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Purpose: The purpose of this study is to elucidate the influence of serum arginine-vasopressin (AVP) level on prognosis of extensive-disease small-cell lung cancer (ED-SCLC)., Methods: We retrospectively investigated the clinical records of 163 patients with ED-SCLC, who were admitted to Okayama University Hospital or National Shikoku Cancer Center Hospital. The influence of 14 pretreatment variables on survival was analyzed., Results: In a multivariate analysis of 163 patients, elevation of serum LDH level (P = 0.028) and poor performance status (PS > or = 2, P = 0.002) were independent poor prognostic factors. In 34 patients whose serum AVP levels were available, high serum AVP level was related to the poor prognosis (P < 0.001). The serum-sodium level did not affect the survival. Median serum level of osmotic pressure in 34 patients was normal (284.9 mOsm/kg), although, serum osmotic pressure was low in four of six patients with high serum AVP level. In all patients with high serum AVP level, serum LDH level was elevated., Conclusions: The data from the current study suggested that serum LDH level and PS were the poor prognostic factors for ED-SCLC. But we additionally identified the prognostic significance of serum AVP level, which may be a more useful factor than serum-sodium level.

Purpose: The aim of this trial was to investigate the efficacy and safety of cisplatin (P) and irinotecan (I) (PI) alternating with doxorubicin (A), cyclophosphamide (C) and etoposide (E) (ACE) in patients with extensive-disease small-cell lung cancer (ED-SCLC)., Patients and Methods: Patients with previously untreated ED-SCLC were enrolled in this trial. In the first, third and fifth cycles, PI (P: 60 mg/m(2) on day 1; I: 60 mg/m(2)/day on days 1, 8 and 15) was administered, whereas ACE (A: 50 mg/m(2) on day 1; C: 750 mg/m(2) on day 1; E 80 mg/m(2)/day on days 1-3) was given in the second, fourth and sixth cycles. Each cycle was repeated every 4 weeks. At the end of six cycles, patients who had obtained a complete response were given prophylactic cranial irradiation., Results: In total, 28 patients were enrolled, of whom 27 were assessable for efficacy and safety. Objective responses, including 4 (15%) complete responses, were observed in 25 patients (93%). Median survival time was 12.9 months. The principal toxicity was myelosuppression; grade 4 neutropenia and thrombocytopenia were observed in 89 and 4%, respectively. Febrile neutropenia occurred in 30% of patients. Diarrhea was mild (grade 3-4; 4%). All toxicities were reversible and there were no treatment-related deaths. The mean percentage of the delivered doses, relative to the projected doses, of PI and ACE were 84.6 and 91.1%, respectively., Conclusions: These results indicate the PI-ACE regimen to have promising activity against ED-SCLC with moderate toxicities.

Cisplatin-based chemotherapy is considered to be a standard treatment in patients with relapsed or extensive-disease (ED) small-cell lung cancer (SCLC), the survival benefit remains modest. Relapsed or ED-SCLC patients were enrolled. Topotecan and amrubicin were administered on Days 1-5 and on Days 3-5, respectively. Nine patients received a total of 24 cycles. Since all three patients experienced dose-limiting toxicity (grade 4 neutropenia lasting for more than 4 days, grade 3 febrile neutropenia, and grade 4 thrombocytopenia) at the third dose level (topotecan: 0.75 mg/m2, amrubicin 40 mg/m2), the maximum tolerated dose was determined to be this dose level. Objective response was observed in six patients (67%). The maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) of amrubicin increased in a dose-dependent manner. Amrubicin did not influence the pharmacokinetics of topotecan. The Cmax and AUC of amrubicin were correlated with the duration of grade 4 neutropenia. The mean Cmax of topotecan on day 2 in responders (22.9+/-3.6) was significantly higher than that in non-responders (10.9+/-0.4). This phase I study showed the safety and activity of two-drug combination of amrubicin and topotecan in patients with relapsed or ED-SCLC.

Irinotecan is one of the most active drugs used in the treatment of small cell lung cancer (SCLC). 7-Ethyl-10-hydroxy-camptothecin (SN-38) is an active metabolite of irinotecan. We established an SN-38-resistant subline (SBC-3/SN-38) by continuous exposure of SN-38 to a human SCLC cell line, SBC-3. Using the 3-[4, 5-dimethyl-thiazol-2-yl] 2, 5-diphenyltetrazolium bromide assay, we evaluated the cytotoxicity of 17 anticancer agents. The SBC-3/SN-38 cells were 73-fold more resistant than the parental SBC-3 cells to SN-38 and showed cross-resistance not only to topoisomerase (topo) I inhibitors (irinotecan and topotecan), but also to topo II inhibitors (adriamycin and etoposide), antimicrotubule agents (vincristine, vindesine, vinorelbine and docetaxel), alkylating agents (cyclophosphamide and ifosfamide), platinum (cisplatin and carboplatin) and antifolate (methotrexate). Interestingly, the resistant subline reserved the sensitivity to bleomycin and 5-fluorouracil. The SBC-3/SN-38 cells had decreased topo I and II activity compared to the parent cells. The SN-38-resistant cell line, SBC-3/SN-38, will be useful to elucidate the mechanism of action of the topo I inhibitors.

A 65-year-old man with limited disease-small cell lung cancer was treated with concurrent chemoradiotherapy which resulted in a partial response. He further received high-dose chemotherapy with autologous peripheral blood stem cell transplantation. Development of non-small cell carcinoma was, however, suspected at a site of the residual nodule in cytological examination using bronchoscopy. He then underwent lobectomy, which revealed that the nodule was composed of necrotic tissue. He has been alive without recurrence for seven years. This multimodality treatment appeared to be effective for this patient. However, further investigation is necessary to clarify the role of multimodality treatment.

To improve the efficacy of a combination of cisplatin and etoposide and concurrent accelerated twice-daily thoracic radiotherapy against limited-stage small-cell lung cancer, we conducted a phase I/II study using an altered schedule of chemotherapy administration. Chemotherapy consisted of four cycles of cisplatin (days 1 and 8) and etoposide (days 1, 2, 8, and 9) every 4 weeks. Accelerated hyperfractionated thoracic radiation (1.5 Gy twice daily x 30 fractions, total dose of 45 Gy) was concurrently given with the first cycle of chemotherapy. The recommended doses of cisplatin and etoposide determined in the phase I study were 40 and 80 mg/m(2), respectively. In the phase II study, the overall response rate was 100% (complete response: 32%, partial response: 68%). By a median follow-up time of 29 months, median radiation-outfield progression-free survival was 13.4 months, while radiation-infield progression-free survival did not reach median value. The median overall survival time was 22.9 months, with survival rate of 48.4% at 2 years. Major toxicities were leukopenia and neutropenia (>/=grade 3, 92% each). The local control and overall survival demonstrated in this study were excellent. However, the insufficient distant control suggests a need for development of more active chemotherapy regimens.

Background: A combination of irinotecan (CPT-11) and cisplatin (CDDP) was shown to be effective for extensive-disease small-cell lung cancer (ED-SCLC). To take maximum advantage of the synergistic effect between CPT-11 and CDDP, we designed a fractionated administration schedule., Patients and Methods: Between August 1995 and September 1998, 15 previously untreated patients with ED-SCLC were enrolled. Both CPT-11 at a dose of 50 mg/m2 and CDDP at a dose of 60 mg/m2 were given on days 1 and 8, and repeated every 4 weeks up to four cycles., Results: Fifteen patients were assessed for response and survival, and fourteen for toxicity. Although twelve patients (80.0%; 95% confidence interval, 51.9-95.7) achieved an objective response, complete response (CR) was not obtained. The median survival time and the actual 1-year survival rate were 9.4 months and 40.0%, respectively. Grade 3 or 4 leukopenia, neutropenia and diarrhea occurred in 71.4%, 100% and 14.3% of the patients, respectively. Enrollment into this study was stopped because CR, which was the primary endpoint, was not obtained in the consecutive 15 patients and the survival appeared to be inferior to the previous multi-institutional study (Kudoh et al, Clin Oncol 16: 1068-1074, 1998). The projected dose intensity in the present study was lower in CPT-11 and higher in CDDP compared to that in the previous report., Conclusion: These results suggest that the dose intensity of CPT-11 may have a major role on the activity of SCLC in this combination.

Background: Parathyroid hormone-related protein (PTH-rP) is a major cause of tumor-induced hypercalcemia (TIH) and frequently is found to be elevated in serum of patients with TIH. In the current study, the authors examined the usefulness of PTH-rP measurement at the time of first presentation in the follow-up of lung carcinoma patients with TIH., Methods: The authors retrospectively studied 23 of 1149 lung carcinoma patients who were found to have TIH at the time of first presentation for the correlation between serum PTH-rP and the development of bone metastases and survival compared with lung carcinoma patients without TIH who were matched by gender, age, Eastern Cooperative Oncology Group performance status, histological type of tumor, and stage of the disease., Results: Twenty-three lung carcinoma patients with TIH demonstrated significantly increased serum levels of PTH-rP (mean +/- standard error [SE], 84.1 +/- 16.5 pmol/L) compared with control patients without TIH (mean +/- SE, 36.2 +/- 2.0 pmol/L) at the time of first presentation, (P < 0.001). In these hypercalcemic patients, patients whose serum PTH-rP was > 150 pmol/L (n = 16) were found to have a significantly increased rate of bone metastases (71.4% vs. 12.5%; P = 0.01) and decreased survival (median survival of 1.4 months vs. 5.4 months; P < 0.015) compared with patients whose serum PTH-rP was < 150 pmol/L (n = 7)., Conclusions: The data from the current study suggest that serum PTH-rP as determined at the time of first presentation is a useful indicator of not only hypercalcemia but also bone metastasis and eventual survival in patients with lung carcinoma., (Copyright 2002 American Cancer Society.)

Background: Bronchioloalveolar carcinoma (BAC) has been reported to have unique clinicopathological features., Patients and Methods: This retrospective study was performed using data base including 871 patients treated for primary lung cancer between 1981 and 1995., Results: The patients with BAC included a larger proportion of female (P = 0.029) and smoked less (P = 0.002) than those with non-BAC. There was no difference in survival between surgically resected patients with BAC and those with non-BAC. Clinical Stage IV patients with BAC had a better response to chemotherapy than did those with non-BAC. Survival in the former group was better than that in the latter on univariate analysis, but the significance of this difference was not confirmed multivariate analysis., Conclusion: The patients with BAC included a larger proportion of females and smoked less than those with non-BAC. Treatment results for BAC was comparable to those for non-BAC.

A combination chemotherapy of irinotecan (CPT-11) and cisplatin (CDDP) has been reported to be active for lung cancer. In the previous trial, however, diarrhoea and leucopenia became the major obstacle for sufficient dose escalation of CPT-11 to improve the treatment outcome. We conducted a phase I study to investigate whether the fractionated administration of CDDP and CPT-11 at escalated dose was feasible and could improve the treatment outcome. Twenty-four previously untreated patients with unresectable non-small-cell lung cancer (NSCLC) or extensive disease of small-cell lung cancer (SCLC) were eligible. Both CDDP and CPT-11 were given on days 1 and 8, and repeated every 4 weeks. The dose of CDDP was fixed at 60 mg m(-2) and given by 1-h infusion before CPT-11 administration. The starting dose of CPT-11 was 40 mg m(-2), and the dose was escalated by an increase of 10 mg m(-2). The maximally tolerated dose of CPT-11 was determined as 60 mg m(-2) because grade 4 haematological or grade 3 or 4 non-haematological toxicities developed in six patients out of 11 patients evaluated. Diarrhoea became a dose-limiting toxicity. The objective response rates were 76% for NSCLC and 100% for SCLC. The recommended dose of CPT-11 and CDDP in a phase II study will be 50 mg m(-2) and 60 mg m(-2) respectively.

Background: In an attempt to determine the efficacy of cyclophosphamide, doxorubicin, and vincristine (CAV)/cisplatin and etoposide (PVP) hybrid chemotherapy (HYB), a rapidly alternating chemotherapy, in patients with small cell lung carcinoma (SCLC), the authors conducted a randomized study to compare HYB with CAV-PVP sequential chemotherapy (SEQ)., Methods: Patients in the HYB group received the 3-drug CAV combination on Day 1 and the 2-drug PVP combination on Day 8, repeated every 4 weeks for up to 6 cycles. Patients in the SEQ group received 3 cycles each of CAV and PVP sequentially every 4 weeks, delivered on Days 1 and 8. All responding patients with limited disease (LD) received thoracic irradiation (50 gray) after chemotherapy., Results: Between April 1988 and October 1992, 129 patients were evaluated fully. There were no significant differences in the treatment outcome between patients in the HYB and SEQ groups in terms of the complete response rate (59% for LD patients and 21% for extensive disease [ED] patients in the HYB group vs. 45% for LD patients and 16% for ED patients in the SEQ group), or median survival time (17.9 months for LD patients and 9.7 months for ED patients in the HYB group vs. 20.6 months for LD patients and 12.2 months for ED patients in the SEQ group)., Conclusions: Hybrid CAV-PVP therapy is effective for the treatment of SCLC, but appears to be no better than sequential therapy with the same regimen.

Background: Vascular endothelial growth factor (VEGF) overexpression has been observed in several malignant tumors, and VEGF level in serum appears to be correlated with tumor burden in cancer patients., Patients and Methods: Serum VEGF levels were measured in 70 patients with lung cancer including 23 with adenocarcinoma, 19 with squamous cell carcinoma, 3 with large cell carcinoma, and 25 with small cell carcinoma, and in 30 patients with benign lung disease and 13 healthy subjects with an enzyme immunoassay., Results: VEGF levels (mean +/- SD; pg/ml) were 834 +/- 699 and 732 +/- 529 in patients with lung cancer and benign lung disease, respectively, and were significantly higher than those in healthy subjects (264 +/- 129) (P < 0.01). There were no differences between VEGF levels categorized by histology, disease stage, or distant metastasis for lung cancer patients., Conclusions: Although serum VEGF levels were increased in lung cancer patients, this increase might not have been related to tumor burden.

A cisplatin-resistant cell line, SBC-3/CDDP, was established from a human small-cell lung cancer cell line, SBC-3. The SBC-3/CDDP cells were 13.1-fold more resistant to cisplatin than the parent SBC-3 cells. We investigated the cellular changes of this cell line with regard to the development of resistance to cisplatin. The SBC-3/CDDP cells showed various characteristics as follows: a) increased intracellular glutathione and glutathione S-transferase content b) decreased intracellular accumulation of cisplatin, c) increased topoisomerase I activity and the same topoisomerase II activity as the parent SBC-3 cells, and 4) strong cross-resistance to the platinum analogues and mitomycin C, moderate cross-resistance to 7-ethyl-10-hydroxy-camptothecin (SN-38), 4-hydroperoxy cyclophosphamide, etoposide, Adriamycin and methotrexate, and collateral sensitivity to vinca alkaloids and 5-fluorouracil. From these observations, the SBC-3/CDDP cells could be useful as a well characterized cisplatin-resistant cell line, and the resistance pattem in this cell line will give us much information for eradication of cisplatin-resistant tumor cells.

Serum hepatocyte growth factor/scatter factor (HGF/SF) levels were measured in 25 patients with small cell lung cancer (SCLC), 16 patients with benign lung diseases and 15 healthy subjects with an enzyme-linked immunosorbent assay. The patients with SCLC did not have bacterial or interstitial pneumonia. Patients with benign lung diseases included eight with bacterial pneumonia, three with interstitial pneumonia, and five with benign lung tumor. Serum HGF/SF levels were significantly higher in patients with SCLC (mean +/- S.D.: 0.40 +/- 0.17 ng/ml) than in healthy subjects (0.26 +/- 0.093 ng/ml) (P = 0.0083). Patients with bacterial pneumonia had significantly higher serum HGF/SF (0.52 +/- 0.19 ng/ml) than did those with benign lung tumors (0.27 +/- 0.058 ng/ml) and healthy subjects (P = 0.013 and P = 0.0019, respectively). By clinical stage of SCLC, HGF/SF levels were 0.34 +/- 0.12 and 0.47 +/- 0.20 ng/ml in patients with limited disease and extensive disease, respectively; this difference was not significant (P = 0.080). Although serum HGF/SF levels were increased in patients with SCLC, this increase might not have been related to tumor burden.

Serum p53 protein levels were measured in 36 patients with small cell lung cancer (SCLC) and 35 patients with benign lung diseases in order to evaluate the relationship of these levels to clinicopathological features of SCLC. Serum levels of p53 protein were measured by an enzyme-linked immunosorbent assay, p53 protein level was 23.92 +/- 6.78 pg/ml in patients with SCLC, and similar to that (17.47 +/- 2.86 pg/ml) in patients with benign lung diseases. By the clinical stage of SCLC, the mean level of p53 protein was 16.68 +/- 4.62 pg/ml in 21 patients with limited disease, and lower than that in 15 patients with extensive disease (34.05 +/- 14.84 pg/ml) (P = 0.23). The levels of p53 protein were not correlated with age, smoking index, or presence of cancer history for patients with SCLC. However, immunohistochemical examination disclosed a mild correlation between the expression of p53 protein by SCLC tumor and p53 protein serum level (r = 0.45, P = 0.02). Two patients with SCLC had an elevated serum level of p53 protein (> 2 S.D. above the mean for benign lung diseases). However, measurement of p53 protein serum level was not found to be clinically useful for detection of SCLC.

Ten patients with stage I-II SCLC received IC-AS between 1984 and 1993. As induction chemotherapy, COMP-VAN alternating chemotherapy and CAV-PVP hybrid chemotherapy were administered. The former consisted of a 4-drug combination of cyclophosphamide (CPA), vincristine (VCR), methotrexate (MTX) and procarbazine alternated with a 3-drug combination of etoposide (ETP), adriamycin (ADM) and nimustine every 4 weeks. In the latter, a 3-drug combination of CPA, ADM and VCR given on day 1, and a 2-drug combination of ETP and cisplatin on day 8, were repeated every 4 weeks. All the patients had an objective response, including one complete response by induction chemotherapy. Post-operative pathology revealed SCLC in 4 patients, adenocarcinoma in 2 and no tumor (pathological CR) in 4. Four patients relapsed, and a intrathoracic relapse was experienced in only 2 patients. Six patients have died: 3 from relapsing SCLC, 2 from stomach cancer, and 1 from squamous lung cancer, who was salvaged from relapsing SCLC. The median survival time was 27.5 months, and the 3-year survival rate 37.5%. These results indicate that IC-AS is highly effective for stage I-II SCLC and warrant additional studies comparing IC-AS with chemo-radiotherapy.

Between 1981 and 1986, a total of 46 patients with small cell lung cancer (SCLC) achieving a complete response by chemotherapy with or without chest irradiation were randomized either to receive prophylactic cranial irradiation (PCI) or not. With a median follow-up time of 8.5 years for both groups, only five of 23 patients (22%) in the PCI group developed brain relapse, while 12 out of 23 (52%) in the no PCI group did so (P < 0.05). The frequency of patients developing a sole brain relapse during their whole clinical course was 4% for the PCI group and 17% for the no PCI group, however, the difference was not statistically significant. Patient survival was better for the PCI group (median survival time of 21 months, and 5-year survival rate of 22%) as compared with the no PCI group (median survival time of 15 months, and 5-year survival rate of 13%), showing a marginal significance (P = 0.097). Late neurologic toxicity was infrequent; only one developed a mild deterioration among seven long-term disease-free survivors in the PCI group. These results appear to warrant further clinical trials to clarify the utility of PCI in patients with SCLC achieving a complete response.

The neural cell adhesion molecule (NCAM) is a family of cell surface sialoglycoproteins mediating homotypic and heterotypic cell-cell adhesion. In tumors, NCAM is supposed to be involved with the malignant features characterized by invasive growth and metastasis. In the present study, we evaluated the correlation between NCAM expression of tumors obtained from small cell lung cancer (SCLC) patients and the clinical outcome. NCAM expression was determined semi-quantitatively by an immunogold-silver staining method using the SCLC cluster 1 monoclonal antibody NCC-LU-243. Of 20 SCLC patients studied, six patients with tumors with high NCAM expression had a poor response to chemotherapy, and a short disease-free (p = 0.011) and overall (p = 0.003) survival as compared with 14 patients having tumors with low NCAM expression. These findings indicate that the therapeutic outcome of SCLC may be partly predicted by determining the NCAM expression of the tumor.

Rhizoxin is a new macrocyclic lactone isolated from the fungus Rhizopus chinensis. In an attempt to predict the effectiveness of rhizoxin in the treatment of lung cancer, we compared the antitumor activity of rhizoxin with those of cisplatin and etoposide using four small cell lung cancer (SCLC) cell lines, SBC-2, -3, -4, and -7, and two non-small cell lung cancer (NSCLC) cell lines, ABC-1 and EBC-1. The concentrations producing 50% inhibition of the growth of these cell lines (IC50) for each drug were obtained by MTT assay. The IC50 of rhizoxin for these cell lines ranged 0.408 nM to 1.56 nM, which were significant lower than those of cisplatin (660 nM to 16,300 nM) and etoposide (275 nM to 31,300 nM). The ratio of IC50 for the most sensitive cell line, SBC-3, to that for the most resistant cell line was less than 4-fold in rhizoxin, in contrast to more than 20-fold in cisplatin and 100-fold in etoposide. Cross-resistance of rhizoxin to cisplatin and etoposide was investigated using a cisplatin-resistant SCLC subline, SBC-3/CDDP, and an etoposide-resistant SCLC subline, SBC-3/ETP. Of interest, the parent cell line, and the resistant sublines were equally sensitive to rhizoxin, indicating rhizoxin being non-cross-resistant to cisplatin and etoposide. In conclusion, rhizoxin may be beneficial in the salvage chemotherapy of drug-resistant SCLC and non-SCLC.

In an attempt to elucidate the tumor properties relating to responsiveness to chemotherapy, we examined immunohistochemically the expression of P-glycoprotein (P-gp) and carcinoembryonic antigen (CEA) in small cell lung cancer (SCLC) tumors. Tumor specimens from 33 patients were obtained at the time of diagnosis and relapse. Four patients expressed P-gp in their initial tumors, and 7 others did in recurrent tumors. The overall response rate to chemotherapy of the initial tumors was 75% for P-gp-positive initial tumors and 86% for P-gp-negative tumors, whereas the disease-free and overall survival times were significantly shorter in the former than the latter. Three patients showed CEA in their initial tumors, and 5 others did in recurrent tumors. The patients with CEA-positive initial tumors tended to relapse earlier than those with CEA-negative tumors. In addition, recurrent tumors expressing CEA were resistant to salvage chemotherapy. A clear correlation between CEA expression by tumors and the CEA level in the serum was observed at diagnosis as well as at relapse. These findings indicate that P-gp and/or CEA expression by a tumor and elevated CEA level in the serum may predict refractoriness of the tumor to chemotherapy.

Using reverse transcription polymerase chain reaction, we determined mRNA expression of topoisomerase (topo) II alpha and beta in adriamycin- and etoposide-resistant small cell lung cancer sublines, SBC-3/ADM 100 and SBC-3/ETP. The expression of topo II alpha mRNA decreased substantially in SBC-3/ADM 100 and SBC-3/ETP as compared with the parent cell line, SBC-3; 0.71-fold in the former and 0.38-fold in the latter. Similarly, that of topo II beta mRNA decreased to an extent of 0.68-fold in SBC-3/ADM 100 and 0.28-fold in SBC-3/ETP as compared with the parent cell line. SBC-3/ADM 100 and SBC-3/ETP were highly resistant to topo II inhibitors such as daunorubicin, epirubicin, pirarubicin, mitoxantrone, and teniposide. However, SBC-3/ADM 100 showed a less resistance to aclarubicin, and SBC-3/ETP was as sensitive to the drug as was in the parent cell line. The resistance to topo II inhibitors excluding for aclarubicin might be partially explained by the decreased expression of topo II alpha and beta mRNA.

A 77-year-old man with small cell lung cancer (SCLC) accompanied by polyneuropathy and SIADH is reported. The patient first developed peripheral hyperesthesia and muscle weakness 6 months before admission. He was diagnosed as having SCLC by sputum cytology and supraclavicular lymph node biopsy. On admission, chest radiography and CT scan revealed a mediastinal mass, and the conduction velocity in peripheral nerves was delayed. He was also found to have SIADH, on the basis of an extremely low level of serum Na (114 mEq/l) and osmotic pressure (251 mOsm/kg) but with normal urinary Na and osmotic pressure. In association with complete disappearance of the mediastinal mass after intensive chemotherapy, SIADH and polyneuropathy also improved remarkably. When SCLC relapsed in the abdominal lymph nodes 11 months after complete disappearance of the mediastinal mass, polyneuropathy and SIADH also reappeared. These results indicate that both SIADH and polyneuropathy comprised a paraneoplastic syndrome.

Between April 1981 and December 1987, 148 patients with newly diagnosed small cell lung cancer (SCLC) were treated using combination chemotherapy with or without thoracic irradiation and prophylactic cranial irradiation (PCI) in a series of cooperative therapeutic trials. With a minimum follow-up of 4.7 years, 13 (9%) patients survived and were free of SCLC. These included 11 (15%) of 76 patients with limited disease and two (3%) of 72 patients with extensive disease. Three died without any evidence of SCLC (one each from second leukemia, non-small cell lung cancer, and unrelated disease). The remaining 10 (7%) patients are currently alive and free of SCLC beyond 4.7 years. Since late relapse beyond 5 years is a very rare event, these patients may have been cured. However, late toxicity of PCI must be kept in mind. Three among the 10 patients have suffered from neuropsychologic symptoms of varying degrees in severity. Although the long-term survival rate is a benchmark in the treatment of SCLC, modifications of therapy that may potentially avoid such toxicities should be considered hereafter.

A 62-year-old male with small cell lung cancer (SCLC) associated with Cushing's syndrome and diabetes insipidus (DI) is reported. The patient was referred to our hospital for treatment of SCLC. A diagnosis of paraneoplastic Cushing's syndrome was made on the basis of an elevated serum ACTH (623.5 pg/ml) level, elevated excretion of urinary 17-OHCS (18.01 mg/day), obesity, hypertension, hyperglycemia, persistent hypokalemia, alkalosis, and no history of diabetes mellitus. He was also diagnosed as having DI based on polyuria and polydipsia, low specific gravity of the urine (1.007-1.010), low serum ADH (1.4 pg/ml) level, normal plasma osmolarity (29 mOsm/kg H2O), and the results of water deprivation test. DI and a left visual field defect was suggestive of metastasis to the pituitary region, but no lesion was detected by either CT scan or MRI scan. The patient failed to show a good response to intensive chemotherapy, and died of the tumor five months after commencing chemotherapy. Post-mortem examination revealed metastases to the hypothalamic-neurohypophyseal region, lungs, liver, adrenal glands, bone, bone marrow, and hilar and mediastinal lymph nodes.

Lonidamine, a unique new type of anticancer agent, has been shown to exert marginal activity in patients with resistant small cell lung cancer. We have assessed cytotoxic activity using seven human small cell lung cancer cell lines and the drug resistant small cell lung cancer sublines, Adriamycin-resistant SBC-3/ADM100, etoposide-resistant SBC-3/ETP and cisplatin-resistant SBC-3/CDDP. Although lonidamine had only a minimal activity in seven human small cell lung cancer cell lines, SBC-3/ADM100 cells were more sensitive to lonidamine than the parent SBC-3 cells to a 1.6-fold extent in terms of IC50. SBC-3/CDDP and SBC-3/ETP had no cross-resistance to lonidamine at all. These observations may be of potential clinical significance in treating small cell lung cancer.

In order to assess the progress and limitation of chemotherapy in the treatment of small cell lung cancer in the elderly, we analyzed 218 patients who had entered into protocol studies between 1982 and 1990. Among those, there were 101 elderly patients (age of greater than or equal to 66 years) and 117 non-elderly patients (age of less than or equal to 65 years). Response to chemotherapy with or without chest irradiation was almost comparable for the elderly and the non-elderly; complete response rate was 52% for limited disease (LD) and 33% for extensive disease (ED) in the elderly, and it was 68% for LD and 23% for ED in the non-elderly. Survival figures of the two groups were quite similar: The median survival time was 12.6 months for the elderly and 14.5 months for the non-elderly, and the 3-year survival rate was 14% for both groups. An improvement of patient survival was observed along with the chronology of the protocols, i.e., with a escalation of dose intensity. Of interest, the improvement was rather evident in the elderly than in the non-elderly. Hematologic toxicity was considerable more frequent and severe in the elderly than in the non-elderly with non-significant statistics. The incidense of fever episodes while neutropenic was significantly more frequent in the elderly. Non-hematologic toxicity was almost comparable for the two groups, with a exception that the elderly showed a trend being predisposed to renal toxicity. In conclusion, such elderly patients as eligible for entry into a protocol study can benefit from intensive treatment as equally as non-elderly patients can.

Small cell lung cancer (SCLC) is one of the most sensitive tumors to drug therapy; however, the majority of patients eventually relapse within a few years. Emergence of drug resistance is thought to play a major role in the dismal course of this disease. However, the mechanism of drug resistance in SCLC still remains obscure. Based on the clinical observation that a significant proportion of patients with relapsing tumor show an elevated serum carcinoembryonic antigen (CEA) concentration while serum neuron-specific enolase (NSE) concentration remains normal, we attempted to determine whether the tissue of CEA is indicative of a clonal change in SCLC, in contrast with the tissue expression of NSE and P-glycoprotein (P-gp). We examined 22 SCLC patients with tumor specimens available both at diagnosis and at relapse. Of the 22 patients, two had CEA expression at diagnosis, and a further three patients showed CEA expression at relapse. It is of note that there were two patients whose tumors expressed NSE alone at diagnosis but expressed CEA alone at relapse. Serum CEA concentration was concordant with the tissue expression of CEA; however, serum NSE concentration was not concordant with the tissue expression of NSE. Tumors with CEA expression at relapse were generally resistant to salvage chemotherapy, while there was no close relationship between the tissue expression of P-gp and refractoriness to drugs at relapse. These findings indicate that the tissue expression of CEA in SCLC is a marker of a clonal change during chemotherapy, and such a clonal change would play a role in the emergence of drug resistance in SCLC.

Development of double cancer was evaluated in 311 small cell lung cancer patients who had received intensive chemotherapy with or without radiotherapy. Of those, 10 patients (3.2%) developed a second malignancy:stomach cancer in four, non-small cell lung cancer in three, acute myelogenous leukemia in two, and liver cancer in one. The cumulative risk for the development of double cancer was 1.0% at 1-year, 17.0% at 3-years, and 100% at 8.1 years. The relative risk for the development of double cancer calculated by person-year method utilizing age and sex adjusted cancer incidence in Japan was 2.96-fold (p less than 0.01). The risk of non-small cell lung cancer (6.65-fold) and acute myelogenous leukemia (54.9-fold) was particularly high. Of 21 patients who survived disease-free for more than 2 years, 8 patients died; four patients (50%) died of second malignancy, two died of infectious disease, and only two patients died from recurrent small cell lung cancer. These results indicate that a cautious follow-up program for the detection of double cancer is indicated in patients surviving small cell lung cancer.