Multicenter randomized phase III trial of epirubicin plus paclitaxel vs epirubicin followed by paclitaxel in metastatic breast cancer patients: focus on cardiac safety.

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.

First-line chemotherapy with epidoxorubicin, paclitaxel, and carboplatin for the treatment of advanced epithelial ovarian cancer patients.

OBJECTIVE: A combination of carboplatin (CBDCA) and paclitaxel (TAX) is the standard treatment in advanced ovarian cancer (AOC) patients. Epidoxorubicin (EDX) is an active treatment in AOC and exhibits nonoverlapping toxicities with CBDCA and TAX; moreover, when added to platinum-based chemotherapy, it improves long-term survival. We have therefore conducted a phase II study to evaluate the tolerability and antitumor activity of an EDX/TAX/CBDCA (ETC) triplet in AOC patients. METHODS: Patients with histologically confirmed suboptimal stage III-IV ovarian cancer who had not previously received cytotoxic drugs were treated with TAX (175 mg/m(2) in a 3-h iv infusion), CBDCA (AUC 6, Calvert formula), and EDX (75 mg/m(2) iv bolus) all given on day 1 every 28 days for a maximum of six courses on an outpatient basis. EDX dosage was chosen after a pilot phase I study. RESULTS: Fifty-five patients were registered, of whom 5 were determined ineligible bacause of age. Forty-two of the 50 are evaluable for response; 27 (64%) achieved a clinical complete response (CR) and 9 (21%) a partial response (PR) for a response rate of 86% (95% CI 71-94%). Thirty-three patients underwent a secondary debulking procedure after a median of 6 courses (range 2-6). Pathological CR and PR were observed in 9 (27.3%) and 21 (63.6%), respectively; among patients with persistent disease a successful cytoreduction (<1 cm) was obtained in 53.8% of patients. At a median follow up of 35.6 months (range 0-55.5) median progression-free survival is 19.5 months and median overall survival is 36 months. The most common adverse effects were G3-4 leukopenia and thrombocytopenia which occurred in 59 and 37% of patients, respectively. CONCLUSIONS: The ETC combination given according to the outlined doses and schedule is highly active in AOC patients with poor prognostic factors and deserves further study.

Accelerated-intensified cyclophosphamide, epirubicin, and fluorouracil (CEF) compared with standard CEF in metastatic breast cancer patients: results of a multicenter, randomized phase III study of the Italian Gruppo Oncologico Nord-Ouest-Mammella Inter Gruppo Group.

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/m(2), epirubicin 60 mg/m(2), and fluorouracil 600 mg/m(2)) administered every 21 days (CEF21) or accelerated-intensified CEF (cyclophosphamide 1,000 mg/m(2), epirubicin 80 mg/m(2), and fluorouracil 600 mg/m(2)) 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.

Advanced ovarian cancer in the elderly: results of consecutive trials with cisplatin-based chemotherapy.

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 patients > or = or <65 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 age >65 years per se was not a negative prognostic factor.

Single agent epirubicin as first line chemotherapy for metastatic breast 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.

Intraperitoneal versus intravenous cisplatin in combination with intravenous cyclophosphamide and epidoxorubicin in optimally cytoreduced advanced epithelial ovarian cancer: a randomized trial of the Gruppo Oncologico Nord-Ovest.

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.

p53 status is neither a predictive nor a prognostic variable in patients with advanced ovarian cancer treated with a paclitaxel-based regimen.

BACKGROUND: The aim of this study was to assess the relationship between p53 status and the clinical outcome of patients with advanced ovarian cancer treated with a paclitaxel-based regimen. PATIENTS AND METHODS: The investigation was conducted on 38 patients with FIGO stage III-IV ovarian cancer from whom tumor tissue samples for p53 protein immunostaining were obtained during initial cytoreductive surgery. All these patients subsequently received six cycles of first-line combination chemotherapy with paclitaxel 175 mg/m2 (3-hour infusion) plus carboplatin AUC 6 with or without epidoxorubicin 75 mg/m2. RESULTS: Positive p53 immunostaining was detected in tissue samples collected from 24 (63.2%) ovarian cancers. A clinical complete response was obtained in 14 (58.3%) of the 24 patients with positive p53 immunostaining compared to 9 (64.3%) of the 14 patients with negative p53 immunostaining (p = 0.717). A pathological complete response was found in 6 (25.0%) of the former compared to 4 (28.6%) of the latter (p = 0.956). Similarly, survival did not correlate with p53 status (p = 0.1271). DISCUSSION: p53 status seems to be neither a predictive nor a prognostic variable in patients with advanced ovarian cancer treated with a paclitaxel-based regimen. These results are consistent with experimental data showing that paclitaxel cytotoxicity in ovarian cancer is likely to be mediated by a p53-independent pathway.

Significance of lymph node sampling in epithelial carcinoma of the ovary.

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.

Intraperitoneal carboplatin with or without interferon-alpha in advanced ovarian cancer patients with minimal residual disease at second look: a prospective randomized trial of 111 patients. G.O.N.O. Gruppo Oncologic Nord Ovest.

From June 1990 to October 1994, 111 advanced ovarian cancer patients with minimal (less than 2 cm) residual disease after platinum-based front-line chemotherapy and second-look laparotomy entered a cooperative randomized study aimed at evaluating the effectiveness and the toxicity of the addition of interferon-alpha2 to carboplatin, both intraperitoneally (ip) administered. Patients were randomized to receive either 3 courses of ip Carboplatin 400 mg/m2 Day 1 q 28 days (54 pts) (CBDCA) or ip interferon-alpha 25 x 10(6) U Day 1 + ip carboplatin 400 mg/m2 Day 2 q 28 days (57 pts) (CBDCA + IFN). Patients treated with interferon experienced more severe (WHO grade 3-4) leukopenia (28% vs 17.1%) and anemia (14% vs 4.2%). Fever (P = 0.000) and flu-like syndrome (P = 0.02) were significantly more frequent in the combination arm. No difference in gastroenteric, neurologic, or renal toxicity was observed. At a median follow-up time of 13 months (range 1-72) 71 patients showed a disease progression (31 CBDCA, 40 CBDCA + IFN) and 44 patients died (21 CBDCA, 23 CBDCA + IFN). Median progression-free survival was 11 months in the CBDCA group and 10 months in the CBDCA + IFN arm. Median survival was 22 and 29 months in CBDCA and CBDCA + IFN arm, respectively. In conclusion, intraperitoneal interferon-alpha does not seem to improve the results achievable with intraperitoneal carboplatin in this subset of patients, while the toxicity and the costs of the combination are consistently higher than with chemotherapy alone.

Antiemetic efficacy of granisetron in patients with gynecological malignancies.

The efficacy and tolerability of granisetron in the management of acute and delayed emesis was compared with that of a multiple antiemetic drug combination regimen, including metoclopramide, dexamethasone, lorazepam and orphenadrine. The trial was a randomized, cross-over study involving 111 patients with gynecological cancers undergoing chemotherapy with cisplatin. Granisetron was significantly more effective than the combination regimen during the first 24 h after chemotherapy; complete response, rates were 67 and 48%, respectively (p = 0.002). There was a significant reduction in the effectiveness of the combination during the second treatment cycle, compared with the first. In contrast, the efficacy of granisetron did not differ between the two cycles. The response rate during the 6 days after chemotherapy was 40.8% in both groups. At the end of the study, 55% of patients preferred granisetron and 23% preferred the combination (p < 0.001). Granisetron was well tolerated. The principal adverse event was headache, which was reported in 7% of patients. The results of this study confirm that granisetron is effective in the treatment of cisplatin-induced nausea and vomiting during the 24 h after chemotherapy.

A randomized trial of chemotherapy with or without estrogenic recruitment in locally advanced breast cancer. North-West Oncology Group (GONO) Study, Italy.

The present phase III trial was carried out to verify whether a kinetic recruitment induced by low doses of diethylstilbestrol (DES) could increase the killing efficacy of chemotherapy in patients with locally advanced breast cancer. One-hundred and seventeen untreated patients with locally advanced breast cancer (stage IIIA/IIIB) were randomized to receive 3 courses of primary chemotherapy consisting of cyclophosphamide (600 mg/m2 i.v.), doxorubicin (50 mg/m2 i.v.) and fluorouracil (600 mg/m2 i.v.) (CAF) on day 1, or DES-CAF (DES, 1 mg orally days 1-3, CAF on day 4). The courses were repeated every 3 weeks. The patients who achieved an objective response were submitted to mastectomy followed by 3 courses of CAF alternated with 3 courses of CMF (cyclophosphamide, 600 mg/m2 i.v.; methotrexate, 40 mg/m2 i.v.; fluorouracil, 600 mg/m2 i.v.), with or without DES. The two treatment arms were well balanced in terms of clinical and pathologic features. There was no significant difference in response rates to induction chemotherapy between the two treatment arms (objective response rate, 63.3% for CAF and 56.1% for DES-CAF). Median overall survival was 49 and 47 months and median progression-free survival was 24 and 21 months for CAF and DES-CAF patients, respectively. Toxicity was not significantly different in the two groups, with the exception of leukopenia: DES chemotherapy was significantly more myelotoxic than the standard treatment, which resulted in a significant reduction in the actual dose intensity. In spite of the attractive experimental evidence, we conclude that so far there is no clinical advantage in the combination of estrogen and chemotherapy. Further research is needed to investigate different schedules of chemotherapy and hormones, or to test the possibility of combining various mitogens.

Multicenter randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer.

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.

Chemotherapy with or without estrogenic recruitment in metastatic breast cancer. A randomized trial of the Gruppo Oncologico Nord Ovest (GONO).

BACKGROUND: This phase III 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.

High-dose versus low-dose cisplatin in combination with cyclophosphamide and epidoxorubicin in suboptimal ovarian cancer: a randomized study of the Gruppo Oncologico Nord-Ovest.

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.

Intraperitoneal infusion of recombinant human tumor necrosis factor and mitoxantrone in neoplastic ascites: a feasibility study.

In cancers limited to the abdominal cavity the intraperitoneal administration of antineoplastic drugs could be the treatment of choice because of both the limited systemic toxicity and the pharmacokinetic advantage. Preclinical studies suggest that the combination of Tumor Necrosis Factor (TNF) and mitoxantrone have a synergistic effect. On this basis, we conducted a study to verify the feasibility of the intraperitoneal administration of these drugs in patients with malignant ascites. Cohorts of three patients were treated with a fixed dose of mitoxantrone (6 mg/m2) and escalating doses of TNF (from 60 up to 200 mcg/m2), intraperitoneally, given for two hours once a week for at least four weeks. Seventeen patients with malignant ascites entered into the study. All but two patients received the planned four cycles. Sixty-six cycles were given. The most common side effects were fever (21-44% of cycles), chills (8-44%), fatigue (19-33%), loss of appetite (17-57%), malaise (25-43%), myalgia (33%), pain injection (25-83%), nausea/vomiting (33-64%). Severe fatigue, malaise and anorexia were observed only at doses of 200 mcg/m2 of TNF. Weekly intraperitoneal administration of mitoxantrone (6 mg/m2) and TNF (200 mcg/m2) is a feasible regimen with acceptable toxicity. The activity of this combination should be studied in properly designed phase II trials.

High-risk early-stage ovarian cancer. Randomized clinical trial comparing cisplatin plus cyclophosphamide versus whole abdominal radiotherapy.

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.

Short-term administration of granulocyte-macrophage colony stimulating factor decreases hematopoietic toxicity of cytostatic drugs.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 (P < 0.001) 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. CONCLUSIONS: Short treatment with GM-CSF can enable the dose intensity of conventional protocols of proven efficacy to be increased.

Cisplatin-based combination chemotherapy with or without doxorubicin in advanced epithelial ovarian cancer: 8-year update of a randomized multicentric clinical trial. The Gruppo Oncologico Nord Ovest (GONO).

One hundred and twenty-five patients with advanced epithelial ovarian cancer (EOC) were postsurgically included in a multicentric clinical trial comparing the association of cisplatin (CDDP) (50 mg/m2 iv day1) + cyclophosphamide (CTX) (600 mg/m2 iv day 1) (PC regimen) versus the combination of PC + doxorubicin (ADM) (45 mg/m2 iv day 1) (PAC regimen), repeated every four weeks. After the sixth course of chemotherapy, patients without clinical evidence of disease or with surgically resectable residual disease (RD) underwent second-look laparotomy. Afterwards patients in surgical complete response (sCR) stopped chemotherapy, while partial responders or patients with stable disease received six more courses of the same regimen used as first-line treatment. Among the 67 patients with measurable RD, PAC regimen achieved a better clinical complete response (40.6% vs 20.0%); the difference approached statistical significance. In the 75 patients who underwent second-look laparotomy, PAC regimen induced a significantly higher sCR rate (62.2% vs 39.5%, p less than 0.05). The median survival (S) and progression free survival (PFS) were better in PAC arm, even if the differences were not statistically significant. Eight-year S and 8-year PFS were 32.7% and 24.7% respectively, for PAC arm, and 23.9% and 14.1%, respectively, for PC arm. These data seem to confirm the clinical advantage provided by the addition of ADM to PC regimen in the treatment of advanced EOC.