A randomized phase II study comparing erlotinib versus erlotinib with alternating chemotherapy in relapsed non-small-cell lung cancer patients: the NVALT-10 study.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) administered concurrently with chemotherapy did not improve outcome in non-small-cell lung cancer (NSCLC). However, in preclinical models and early phase noncomparative studies, pharmacodynamic separation of chemotherapy and TKIs did show a synergistic effect. PATIENTS AND METHODS: A randomized phase II study was carried out in patients with advanced NSCLC who had progressed on or following first-line chemotherapy. Erlotinib 150 mg daily (monotherapy) or erlotinib 150 mg during 15 days intercalated with four 21-day cycles docetaxel for squamous (SQ) or pemetrexed for nonsquamous (NSQ) patients was administered (combination therapy). After completion of chemotherapy, erlotinib was continued daily. Primary end point was progression-free survival (PFS). RESULTS: Two hundred and thirty-one patients were randomized, 115 in the monotherapy arm and 116 in the combination arm. The adjusted hazard ratio for PFS was 0.76 [95% confidence interval (CI) 0.58-1.02; P = 0.06], for overall survival (OS) 0.67 (95% CI 0.49-0.91; P = 0.01) favoring the combination arm. This improvement was primarily observed in NSQ subgroup. Common Toxicity Criteria grade 3+ toxic effect occurred in 20% versus 56%, rash in 7% versus 15% and febrile neutropenia in 0% versus 6% in monotherapy and combination therapy, respectively. CONCLUSIONS: PFS was not significantly different between the arms. OS was significantly improved in the combination arm, an effect restricted to NSQ histology. STUDY REGISTRATION NUMBER: NCT00835471.

Quality of life, geriatric assessment and survival in elderly patients with non-small-cell lung cancer treated with carboplatin-gemcitabine or carboplatin-paclitaxel: NVALT-3 a phase III study.

BACKGROUND: Elderly patients with advanced non-small-cell lung cancer (NSCLC) may derive similar benefit from platinum-based chemotherapy as younger patients. Quality of life (QoL) and comprehensive geriatric assessment (CGA) is often advocated to assess benefits and risks. PATIENTS AND METHODS: A total of 181 chemotherapy-naive patients [≥70 years, performance score (PS) of 0-2] with stage III-IV NSCLC received carboplatin and gemcitabine (CG) (n = 90) or carboplatin and paclitaxel (CP) (n = 91) every 3 weeks for up to four cycles. Primary end point was change in global QoL from baseline compared with week 18. Pretreatment CGA and mini geriatric assessment during and after treatment were undertaken. A principal component (PC) analysis was carried out to determine the underlying dimensions of CGA and QoL and subsequently related to survival. RESULTS: There were no changes in QoL after treatment. The number of QoL responders (CG arm, 12%; CP arm, 5%) was not significantly different. CGA items were only associated with neuropsychiatric toxicity. Quality-adjusted survival was not different between treatment arms. The PC analysis derived from nine CGA, six QoL and one PS score indicated only one dominant dimension. This dimension was strongly prognostic, and physical and role functioning, Groningen Frailty Indicator and Geriatric Depression Scale were its largest contributors. CONCLUSIONS: Paclitaxel or gemcitabine added to carboplatin did not have a differential effect on global QoL. CGA was associated with toxic effects in a very limited manner. CGA and QoL items measure one underlying dimension, which is highly prognostic.

The effectiveness of chlorhexidine-silver sulfadiazine impregnated central venous catheters in patients receiving high-dose chemotherapy followed by peripheral stem cell transplantation.

Immuno-compromised patients are at high risk for all kind of infections. Unfortunately, they need central venous catheters (CVCs), which are associated with infectious complications. In this study we examined the effectiveness of chlorhexidine-silver sulfadiazine impregnated CVCs to prevent catheter-related infections in patients receiving high-dose chemotherapy followed by peripheral stem cell transplantation. This historical cohort study evaluated 139 patients of whom 70 patients were provided with non-impregnated CVCs and 69 patients with impregnated CVCs. Patients were treated for different diagnoses. The median number of days a CVC stayed in situ was 18 in the non-impregnated group and 16 in the impregnated group. The median duration of neutropenia of patients with non-impregnated CVCs was 9 days compared with 7 days of patients with impregnated CVCs. We found less catheter colonization (CC) in patients with chlorhexidine-silver sulfadiazine CVCs (RR 0.63, 95% CI 0.41-0.96; P = 0.03). Catheter-related blood stream infections (CR-BSI) were also diminished, but this result was not statistically significant (RR 0.15, 95% CI 0.02-1.15; P = 0.06). The reduction in CC and CR-BSI did not diminish the incidence of fever. We conclude that the use of chlorhexidine-silver sulfadiazine impregnated CVCs provide an important improvement in the attempt to reduce CC and CR-BSI.

Relationship between K-ras oncogene activation and smoking in adenocarcinoma of the human lung.

To investigate a possible relationship between the exposure to tobacco smoke and the presence of ras point mutations, we examined lung adenocarcinoma samples from 27 smokers and from 27 nonsmokers. Activating point mutations in K-ras (also known as KRAS2) and N-ras (also known as NRAS) were determined by using the polymerase chain reaction and oligonucleotide hybridization to detect the mutated sequences. Mutations were more often found in adenocarcinomas obtained from smokers (eight of 27) than in adenocarcinomas obtained from nonsmokers (two of 27) (P = .044, Fisher's exact test). All mutations were present in K-ras codon 12. None of the other parameters examined differed significantly between the ras-positive and ras-negative groups. We conclude that exposure to carcinogenic agents in tobacco smoke is an important factor in the induction of point mutations in K-ras in human lung adenocarcinomas, but that K-ras mutations may also infrequently occur in tumors of non-smokers.

EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the EUropean Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups.

BACKGROUND: Preclinical evidence suggests that retinoids and antioxidants may prevent or delay the occurrence of cancer in the upper or lower airways, but such effects have not been reliably established in clinical studies. To assess the chemopreventive effects of vitamin A (retinyl palmitate) and N-acetylcysteine, we conducted a large randomized intervention study in patients with head and neck cancer or with lung cancer, most of whom had a history of smoking. METHODS: From June 1988 through July 1994, a total of 2592 patients (60% with head and neck cancer and 40% with lung cancer) were randomly assigned to receive 1) retinyl palmitate (300000 IU daily for 1 year followed by 150000 IU for a 2(nd) year), 2) N-acetylcysteine (600 mg daily for 2 years), 3) both compounds, or 4) no intervention. All statistical tests were two-sided. RESULTS: Of the patients, 93.5% had smoked tobacco at sometime in their lives (and 25% continued to smoke after cancer diagnosis). After a median follow-up of 49 months, 916 patients were reported with an event (recurrence, second primary tumor, or death). No statistically significant difference was observed in overall survival or event-free survival between patients who received retinyl palmitate and patients who did not. Similarly, no difference was seen in overall survival or event-free survival between patients who received N-acetylcysteine and patients who did not. There was a lower incidence of second primary tumors in the no intervention arm, but the difference was not statistically significant. CONCLUSION: A 2-year supplementation of retinyl palmitate and/or N-acetylcysteine resulted in no benefit-in terms of survival, event-free survival, or second primary tumors-for patients with head and neck cancer or with lung cancer, most of whom were previous or current smokers.

Differential expression of DNA topoisomerases in non-small cell lung cancer and normal lung.

UNLABELLED: DNA topoisomerases are ubiquitous nuclear enzymes, and important targets of cancer chemotherapy. Expression of topoisomerase genes is often correlated with in vitro chemosensitivity. We investigated the expression of the topoisomerase genes in normal lung and non-small cell lung cancer. Expression of topoisomerase II-alpha, topoisomerase II-beta, and topoisomerase I genes has been assessed in tumor samples of 60 patients who underwent operation for a non-small cell lung carcinoma, by RNase protection assay, and by immunohistochemistry. The expression of topoisomerase II-alpha gene was either undetectable or very low in normal lung, while most NSCLC expressed readily quantifiable levels of this gene. No alteration of the topoisomerase II-alpha gene was found by Southern blotting in the NSCLC samples. In contrast to topoisomerase II-alpha, topoisomerase II-beta was expressed in most normal as well as in tumor tissue samples, at a similar level. The levels of expression of both topoisomerase II isoforms was lower than that of human lung cancer cell lines. The results of the topoisomerase II mRNA expression were confirmed by immunohistochemistry. Whereas topoisomerase II-alpha staining was mainly limited to the nucleus, staining with topoisomerase II-beta antibody was exclusively observed in nucleoli. Topoisomerase I was localized in the nuclei and expression was mainly limited to tumor cells. By RNase protection, topoisomerase I expression in NSCLC samples was in the range of that of human lung cancer cell lines. The expression of the topoisomerase genes did not seem to be coordinated. In tumor cells, there was a positive association between expression of topoisomerase II-alpha and Ki-67, a marker of cell proliferation, as assessed by immunohistochemistry, but not with topoisomerase II-beta or topoisomerase I. Clinical characteristics of the patients, and their survival did not appear to be correlated to the level of expression of any of the topoisomerase genes, although a trend towards a shorter survival was observed in patients whose tumors expressed relatively high topoisomerase II-alpha mRNA levels. IN CONCLUSION: (1) the two isoforms of topoisomerase II are differentially expressed in normal lung and NSCLC cells; (2) higher topoisomerase II-alpha expression is associated with higher cell proliferation in NSCLC; (3) the expression of topoisomerase II-alpha and topoisomerase I, but not of topoisomerase II-beta, was higher in tumor cells compared to normal lung. Given the differential expression of topoisomerases in normal lung and tumors, research of more potent and specific topoisomerase inhibitors might prove beneficial in non-small cell lung cancer. Immunohistochemistry may be indicated in prospectively investigating the correlation between expression of topoisomerases and results of chemotherapy treatment.

An EORTC Gastrointestinal Group evaluation of the combination of sequential methotrexate and 5-fluorouracil, combined with adriamycin in advanced measurable gastric cancer.

In a phase II multicenter trial, 71 patients with advanced measurable gastric cancer were registered to receive sequential high-dose methotrexate (MTX) and 5-fluorouracil (5-FU) combined with Adriamycin (A [Adria Laboratories, Columbus, OH]). The response rate was 33% (22 of 67), including all eligible patients. There were nine complete responders (CRs). The median survival for all patients was 6 months. There has been one toxic death; however, three other patients died from toxicity associated with major protocol violations. It is concluded that this protocol is active in gastric cancer. Toxicity, partly because of nonprotocol adherence, is considerable and is now under further investigation in a randomized trial comparing this schedule with a combination of 5-FU, Adriamycin, and mitomycin C (FAM).

An EORTC Gastrointestinal Group phase III evaluation of combinations of methyl-CCNU, 5-fluorouracil, and adriamycin in advanced gastric cancer.

In a prospective phase III multicenter trial, 189 patients with advanced measurable and nonmeasurable gastric cancer were randomized to receive 5-fluorouracil (5-FU) combined with Adriamycin (FA) or FA plus methyl-CCNU (MeFA). The response rate in patients with measurable disease was 10% (three of 29), and 18% (five of 28), respectively. No difference in the duration of survival was detected (P = .14; log rank test). Median survivals were 21 and 32 weeks, respectively. Toxicity was moderate, but there have been two toxic deaths among the patients who received FA. Because of the low response rate and the short survival, neither regimen can be recommended for the treatment of advanced gastric cancer.

Maintenance chemotherapy in small-cell lung cancer: long-term results of a randomized trial. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group.

PURPOSE: The present study investigates the role of short chemotherapy (five cycles) versus prolonged (12 cycles) chemotherapy in small-cell lung cancer (SCLC). PATIENTS AND METHODS: Six hundred eighty-seven patients with SCLC were registered in a multicenter study to receive five cycles of chemotherapy consisting of cyclophosphamide 1 g/m2 on day 1, doxorubicin 45 mg/m2 on day 1, and etoposide 100 mg/m2 on days 1, 3 and 5 (CDE), every 3 weeks. Four hundred thirty-four nonprogressing patients after five cycles of chemotherapy were randomized either to receive seven further cycles of the same chemotherapy or to follow-up. RESULTS: The response rate of 585 assessable patients was 79%, with 36% attaining a complete response. Toxicity was mainly hematologic, with 16 toxic deaths (2.4% of all eligible patients), 13 of which were due to sepsis. Median survival time from registration of all patients was 326 days (396 and 267 days for limited and extensive disease, respectively) with 3.2% of patients alive at 5 years. No difference in survival between the two arms was observed, with the same number of 5-year survivors in both arms. The patients randomized to the maintenance arm had a progression-free survival (PFS) duration approximately 2 months longer than the patients randomized to follow-up (median of 177 days v 114 days from randomization; P = .0004). Among patients with a partial response who were randomized to receive maintenance chemotherapy, 12 achieved a complete response after 12 cycles. More patients in the follow-up arm than in the maintenance arm received subsequent treatment on progression and responded more frequently to that treatment. Twelve patients developed second malignancies (seven non-small-cell lung cancers). CONCLUSION: Prolonged chemotherapy does not offer a better chance of cure than short chemotherapy (five cycles) and does not prolong survival in patients with SCLC. Short, combination chemotherapy appears to be a reasonable choice for standard treatment of SCLC and for attempts to improve the cure rate of this disease.

Randomized trial of alternating versus sequential radiotherapy/chemotherapy in limited-disease patients with small-cell lung cancer: a European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group Study.

PURPOSE: To evaluate the effectiveness of alternating or sequential schedules of cyclophosphamide, doxorubicin, and etoposide (CDE) chemotherapy and irradiation in patients with previously untreated small-cell lung cancer (SCLC). MATERIALS AND METHODS: A total of 335 eligible patients were randomized between five courses of CDE chemotherapy followed by thoracic irradiation 50 Gy in 20 daily fractions (S) and the same total dose of chemotherapy and irradiation split into four courses of five daily fractions delivered on days 14 to 21 of the second and subsequent chemotherapy courses (A). Patients had a median age of 61 years (range, 33 to 75); 224 (66%) were male; the Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0 or 1 in 311; and 254 had weight loss less than 10%. RESULTS: The overall median survival duration was 15 months, with 62% (95% confidence interval [CI], 57% to 67%) 1-year, 25% (95% CI, 20% to 30%) 2-year, and 14% (95% CI, 10% to 18%) 3-year survival rates. There was no significant difference between the arms. The median survival time was 14 months in A and 15 months in S. One-year survival was 60% in A (95% CI, 53% to 67%) and 64% in S (95% CI, 57% to 71%); 2-year survival was 26% in A (95% CI, 19% to 33%) and 23% in S (95% CI, 16% to 30%); and 3-year survival was 12% in A (95% CI, 6% to 18%) and 15% in S (95% CI, 9% to 21%). World Health Organization (WHO) grade 3 and 4 neutropenia occurred in 90% of A and 77% of S patients (P < .001) and WHO grade 3 and 4 thrombocytopenia in 33% of A and 20% of S patients (P < .001). Rates of other acute and late toxicities were similar in both arms. Hematologic toxicity compromised treatment dose delivery; less than 50% of A patients received greater than 95% of prescribed chemotherapy and 77% their full radiation course, compared with 60% and 93% for arm S (P < .009). Local relapse was the site of first failure in 60% of all patients and 75% of these suffered an in-field relapse; no difference could be seen between the two arms. CONCLUSION: This trial failed to confirm the superiority of an alternating schedule of delivery. For this combination of chemotherapy and irradiation, hematologic toxicity compromised treatment delivery and could have contributed to the overall result. The poor rates of local control are disappointing and require intensification of the radiation therapy strategy.

Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and dose-sequencing study in patients with non-small-cell lung cancer. The European Cancer Centre.

PURPOSE: To investigate the pharmacokinetics and pharmacodynamics of paclitaxel (P) and carboplatin (C) in a sequence-finding and dose-escalating study in untreated non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Fifty-five chemotherapy-naive patients with NSCLC were entered onto the pharmacokinetic part of a large phase I trial in which P was administered as a 3-hour infusion at dosages of 100 to 250 mg/m2, and C over 30 minutes at dosages of 300 to 400 mg/m2. Patients were randomized for the sequence of administration, first C followed by P or vice versa. Each patient received the alternate sequence during the second and subsequent courses. RESULTS: The most important hematologic toxicity encountered-was neutropenia. Hematologic toxicity was not dependent on the sequence in which P and C were administered, but there was cumulative neutropenia. Nonhematologic toxicities consisted mainly of vomiting, myalgia, and arthralgia. No sequence-dependent pharmacokinetic interactions for the P area under the concentration-time curve (P-AUC), maximal plasma concentration (P-Cmax), or time above a threshold concentration of 0.1 mumol/L (P-T > or = 0.1 mumol/L) were observed. However, there was a significant difference for the metabolite 6 alpha-hydroxypaclitaxel AUC (6OHP-AUC). Higher 6OHP-AUCs were observed when C was administered before P. The mean plasma ultrafiltrate AUC of C (CpUF-AUC) at the dosage of 300 mg/m2 for the sequence C-->P was 3.52 mg/mL.min (range, 1.94 to 5.83) and 3.62 mg/mL.min for the sequence P-->C (range, 1.91 to 5.01), which is not significantly different (P = .55). Of 45 assessable patients, there were five major responders (three complete responders and two partial responders). Four of five responses occurred at dosages above dose level 4 (P 175 mg/m2 + C 300 mg/m2). The median survival duration was best correlated with the P dose (4.8 months for doses < 175 mg/m2 v 7.9 months for doses > or = 175 mg/m2, P = .07; P-T > or = 0.1 mumol/L, 4.8 months for < 15 hours v 8.2 months for > or = 15 hours, P = .06). CONCLUSION: There was no pharmacokinetic-sequence interaction between C and P in this study. A clear dose-response relation with respect to response rate and survival was observed. The pharmacokinetic parameter P-T > or = 0.1 mumol/L was related to improved survival in this study.

Carboplatin in combination therapy for ovarian cancer.

Cisplatin today is a cornerstone of combination chemotherapy for ovarian cancer. Carboplatin seems equal to cisplatin in antitumour activity, but has a different toxicity profile. After a feasibility study, a randomized phase III study in ovarian cancer stage II, III, and IV was undertaken, comparing carboplatin with cisplatin in combination with cyclophosphamide, doxorubicin and hexamethylmelamine. Preliminary analysis of this study reveals no statistically significant difference in response rate. Notwithstanding equal haematological toxicity, the other side effects evoked by carboplatin in combination treatment are much milder than those evoked by cisplatin. Further analysis will be necessary to draw definite conclusions about the results obtained.

Mitoxantrone in malignant pleural mesothelioma: a study by the EORTC Lung Cancer Cooperative Group.

46 patients with malignant pleural mesothelioma were entered in a phase II study of mitoxantrone 14 mg/m2 every 3 weeks. Histology was confirmed by a pathology panel. None of the patients had received previous chemotherapy. Toxicity was mainly mild gastrointestinal and haematological side-effects. Out of 34 patients evaluated for response, only 1 partial response was recorded. Mitoxantrone at this dose and schedule has marginal activity in malignant mesothelioma.

Phase II trial for intraperitoneal cisplatin plus intravenous sodium thiosulphate in advanced ovarian carcinoma patients with minimal residual disease after cisplatin-based chemotherapy--a phase II study of the EORTC Gynaecological Cancer Cooperative Group.

On the basis of its efficacy against ovarian carcinoma and its safe peritoneal administration, cisplatin administered by the intraperitoneal route was studied in a phase II multicentric trial. 34 patients with good performance status and residual disease less than 1 cm were treated with a 90 mg/m2 dose (60 mg/m2 at first cycle), administered in the abdominal cavity every 3 weeks for at least four cycles. In case of haematological or renal toxicity, intravenous sodium thiosulphate was perfused simultaneously with intraperitoneal cisplatin with protective intent. 25 patients were evaluable for response: 3 patients had pathological complete response and 1 patient had a microscopic disease (16% response rate in evaluable patients). Systemic toxicity was mild, and sodium thiosulphate clearly protected against leucopenia (6 patients) and renal toxicity (8 patients). Local side-effects were evaluable in 34 patients with 2 cases of infectious peritonitis, 1 of wound infection and 2 of haemorrhage. Of the 147 evaluable chemotherapy cycles, nine resulted in partial and one in total inflow obstruction, for which 4 patients needed surgical procedures for catheter-related complications, and 1 patient died of acute abdominal complications after such a procedure. We conclude that 90 mg/m2 intraperitoneal cisplatin has activity in pretreated patients with minimal residual disease, and that thiosulphate protects against haematological and renal toxicities. Only a randomised study can demonstrate a true benefit, which will have to be balanced with the toxicity of intraperitoneal drug administration.

Neural cell adhesion molecule expression, neuroendocrine differentiation and prognosis in lung carcinoma.

We investigated the expression of the neural cell adhesion molecule (NCAM) in a series of surgically resected lung carcinomas of various histological subtypes by means of a panel of monoclonal antibodies recognising different N-CAM epitopes. In a subgroup of 56 tumours, the results of immunostaining with MAb 123C3--the antibody studied most extensively in our material--were compared to the ultrastructure, and in 231 radically resected non-small cell carcinomas, with histological tumour type and with clinical follow-up data. N-CAM expression was not limited to neuroendocrine tumours, as assessed ultrastructurally. Non-small cell lung carcinomas positive for MAb 123C3 showed post-operative overall and disease-free survival times significantly shorter than 123C3-negative non-small cell carcinomas.

Role of recombinant interferon-gamma maintenance in responding patients with small cell lung cancer. A randomised phase III study of the EORTC Lung Cancer Cooperative Group.

This study was undertaken to determine if recombinant interferon-gamma (rIFN-gamma) given every other day as maintenance therapy could prolong the survival of patients with small cell lung cancer (SCLC) who achieved a complete or nearly-complete response to induction therapy. A secondary endpoint was to assess the toxicity of alternate day doses of this treatment. One hundred and seventy seven patients in complete or nearly-complete response following chemotherapy with or without thoracic radiotherapy were studied. Patients were randomised to receive either rIFN-gamma 4 million units (0.2 mg) subcutaneously every other day for 4 months or observation. One hundred and twenty of the 127 registered patients were eligible; 59 patients received IFN and 61 patients without maintenance therapy were followed. Alternate day IFN was reasonably well tolerated by the majority of patients, but in 12% substantial non-haematological toxicity (including flu-like syndrome) occurred. One of 3 patients with pneumonitis died after having received 3.6 mg IFN. The median survival time from the date of randomisation was 8.9 months for the IFN arm and 9.9 months for the observation arm. rIFN-gamma at the dose and schedule used in this study failed to prolong response duration and survival in SCLC patients in complete or nearly-complete response. The toxicity seen with every other day doses of IFN was less than that reported with daily dosing. The hypothesis that this agent may increase the deleterious effects of radiation on normal lung tissue was supported by the development of pneumonitis in 3 cases of whom 1 had a fatal outcome. The results do not warrant further studies with rIFN-gamma on maintaining response in SCLC.

Platinum-based chemotherapy in non-small cell lung cancer: the experience of the European Organization for the Research and Treatment of Cancer.

The history of chemotherapy for non-small cell lung carcinoma is one of very slow progress. Consequently, the categories of patients who will ultimately benefit from this modality are still debated. Recent European Organization for Research and Treatment of Cancer studies show that there is less concern about the importance of platinum as an ingredient of combination regimens or as an adjunct to radiotherapy. The presence of cisplatin is related to better response and survival in patients with locoregional and distant metastatic disease.

The European Organization for Research and Treatment of Cancer experience with teniposide: preliminary results of a randomized study in non-small cell lung cancer.

Chemotherapy for non-small cell lung cancer (NSCLC) is unsatisfactory, and the search for new active drugs has been relatively unsuccessful. Most polychemotherapy regimens in NSCLC include cisplatin with a vinca alkaloid or etoposide. Among the new agents tested in recent years, teniposide produced a 17% response rate in 42 evaluable patients, with a 21% response rate in untreated patients. The Lung Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer has started a randomized trial comparing two different schedules of teniposide administration with and without cisplatin. This paper reports the preliminary findings for the initial 80 patients in this randomized study.

Paclitaxel plus carboplatin in the treatment of ovarian cancer.

Second-line treatment with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) may achieve remissions in patients suffering from ovarian cancer who have failed primary chemotherapy with cisplatin- or carboplatin-based regimens. Introduction of paclitaxel in combination with cisplatin into the first-line treatment strategy was therefore the next logical step in the development of chemotherapy against ovarian cancer. Data already have shown that this may result in better survival. Since carboplatin may replace cisplatin, the combination of paclitaxel with carboplatin seemed a further necessary step. We therefore embarked on a dose-finding study of paclitaxel and carboplatin. Fourteen patients with International Federal of Gynecology and Obstetrics stage III and IV ovarian cancer with a median age of 55.5 years entered this study of escalating doses of either carboplatin or paclitaxel. Doses of carboplatin could be escalated from 300 to 450 mg/m2 and paclitaxel could be escalated from 125 to 175 mg/m2 without dose-limiting myelosuppression. At the highest dose level reported here, only transient short-lived leukopenia was observed. Other toxicities consisted of nausea and vomiting, peripheral neurotoxicity, and arthralgia, all mild. In the first 14 patients, 10 of whom are evaluable, complete remissions were seen in two patients and partial remissions in six. This study will escalate the doses of paclitaxel and carboplatin further. This treatment is well tolerated and yields satisfactory antitumor results.

Carboplatin and paclitaxel in patients with advanced ovarian cancer: a dose-finding study.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) combined with cisplatin seems the new standard of care for ovarian cancer patients. Since carboplatin lacks the neurotoxicity of cisplatin with an equal antitumor activity against ovarian cancer, it was chosen as the next logical step for combination chemotherapy with paclitaxel. In 46 patients an alternating dose-escalation trial has been performed. The maximum tolerated doses are carboplatin 500 mg (area under the concentration-time curve of 9) and paclitaxel 200 mg/m2 given every 3 weeks. The dose-limiting toxicity is thrombocytopenia, which emerges in the later stages of the treatment. A true platelet-sparing effect of the combination seems highly probable. The antitumor activity of the combination equals that reported for the new standard paclitaxel/cisplatin treatment. Further phase III studies are warranted.