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Carboplatin is a close relative of the chemotherapeutic agent cisplatin, but it lacks some of the toxic effects of cisplatin. Both carboplatin and another agent, ifosfamide, have been shown to be active against small cell lung cancer. A study was therefore undertaken to evaluate the combined use of carboplatin and ifosfamide in the treatment of advanced small cell lung cancer. A total of 30 patients were included in the study; none had been previously treated and all had metastatic cancer, which had spread to at least one other part of the body. In 18 cases, the cancer had spread to at least two other parts of the body. Generally, the prognosis for metastatic small cell lung cancer is dismal. In the present series of patients, one patient achieved a complete response and 18 others achieved partial responses. However, the midpoint survival time of the patients was only eight months. An important finding was that 4 of 11 patients who did not respond to the combination of carboplatin and ifosfamide responded when subsequently treated with doxorubicin and etoposide, either with or without cisplatin. These four cases indicate that there is no cross-resistance between the two different chemotherapeutic regimens. Therefore, effective treatments might consist of alternating two different treatment protocols. (Consumer Summary produced by Reliance Medical Information, Inc.)

Pemetrexed is a new multitargeted antifolate that can be easily administered as a 10-min infusion every 3 weeks. The use of folic acid, vitamin B12, and corticoid prophylaxis has significantly reduced pemetrexed-induced toxicity. Single-agent pemetrexed has shown antitumor activity in a wide range of solid tumors, including non-small cell lung cancer (NSCLC). Association with vinorelbine, cisplatin, carboplatin, and oxaliplatin have been tried, but the pemetrexed and gemcitabine combination, an easy to administer cisplatin-free doublet, has been documented in many phase 2 trials in the first-line treatment of advanced NSCLC. In vitrocytotoxic assays and phase I studies have defined several schedules of administration for pemetrexed and gemcitabine. The recommended dose is pemetrexed 500 mg/m2on day 1 or 8, and gemcitabine 1250 mg/m2on day 1 and 8, but it is unknown if pemetrexed should precede or follow gemcitabine and at what time interval. Published studies have failed to show significant differences in overall survival times despites response rates oscillating between 15% and 41%. The main toxicities are neutropenia, fatigue, skin rashes and elevated transaminases and seem to occur with similar rates in the many phase 2 trials. Hopes for the future are in tailored chemotherapy, since molecular markers of sensitivity are available for gemcitabine and pemetrexed, allowing to determinate in the future which patients will be most likely to benefit from the gemcitabine-pemetrexed doublet.

In the period 1989‐1991, 612 patients with inoperable stage IIIA/B and IV non‐small cell lung cancer (NSCLC) were randomized in a phase III trial comparing three chemotherapy regimens. Survival data at five and six years of follow‐up confirm the overall benefit of treatment with a combination of vinorelbine and cisplatin compared to vindesine plus cisplatin or vinorelbine alone. Of the 612 patients randomized at the start of the study, 17 have survived beyond five years. Of these patients, eight had entered the trial with metastatic disease. Multivariate analysis to detect prognostic factors suggested a possible interaction between the effect of having cisplatin in the chemotherapy received and baseline performance status. Subgroup analysis subsequently confirmed that the survival benefit of the vinorelbine plus chemotherapy regimen is evident only in patients with initial World Health Organization performance status (PS) of 0‐1. Among these patients, the one‐year survival rate is 38% for the vinorelbine/cisplatin arm, 29% for vindesine/cisplatin and 34% for vinorelbine alone. The corresponding figures for median survival are 43, 33 and 36 weeks. Among inoperable NSCLC patients with a PS of 2, who appear from this trial not to have benefited from the presence of cisplatin in their chemotherapy, use of single agent vinorelbine is an appropriate treatment option.

To assess, using a large homogeneous retrospective series, the prognostic value of the number of resected pulmonary metastases, and thus, to determine to what extent the number of resectable metastases should influence the surgical decision.

A phase II study was designed to evaluate objective response rate and toxicity of fotemustine as single-drug chemotherapy in non-small-cell lung cancer. Eighty-seven patients with unresectable non-small-cell lung cancer took part in the study. Seventy-seven were evaluable for response. Of these, 60% had received prior chemotherapy and 74% had metastatic disease. Moreover, 22 patients had central nervous system metastases (of whom 12 were evaluable for this site). Treatment consisted of fotemustine 100 mg m-2 administered on days 1 and 8 followed by a 5 week rest period. Afterwards, responding or stabilised patients received fotemustine 100 mg m-2 every 3 weeks as a maintenance therapy. Toxicity and quality of life were recorded during therapy. Thirteen patients (17%; 95% CI 9-25%) had an objective response (11% for pretreated, 26% for non-pretreated) with a median duration of 22 weeks (range 7-41 weeks). Two objective responses were observed among the 12 patients with evaluable brain metastases. No response was observed among the 14 patients with adenocarcinoma. Haematological, gastrointestinal, hepatic and renal toxicities were mild to moderate and manageable. The most frequent biological adverse reactions were delayed thrombocytopenia and neutropenia. Quality of life did not significantly decrease during the first 6 treatment weeks. Moreover, it remained stable during the study period in patients with response or stabilisation, whereas it significantly decreased in patients who experienced progression of the disease. Fotemustine is feasible for single-drug chemotherapy in non-small-cell lung cancer even though poor prognostic variables such as brain metastases are present. It can be administered on an outpatient basis and toxicity is moderate and manageable. Thus, fotemustine can be considered as a putative drug in further combinations.

Between 1970 and 1982, 592 patients with T1and small T2breast cancers were treated at the Institut Gustave-Roussy by a combination of conservative surgery and radiotherapy. Mean follow-up was 78 months. The actuarial survival rate at 5 and 10 years was 92 per cent and 80 per cent respectively. There were 36 locoregional relapses of which 26 were within the treated breast. The actuarial relapse rate within the breast was 5 per cent at 5 years. If operable, a relapse within the breast did not significantly affect overall survival. The efficacy of conservative management of small breast tumours is confirmed.

Seven consecutive patients with intra-abdominal desmoplastic small round-cell tumours were screened at presentation for carcinoembryonic antigen (CEA), Ca19-9, Ca15-3, Ca125, alpha-fetoprotein (AFP), human chorionic gonadotrophin (hCG) and neuron-specific enolase (NSE). Initially elevated tumour markers were used to monitor therapy and follow-up. Tumour marker assays were all in the normal range, with the exception of Ca125 and NSE. The Ca125 level was initially high in six of the seven patients (86%) with a median value of 200 U ml-1 and a range of 22-735 U ml-1. The NSE value was elevated before therapy in three of the five patients (60%) for whom assay results were available, with a median of 19 ng ml-1 and a range of 6.8-37.5 ng ml-1 . Ca1 25 normalized in five out of six cases and NSE always normalized during chemotherapy, but neither of these two tumour markers correlated specifically with response, as only one patient experienced a partial response, five tumour stabilization and the remaining patient tumour progression. At progression, Ca125 was again elevated in two out of four cases several weeks before clinical relapse and NSE in only one out of three cases. Ca125 and NSE are frequently raised in the serum of patients with intra-abdominal desmoplastic small round-cell tumours before therapy, but are not reliable monitors of the course of the disease. However, normalization is frequently associated with an improvement of symptoms or a moderate clinical response.

Raltitrexed, a thymidylate synthase inhibitor, was given to 21 patients with advanced small-cell lung cancer, at a dose of 3 mg m(-2) as a 15-min intravenous infusion at 21-day intervals. All of the patients had extensive disease and 17 had received prior therapy. Patients with disease refractory to primary chemotherapy were excluded. Forty-one treatment cycles were given (median two, range one to four). The drug was well tolerated. No objective tumour response was documented. The patients had chemoresistant disease, as shown by a response in only one of ten patients who went on to receive alternative cytotoxic regimens. We conclude that raltitrexed given in this schedule is inactive as second line therapy for small-cell lung cancer.

Docetaxel is a tubulin polymerizing agent that shows activity as a single agent in advanced NSCLC. Its combination with cisplatin has been investigated in different phase II trials. In this study, we used a treatment schedule consisting of docetaxel 75mg/m2and cisplatin 100mg/m2every 3 weeks during 3 cycles and then every 6 weeks, with a standard premedication: dexamethasone, antihistaminic, antiemetic and hyperhydration. Evaluation of activity was performed every 6 weeks. Eligible patients (pts) had histologically proven locally advanced or metastatic NSCLC, measurable tumor, no previous chemotherapy, KPS≥60, age≤75, normal hematological, hepatic and renal functions, no brain or leptomeningeal involvement and signed informed consent. Fifty-one patients have been included: 3 were not eligible, the characteristics of the 48 remaining pts are: 44 males, 4 females; mean age: 54 years (range 34–75); stage IIIB: 13%, stage IV: 87%; they received a mean of 4 cycles (range 1–6). Among these 48 pts, 1 CR and 13 PR (29%) were observed, including 9 PR continned today by an independent panel, lasting from 15+ to 31+ weeks. Main toxicities (G 3–4) were: febrile neutropenia: 5 pts, documented sepsis: 5 patients. No toxic death was reported. As a result of using routine premedication, previously reported side effects were considerably lessened Based on this preliminary analysis combination of docetaxel 75mg/m2and cisplatin 100mg/m2, indicates an interesting result which should deserve other investigations of this drug combination.

Adult patients (pts) with ASTS who relapse or fail to respond to a first line ADR-containing chemotherapy regimen are candidates for investigational treatment. Based on a concept of possible antitumor interactions and anticipated biochemical and pharmacological synergism between cytokines and cytotoxic drugs, we designed a phase II study in which ADR was concurrently administered with subcutaneous (SC) r-L2 in ADR-refractory or resistant ASTS. Pts received one injection of ADR alone (70mg/m2) and three weeks later a combination of r-IL2 (18MIU/m2dl to d5 SC) and ADR at the same dose either 1) 3 hours after the first r-IL2 injection (dl) or 2) at lymphocyte rebounds (d8). The same combination was repeated every 4 weeks according to the status of the disease. The main objective of this trial was to evaluate the impact of r-IL2 on ADR pharmacokinetic parameters. In this ongoing study, started in 6/94, 11 pts have been included, of whom, nine have received the two planned courses (c). As expected, in these 9 heavily ADR-pretreated pts, both local relapses and metastatic lesions remained unchanged (3 pts) or exhibited progression (6 pts) after ADR alone. Interestingly, 2 pts achieved a PR after 4 and 2 IL2/ADR c (1 PR in both arms), 2 a MR after 1 c (pts still on treatment), and 1 pt a dissociated response. The toxicity (T) of the combination was more substantial than with ADR alone: grade 3_4leukoneutropenia (7 pts), grade 3_4 thrombocytopenia (2 pts) and mucitis (5 pts). Total dose of ADR was reduced by 25% in all subsequent c. ADR infusion on dl IL2 c prevents lymphocyte rebounds in all pts. The evaluation of the impact of r-IL2 on ADR metabolism, the determination of immunological profiles in the two treatment arms and an analysis supporting a modulation of resistance to ADR by r-IL2 will be presented.

The standard combination chemotherapy of SCLC is an etoposide based regimen. After failure of this regimen the prognosis is very poor although the use of a rescue regimen still displays clinical activity.It has been already suggested that investigational new drugs should to be assessed in second line therapy in SCLC and that a RR≥10% among 29 patients would be relevant for the screening of active new compounds.CPT11 is a new DNA topoisomerase I inhibitor active in colorectal cancer and other solid adult tumors.22 patients with progressive extensive SCLC after a prior response on a VP16-based chemotherapy have been so far entered onto the study. Sex ratio M/F=19/3; median age=57.2 (43–72). Performance Status 0=14%; 1=45%; 2=41%. Median number of involved organ 4 (1–6) with liver (27%), lung (22%), lymph nodes (16%) and brain (11% of patients).57 cycles at the planned dose of 350mg/m2every 3 weeks have been delivered with a median Relative Dose Intensity of 0.95 (0.78–1. 03).Efficacy: One CR and three PR have been observed among the 15 evaluable patients.Safety: The incidence of grade 3 and 4 toxicity per cycle has been: neutropenia: 49% (with febrile neutropenia sepsis in 14%), delayed diarrhea: 18%, nausea vomiting: 14%.

A 25%–33% increase in initial doses of cisplatin (CDDP) and cyclophosphamide (CPM), when combined with standard doses of doxorubicin and etoposide, has been found sufficient to significantly improve both disease free and overall survival in patients with limited SCLC (NEJM 1993, 329, 1148–1152). In this following trial, we are testing whether or not an increase in dose-intensity of a quite similar 4drug regimen leads to an improvement in survival. From October 1991 to December 1994, 123 patients with untreated SCLC were enrolled in this study comparing “standard dose” (SD) PEVEP for 6 cycles versus “high dose” (HD) PEVEP+rh-GMCSF (E. Coli derived) for 4 cycles. SD PEVEP consisted of: Epirubicin 40mg/m2dl, CDDP 100mg/m2d2, Etoposide 75mg/m2/d dl-3, CPM 400mg/m2/d dl-3. In the HD PEVEP arm the intended doses for each cycle were increased by 50%, except for CDDP: 25%. This HD PEVEP arm was supported by a systematic use ofrh-GMCSF (5 μg/hg/d s. c.) administered from d4 to dl3. Thus, the cumulative doses in both arms were roughly similar. Responding patients with residual disease confined to the chest were eligible for thoracic radiation. Complete responders were eligible for prophylactic cranial radiation. An interim analysis was performed as planned by the protocol after the inclusion of 50% of 200 patients required to demonstrate a 50% improvement in median survival. Accrual has been closed prematurely on 12/23/94 due to a significant survival difference between the two arms. An updated analysis will be presented.

A recent meta-analysis using individual data from 54 trials included more than 9000 NSCLC patients in three adjuvant settings (surgery + chemotherapy (CT), surgery ± radiotherapy (RT) ± CT, radical RT ± CT) and in the supportive care setting. Of the 14 trials analysing the first adjuvant setting, only 7 including 1062 patients, used a cisplatin based regimen. Even if the CT protocols would be now considered sub-optimal, the results suggested a relative benefit of CT of 13% in terms of death reduction. This is equivalent to an absolute improvement of survival of 5% at 5 years (from 47% to 52%). Chemotherapy after curative resection of NSCLC could therefore improve survival. The main objective of IALT is to evaluate the effect on overall survival of 3 or 4 cycles of cisplatin-based CT at a dose ranging from 80 to 120mg/m2combined with a vinca-alkaloid or etoposide compared with no adjuvant CT. in stage I to IIIA completely resected lung cancer. This hypothesis deserves to be tested in a large-scale trial in order to obtain clear evidence on the value of adjuvant CT With widespread collaboration, it will be possible to include the necessary 3000 patients for randomisation in only a few years.

Endobronchial high dose rate brachytherapy (BT) is an alternative treatment for very small and limited bronchial carcinomas in patients with chronic respiratory deficiency after past history of lung cancer treated by surgery and/or external radiotherapy.Study of toxicity and results of high dose rate B.T. in 18 patients with 21 limited and endoscopically visible lesions.