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BACKGROUND The authors performed a randomized trial comprising patients with metastatic breast carcinoma (MBC). They used a noninferiority design to evaluate whether the results of sequential administration of epirubicin and paclitaxel were not markedly worse than the concomitant administration in terms of objective response rates (ORRs). Toxicity profile, quality of life (QOL), and pharmacoeconomic evaluations were evaluated as well. METHODS In the current study, 202 patients with MBC were randomized to receive either the combination of epirubicin at a dose of 90 mg/m2 plus paclitaxel at a dose of 200 mg/m2 for 8 cycles (concomitant arm, n = 108) or epirubicin at a dose of 120 mg/m2 for 4 cycles followed by paclitaxel at a dose of 250 mg/m2 over 3 hours for 4 cycles every 21 days (sequential arm, n = 94). RESULTS The authors rejected the null hypothesis that the sequential treatment is less active than the standard concomitant regimen (ORRs: concomitant = 58.5%, sequential = 57.6%). The median progression-free and overall survival periods were 11.0 months (95% confidence interval [95% CI], 9.7–12.3) and 20.0 months (95% CI, 17.2–22.6), respectively, in the concomitant arm and 10.8 months (95% CI, 7.9–13.6) and 26 months (95% CI, 18.1–33.8), respectively, in the sequential arm (P = not significant). Patients who received the sequential regimen experienced a higher incidence of Grade 3/4 (according to the World Health Organization grading system) neutropenia (62.2% of courses vs. 50.62%; P = 0.003) and Grade ≥ 2 neuropathy (45.5% vs. 30.4% of patients; P = 0.03), whereas 6 patients who received the concomitant regimen developed Grade II cardiotoxicity according to New York Heart Association criteria. QOL analyses failed to provide clear differences. CONCLUSIONS The sequential administration of epirubicin and paclitaxel at full doses was found to be as active as their association. Therefore, both the sequential and the combined administration were acceptable options. Cancer 2004. © 2004 American Cancer Society.

87 patients with high risk of recurrence FIGO stage I and II ovarian carcinoma were treated with adjuvant chemotherapy consisting of cisplatin 50 mg/m2 plus cyclophosphamide 600 mg/m2 on day 1 every 28 days for 6 courses. Toxicity and efficacy of the regimen was evaluated after a median follow-up of 45 months. Treatment-related toxicity was mild and reversible, consisting chiefly of acute WHO grade 2 myelosuppression (10% of patients) and controllable grade 3 emesis (55%). No late toxicity was observed. Actuarial 7-year survival and relapse-free survival (RFS) were 76% and 61%, respectively; a statistically significant difference in outcome was observed for undifferentiated grade tumour (G1 vs. G2 vs. G3: P less than 0.01) but not for FIGO stage disease (stage I vs. stage II). In our opinion, short-term chemotherapy including the most active single agent, i.e. cisplatin, appears a tolerable and effective treatment which deserves further evaluation in large randomised trials.

The aim of the study was to evaluate cardiac safety of two different schedules of Epirubicin and Paclitaxel in advanced breast cancer patients enrolled into a multicenter randomized phase III trial. Patients received Epirubicin 90 mg m(-2) plus Paclitaxel 200 mg m(-2) (3-h infusion) on day 1 every 3 weeks for eight courses (arm A), or Epirubicin 120 mg m(-2) on day 1 every 3 weeks for four courses followed by four courses of Paclitaxel 250 mg m(-2) on day 1 every 3 weeks (arm B). Left ventricular ejection fraction was evaluated by bidimesional echocardiography at baseline, after four and eight courses of chemotherapy and every 4 months during follow-up. Baseline median left ventricular ejection fraction was 60% in arm A and 65% in arm B; after four courses, figures were 57 and 60%, respectively. After eight courses, the median left ventricular ejection fraction in arm A declined to 50% while no further reduction was detected in arm B by adding four courses of high-dose Paclitaxel. Seven episodes of congestive heart failure were observed during treatment in arm A. Present monitoring demonstrated that the risk of congestive heart failure or impairment in the cardiac function correlated only with the cumulative dose of Epirubicin; no impact on cardiotoxicity can be attributed to high-dose Paclitaxel.

PURPOSE: To evaluate whether an accelerated-intensified cyclophosphamide, epirubicin, and fluorouracil (CEF) chemotherapy regimen with the support of granulocyte colony-stimulating factor (G-CSF) induces a higher activity and efficacy compared with standard CEF in metastatic breast cancer patients. PATIENTS AND METHODS: Stage IV breast cancer patients were randomized to receive as first-line chemotherapy either standard CEF (cyclophosphamide 600 mg/m2, epirubicin 60 mg/m2, and fluorouracil 600 mg/m2) administered every 21 days (CEF21) or accelerated-intensified CEF (cyclophosphamide 1,000 mg/m2, epirubicin 80 mg/m2, and fluorouracil 600 mg/m2) administered every 14 days (HD-CEF14) with the support of G-CSF. Treatment was administered for eight cycles. RESULTS: A total of 151 patients were randomized (74 patients on the CEF21 arm and 77 on the HD-CEF14 arm). In both arms, the median number of administered cycles was eight. The dose-intensity actually administered was 93% and 86% of that planned, in CEF21- and HD-CEF14–treated patients, respectively. Compared with the CEF21 arm, the dose-intensity increase in the HD-CEF14 arm was 80%. Both nonhematologic and hematologic toxicities were higher in the HD-CEF14 arm than in the CEF21 arm. During chemotherapy, four deaths occurred in the HD-CEF14 arm. No difference in overall response rate (complete plus partial responses) was observed: 49% and 51% in the CEF21 and HD-CEF14 arms, respectively (P = .94). A slightly non–statistically significant higher percentage of complete response was observed in the HD-CEF14 arm (20% v 15%). No difference in efficacy was observed. The median time to progression was 14.3 and 12.8 months in the CEF21 and HD-CEF14 arms, respectively (P = .69). Median overall survival was 32.7 and 27.2 months in the CEF21 and HD-CEF14 arms, respectively (P = .16). CONCLUSION: In metastatic breast cancer patients, an 80% increase in dose-intensity of the CEF regimen, obtained by both acceleration and dose intensification, does not improve the activity and the efficacy compared with a standard dose-intensity CEF regimen.

From 1982 through 1996, 547 untreated advanced ovarian cancer patients were entered onto Gruppo Oncologico Nord-Ovest (GONO) consecutive randomized trials including cisplatin-based chemotherapy. End points of analysis included the influence of age on prognosis, toxicity, clinical/surgical response rates, progression-free survival and survival. Of the entire study group, 116 patients were 65 years of age or older at diagnosis. WHO main toxicity (any grade) consisted of: emesis (93% of patients), myelotoxicity (leukopenia in 52%, anemia in 51% and thrombocytopenia in 17% of patients), nephrotoxicity in 13% of patients and neurotoxicity in 10% of patients. No significant difference in toxicity was evident between patientsor = or65 years. Refusal of CT and early (or =2 courses) interruption of CT due to toxicity were more frequent in elderly patients (3.4 vs. 1.4%; 3.4 vs. 0.7%, respectively). After a median follow-up of 71 months no difference was observed in survival and progression-free survival between younger and older patients. Cox multiple regression analysis of the entire study population demonstrated that age65 years per se was not a negative prognostic factor.

Intraperitoneal chemotherapy has a strong biological and pharmacological rationale in the treatment of ovarian cancer. From 1989 to 1996 the present study included 113 patients with FIGO stage II-IV ovarian cancer with residual disease less than 2 cm who were randomly allocated to receive 50 mg/m(2) intraperitoneal cisplatin (CDDP) plus 60 mg/m(2) intravenous epidoxorubicin (EPIDOX) and 600 mg/m(2) intravenous cyclophosphamide (CTX) (ipPEC arm) or 50 mg/m(2) intravenous CDDP plus 60 mg/m(2) intravenous EPIDOX and 600 mg/m(2) intravenous CTX (ivPEC arm). Chemotherapy was repeated every 4 weeks for six cycles. Treatment protocol was changed in 22 patients, 2 from the iv arm (who received single-agent carboplatin) and 20 from the ip arm (who were crossed to systemic chemotherapy, ivPEC, or single-agent carboplatin). At the end of chemotherapy, a second-look was performed in 33 of the 54 patients from the ip arm and in 34 of the 57 patients from the systemic arm. The pathologic complete response rate was 41% of all entered patients and 69% of patients submitted to second-look. No significant difference in pathologic response rate as well as in hematologic and nonhematologic toxicities was seen between the two arms. Up to September 1998, 72 patients showed a disease recurrence (33 treated with ipPEC and 39 treated with ivPEC), 55 died (22 ipPEC and 30 ivPEC), and 10 were lost to follow-up (6 ipPEC and 4 ivPEC). Median progression-free survival was 42 and 25 months for ipPEC and ivPEC, respectively (p = 0.13). Median overall survival was 67 and 51 months for ipPEC and ivPEC, respectively (p = 0.14). In conclusion, besides confirming that intraperitoneal chemotherapy is feasible with acceptable toxicity but with poor compliance in community hospitals, this trial showed that intraperitoneal CDDP compared with intravenous CDDP in combination with EPIDOX and CTX obtained a slight (not significant) improvement in progression-free survival and overall survival of optimally cytoreduced advanced ovarian cancer patients.

In order to better explore the toxicity and the activity of high dose epirubicin (120 mg/m2, 3 weeks) we analyzed a population of 127 metastatic breast cancer patients, treated in a randomized clinical trial conducted to evaluate the cardioprotective effect of dexrazoxane against epirubicin induced cardiotoxicity. All the patients had a diagnosis of metastatic breast cancer, an ECOG performance status < or = 2 and normal hematologic, renal, hepatic and cardiac function. No prior adjuvant chemotherapy including anthracycline was allowed. Epirubicin was given at the dose of 120 mg/m2 i.v. bolus every 3 weeks. One hundred twenty five patients were evaluable for toxicity and response. Seventeen patients (11%) had a complete response and 47 patients (37%) a partial response, for an overall response rate of 48%. The median progression free and overall survivals were 8.3 months and 18.3 months, respectively. Grade 3 and 4 leukopenia were observed in 8% and 7% of the patients, respectively. The most frequent nonhematological grade 3 toxicities were alopecia (87%), nausea and vomiting (16%), and mucositis (8%). Cardiotoxicity, defined as occurrence of congestive heart failure, decrease in resting left ventricular ejection fraction (L-VEF) to < or = 45%, or 20 EF units decrease from baseline L-VEF, was observed in 19% of the patients, after a median cumulative dose of epirubicin of 720 mg/m2 (range 120-1440). This study confirms in a large series of patients the activity of high dose epirubicin; however, the high incidence of cardiotoxicity requires a careful evaluation of cardiac risk factors before treatment.

From 1979 to 1984, 127 patients operated on for ovarian cancer underwent pelvic, para-aortic, or pelvic and para-aortic lymph node sampling. Forty-seven patients proved to be stage I (14 IA and 33 IC), 14 were stage II (3 IIA, 8 IIB, and 3 IIC), 58 were stage III (7 IIIA, 13 IIIB, and 38 IIIC), and 8 were stage IV. Positive lymph nodes were found in 4.2% of patients at stage I, 35.7% at stage II, 41.3% at stage III, and 87.5% at stage IV. With regard to grading, positive lymph nodes were found in 4.4% of G1, in 21.6% of G2, and in 49.1% of G3. A significant increase in survival ( P = 0.04) was found for patients classified as stage IIIC only according to lymph node involvement compared to patients in peritoneal stage IIIC with positive lymph nodes (3-year survival: 46% vs 12%). A small increase in survival was observed for N− patients compared to N+ patients, at both stage III and IV, even with same residual tumor size, but the difference is not statistically significant. All other things being equal, because the prevalence of lymph node positivity depends closely on the number of lymph nodes removed and examined (OR = 3.9 for >10 lymph nodes removed compared to 1–5 lymph nodes removed), lymph node sampling does not seem to be a reliable method for evaluating the retroperitoneal status. With regard to the therapeutic role of systematic lymphadenectomy, few data in literature are available and, most important, are not derived from experimental studies. Probably, only randomized studies with a large number of patients will provide useful answers.

Summary Background: This phase HI study was carried out to verify whether a kinetic recruitment induced with low doses of diethylstilbestrol (DES) could increase the antitumor activity of chemotherapy in patients with advanced breast cancer. Patients and methods: Two hundred fifty-eight women with metastatic breast cancer were randomized to receive chemotherapy consisting of cyclophosphamide 600 mg/sqm i.v., epidoxorubicin 60 mg/sqm i.v. and fluorouracil 600 mg/ sqm i.v. (CEF) on day 1 or DES-CEF (diethylstilbestrol 1 mg orally days 1-3 CEF on day 4) every 21 days. Patients were treated until progression or, if responsive, for a maximum of 10 courses. Results: There were no significant differences between the two treatment arms in response rates (51.3% to CEF and 49.6% for DES-CEF); median progression-free survival (9.4 months for CEF and 11 months for DES-CEF group) or median overall survival (17.3 and 20 months for CEF and DES-CEF arms, respectively). Non-hematological toxicities were superimposable in the two arms, while DES-chemotherapy was more myelotoxic. Conclusions: This trial confirms that chemotherapy preceded by estrogenic recruitment is still in an experimental phase and that, at present, it has no role in clinical practice. Further research is needed to test the possibility of combining different mitogens in the light of new information about breast cancer cell growth.

PURPOSE Dexrazoxane was found effective in reducing doxorubicin cardiotoxicity when given at a dose ratio (dexrazoxane: doxorubicin) of 20:1. Preclinical studies indicated that dexrazoxane at a dose ratio of 10 to 15:1 also protected against epirubicin-induced cardiotoxicity. The main objective of this study was to investigate the efficacy of dexrazoxane, given at a dose ratio of 10:1 against epirubicin cardiotoxicity. PATIENTS AND METHODS One hundred sixty-two advanced breast cancer patients were randomized to receive epirubicin-based chemotherapy with or without dexrazoxane. Patients who had previously received adjuvant chemotherapy that contained anthracyclines were treated with cyclophosphamide 600 mg/m2 intravenously (IV), epirubicin 60 mg/m2 IV, and fluorouracil 600 mg/m2 IV, on day 1 every 3 weeks. The other patients were treated with epirubicin 120 mg/m2 IV on day 1 every 3 weeks. Cardiac toxicity was defined as clinical signs of congestive heart failure, a decrease in resting left ventricular ejection fraction (LVEF) to < or = 45%, or a decrease from baseline resting LVEF of > or = 20 EF units. RESULTS One hundred sixty patients were evaluated. Cardiotoxicity was recorded in 18 of 78 patients (23.1%) in the control arm and in six of 82 (7.3%) in the dexrazoxone arm. The cumulative probability of developing cardiotoxicity was significantly lower in dexrazoxane-treated patients than in control patients (P = .006; odds ratio, 0.29; 95% confidence limit [CL], 0.09 to 0.78). Noncardiac toxicity, objective response, progression-free survival, and overall survival were similar in both arms. CONCLUSION Dexrazoxane given at a dexrazoxane:epirubicin dose ratio of 10:1 protects against epirubicin-induced cardiotoxicity and does not affect the clinical activity and the noncardiac toxicity of epirubicin. The clinical use of dexrazoxane should be recommended in patients whose risk of developing cardiotoxicity could hamper the eventual use and possible benefit of epirubicin.

PURPOSE The aim of the study was to compare high-versus low-dose cisplatin in combination with cyclophosphamide and epidoxorubicin as primary chemotherapy for suboptimal stage III and IV ovarian cancer. PATIENTS AND METHODS One hundred forty-five patients were randomized to receive six courses of cisplatin 50 or 100 mg/m2 plus epidoxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2. The two treatment arms were well balanced; all patients had greater than 2 cm and 37.2% had greater than 5 cm of residual disease; 29.6% had stage IV disease. RESULTS Patients in the high-dose arm received a double dose-intensity and double total dose of cisplatin. The high-dose regimen induced significantly more episodes of leukopenia (47.8% v 32.8%, P = .05), thrombocytopenia (21.7% v 3.2%, P = .003), anemia (37.6% v 12.5%, P = .002), nephrotoxicity (six v one patient), and neurotoxicity (30.4% v 6.3%, P = .002). There were no significant differences in efficacy in terms of clinical response rate (high-dose 57.5% v low-dose 61.1%), pathologic complete response (CR) (9.6% v 18.1%), median survival times (29 v 24 months), and median progression-free survival (18 v 13 months). CONCLUSION This study shows that doubling the dose-intensity and total dose of cisplatin in combination with epidoxorubicin and cyclophosphamide has significant toxic effects and does not improve clinical outcome in patients with suboptimal ovarian cancer.

From 1985 to 1989 70 patients with high-risk FIGO Stage I-II ovarian carcinoma entered a randomized trial comparing chemotherapy (CT: cisplatin 50 mg/m2 + cyclophosphamide 600 mg/m2 day 1 every 28 days for 6 courses) versus whole abdominal radiotherapy (WAR) given according to the open-field technique (43.2 Gy/24 fractions to the pelvis and 30.2 Gy to the upper abdomen). Protocol violations occurred in 8 patients randomized to WAR who received CT because of their own and/or physician's decision. Since protocol compliance was poor and accrual low the study was prematurely closed. Treatment-related toxicity for patients receiving CT was mild and tolerable, consisting chiefly of controllable grade 3 emesis (71%). Grade 3-4 diarrhea was experienced by 28% of patients treated with WAR; severe enteritis requiring hospitalization was observed in 2 patients. Late bowel obstruction requiring surgery was observed in 1 patient. At a median follow-up of 60 months, 21 patients died and 23 relapsed. Five-year survival was 71% and 53% (p = .16), while relapse-free survival was 74% and 50% (p = .07) for CT and WAR, respectively. Although no firm conclusion can be drawn from the present study, a short-term CT, including cisplatin, appears a safe treatment in comparison to WAR.

Administration of granulocyte-macrophage colony stimulating factor (GM-CSF) is followed by a rapid increase in the proliferative activity of the hematopoietic precursors. Within 72 hours after its suspension, however, establishment of a negative feedback results in a reduction of the proliferative activity of the hyperplastic marrow to values below the baseline, suggesting refractoriness of hematopoietic progenitors to the action of cell-cycle-specific cytostatic agents.The hypothesis that short treatment with GM-CSF before chemotherapy could reduce the hematopoietic toxicity of cytostatics was investigated by administering GM-CSF glycosylate (Sandoz, Basel, Switzerland/Schering-Plough, Kenilworth, NJ) subcutaneously with a 5.5 micrograms/kg protein dosage per day from day-6-day-4 before each course of adjuvant chemotherapy (cyclophosphamide, epirubicin, 5-fluorouracil/cyclophosphamide, methotrexate, 5-fluorouracil alternate) in patients with node-positive breast cancer. Twelve patients were randomized to receive GM-CSF before chemotherapy or only at chemotherapy. The hematologic picture and dose intensity of chemotherapy were compared in the two groups of patients.In the group of patients receiving chemotherapy only, 22% of the cycles had to be postponed because of leukopenia, with a consequent reduction of the dose intensity, whereas in the GM-CSF group, the neutrophil counts remained at significantly (P0.001) higher levels, and there were no delays in chemotherapy administration. No substantial systemic toxicity was associated with this brief GM-CSF schedule. Moreover, GM-CSF treatment did not result in delayed depletion of the hematopoietic pool.Short treatment with GM-CSF can enable the dose intensity of conventional protocols of proven efficacy to be increased.

One hundred sixty-four patients with stage III-IV epithelial ovarian carcinoma were randomized to receive cisplatin (CDDP) 50 mg/mq, doxorubicin 45 mg/mq, and cyclophosphamide 600 mg/mq (PAC) or carboplatin 200 mg/mq, doxorubicin 45 mg/m2, and cyclophosphamide 600 mg/mq (CAC). To administer equitoxic doses at each cycle, the drug dosages were adjusted according to the hematologic toxicities experienced after the previous course; 44.7% of CAC and 21.1% of PAC patients required a dosage reduction at the second course (P = .002). Neither CAC nor PAC caused any clinically relevant neuro-nephrotoxicity; however, CDDP was administered with hydration and forced diuresis, while carboplatin was administered by rapid intravenous (IV) infusion. After six cycles, response rates were superimposable: 62.5% and 66.6% for CAC and PAC, respectively; pathologic complete responses (pCRs) were 16.7% for CAC and 23.2% for PAC; among patients with more than 2 cm residual disease, PAC induced more pCRs than CAC (eight of 52 or 15.4% v one of 42 or 2.4%, P = .07). Median survivals and progression-free survivals (PFSs) were 22.6 and 13.2 months for PAC, and 23.1 and 15.5 months for CAC, respectively; these differences are not significant. In conclusion, this trial demonstrates that equitoxic doses of PAC or CAC result in a similar response rate, PFS, and survival.

Sixteen FIGO stage IIB-IV ovarian carcinoma patients who completed six to 12 courses of a cisplatinum-based combination chemotherapy and with minimal (less than 2 cm), microscopic, or no residual disease at second-look laparatomy received moving-strip abdomino-pelvic radiotherapy. Radiation treatment was feasible with acceptable toxicity; two patients had to interrupt therapy--one pretreated with 12 PAC courses because of WHO grade III leukopenia and the other because of grade III diarrhea. A third patient required surgery because of intestinal obstruction 1 month after cessation of radiotherapy. In patients with minimal residual disease at second look, the therapeutic value of sequential radiotherapy was unsatisfactory (five of six progressed), while further investigations were warranted in patients with no or microscopic residuum after second-look operation.

Thirty-nine patients with locally advanced breast cancer (T3b-4, N1-3 or inflammatory carcinoma) received 3 cycles of induction chemotherapy with estrogenic recruitment before surgery. The therapeutic regimen consisted of diethylstilbestrol (DES) orally on days 1-3, 5-Fluorouracil + Doxorubicin + Cyclophosphamide on day 4 q 21 days (DES-FAC). After surgery 6 additional cycles of chemotherapy (3 DES-FAC alternating with 3 DES-CMF with Methotrexate + F and C as in FAC) were administered. The objective response rate was 71.8% with 15.4% CR, and 56.4% PR; after surgery 36/39 (92.3%) patients were rendered disease-free. So far, 13 of 26 patients in stage IIIb have relapsed (9 of 13 with inflammatory carcinomas). Three-year survival and progression-free survival are 60% and 53.5%, respectively. Twenty-three of the 39 patients were subjected to serial tumor biopsies during the first DES-FAC regimen to allow for tumor-cell kinetic studies during DES and chemotherapy. A significant estrogenic recruitment occurred in 16 patients (69.6%), irrespective of estrogen-receptor status. At surgery, 3-4 weeks after induction chemotherapy, tumor proliferative activity was significantly depressed in comparison to basal values. These results indicate that breast cancer cells can be recruited in vivo with DES and that chemotherapy following estrogenic stimulation is effective and feasible with acceptable toxicity.

Eleven untreated patients with advanced ovarian cancer were studied for tolerance and response to combination treatment with fixed doses of adriamycin (45 mg/m2) and cyclophosphamide (600 mg/m2) + escalating doses of carboplatin. At the first dose level of carboplatin (200 mg/m2), toxicity was acceptable. With carboplatin at 300 mg/m2, severe hematologic toxicity was observed. The dose-limiting toxicity was leukopenia. Although carboplatin was administered without any hydration, no patient experienced renal toxicity. Eight objective responses were observed in 9 clinically evaluable patients. At second look surgery, 3 complete responses and 4 partial responses were documented. Polychemotherapy with JAC (carboplatin, 200 mg/m2, adriamycin, 45 mg/m2, and cyclophosphamide, 600 mg/m2) is administrable with acceptable toxicity.

Thirty patients with bulky advanced ovarian cancer surgically not resectable, received combination chemotherapy (median of 4.1 cycles; range, 3-7) including cisplatin or carboplatin, followed by a second surgical effort. Clinical CR+PR was observed in 24/30 (80 %) patients after chemotherapy. Our study deals only with these 24 patients, and the 6 patients who did not respond to chemotherapy are not part of this report. At debulking, 7/24 (29.1 %) patients had a complete macroscopic resection; 9/24 (37.5 %) patients had a partial resection (residual tumor