Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial.

BACKGROUND: Previously, we have shown that the combination of cyclophosphamide, doxorubicin, and cisplatin (CAP) and single-agent carboplatin produce similar survival and progression-free survival rates in women with ovarian cancer. Subsequently, paclitaxel combined with platinum has become a widely accepted treatment for the disease. We aimed to compare the safety and efficacy of paclitaxel plus carboplatin with a control of either CAP or carboplatin alone. METHODS: Between February, 1995, and October, 1998, we enrolled 2074 patients from 130 centres in eight countries. Women were randomly assigned paclitaxel plus carboplatin or control, the control (CAP or single-agent carboplatin) being chosen by the patient and clinician before randomisation. The primary outcome measure was overall survival. Secondary outcomes were progression-free survival and toxicity. Analysis was by intention to treat. FINDINGS: With a median follow-up of 51 months, 1265 patients had died, and survival curves showed no evidence of a difference in overall survival between paclitaxel plus carboplatin and control (hazard ratio 0.98, 95% CI 0.87-1.10, p=0.74). The median overall survival was 36.1 months on paclitaxel plus carboplatin and 35.4 months on control (difference 0.7 months, 95% CI -3.6 to 4.7). 1538 patients had progressive disease or died, and again, Kaplan-Meier curves showed no evidence of a difference between the groups (hazard ratio 0.93, 95% CI 0.84-1.03, p=0.16). Median progression-free survival was 17.3 months on paclitaxel plus carboplatin and 16.1 months on control (difference 1.2 months, 95% CI -0.5 to 2.8). Paclitaxel plus carboplatin caused more alopecia, fever, and sensory neuropathy than carboplatin alone, and more sensory neuropathy than CAP. CAP was associated with more fever than paclitaxel plus carboplatin. INTERPRETATION: Single-agent carboplatin and CAP are as effective as paclitaxel plus carboplatin as first-line treatment for women requiring chemotherapy for ovarian cancer. The favourable toxicity profile of single-agent carboplatin suggests that this drug is a reasonable option as first-line chemo therapy for ovarian cancer.

A prognostic index for multiple myeloma.

The current prognostic systems have failed to identify multiple myeloma (MM) patients who require aggressive therapy. These staging systems do not reliably distinguish patients with different prognoses. This paper explores the possibility of improving the prognostic forecast in MM by considering some clinical characteristics at diagnosis together with response to first-line chemotherapy. A total of 231 patients were prospectively randomised in a multicentre trial to no therapy vs melphalan + prednisone (MP) for stage I, MP in stage II, and MP vs peptichemio, vincristine and prednisone for stage III. The clinical features of these groups were evaluated for prognostic variables predictive of overall survival by means of univariate and multivariate analysis. The independently significant variables were incorporated into a model that identified three groups of patients with different risks of death and different overall survival. Three variables retained statistical significance: the staging system proposed by the British Medical Research Council, a composite parameter integrating the percentage of bone marrow plasma cells with cytological features of the infiltrating elements (plasma cell vs plasmablast), and response to 6 months of first-line chemotherapy. These three variables led the proposal of a scoring system able to identify three different risk classes (with median overall survival of 52, 28 and 13 months respectively) and to estimate individual patient prognosis more flexibly. The proposed risk classes, drawn from both diagnostic and therapeutic parameters, are thought to be a clinical and investigational instrument for separating MM patients into comparable groups, for selecting the best available therapy and for evaluating response with respect to the disease of each new patient.

Pharmacokinetics of peptichemio in myeloma patients: release of m-L-sarcolysin in vivo and in vitro.

Peptichemio (PTC) is a mixture of six synthetic oligopeptides, each of which contains the alkylating residue m-[di(2-chloroethyl)amino]-L-phenylalanine (L-mSL). The fate of PTC was investigated in eight patients with multiple myeloma after intravenous infusion of the drug. The quantitative analysis of the plasma samples was performed by liquid chromatography with fluorometric detection. L-mSL was rapidly released from the peptides and reached its maximal plasma concentration at the end of the infusion. Its median elimination half-life was 1.73 (range, 0.72-2.41) h. It was possible to follow the concentration of only one of the peptides, L-mSL-L-Arg(NO2)-L-Nval.OEt, during and shortly after the infusion of PTC. The stability of L-mSL and the peptides was studied in buffer solution (pH 7.3), plasma, and blood. The stability of some of the peptides was drastically decreased in blood, the degradation half-lives being only about 1 min. We conclude that L-mSL plays an important role in the mechanism of action of PTC.

Expression of p170 protein in multiple myeloma: a clinical study.

The expression of the p170 multidrug resistance protein by bone marrow plasma cells (BMPC) was assessed at clinical presentation in 53 patients with multiple myeloma (MM) using the C219 monoclonal antibody. Twenty-two of the 53 (41 per cent) patients had variable aliquots (1-60 per cent, median = 6 per cent) of p170+ BMPC by immunocytochemistry. Five of 10 patients studied using bivariate flow cytometry had both diploid and hyperdiploid (DNA index ranged from 1.2 to 1.5) BMPC with hyperdiploid clones having significantly greater p170 expression than diploid ones. Of the 37 patients evaluated for a response, 20 (54 per cent) had responded to induction chemotherapy. The presence of p170+ BMPC was a negative indicator for achieving response. The response rate was 75 per cent for p170- and 25 per cent for p170+ cases (p < 0.01), with no difference on the basis of treatment schedule (melphalan and prednisone, 24 patients; peptichemio, vincristine and prednisone, 13 patients). No difference in response and survival duration was found between p170+ and p170- patients. In six of nine patients studied both at diagnosis and following induction chemotherapy the p170+ BMPC% increased irrespective of the type of treatment or outcome.

CA 125 regression: a model for epithelial ovarian cancer response.

The rate of decline of CA 125 in effectively treated epithelial ovarian cancer is described by the exponential regression curve CA 125 = EXP [i - s (days after surgery)]. In this equation i, the y-axis intercept, measures initial tumor burden whereas s, the slope of the regression curve, is determined by the extent of cytoreductive surgery and the subsequent response to chemotherapy. Departure from the regression curve uniformly results in progressive disease. In patients whose cancers had been completely removed, we calculated the mean half-life of CA 125 to be 10.4 days (range 4 to 21). In this case s = 0.0835 and characterizes the ideal regression rate. The model predicts that high-dose cisplatin chemotherapy (s = 0.0671) is more effective than low-dose cisplatin (s = 0.0380) (p less than 0.03) in eliminating residual cancer. Because s can be calculated within 2 to 3 months of treatment and then compared with s for the ideal regression curve and with the values of s reported for standard chemotherapy, evaluation of any new treatment protocol can be facilitated with this method.

cis-platinum-based alternating non-cross-resistant chemotherapy as a first-line treatment in metastatic breast cancer. A phase II study.

Exposure to multiple non-cross-resistant drugs should increase cell kill and the chance of achieving more complete and partial responses. Our earlier study in breast cancer showed that second-line CAP (cyclophosphamide, adriamycin, cis-platinum) treatment was not cross-resistant to the CMFVP (cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, prednisolone) regimen and produced a 51% response rate. These facts initiated a phase II study which used an alternating CMFVP/CAP regimen. Altogether, 49 patients entered the study and 45 were evaluated (greater than 2 cycles). The CMFVP regimen consisted of cyclophosphamide (200 mg/m2 on days 1, 2, 3, 4 and 5), methotrexate (30 mg/m2 on days 2 and 4), 5-fluorouracil (500 mg/m2 on days 1, 3 and 5), vincristine (1.4 mg/m2 on days 1 and 5), and prednisolone (40 mg p.o. on days 1-5), and was alternated with the CAP schedule (300 mg/m2 cyclophosphamide on days 1, 3 and 5, 50 mg/m2 adriamycin on day 1, and 30 mg/m2 cis-platinum on days 1, 3 and 5). Overall response was high, and 37 patients out of 45 responded (82%), with a 28% CR rate (13/45). A particularly high response rate was observed in soft tissues (86%, 18/21) and visceral organs (84%, 16/19). Only 1 patient progressed (3%). The duration of remission was 4-21+ months (median, 12 months). Six of 13 CR patients were still disease free 15 months after the treatment was stopped. The duration of survival was 5-25+ months (median, 15+ months). Toxicity was moderate (myelosuppression in 53% of patients, mainly grade I-II; stomatitis in 11%, except for 100% alopecia and 90% nausea and vomiting). One drug-related death (bone marrow aplasia) was recorded. The high antitumorigenic activity of the alternating regimen used is encouraging and may call for a randomized study for the ultimate evaluation of this treatment approach.

Clinical aspects of ovarian tumors of low malignant potential.

A review of 21 cases of ovarian tumors of low-malignant potential diagnosed in our department over a period of 13 years was undertaken. Ninety percent of the patients presented with stage I disease. The average age at diagnosis (45 years) was younger than commonly found in patients with invasive epithelial cancer. Three patients received postoperative chemotherapy, and all of those were evaluated by second-look laparotomy. One of our patients with stage Ic serous tumor recurred with lung metastases. In two other patients with mucinous tumors, mucocele of the appendix was found. The five year survival in this series was 100%. Our study emphasizes the need for a prospective study to evaluate the value of adjuvant therapy in the various stages of these ovarian neoplasms.

Long-term follow-up of patients with advanced ovarian carcinoma treated with debulking surgery and chemotherapy consisting of cisplatin, doxorubicin, and cyclophosphamide. Gynecologic Oncology Group of the Comprehensive Cancer Center.

Between June 1980 and December 1984, 88 patients with stage III-IV ovarian carcinoma were entered in a study evaluating the role of debulking surgery and chemotherapy consisting of cyclophosphamide, doxorubicin, and cisplatin intravenously on day 1, every 4 weeks (CAP-1). The results after a median follow-up of 62 months (range 41-93 months) are presented. The median survival of all patients was 24 months (30 alive, 58 dead). The 5-year progression-free survival of all patients was 27% and the overall survival was 33%. Of patients with stage III disease debulked to lesions less than or equal to 1.5 cm before the initiation of chemotherapy (n = 34) the 5-year progression-free survival was 52%. Of 31 patients with a histologically documented complete response the median survival was 55+ months; 9 (29%) of them relapsed as opposed to 8 of 10 achieving microscopic residual disease at second look. Of 22 patients with stage IV disease, 20 died. This report confirms that patients who have undergone surgical removal of of bulk tumor and who achieve a complete remission have an improved survival outcome.

Ovarian epithelial tumors of low malignant potential.

Forty-one patients with epithelial ovarian tumors of low malignant potential are discussed. Twenty-three patients presented with Stage I, four with Stage II and 14 with Stage III disease. All patients with Stage I disease were solely treated surgically. Twelve patients with Stage II and III disease also received postoperative chemotherapy. Four of ten patients had persistent disease at second look laparotomy. Chemotherapy was not used in six patients with Stage II and III disease when the tumor was considered to have been removed completely. Forty of the 41 patients are currently alive and free of disease at two to nine years of follow-up study. Vigorous and, at times, multiple surgical procedures remain the primary treatment of ovarian tumors of low malignant potential.

High dose peptichemio in pretreated neuroblastoma.

The aim of this study was to evaluate the antitumor effect and toxicity of a single course of Peptichemio at high dose (450 mg/sq m) given to children with neuroblastoma resistant to first line treatment or at relapse. A total of 28 children were treated. Seven children showed partial response, 4 minor response, 8 had stable disease, and in 8 the tumor progressed. The principal toxic effect was myelosuppression. Hemorrhagic enteritis with liver failure and toxic death occurred in 1 patient. High dose Peptichemio can be administered with tolerable toxicity, inducing tumor regression in one third of previously treated patients.

Combination of cyclophosphamide, adriamycin and platinum (CAP) versus 5-fluorouracil, adriamycin and cyclophosphamide (FAC) as primary treatment in metastatic breast cancer: results of a prospective randomized study.

Based on favorable results we reported earlier with the CAP regimen in breast cancer (CAP vs CMFVP), the present study compared the CAP with the FAC regimen, which is so far one of the most active adriamycin containing chemotherapy regimens in breast cancer. The aim of the study was to find the optimal first line treatment and possibly evaluate the role of cis platinum in breast cancer chemotherapy. The CAP schedule consisted of cyclophosphamide 200 mg/m2 i.v. days 1, 3 and 5, adriamycin 40 mg/m2 i.v. day 1, and platinum 30 mg/m2 i.v. day 1, 3 and 5. The FAC schedule included 5-FU 500 mg/m2 days 1 and 8, adriamycin 50 mg/m2 day 1, and cyclophosphamide 500 mg/m2 day 1. One hundred and twenty-six previously untreated patients received greater than 2 cycles and were evaluated. In the CAP arm 15 complete (26%) and 24 partial remissions were observed, resulting in a 67% overall response rate (39/58). The response in soft tissue and visceral organs was notable (78% - 22/28, 71% - 15/21) with an important complete response rate (32%). In the FAC arm there was an overall response in 41% (28/68) of patients, with 8 complete (12%) and 20 partial responses. The difference in overall response, complete response, and response in soft tissue and visceral organs, was statistically significant in favor of the CAP arm (P less than 0.005). Concerning bone metastases there was no difference between the two schedules in response rate, nor in the median remission duration (CAP 11, FAC 10 months). In spite of a somewhat longer median survival in the CAP group, the difference (13 months vs 9 months) was not statistically significant (P = 0.10). Toxicity was moderate and tolerable in both regimens with more pronounced myelosuppression and vomiting in the CAP group. Compared with the FAC schedule the platinum containing combination chemotherapy (CAP) showed higher antitumor activity with no reflection on remission duration and survival.

Cisplatin-based chemotherapy for neoplasms arising from salivary glands and contiguous structures in the head and neck.

We observed a 38% response rate from platinum-based chemotherapy among 34 patients with locally recurrent or disseminated neoplasms from salivary glands or contiguous structures. Adenocarcinoma was the predominant histology. Eleven patients manifested partial response or regression, and two had complete regressions of soft tissue disease. The most durable visceral responses were partial regressions (lung, 11 months; and central nervous system, 34 months). Eleven of the 13 responders showed tumor regression within 3 months of commencing therapy, and the median response duration was 7 months (range 2-34 months). The median survival among all 34 patients was 15 months, and was 18 months among the 13 responders. Hence, a response to treatment did not necessarily confer any long-term survival advantage. Although gastrointestinal toxicities were troublesome with the earlier regimens, contemporary antiemetics (dexamethasone, metoclopramide) have substantially modified these sequelae. Platinum programs may provide useful palliation for selected patients with these neoplasms, but the impact on survival is negligible.

Cisplatin (P) versus cyclophosphamide, adriamycin and cisplatin (CAP) for stage III-IV epithelial ovarian carcinoma: a prospective randomized trial.

In 1982 a randomized trial was started to compare a cisplatin-containing polychemotherapy (CAP: cyclophosphamide - CPA 750 mg/m2, adriamycin - ADM 50 mg/m2, cisplatin - P 50 mg/m2 on day 1 every 21 days) with full-dose cisplatin as single agent (P 60 mg/m2/day on days 1 and 2 every 28 days) in 44 patients undergoing exploratory laparotomy or debulking surgery for stage III-IV epithelial ovarian carcinoma with residual disease greater than 5 cm. The response was evaluated at second-look surgery with random biopsies and peritoneal washing. On the basis of the final results the authors underline some data which, although merely indicative (because of the small number of patients) appear to be worth considering since they are in accordance with the latest reports: a) similar response rate (CR + PR = 47%) to first-line treatment in the two groups; b) the CAP treatment may achieve a longer median duration of CRs than the P treatment (20 versus 11 months); c) overall survival seems similar in the two groups of patients (19 versus 18 months), whereas the survival of CRs seems longer in the CAP treated patients (greater than 32 versus 25 months). The authors also discuss some observations on a possible salvage therapy.

The role of chemotherapy in non-small cell lung cancer: the community perspective.

In the past decade, several drugs have been identified that possess activity in treating non-small cell lung cancer (NSCLC). The combination of mitomycin C, vinblastine, and cisplatin (MVP) was studied in 56 previously untreated patients with advanced NSCLC in Bridgeport Hospital from 1981 to 1984. In a selected patient population, 73% of 52 evaluable patients had complete (four patients) or partial (34 patients) responses. Response rate was 88% in epidermoid carcinoma, 70% in adenocarcinoma, and 50% in undifferentiated carcinoma. Median survival was 10 months in responding patients v 4 months in nonresponders. Performance status was the most important factor predictive of prolonged survival. MVP cannot be recommended for patients with poor performance status but may offer worthwhile palliation to patients with advanced NSCLC. Active drug combinations must now be studied as part of a multidisciplinary approach to the primary management of patients with clinically localized NSCLC.

[A case of malignant peritoneal mesothelioma with a good response to treatment].

A rare case of malignant peritoneal mesothelioma in a 49-year-old Japanese woman is presented. The tumor was limited to the peritoneum, and was cytologically and histologically identified as being composed of two components, epithelial and non-epithelial forms. The transition in her CA-125 level suggested that this tumor had good prospects of developing into a malignant mesothelioma. The good prognosis of the patient is considered to be attributed to detecting this tumor in its early stage and to aggressive chemotherapy.

Localized neuroblastoma. Surgical and pathologic staging.

Sixty-five children with neuroblastoma without evidence of distant metastases underwent initial tumor resection. Seventeen with no evidence of lymph node involvement in whom tumor resection was complete (Group 1) received no further antitumor therapy. One child died postoperatively; disease recurred in the bone marrow of one child at 52 months, the child subsequently died. Fifteen were alive without disease, giving an 82% actuarial five year survival. Forty-eight children with minimal residual tumor and/or regional lymph node involvement (Group 2) received two 5-day courses of Peptichemio (1.2 mg/kg/d) and the 29 children in this group who were older than 1 year of age at diagnosis were randomized to receive either radiotherapy to the tumor bed in addition or no radiotherapy. In Group 2, ten of the 48 have relapsed: six of 17 with initial lymph node involvement, three of four with tumor rupture at operation, and one of eight with tumor extension to the intervertebral foramen. No relapses were seen in the 19 children with minimal residual tumor confined to the tumor bed. Only one of the 18 Group 2 children who were younger than 1 year of age at diagnosis relapsed. Of the 29 Group 2 children who were older than 1 year of age at diagnosis, five relapses occurred in the 14 who received radiotherapy and four relapses in the 15 who did not receive radiotherapy. All six children with disseminated relapse died. Actuarial 5-year survival in Group 2 is 87%, and actuarial relapse-free survival, 76%.