Chemotherapy-induced neutropenia as a prognostic factor in advanced non-small-cell lung cancer: results from Japan Multinational Trial Organization LC00-03.

BACKGROUND: Neutropenia is a common adverse reaction of chemotherapy. We assessed whether chemotherapy-induced neutropenia could be a predictor of survival for patients with non-small-cell lung cancer (NSCLC). METHODS: A total of 387 chemotherapy-naïve patients who received chemotherapy (vinorelbine and gemcitabine followed by docetaxel, or paclitaxel and carboplatin) in a randomised controlled trial were evaluated. The proportional-hazards regression model was used to examine the effects of chemotherapy-induced neutropenia and tumour response on overall survival. Landmark analysis was used to lessen the bias of more severe neutropenia resulting from more treatment cycles allowed by longer survival, whereby patients who died within 126 days of starting chemotherapy were excluded. RESULTS: The adjusted hazard ratios for patients with grade-1 to 2 neutropenia or grade-3 to 4 neutropenia compared with no neutropenia were 0.59 (95% confidence interval (CI), 0.36-0.97) and 0.71 (95% CI, 0.49-1.03), respectively. The hazard ratios did not differ significantly between the patients who developed neutropenia with stable disease (SD), and those who lacked neutropenia with partial response (PR). CONCLUSION: Chemotherapy-induced neutropenia is a predictor of better survival for patients with advanced NSCLC. Prospective randomised trials of early-dose increases guided by chemotherapy-induced toxicities are warranted.

Photon emissions from rice cells elicited by N-acetylchitooligosaccharide are generated through phospholipid signaling in close association with the production of reactive oxygen species.

Biophotons are ultraweak light emissions from biochemical reactions in a living body. They increase in suspension-cultured rice (Oryza sativa L.) cells when elicited by N-acetylchitooligosaccharide. Biochemical analyses were undertaken to investigate the relationship between disease response and biophotons in order to clarify the emission mechanism of biophotons caused by this elicitor. Photon emissions induced by N-acetylchitohexaose were suppressed when cells were pretreated with the reactive oxygen species (ROS)-generating inhibitors: pyrocatechol-3,5-disulfonic acid disodium salt (Tiron); diphenylene iodonium (DPI); and salicylhydroxamic acid (SHAM). Conversely, exogenously applied ROS (superoxide and hydrogen peroxide) were able to induce photon emissions. The effects of protein phosphorylation (K-252a) and the Ca(2+) signaling inhibitors, ethylene glycol-bis(beta-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA) and LaCl(3), caused photon emissions to decrease. It is clear that photon emissions from rice cells elicited by N-acetylchitohexaose are closely associated with the ROS-generating system, and are regulated by Ca(2+) signaling and protein phosphorylation. Exogenously applied phosphatidic acid (PA), the second messenger in the signal transduction of disease response, raised photon emissions in rice cells. Comparisons of photon emissions from PA and N-acetylchitohexaose regarding time courses, spectral compositions, and the inhibition ratios of several inhibitors, as well as a loss- and gain-of-function assay using the protein synthesis inhibitor cycloheximide (CHX) and PA, showed the possibility that photon emissions from rice cells elicited by N-acetylchitooligosaccharide were generated through PA, an intermediate of phospholipid signaling.

[A resected case of malignant fibrous histiocytoma of the chest wall].

We report a 74-year-old woman with malignant fibrous histiocytoma (MFH), treated successfully by radiation and followed with chest wall resection and reconstruction. The patient suffered from right back pain and her chest X-ray showed a clear round shadow in the middle field of the right lung. Chest computed tomography (CT) showed a 5 x 5 cm tumor in diameter, involving the right 8 rib with destructive changes. After radiation therapy of total 30 Gy to the tumor to obtain the safety surgical margin, we widely resected 10 x 9 cm chest wall with 3 ribs in area under thoracoscopy and performed reconstruction using GORE-TEX Soft Tissue Patch. The pathological and immuno-histochemical diagnosis showed pleomorphic type of MFH. Final result of the tumor negative in surgical margin manifested that our technique of chest wall resection and reconstruction using thoracoscope after the irradiation to the tumor was very safe and useful.

Gemcitabine and vinorelbine followed by docetaxel in patients with advanced non-small-cell lung cancer: a multi-institutional phase II trial of nonplatinum sequential triplet combination chemotherapy (JMTO LC00-02).

To evaluate the efficacy and toxicity of the sequential nonplatinum combination chemotherapy consisting of gemcitabine (GEM) and vinorelbine (VNR) followed by docetaxel (DOC) in patients with advanced non-small-cell lung cancer (NSCLC), we conducted the multiinstitutional phase II study. A total of 44 chemotherapy-naive patients with advanced NSCLC were treated with GEM 1000 mg m(-2) and VNR 25 mg m(-2) intravenously on days 1 and 8 every 3 weeks for three cycles. DOC 60 mg m(-2) was then administrated intravenously at 3-week intervals for three cycles. Patients were evaluated for response and toxicity with each cycle of the treatment. The major objective response rate was 47.7% (95% confidence interval (CI), 33.8-62.1%). Median survival time (MST) was 15.7 months and 1-year survival rate was 59%. In the GEM/VNR cycle, grade 3/4 neutropenia occurred in 36.3%, grade 3/4 anaemia in two patients (4.5%) and grade 3 thrombocytopenia in one patient (2.3%). Grade 3 pneumonitis occurred in two patients (4.5%) in GEM/VNR cycles. In the DOC cycles, grade 3/4 neutropenia occurred in 39.4% but no patient experienced grade 3/4 anaemia or thrombocytopenia. Of the 44 eligible patients, 33 patients completed three cycles of GEM/VNR and 22 patients completed six cycles of planned chemotherapy (three cycles of GEM/VNR followed by three cycles of DOC). The sequential triplet nonplatinum chemotherapy consisted of GEM/VNR followed by DOC, and was very active and well tolerated. This study forms the basis for an ongoing phase III trial that compares this nonplatinum triplet and standard platinum doublet combination (carboplatin/paclitaxel).

Critical factors for patient management.

The main critical factors for lung cancer patient management, apart from TNM staging, include expertise required to offer optimal management and conditions related to the patient, including performance status and weight loss and the presence of lung, cardiac or other comorbidities. Performance status and weight loss must be assessed for all patients. The minimal pulmonary functional evaluation should include spirometry. The minimal cardiac evaluation should consist of a clinical history and evaluation for cardiac risk factors and disease and at least preoperatively, and ECG. Age per se is not a contraindication for curative treatment.

Consensus: the follow-up of the treated patient.

This is the first consensus document on the follow-up of the treated patient with non-small cell lung cancer that has been written by this group. The document has been drawn up by doctors coming from many different cultures and philosophical backgrounds. It acknowledges that there are published guidelines on the follow-up particularly those in trials, and does not wish to contradict these. There is lack of evidence-based medicine to recommend a strong general policy in this area. For those patients who were treated with curative intent the initial follow-up will depend upon the toxicity that is evident from the treatment given. Thereafter the interval between follow-up visits should be every 3 months for the first two years, then every 6 months for up to five years. Rapid and easy access to the multidisciplinary team should be available. Full examination and chest X-ray should be carried out on each visit but other investigations should be determined by clinical need. For those patients treated with palliative intent the interval between follow-up visits once the acute reactions have settled will depend upon the adequacy of the control of the symptom and the availability of separate palliative care teams. At all times the patient should have rapid access to the multidisciplinary team and in general frequent follow-up, that is at intervals of one to two months, may be appropriate during the first six months. Follow-up constitutes an important part of lung cancer management. Efforts should be made to gain clinical material to give us evidence-based guidelines.

Early phase II study of S-1, a new oral fluoropyrimidine, for advanced non-small-cell lung cancer.

BACKGROUND: The efficacy and safety of S-1, a new oral fluoropyrimidine, were evaluated in patients with non-small-cell lung cancer (NSCLC). The objective of this study was to determine whether the drug should be investigated in a late phase II study. METHODS: Each treatment course consisted of an oral dose of S-1, 50 mg/body or 75 mg/body, twice a day for 28 days followed by a 2-week washout period. RESULTS: Fifty-six eligible patients were enrolled. Five of the 40 previously untreated patients (12.5%; 90% confidence interval, 6.2%-23.5%) showed a partial response (PR), and no tumor response was observed in the 16 previously treated patients. The median survival duration in all eligible patients was 8.4 months, with a 1-year survival rate of 27.3%. The incidences of grade 3 or more severe adverse effects were: anemia, 5.4%; leukopenia, 5.4%; neutropenia, 5.4%; thrombocytopenia, 1.8%; anorexia, 3.6%; diarrhea, 3.6%; and general fatigue, 5.4%. These effects disappeared after cessation of the drug or appropriate treatment. One patient died as a result of aggravated interstitial pneumonitis, but the relationship of this event to S-1 was not clear. CONCLUSION: S-1 showed modest activity with mild toxicity in the treatment of non-small-cell lung cancer. Based on this result, we will progress to the next stage of a late phase II study for advanced NSCLC, and a phase II study of S-1 and cisplatin for advanced gastric cancer. Final results will be reported as they are obtained.

Phase II study of S-1, a novel oral fluorouracil, in advanced non-small-cell lung cancer.

The purpose of this study was to evaluate the efficacy and safety of a novel oral anticancer fluoropyrimidine derivative, S-1, in patients receiving initial chemotherapy for unresectable, advanced non-small-cell lung cancer (NSCLC). Between June 1996 and July 1998, 62 patients with NSCLC who had not received previous chemotherapy for advanced disease were enrolled in this study. 59 patients (22 stage IIIB and 37 stage IV) were eligible for the evaluation of efficacy and safety. S-1 was administered orally, twice daily, after meals. 3 dosages of S-1 were prescribed according to body surface area (BSA) so that they would be approximately equivalent to 80 mg m(-2)day(-1): BSA < 1.25 m(2), 40 mg b.i.d.; BSA> or =1.25 but <1.5 m(2); 50 mg b.i.d., and BSA> or =1.5 m(2): 60 mg b.i.d. One cycle consisted of consecutive administration of S-1 for 28 days followed by a 2-week rest period, and cycles were repeated up to 4 times. The partial response (PR) rate of the eligible patients was 22.0% (13/59); (95% confidence interval: 12.3-34.7%). A PR was observed in 22.7% (5/22) of the stage IIIB patients and 21.6% (8/37) of the stage IV patients. The median response duration was 3.4 months (1.1-13.7 months or longer). Grade 4 neutropenia was observed in one of the 59 patients (1.7%). The grade 3 or 4 toxicities consisted of decreased haemoglobin level in 1.7% of patients (1/59), neutropenia in 6.8% (4/59), thrombocytopenia in 1.7% (1/59), anorexia in 10.2% (6/59), diarrhoea in 8.5% (5/59), stomatitis in 1.7% (1/59), and malaise in 6.8% (4/59), and their incidences were relatively low. There were no irreversible, severe or unexpected toxicities. The median survival time (MST) of all patients was 10.2 months (95% confidence interval: 7.7-14.5 months), and the one-year survival rate was 41.1%. The MST of the stage IIIB patients was 7.9 months, and that of the stage IV patients was 11.1 months. The one-year survival rates of the stage IIIB and IV patients were 30.7% and 47.4%, respectively. S-1 was considered to be an active single agent against NSCLC. Further study of S-1 with other active agents is warranted.

Conversion of zonulae occludentes from tight to leaky strand type by introducing claudin-2 into Madin-Darby canine kidney I cells.

There are two strains of MDCK cells, MDCK I and II. MDCK I cells show much higher transepithelial electric resistance (TER) than MDCK II cells, although they bear similar numbers of tight junction (TJ) strands. We examined the expression pattern of claudins, the major components of TJ strands, in these cells: claudin-1 and -4 were expressed both in MDCK I and II cells, whereas the expression of claudin-2 was restricted to MDCK II cells. The dog claudin-2 cDNA was then introduced into MDCK I cells to mimic the claudin expression pattern of MDCK II cells. Interestingly, the TER values of MDCK I clones stably expressing claudin-2 (dCL2-MDCK I) fell to the levels of MDCK II cells (>20-fold decrease). In contrast, when dog claudin-3 was introduced into MDCK I cells, no change was detected in their TER. Similar results were obtained in mouse epithelial cells, Eph4. Morphometric analyses identified no significant differences in the density of TJs or in the number of TJ strands between dCL2-MDCK I and control MDCK I cells. These findings indicated that the addition of claudin-2 markedly decreased the tightness of individual claudin-1/4-based TJ strands, leading to the speculation that the combination and mixing ratios of claudin species determine the barrier properties of individual TJ strands.

Double-blind randomized control trial of the effect of recombinant human erythropoietin on chemotherapy-induced anemia in patients with non-small cell lung cancer.

BACKGROUND: We studied the clinical effect of recombinant human erythropoietin (r-huEPO) on anemia induced by two courses of cisplatin-based chemotherapy in patients with non-small cell lung cancer (NSCLC). METHODS: Seventy-two patients with NSCLC were randomized into three groups, receiving 100, or 200 IU/kg of r-huEPO, or placebo. The r-huEPO and placebo were administered subcutaneously three times a week for 6 weeks, starting 2 weeks after the initiation of chemotherapy. RESULTS: In the 53 evaluable patients, hemoglobin (Hb) levels at the nadir after the second cycle of chemotherapy were significantly elevated compared with the nadir after the first cycle in both r-huEPO treated groups, while this level was decreased in the placebo group. Hb levels at the end of the second course of chemotherapy (week 8) in both r-huEPO groups were higher than that in the placebo groups. No adverse drug reaction attributable to r-huEPO was observed. Serum erythropoietin levels after the administration of r-huEPO were higher than those after placebo administration. CONCLUSIONS: r-huEPO had an effect in preventing anemia in patients with NSCLC who had cisplatin-based chemotherapy.

Comparison of K-ras point mutations at codon 12 and p21 expression in pancreatic cancer between Japanese and Chinese patients.

BACKGROUND AND OBJECTIVES: K-ras (Kirsten-ras) point mutation (PM) in codon 12 are suggested to be significantly associated with the tumorigenesis of pancreatic cancer. The incidences of K-ras PMs in human pancreatic cancer are reported to be different between Europeans and Japanese. The present study was designed to compare the incidences and profile of K-ras PMs and ras-p21 expression in primary invasive ductal carcinoma (IDC) of the pancreas between Japanese and Chinese. METHODS: The specimens included 51 Japanese and 34 Chinese patients with the primary IDC of the pancreas. K-ras PMs were tested by allele specific oligonucleotide dot blot hybridization methods and ras-p21 expression was stained by the immunohistochemical method. RESULTS: K-ras PMs were detected in 48 Japanese IDCs (94%) and in 24 Chinese ones (71%). There was a significant difference between the two groups. The GAT mutation was more frequent both in Japanese (61%, 33/54) and in Chinese (60%, 18/30) IDCs. The transitions/transversions ratio in the Japanese group was 2.4 in this study. By contrast, that in the Chinese group was 1.5. The expression of p21 was detected in 24 Japanese IDCs (47%) and in 24 Chinese IDCs (71%). There was a significant difference between the two groups. The expression of p21 and the patterns of K-ras PMs did not show any significant influence on the survival of the patients both in Japanese and Chinese. In the present study, Chinese IDC had a lower frequency of K-ras PMs in codon 12 than Japanese IDC. The pattern of K-ras PMs in Chinese IDC was different from that in Japanese and European IDC, respectively. CONCLUSIONS: Ki-ras PM and p21 expression were frequently seen both in Japanese and Chinese patients with pancreatic cancer. Factors such as lifestyle and environment may have influences on pancreatic carcinogenesis in various populations.

Originality benefit and difficulty of clinical research in the West Japan Lung Cancer Group.

The West Japan Lung Cancer Study Group (recently renamed the West Japan Thoracic Oncology Group) is a non-government, non-profit regional scientific organization whose objectives are to conduct clinical research and treatment of lung cancer, and to promote lung cancer expertise among thoracic physicians and radiologists in west Japan. Since 1990, a total of 46 institutes have joined and established the rules of a society. Our major interests are phase II and III trials of chemotherapy in lung cancer. We also have participated in activities with the Japan Clinical Oncology Group (JCOG), which is supported by the National Cancer Center in Tokyo. Additionally, we have conducted phase II and III trials with the support of Japanese pharmaceutical companies. This support allows us to conduct reliable, large-scale randomized trials. Our organization's main problems are unrefined data management and few qualified statisticians, due in part to a lack of funding.

Retrospective comparison of toxicity and efficacy in phase II trials of 3-h infusions of paclitaxel for patients 70 years of age or older and patients under 70 years of age.

PURPOSE: To evaluate the safety and efficacy of paclitaxel in elderly patients with advanced non-small-cell lung cancer (NSCLC). METHODS: We compared the toxicity, response, survival and pharmacokinetic parameters between patients between 70 and 75 years of age (elderly group) and those under 70 years of age (younger group) who were enrolled in two phase II trials of 3-h infusions of paclitaxel. RESULTS: A total of 120 patients were eligible for the studies, of whom 28 were in the elderly group and 92 in the younger group. Neutropenia was the most prominent toxicity. Grade 3-4 neutropenia was recorded in 89.3% of the elderly group and in 73.9% of the younger group (P = 0.13). Other hematological and non-hematological toxicities were mild regardless of age. Tumor response (46.4% vs 32.2%) and median survival time (9.8 months vs 6.8 months) did not differ between the elderly and younger groups. Pharmacokinetic studies failed to detect any difference between the two groups. CONCLUSION: Intravenous 3-h infusions of paclitaxel are as safe and effective in elderly patients with NSCLC as in younger patients.

Synchronous primary adenocarcinoma of the lung and leiomyosarcoma of the small intestine.

The occurrence of synchronous epithelial cancer of the lung and leiomyosarcoma of the small intestine is rare. We report here the case of a 62-year-old man with adenocarcinoma of the lung in clinical stage IIIB (T4N0M0). After two courses of chemotherapy (cisplatin, 80 mg/m2 and mitomycin C, 8 mg/m2) the patient developed symptoms of a small bowel obstruction. Palliative surgical resection was performed and a leiomyosarcoma of the small intestine was found and defined by an immunohistological study. The resection ameliorated the patient's symptoms. The patient died of disseminated adenocarcinoma 26 months following chemotherapy.

Phase II study of concurrent chemotherapy and radiotherapy for unresectable stage III non-small-cell lung cancer: long-term follow-up results. Japan Clinical Oncology Group Protocol 8902.

BACKGROUND: Although chemoradiotherapy is standard treatment for unresectable stage III non-small-cell lung cancer (NSCLC), few long-term survival data exist. PATIENTS AND METHODS: Between October 1989 and December 1991, 74 patients with histologically or cytologically proven NSCLC, unresectable stage IIIA or IIIB, were entered into this study. Seventy patients were eligible and evaluable for response, toxicity, and survival analysis. Chemotherapy consisted of cisplatin (100 mg/m2 on days 1, 29, and 57) and vindesine (3 mg/m2 on days 1, 8, 29, 36, 57, and 64). Thoracic radiotherapy was administered for two weeks (2 Gy given 10 times, five fractions per week), and after a 14-day rest period, the previous schedule of radiotherapy was repeated for two weeks. A 10-Gy to 20-Gy dose of radiotherapy was administered during the third cycle of chemotherapy. RESULTS: Of the 70 evaluable patients, 1 (1.4%) had a complete response (CR) and 51 (72.9%) had a partial response (PR). The median survival time was 14.8 months, and the five-year survival rate was 14.8%. The major toxicity was leukopenia (> or = grade 3, 93%). Other toxicities > or = grade 3 included anemia (34%), nausea/vomiting (27%), alopecia (7%), thrombocytopenia (4%), and serum creatinine elevation (1%). Treatment related death occurred in two patients (2.8%). One patient died of pneumonia and pneumothorax, and the other of hemoptysis. CONCLUSIONS: Concurrent chemotherapy and radiotherapy has the potential to provide long-term survival with acceptable toxicities.

Phase II trial of daily low-dose carboplatin and thoracic radiotherapy in elderly patients with locally advanced non-small cell lung cancer.

BACKGROUND: The purpose of this study was to investigate the feasibility of concurrent thoracic radiotherapy (TRT) and daily low-dose carboplatin (CBDCA) in elderly patients with locally advanced non-small cell lung cancer (NSCLC) and to estimate tumor response, toxicity and survival. METHODS: Forty patients were entered in a multicenter phase II study. All were patients with pathologically documented unresectable stage IIIA or IIIB or medically inoperable stage I, II NSCLC. CBDCA 30 mg/m2 was given on days 1-5 in weeks 1-4 concurrently with TRT, mainly for radiosensitization. TRT was started 1 h after CBDCA (30 min infusion) was given. TRT was given in 2 Gy/fraction/day, 5 days a week for a total of 50-60Gy. RESULTS: Thirty-eight patients were assessable for treatment response and toxicity. One patient had a CR and 18 patients PRs with a response rate of 50% (95% CI, 33.4-66.6%). The main toxicities were hematological toxicity. Other toxicities were grade > or =2 esophagitis in one patient, grade 3 nausea/vomiting in one and grade > or =3 pulmonary toxicity in two. There was one treatment-related death due to pulmonary toxicity. For stage IIIA + IIIB patients, the median survival time was 15.1 months and 1-and 2-year actuarial survival rates were 52.6 and 20.5%, respectively. For stage I + II patients, 1- and 3-year actuarial survival rates were 90.9 and 69.3%, respectively. CONCLUSIONS: The data suggest that TRT with daily low-dose CBDCA in elderly patients is effective and feasible because of its low toxicity and survival.

Immunohistochemical analysis of Bcl-2 protein in early squamous cell carcinoma of the bronchus treated with photodynamic therapy.

Photodynamic therapy (PDT) in early squamous cell carcinoma of the bronchus has been shown to result in complete response (CR) and cure. However, local recurrence after PDT develops frequently even after complete remission. Because the effect of PDT had been reported to depend on apoptosis, and apoptosis is inhibited by bcl-2 protein, the relationship between the expression of bcl-2 protein and local recurrence after PDT was examined immunohistochemically. From 1983 to 1997, 50 patients with 59 early squamous cell carcinoma of the bronchus received PDT, and a CR was obtained in 43 lesions (72.8%). As there was no recurrence among tumours that were disease-free for more than 2 years, in this study the tumours were defined as cured when recurrence did not occur 2 years subsequent to the receiving of PDT. Of these CR lesions, 31 carcinomas (53.4%) resulted in a cure. Bcl-2 immunoreactivity was detected in 23 tumours (46.9%) and p53 immunoreactivity was detected in 22 tumours (44.9%). When all tumours were divided into either a large tumour with a longitudinal tumour length of 10 mm or more, or a small tumour with a length of less than 10 mm, the large tumour expressed more bcl-2 protein than the small tumour (P = 0.0155). The degree of bcl-2 expression was significantly related with tumour size (P = 0.0155). The expression of bcl-2 and p53 protein was not associated with the cure rate due to PDT. Tumour length and T status in TNM staging were significantly related to the cure by univariate analysis. T status was the only predictor of the cure according to mutivariate analysis. Of 42 CR lesions, the expression of neither bcl-2 nor p53 protein was associated with local recurrence; only T status was significantly associated (P = 0.008). The relationship between the expression of oncoprotein and local recurrence after PDT was not documented in this study. The success of PDT may depend on the exact assessment of tumour size under optimized PDT illumination.

[Autopsy case of adenoid cystic carcinoma of the trachea: endobronchial treatment improves quality of life].

A 67-year-old man presented with dyspnea on exertion. Bronchoscopic examination revealed a tumor arising from the middle portion of the trachea and extending to the right main bronchus. The pathological diagnosis was adenoid cystic carcinoma. Radiotherapy and subsequent endobronchial electrocautery were performed, and elicited a partial response. In the clinical course. Dumon and Ultraflex stents were placed in the trachea asynchronically. Brachytherapy and esophageal stent placement were also performed for tumor control in the trachea and esophagus. Autopsy revealed that the tumor had invaded the trachea and esophagus, and bacterial mediastinitis was also demonstrated. Because the tumor was successfully controlled during the following 4 years and 9 months, we concluded that endobronchial therapy such as stent placement or electrocautery is useful for maintaining good quality of life.

Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer.

PURPOSE: A phase III study was performed to determine whether concurrent or sequential treatment with radiotherapy (RT) and chemotherapy (CT) improves survival in unresectable stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were assigned to the two treatment arms. In the concurrent arm, chemotherapy consisted of cisplatin (80 mg/m(2) on days 1 and 29), vindesine (3 mg/m(2) on days 1, 8, 29, and 36), and mitomycin (8 mg/m(2) on days 1 and 29). RT began on day 2 at a dose of 28 Gy (2 Gy per fraction and 5 fractions per week for a total of 14 fractions) followed by a rest period of 10 days, and then repeated. In the sequential arm, the same CT was given, but RT was initiated after completing CT and consisted of 56 Gy (2 Gy per fraction and 5 fractions per week for a total of 28 fractions). RESULTS: Three hundred twenty patients were entered onto the study. Pretreatment characteristics were well balanced between the treatment arms. The response rate for the concurrent arm was significantly higher (84. 0%) than that of the sequential arm (66%) (P =.0002). The median survival duration was significantly superior in patients receiving concurrent therapy (16.5 months), as compared with those receiving sequential therapy (13.3 months) (P =.03998). Two-, 3-, 4-, and 5-year survival rates in the concurrent group (34.6%, 22.3%, 16.9%, and 15.8%, respectively) were better than those in the sequential group (27.4%, 14.7%, 10.1%, and 8.9%, respectively). Myelosuppression was significantly greater among patients on the concurrent arm than on the sequential arm (P =.0001). CONCLUSION: In selected patients with unresectable stage III NSCLC, the concurrent approach yields a significantly increased response rate and enhanced median survival duration when compared with the sequential approach.

Phase I/II study of vinorelbine, mitomycin, and cisplatin for stage IIIB or IV non-small-cell lung cancer.

PURPOSE: To determine the maximum-tolerated doses (MTDs) of vinorelbine (VRB), mitomycin (MMC), and cisplatin (P), given in two courses every 28 days to previously untreated patients with stage IIIB or IV non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: At least three or four patients were entered at each dose level. The starting dose was 20 mg/m(2) for VRB on days 1 and 8 and 4 mg/m(2) for MMC on day 1, with a fixed dose of P 80 mg/m(2) on day 1 every 4 weeks. MMC was increased to 6 mg/m(2) at dose level 2 and subsequently to 8 mg/m(2) at dose level 4. At dose level 3, VRB was increased to 25 mg/m(2). Twenty-five patients were entered onto the phase I study and 19 patients were entered onto phase II study. RESULTS: Nadir leukocyte and platelet counts decreased at each dose level. At dose levels 1 and 2, the dose-limiting toxicity (DLT) was not seen, but at dose levels 3 and 4, DLT was encountered in two patients. Nearly half the patients at dose level 4 had dose reduction due to grade 4 leukopenia. A mathematic model of all toxicity suggested that dose level 4 (VRB 25 mg/m(2) on days 1 and 8 and MMC 8 mg/m(2) and P 80 mg/m(2) on day 1, every 4 weeks) would be the recommended dose for phase II study at which grade 4 toxicity is expected in