% for treatment with combination therapy. The median survival time was significantly greater in the 5-FU-alone arm (8.4 months vs. 5.6 months, P less than 0.05). In both arms, survival was correlated with the nadir white blood count (WBC) achieved during therapy (P less than 0.02). Fourteen patients had pretreatment WBC of greater than 12,000/mm3. None of them had fever, bone marrow involvement with tumor, or recognizable infection at study entry. The 14 patients had a median survival time of 2.3 months, significantly shorter than that of patients with normal pretreatment WBC (P less than 0.05). A pretreatment lymphocyte count was available for all patients. No association between this value and either response to chemotherapy or survival time was noted. These results support the superiority of 5-FU to the combination of 5-FU and cytoxan in the treatment of colon carcinoma, and point to the prognostic significance of the pretreatment WBC in this disease.     

Randomized trial of high-dose chemotherapy and autologous hematopoietic stem cell support for high-risk primary breast carcinoma: follow-up at 12 years

BACKGROUND: The authors previously reported results from a randomized trial of standard-dose chemotherapy with combined 5-fluorouracil (1000 mg/m2 per cycle), doxorubicin (50 mg/m2 per cycle), and cyclophosphamide (500 mg/m2 per cycle) (FAC) versus FAC followed by high-dose chemotherapy (HDCT) and autologous stem cell support (ASCS) for patients with high-risk primary breast carcinoma. After a median follow-up of 6.5 years, no significant differences were observed in recurrence-free survival (RFS) or overall survival (OS) between the 2 arms. This report updates the survival analyses. METHODS: Patients with >or=10 positive axillary lymph nodes after primary surgery or >or=4 positive lymph nodes at surgery after neoadjuvant chemotherapy were eligible. All patients were to receive 8 cycles of FAC. Patients were assigned randomly to receive either no further chemotherapy or 2 cycles of combined high-dose cyclophosphamide (5250 mg/m2 per cycle), etoposide (1200 mg/m2 per cycle), and cisplatin (165 mg/m2 per cycle) with ASCS. Primary endpoints were RFS and OS. RFS and OS were calculated by using the Kaplan-Meier method. The log-rank statistic was used to compare treatment arms. RESULTS: Between 1990 and 1997, 78 patients were registered, and 39 patients were assigned randomly to each arm. The median follow-up for all patients who were alive at last follow-up was 142.5 months (range, 45-169 months). An intention-to-treat analysis showed no significant difference between the 2 arms in terms of RFS (at 10 years: 40% with FAC vs. 26% with FAC plus HDCT; P=.11) or OS (at 10 years: 47% with FAC vs. 42% with FAC plus HDCT; P=.13). CONCLUSIONS: With a median follow-up of nearly 12 years for patients who remained alive, this trial continued to demonstrate no RFS or OS advantage for patients with high-risk primary breast carcinoma treated with HDCT after standard-dose FAC chemotherapy.     

Chemotherapy of small-cell carcinoma of lung: a randomized comparison of alternating and sequential combination chemotherapy programs

One hundred forty-seven eligible patients with small-cell carcinoma of the lung (SCCL) have been randomized to receive alternating (A) or sequential (S) combination chemotherapy. Initial treatment was with three cycles of VAM (A) or two cycles of POCC (S). VAM consists of VP16-213 200 mg/m2 intravenously (IV) day 1, Adriamycin (Adria Laboratories, Columbus, Ohio) 50 mg/m2 IV day 1, and methotrexate 30 mg/m2 IV day 1 repeated at 21-day intervals. POCC consists of cyclophosphamide 600 mg/m2 IV days 1 and 8, vincristine 1.5 mg/m2 (maximum, 2 mg) IV days 1 and 8, CCNU 60 mg/m2 po day 1, and procarbazine 100 mg/m2 po days 2 through 15. After initial treatment, all patients received whole brain radiation therapy (3,000 rad/10 fractions/2 wk). Patients with limited disease in addition received irradiation encompassing the tumor, hilar, mediastinal, and supraclavicular regions (5,000 rad/25 fractions/5 wk). After radiation, patients on arm A received POCC alternating with VAM; patients on arm S received POCC until progression when they were to be treated with VAM. The alternating arm was superior with respect to rate of complete remission (CR), median disease-free survival (MDFS), and median survival (MS). The advantage of alternating therapy was not as clearly demonstrated in the limited disease groups when interposition of involved field radiation delayed the initiation of the alternating schedule. In limited disease alone, comparing arm A with arm S, no statistically significant differences were noted. The CR rate was 42% v 54%, MDFS was 14 v 10 months, and MS was 16 v 10 months. In extensive disease, the CR rate was 44% v 20% (P = .03), MDFS was 6 v 4 months (P = .003), and MS was 10 v 7 months (P = .001). Improved treatment outcome in SCCL is achieved when combination chemotherapy regimens of similar effectiveness are administered in an alternating rather than sequential schedule.     

Ifosfamide, paclitaxel and cisplatin first-line chemotherapy in advanced, suboptimally debulked epithelial ovarian cancer.

BACKGROUND: The combination of paclitaxel with a platinum analogue is the preferred chemotherapy regimen in the treatment of advanced epithelial ovarian carcinoma. The alkylating agent ifosfamide has shown activity in refractory or recurrent ovarian cancer. We conducted a Phase II study with the combination of ifosfamide, paclitaxel, and cisplatin for the treatment of newly diagnosed patients with advanced, suboptimally debulked ovarian carcinoma. METHODS: Thirty-five consecutive patients with advanced ovarian carcinoma (International Federation of Gynecology and Obstetrics [FIGO] Stage III or IV) and residual disease larger than 2 cm after staging laparotomy and cytoreductive surgery were treated with paclitaxel, 175 mg/m(2), as a 3-hour intravenous infusion on Day 1, cisplatin 75 mg/m(2) intravenously over 2 hours on Day 2, and ifosfamide 1500 mg/m(2) intravenously over 1 hour on Days 1-3 (with sodium 2-mercaptoethane sulfonate [MESNA] uroprotection). Courses were administered every 3 weeks on an outpatient basis. Granulocyte-colony stimulating factor was given at a dose of 5 microg/kg/day on Days 7-11. RESULTS: Among 26 patients with measurable disease, 22 (85%) achieved an objective response including 15 complete and 7 partial responses. With a minimum follow-up of 46 months, the median overall survival was 52.8 months (range, 5.3-56.6+ mos), whereas the median time to progression for all patients was 22.2 months. The median remission duration for women with measurable disease who responded to treatment was 12.6 months. The treatment was tolerated relatively well without toxic deaths; the most common toxicity was Grade 3 or 4 neutropenia that occurred in 42% of patients. Significant peripheral neuropathy (Grade 2 or higher) developed in 35% of patients. CONCLUSION: The combination of ifosfamide, paclitaxel, and cisplatin is a well-tolerated outpatient regimen with significant activity in the treatment of newly diagnosed FIGO Stage III or IV epithelial ovarian carcinoma. Further evaluation is justified to clearly define the role of ifosfamide as an additional agent to the current platinum and paclitaxel regimens.     

Adriamycin, BCNU, ftorafur chemotherapy of pancreatic and biliary tract cancer.

Twenty-six evaluable patients with disseminated or locally unresectable pancreatic or biliary tract carcinoma received Ftorafur (4 g/m2 iv day 1 and 22 and 2 g/m2 iv day 4 and 26), Adriamycin (60 mg/m1 IV day 1 and 45 mg/m2 iv day 22) and BCNU (150 MG/M2 IV DAY 1) combination chemotherapy (FAB) repeated at 6--8 week intervals. Two (29%) complete and one (14%) partial remissions were observed in 7 patients with biliary carcinoma while 5 of 19 (26%) patients with pancreatic carcinoma achieved partial remissions. Median survival for responding patients was approximately 11 months (range 7--16+) with median survivals of about 6 months (p less than 0.05 and about 3 months (p less than 0.05) for patients with stable and progressive disease. Major drug toxicity was myelosuppression with median lowest granulocyte counts of 1,000/microliters and platelet counts of 88,000/microliters. Approximately 25% of patients required antibiotic therapy for fever of unknown origin or documented infections. Other tolerable drug toxicities included nausea, vomiting and mucositis. The FAB regimen appears quite promising in biliary tract cancer and has efficacy in pancreatic carcinoma that warrants further clinical trials. Because of myelotoxicity observed with this regimen we now recommend a BCNU starting dose of 100 mg/m2 instead of 150 mg/m2.     

A retrospective analysis of patients receiving surgery after chemotherapy for small cell lung cancer.

From 1984 to 1989, 20 of 142 patients with small cell carcinoma of the lung received surgery after intensive chemotherapy alone or chemotherapy combined with thoracic irradiation. All patients giving informed consent and having an Eastern Cooperative Oncology Group (ECOG) performance status 0-1 were included in the present retrospective study. Ages ranged from 37-74 (median 58) years. All patients received 1-10 cycles of chemotherapy intravenously every three or four weeks (PVP: 80 mg cisplatin/m2, 100 mg etoposide/m2 x 3; CAV: 800 mg cyclophosphamide/m2, 50 mg doxorubicin/m2, 1.4 mg vincristine/m2, and other combinations) and were evaluated for surgery 1-27 months after the initial systemic chemotherapy. Clinically, two, three, eleven and for patients were diagnosed as having stages I, II, III and IV disease, respectively at the beginning of treatment. At the time of reevaluation after chemotherapy or chemotherapy plus chest radiotherapy there were one (5%) complete responder, 17 (85%) partial responders, and two (10%) with stable disease. Twenty patients underwent thoracotomy consisting of nine lobectomies and 11 pneumonectomies. Eighteen of the 20 had resectable lesions. According to postoperative pathological findings, there were six, one, seven and two patients with stages I, II, III and IV disease, respectively. In two patients no tumor was demonstrated pathologically. Small cell carcinoma was detected in 15 specimens and three had non-small cell carcinoma. Two of the 20 patients survived for more than five years. The median survival of the 20 patients was 22 months. It would appear that resection is applicable in only a selected subset of patients with small cell carcinoma of the lung.     

Doxorubicin, cyclophosphamide, CCNU, and vincristine with or without cisplatinum in non-small cell lung cancer

To evaluate the role of cisplatinum in the treatment of advanced non-small cell lung cancer, 48 patients received either a doxorubicin (adriamycin) 50 mg/m2 I.V., cyclophosphamide 300 mg/m2 I.V., lomustine (CCNU) 50 mg/m2 p.o., vincristine (oncovin) 1.2 mg/m2 I.V. (ACCO) combination or the same drugs plus cisplatinum 50 mg/m2 I.V. (PACCO) in a prospective sequential trial. No patient had received prior chemotherapy. Patients receiving the two regimens were comparable with regard to median age, performance status, histologic subtype, disease extent, and weight loss. Objective response frequency was only 5% in the initial 20 patients receiving ACCO treatment compared to a response frequency of 28% (7% complete) in the 28 patients receiving cisplatinum in the PACCO treatment arm (p less than 0.06). Patients achieving objective response lived significantly longer than nonresponders (9.1 months vs. 3.8 months, p less than 0.05). Although median survival was similar on the two regimens (6.1 months for ACCO vs. 7.6 months for PACCO), more than four times as many patients were alive after 1 year in the PACCO treatment group (24% vs. 5%). Predominant toxicity consisted of moderately severe nausea and vomiting (63% on PACCO vs. 34% on ACCO, p less than 0.05) and myelosuppression with WBC less than 3,000/mm3 occurring in the majority of patients on both regimens. These results suggest cisplatinum addition to a doxorubicin, cyclophosphamide, lomustine, and vincristine combination may be associated with increased 1-year survival in the non-small cell lung cancer patient population.     

Cyclophosphamide, methotrexate,5-fluorouracil, alternating with adriamycin and mitomycin C in metastatic breast cancer: a pilot study

To explore the clinical applicability of the Goldie and Coldman hypothesis, we treated 28 patients with metastatic breast cancer with alternating non-cross-resistant chemotherapy. The patients received cyclophosphamide, 600 mg/m2, 5-fluorouracil, 600 mg/m2, methotrexate, 40 mg/m2, alternated every three weeks with adriamycin, 60 mg/m2, and mitomycin C, 10 mg/m2. Only one patient had previously received palliative chemotherapy. Six patients had received adjuvant CMF, and 17 patients had been pretreated with endocrine therapy (13 for advanced disease, 4 as adjuvant). Fourteen patients had bone involvement, and 10 had visceral metastases. A mean of 12 cycles was given to 24 evaluable patients. The objective response rate was 67%: 11 patients (46%) achieved complete and 5 (21%) partial remission. Response rate in soft tissues was 83.3%, in bone 50%, in liver 100%, and in lung 80%. The median duration of response was 14 months, with 7 patients still in remission. No life-threatening toxicity was observed. Our preliminary results support the validity of this approach and the efficacy of this combination chemotherapy. A large-scale randomized study is warranted.     

Combination of cisplatin-doxorubicin-cyclophosphamide in adenocarcinoma of unknown primary site: a phase II trial

The purpose of this report is to evaluate toxicity, response, and survival of the cyclophosphamide-doxorubicin-cisplatin (CAP) chemotherapy regimen in patients with adenocarcinoma of unknown primary site (ACUP). Twenty-two patients with ACUP were eligible for this study between June 1992 and April 1999. There were 13 men (59%) and 9 women (41%) with a median age of 53.5 years (range: 29--78 years). Lung (seven), liver (six), vertebral bone site (six), and abdominal nodes (six) were the most common metastatic sites. Treatment consisted of doxorubicin 50 mg/m(2), cyclophosphamide 1,000 mg/m(2), and cisplatin 100 mg/m(2) (CAP), administered every 3 weeks; a total of six courses were planned. Twenty-two patients were assessable for toxicity and 20 patients were assessable for response. Grade III to IV neutropenia was observed in 14 patients (64%); febrile neutropenia occurred in 6 patients (27%) and in 10 cycles (12.5%). Grade III to IV anemia and thrombocytopenia were found in 12 (54.5%) and 9 patients (41%), respectively. Grade III to IV nausea and vomiting was observed in 9 patients (41%). Ten patients, 50% of the assessable population, obtained an objective response, including 3 complete (15%) and 7 partial (35%) responses. The median response duration was 3.9 months (range: 0.5--13.3 months). One patient (5%) had stable disease and 5 patients (25%) had progressive disease. The median overall survival and the median time to progression were 10.7 months (range: 0.4--56.9 months) and 8.8 months (range: 6.6--16.5 months), respectively. The CAP regimen in patients with ACUP had significant activity. This chemotherapy regimen induced a high level of grade III to IV toxicities and could not be considered as a treatment of reference. However, the emergence of long-term survivors among responder patients highlighted the need to search for an active treatment for patients with ACUP.     

Treatment of limited small-cell lung cancer with etoposide and cisplatin alternating with vincristine, doxorubicin, and cyclophosphamide versus concurrent etoposide, vincristine, doxorubicin, and cyclophosphamide and chest radiotherapy: a Southwest Oncology Group Study

The Goldie-Coldman model explaining the kinetics of tumor cell kill and drug resistance has a potential application in designing chemotherapy regimes. In this Southwest Oncology Group (SWOG) trial we tested the alternation of two potentially noncrossresistant drug combinations with a concurrent drug combination in patients with limited small-cell lung cancer. The concurrent drug combination consisted of etoposide (VP-16), 75 mg/m2/intravenously (IV), days 1, 2, and 3; vincristine, 1.0 mg/m2/IV, days 1 and 8; Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), 40 mg/m2/IV, day 1; and cyclophosphamide, 750 mg/m2/IV, day 1 (EVAC). The alternating combination consisted of VP-16, 100 mg/m2/IV, days 1, 2, and 3; and cisplatin (CDDP), 100 mg/m2/IV, day 1, alternating with vincristine, 1.0 mg/m2/IV, days 1 and 8; Adriamycin, 50 mg/m2/IV, day 1; and cyclophosphamide, 750 mg/m2/IV, day 1 (VP-16/CDDP-VAC). Chemotherapy was administered at 3-week intervals for six cycles both before and after chest (5,000 rads/5 weeks) and whole brain radiotherapy (3,000 rads/2 weeks). One hundred ninety-nine patients received EVAC and 201 received the alternating combination. There was no significant difference in the response rate to the initial six cycles of treatment with EVAC (CR, 40%) versus the alternating combination (CR, 38%). There was no significant difference between the best response, EVAC (CR, 48%) and VP-16/CDDP-VAC (CR, 51%). Median survival for all randomized patients on EVAC is 15.1 months versus 16.5 months on the alternating combination (P = .58). Toxicities consisted primarily of bone marrow suppression, anorexia, nausea and vomiting, peripheral neuropathies, and alopecia. As in previous trials, the chest was the most common site of relapse (33%). There were no differences in the incidence and sites of relapse between the two treatment arms. These treatments appear equally effective at inducing remission and prolonging survival in patients with small-cell lung cancer.