Limited-disease Small-cell Lung Cancer Research Articles

A Phase II Study of Combined Chemoradiotherapy for Limited Disease–Small-Cell Lung Cancer

A study to evaluate the efficacy of cisplatin, doxorubicin, and etoposide chemotherapy with combined radiotherapy was undertaken in 26 patients with limited disease-small-cell lung cancer. Patients were treated with cisplatin (80 mg/m2) intravenously (i.v.) on day 1, doxorubicin (30 mg/m2) i.v. on day 1, and etoposide (80 mg/m2) i.v. on days 1, 3, and 5, every 4 weeks for four cycles. Thoracic irradiation of 40 Gy in 20 fractions was delivered during 4 weeks to the primary site starting on day 8 of the second cycle of chemotherapy. The objective response rate was 100%. A complete response was observed in 10 patients (38%). The median survival time was 23 months, and the 3-year survival rate was 42%. Seven patients (27%) continued to survive at least 8 years and remain free from disease. Grade III/IV leukopenia was observed in 25 patients (96%). Grade III/IV thrombocytopenia developed in 19 patients (73%). Grade III/IV esophagitis was not seen. Interstitial pneumonitis occurred in two patients. This regimen is effective and has acceptable toxicity for use in the treatment of limited disease-small-cell lung cancer.

Chest radiotherapy in limited-stage small cell lung cancer: facts, questions, prospects

Objective and study design: Limited-disease small cell lung cancer (LD-SCLC) is initially very sensitive to both radiotherapy and chemotherapy. However, the 5-year survival is generally only 10–15%, with most patients failing with therapy refractory relapses, both locally and in distant sites. The addition of chest irradiation to chemotherapy increases the absolute survival by approximately 5%. We reviewed the many controversies regarding optimal timing and irradiation technique. Results: No strong data support total radiation doses over 50 Gy. According to one phase III trial and several retrospective studies, increasing the volume of the radiation fields to the pre-chemotherapy tumour volume instead of the post-chemotherapy volume does not improve local control. Conclusions: The total time in which the entire combined-modality treatment is delivered may be important. From seven randomized trials, it can be concluded that the timing of the radiotherapy as such is not very important. Some phase III trials support the use of accelerated chest radiation together with cisplatin–etoposide chemotherapy, delivered from the first day of treatment, although no firm conclusions can be drawn from the available data. The best results are reported in studies in which the time from the start of treatment to the end of the radiotherapy was less than 30 days. This has to be taken into consideration when treatment modalities incorporating new chemotherapeutic agents and radiotherapy are considered.

Moderate dose-escalation of combination chemotherapy with concomitant thoracic radiotherapy in limited-disease small-cell lung cancer: Prolonged intrathoracic tumor control and high central nervous system relapse rate

The role of chemotherapy dose-intensification in small-cell lung cancer (SCLC) remains unclear. This phase I-II study evaluates feasibility and outcome of combination chemotherapy at moderately elevated doses with concomitant thoracic radiotherapy in limited-disease SCLC. Moderately elevated doses of ifosfamide-epirubicin (cycles 1 and 3) and of carboplatin-etoposide (cycles 2 and 4) were given with G-CSF and peripheral blood stem-cell (PBSC) support. Thoracic radiotherapy (40 Gy) was given once daily during the first five days of each cycle. Overall toxicity was acceptable; most common side-effects were myelosuppression and asthenia. All 35 eligible patients responded (23 CR, 12 PR). Median time to progression was 15 months: median overall survival was 24.6 months. Only 6 of 25 relapsing patients (24%) presented with a locoregional recurrence while 12 of 25 (48%) relapsed in the central nervous system (CNS). This regimen is a feasible dose-intensification with an acceptable toxicity profile. Its efficacy was demonstrated by a 100% response rate, an excellent local tumor control rate and a median survival of 24.6 months. In the absence of PCI, CNS relapse is a major problem if adequate local control is achieved.

Intervention with the hypoxic tumor cell sensitizer etanidazole in the combined modality treatment of limited stage small-cell lung cancer. A one-institution study

We report the toxicity, patterns of failure and survival of a cohort of patients with limited disease (LD) small-cell lung cancer (SCLC) treated with combined radiation and chemotherapy. During the course of thoracic irradiation, we added intravenous (i.v.) etanidazole (SR-2508, a third-generation 2-nitroimidazole) as a hypoxic cell sensitizer in an attempt to reduce the primary local failure rate and improve survival. Between July 1988 and August 1990, 30 consecutive patients with limited disease SCLC were enrolled and treated on a Phase II protocol receiving a standard combination chemotherapy regimen utilizing i.v. cisplatin 25 mg/m2/day x 3 days, i.v. etoposide 100 mg/m2/day x 3 days alternating with intravenous cyclophosphamide 1000 mg/m2/day, intravenous doxorubicin 15 mg/m2, and intravenous vincristine 2 mg (CAV) to a total of six cycles every 3 weeks. Radiotherapy and etanidazole were started after the first cycle of chemotherapy. Etanidazole was administered intravenously at a dose of 2 g/m2 three times per week for a total of 30 g/m2 during the course of thoracic radiation that delivered 50.00 Gy tumor dose in 25 fractions in an overall time of 6 weeks. The overall response rate of the primary lesion in the thorax was 96% (CR + PR), with 64% complete responses. The median time to treatment failure was 18 months. Of the patients that have relapsed, only 18% failed in the thorax (alone or concomitant with other sites). This is a marked improvement compared to the 40-50% rate reported in the literature. The 2-year crude survival was 46%. The 3- and 5-year crude survival rate with no evidence of disease was 33 and 30%, respectively. We have observed a 10% increase in the incidence of transient etanidazole related peripheral neuropathies compared to previous etanidazole studies not utilizing systemic chemotherapy. There was no increased incidence of radiation esophagitis, pulmonary toxicity, or nephro- or myelotoxicity over and above what has been routinely observed with this radio/chemotherapy regimen. There were no treatment related deaths. The moderate increase in etanidazole-related transient peripheral neuropathies could have been related to the concomitant use of etanidazole with vincristine and cisplatin. Although the almost 50% improvement in the incidence of tumor failure rate in the thorax in this small group of patients did not correlate with an equal marked improvement in their survival, the 5-year survival outcome in our series is at least equal or better than the best reports in the literature of larger clinical trials. We believe there is sufficient data from this study, particularly the improvement of local tumor control, to warrant a large randomized controlled clinical trial, using the most current systemic chemotherapy with concomitant thoracic irradiation with or without the most effective available hypoxic cell cytotoxic/sensitizer.

The Diagnostic Value of Pretreatment Serum LDH in Patients with Limited Disease Small-Cell Lung Carcinoma

In patients with limited disease SCLC, the overall survival is still poor. Therefore, a retrospective study was performed involving 48 patients with limited disease SCLC to select a parameter which can identify prognostic subgroups at the time of diagnosis. Follow-up ranged from 3 to 96 months, during which period 38 patients died. Based on clinical outcome, patients were classified into 3 groups: complete remission (CR) (n = 16), local recurrence (LOC) (n = 7) and distant recurrence (DIS) (n = 25). Age, gender and pretreatment biochemical parameters were correlated with clinical outcome and survival. For survival 70 patients staged as having extensive disease (ED) served as a control group. No differences in survival were found in patients with LOC (14% 2 year survival) and DIS (16% 2-year survival) (p = 0.67). Patients achieving a complete remission had a significantly better survival (75% two-year survival). LDH was found to be the only significant correlate of both tumor progression and survival. All patients with pretreatment LDH levels < 240 U/L (n = 13) had tumor recurrence. The survival rate of patients with LDH levels, 240 U/L (41% 2-year survival) was much better than that of patients with LDH levels > 240 U/L 8% 2-year survival) (p = 0.0001). No significant difference in survival (p = 0.33) was found between patients with LD and LDH > 240 U/L and patients with ED and LDH < 400 U/L. Patients with ED and LDH values > 400 U/L showed the poorest outcome. LDH may be used for the identification of prognostic subgroups in SCLC. Patients showing pretreatment LDH levels > 240 U/L have an extremely high risk of tumor recurrence, while their survival is poor and comparable to that of patients staged as having extensive disease and LDH values < 400 U/L.

Early high-dose chemotherapy and peripheral blood progenitor cell transplantation in limited-disease small-cell lung cancer. Results of a single center phase II study

Early high-dose chemotherapy and peripheral blood progenitor cell transplantation in limited-disease small-cell lung cancer. Results of a single center phase II study

Early high-dose chemotherapy and peripheral blood progenitor cell transplantation in limited-disease small-cell lung cancer. Results of a single center phase II study

Early high-dose chemotherapy and peripheral blood progenitor cell transplantation in limited-disease small-cell lung cancer. Results of a single center phase II study

504 Early vs late bifractionated chest irradiation concurrently with chemotherapy in limited disease (LD) small-cell lung cancer (SCLC) (Preliminary results)

504 Early vs late bifractionated chest irradiation concurrently with chemotherapy in limited disease (LD) small-cell lung cancer (SCLC) (Preliminary results)

Validation of an algorithm able to differentiate small-cell lung cancer (SCLC) from non-small-cell lung cancer (NSCLC) patients by means of a tumour marker panel: analysis of the errors

By means of a mathematical score previously generated by discriminant analysis on 90 lung cancer patients, a new and larger group of 261 subjects [209 with non-small-cell lung cancer (NSCLC) and 52 with small-cell lung cancer (SCLC)] was analysed to confirm the ability of the method to distinguish between these two types of cancers. The score, which included the serum neuron-specific enolase (NSE) and CYFRA-21.1 levels, permitted correct classification of 93% of the patients. When the misclassifications were analysed in detail, the most frequent errors were associated with limited disease SCLC with low NSE levels and with advanced NSCLC with high NSE levels. This demonstrates the importance of the marker in correctly categorizing patients.

Full Chemotheraphy in Elderly Patients with Small Cell Bronchial Carcinoma

Data on small cell lung cancer (SCLC) in elderly patients with full chemotherapy are sparse. We present material of 345 patients treated with chemotherapy (CT) with no age limits. CT was given with 2 different types of 4-drug combinations, including cyclophosphamide, doxorubicin, vincristine, methotrexate, lomustine and etoposide. Radiotherapy 40 Gy was given to 85% of the limited disease (LD) and 15% of the extensive disease (ED) patients. In 345 consecutive SCLC patients (50% LD and 50% ED) with a median survival time (MST) of 10 months and a disease-free 5-year survival 3.8%. Multivariate analysis showed clear correlation between stage of disease and survival as well as between age and survival though less pronounced. One hundred and ten patients were > 70 years of age with a median survival time of 7.4 months (LD 12.3 and ED 4.6) and 235 patients < 70 years of age had a median survival time of 10.9 months (LD 14.4 and ED 7.5) and a disease-free 5-year survival of 5.1%. The survival differences were statistically significant. Treatment toxicity was higher in patients > 70 years of age. Seventy-seven patients 70-75 years of age had an MST of 9.5 months (LD 13.2 and ED 6.2) and a disease-free 5-year survival of 1.3%. The survival differences between patients 70-75 years old and those < 70 years of age were small but statistically significant in LD at 5% level but not in ED. There were more septicemias per courses CT given in all patients 70-75 years of age and also more lethal septicemias in ED patients. Patients with LD SCLC 70-75 years of age might benefit from full treatment in terms of median and long-term survival.

86 Preliminary results of a stage oriented multimodality treatment including surgery for selected subgroups of limited disease small cell lung cancer (SCLC)

Since 6/91, 38 patients (pts) with limited disease SCLC (mediastinoscopy obligatory) have been entered into this ongoing trial. Pts with stage, I and II were treated with 4 cycles cisplatin (50 mg/m 2 d 1 + 7) and etoposide (170 mg/m 2 d 3, 4, 5) = PE, q d 22 followed by restaging and surgery. IIIa pts were treated with 3 cycles of PE, q d 22 followed by one cycle simultaneous RTx/CTx (45 Gy, 1,5 Gy twice daily within 3 weeks; P 50 mg/m d 2 + 9 of RTx, E 100 mg/m2 d 4, 5, 6 of RTx) followed by remediastinoscopy and operation. III b pts were treated with 4 cycles PE q d 22 followed by sequential RTx or 3 cycles PE plus 1 cycle of PE with simultaneous RTx (50 Gy, conventional fractionation, 2 Gy daily for 5 weeks). Pts characteristics m/f 26/12; age 55 (34–69); PS 1 (0–1); Stage I6, II2, IIIa 17, IIIb 13. Results after CTx +/− RTx cCR 14; PR 21, CR/PR 35 (92%), MR 2. TOXICITY (WHO): lucopenia 3° 25%, 4° 10%; Infection 3 ° 10%, 4° 5%; thrombocytopenia 3°/4° 20%; diarrhea 3° 5%. One pt died of treatment related septicemia. Seventeen out of 25 (68% (stage I 6/6; stage II 2/2; stage IIIA 9/17)) pts underwent R0 resection including 7 (28%) pCR's. So far CNS relapses were the only site of failure in 7/17 pts who had RO resection. None of them failed locoregionally. The median observation time for pts alive is 15 (3–46) months (MTS). The median survival for all 38 pts is 29 (3+–46+) MTS; stage I–III A not yet reached (3+–46+ MTS), and RO resection not yet reached (5+–46+ MTS, 71% at 27 MTS); stage IIIB 15 (6+–35+) MTS. Conclusions This intensive stage oriented multimodailty program is tolerable and highly effective for LD SCLC. Of note is the high local tumor control rate (100%) of pts with stage I-IIIA who underwent R0 resection.

Use of high-dose etoposide/ifosfamide/carboplatin/epirubicin and peripheral blood progenitor cell transplantation in limiteddisease small cell lung cancer: Brugger W, Frommhold H, Pressler K, Mertelsmann R, Kanz L. Department of Hematology/Oncology, University of Freiburg Medical Ctr., Hugstetter Str 55, 79106 Freiburg. Semin Oncol 1995;22:Suppl 2:3–8

Conventional-dose chemotherapy for limited-disease small cell lung cancer has resulted in high response rates, but rarely in a cure. In an ongoing phase I-II trial, limited-disease small cell lung cancer patients received high-dose chemotherapy and autologous peripheral blood progenitor cell (PBPC) transplantation as part of an early intensification strategy after two cycles of induction chemotherapy. Eligible patients (n = 18) were initially treated with two cycles of etoposide (500 mg/m2), ifosfamide (4 g/m2), cisplatin (50 mg/m2), epirubicin (50 mg/m2) and granulocyte colony-stimulating factor to combine an effective, standard-dose chemotherapy regimen with simultaneous mobilization of PBPCs. Patients who were in partial remission or complete remission after two cycles of induction chemotherapy received high-dose intensification chemotherapy with cumulative doses of 1,500 mg/m2 etoposide, 12 g/m2 ifosfamide, 750 mg/m2 carboplatin, and 150 mg/m2 epirubicin, followed by autologous PBPC transplantation and granulocyte colony-stimulating factor. The duration of the complete chemotherapy program was 9 weeks. All patients received chest irradiation posttransplantation (50 Gy), and those in complete remission received additional prophylactic cranial irradiation (30 Gy). To date, 13 patients with a median age of 49 years (age range, 34 to 62 years) have been treated within this combined-modality treatment protocol. At a median follow-up of 14 months (range, 3 to 45 months) after transplantation, 11 patients were alive and nine were still in complete remission. Nonhematologic toxicity was acceptable; World Health Organization grades 2 to 4 oral mucositis was the most frequently observed (85%) adverse event. No toxic deaths were observed, and hematopoietic reconstitution occurred rapidly after PBPC transplantation; platelet transfusion independence (> 20,000 microL) and neutrophil counts greater than 500 microL were observed at study day 12+. The median survival time was not yet reached. These preliminary data demonstrate that early, high-dose chemotherapy and PBPC transplantation followed by local radiotherapy is safe and may lead to prolonged disease-free survival in some patients. Prospective, randomized studies in a larger series of patients will be required to provide definitive proof of the role of early high-dose chemotherapy in the management of limited-disease small cell lung cancer.

Radiotherapy in limited small cell lung cancer: Fractionation and timing of modalities

The use of thoracic radiotherapy is important to survival in the treatment of limited disease small-cell lung cancer. How to administer that therapy is the subject of continuing clinical trials and ongoing clinical debates. This article focuses on the issues of fractionation of the radiotherapy and describes the rationale for accelerated treatment and hyperfractionated treatment in small cell lung cancer. Theoretical and clinical concepts and recent trials are discussed. Altered fractionation schemes appear to increase acute responding reactions, but are associated with improved local control. The issue of fractionation and central nervous system tolerance is reviewed. Since the cornerstone therapy for this systemic disease is multiagent chemotherapy, strategies for integration of thoracic radiotherapy and systemic chemotherapy are reviewed. The concepts of sequential, alternating, and concurrent therapy are discussed in the context of clinical trials. The issue of integration in the course of treatment is also discussed. Early versus delayed radiation treatment may have different meanings for clinicians and investigators dealing with this disease. All of these issues are covered for the modern cisplatin-etoposide era.

Current trends in the treatment of limited-disease small cell lung cancer : Andrew T. Turrisi University of Michigan Medical Center, Ann Arbor, Michigan

Current trends in the treatment of limited-disease small cell lung cancer : Andrew T. Turrisi University of Michigan Medical Center, Ann Arbor, Michigan

Intensive combination chemotherapy, concurrent chest irradiation, and warfarin for the treatment of limited-disease small-cell lung cancer: a Cancer and Leukemia Group B pilot study.

In prior Cancer and Leukemia Group B (CALGB) studies, combined chemotherapy and thoracic irradiation was superior to chemotherapy alone in limited-disease (LD) small-cell lung cancer (SCLC). A combined modality pilot study was performed to test the feasibility of adding warfarin to aggressive chemoradiotherapy for LD SCLC. Combination chemotherapy with doxorubicin 45 mg/m2 intravenously (IV) on day 1, cyclophosphamide 800 mg/m2 IV on day 1, and etoposide (ACE) 80 mg/m2 on days 1 to 3 was given every 21 days for the first three courses. The fourth and fifth courses substituted cisplatin 33 mg/m2 IV on days 1 to 3 for the doxorubicin, with concurrent chest irradiation to a total of 4,000 cGy given in 20 fractions during a 4-week period followed by a boost of 1,000 cGy in five fractions during a 1-week period. Prophylactic cranial irradiation, 3,000 cGy was given concurrently in 10 fractions during a 2-week period. Courses 6 to 8 again used ACE chemotherapy, but courses 4 to 8 were given on a 28-day schedule with dose adjustment for hematologic or renal toxicity. Warfarin was given throughout the treatment period titrated to achieve a prothrombin time (PT) of 1.5 to 2 times the control. Patients with histologically proven limited-stage SCLC, good performance status, and normal renal, hematologic, and hepatic functions were eligible. Sixty-one of 66 patients entered onto the study were eligible and assessable. Fifty-four (89%) (95%) confidence interval [CI], 78% to 95%) experienced an objective response, 35 (57%) achieved a complete response (CR) (95% CI, 44% to 70%), and 17 (28%) achieved a partial response (95% CI, 16% to 39%). Median durations were CR, 26.3 months; failure-free survival, 11.8 months; and survival, 18 months. Forty-one percent of the patients were alive at 2 years, 33% were alive at 3 years, and 25% were alive at 4 or more years. Median follow-up for survivors is 5 years (range, 3.5 to 5.9 years). Severe or life-threatening myelosuppression occurred in 90%, infection occurred in 34%, fever without documented infection occurred in 26%, and pulmonary toxicity occurred in 6%. Another 6% of patients experienced severe or life-threatening hemorrhages. There were four treatment-related fatalities. The pulmonary toxicities have been associated with the resumption of ACE chemotherapy after chest irradiation. These highly encouraging response and survival results compare favorably with any prior CALGB group study. Although they are somewhat more toxic, they are comparable to the best published results. A randomized study that examines the role of warfarin is underway.

Limited small cell lung cancer: The effect of radiotherapy on local control following response to chemotherapy

The survival and rate of chest infield relapse was examined in 48 patients with limited disease small cell lung cancer (LSCLC) who had achieved complete (CR) or partial response (PR) following three courses of chemotherapy. During 1985–1986 chemotherapy consisted of carboplatin and etoposide and during 1986–1987, of etoposide, carboplatin, cyclophosphamide, and vincristine (ECCO). After three courses of chemotherapy, chest irradiation (50 Gy in 25 fractions over 5 weeks) was given to encompass the original tumor volume. Complete responders were also given prophylactic cranial irradiation, 30 Gy in 10 fractions over 2 weeks. Overall median survival of all patients receiving chest irradiation was 17 months from commencement of radiotherapy. The infield relapse-free survival at 24 months was 49% (95% confidence interval: 32–66%). Patients who had only achieved a PR at the time of irradiation were more likely to relapse in the chest than complete responders (p = 0.09). We conclude that local relapse remains a major cause of failure in patients with LSCLC in spite of sequential high dose radiotherapy given to patients who have responded to chemotherapy.

Sequential hemibody irradiation integrated into a chemotherapy—local radiotherapy program for limited disease small cell lung cancer

Twenty-four patients with limited disease small cell lung cancer (SCLC) were treated with sequential hemibody irradiation (SHB) integrated into a conventional chemotherapy—local radiotherapy (LRT) program. Among 23 evaluable patients, 12 (52%) attained a complete response (CR) and 8 (35%) attained a partial response for an overall major response rate of 87%. The median time since study entry is 29 months. Durations of response are 9.9 months for all patients and 16.5 months for patients who achieved a CR. The primary site was the predominant area of recurrence. The median survival is 13.2 months for all patients and 23.2 months for the 12 patients who attained a CR. Myelosuppression, especially thrombocytopenia, was the major toxicity. Acute radiation toxicities and subacute pneumonitis previously associated with hemibody radiotherapy were well controlled or prevented using the current dose, premedication, and shielding techniques. This integrated program of systemic therapies with SHB and combination chemotherapy plus LRT is feasible for limited disease SCLC; it may prolong survival in patients who attain a CR but compared to similar programs without hemibody irradiation, there was no improvement in overall response rate, response duration, or survival.