Twice-daily Thoracic Radiotherapy Research Articles

A Phase I Study of Chemoradiotherapy With Use of Involved-Field Conformal Radiotherapy and Accelerated Hyperfractionation for Stage III Non-Small Cell Lung Cancer: WJTOG 3305

A Phase I study to determine a recommended dose of thoracic radiotherapy using accelerated hyperfractionation for unresectable non-small-cell lung cancer was conducted. Patients with unresectable Stage III non-small-cell lung cancer were treated intravenously with carboplatin (area under the concentration curve 2) and paclitaxel (40 mg/m(2)) on Days 1, 8, 15, and 22 with concurrent twice-daily thoracic radiotherapy (1.5 Gy per fraction) beginning on Day 1 followed by two cycles of consolidation chemotherapy using carboplatin (area under the concentration curve 5) and paclitaxel (200 mg/m(2)). Total doses were 54 Gy in 36 fractions, 60 Gy in 40 fractions, 66 Gy in 44 fractions, and 72 Gy in 48 fractions at Levels 1 to 4. The dose-limiting toxicity, defined as Grade ≥4 esophagitis and neutropenic fever and Grade ≥3 other nonhematologic toxicities, was monitored for 90 days. Of 26 patients enrolled, 22 patients were assessable for response and toxicity. When 4 patients entered Level 4, enrollment was closed to avoid severe late toxicities. Dose-limiting toxicities occurred in 3 patients. They were Grade 3 neuropathy at Level 1 and Level 3 and Grade 3 infection at Level 1. However, the maximum tolerated dose was not reached. The median survival time was 28.6 months for all patients. The maximum tolerated dose was not reached, although the dose of radiation was escalated to 72 Gy in 48 fractions. However, a dose of 66 Gy in 44 fractions was adopted for this study because late toxicity data were insufficient.

Cisplatin and Etoposide Chemotherapy Combined with Early Concurrent Twice-daily Thoracic Radiotherapy for Limited-disease Small Cell Lung Cancer in Elderly Patients

The optimal management of elderly patients with limited-disease small cell lung cancer (LD-SCLC) has not been established. The records of elderly (>or=70 years of age) patients with LD-SCLC who had been treated with etoposide and cisplatin chemotherapy with early concurrent twice-daily thoracic radiotherapy (TRT) were reviewed retrospectively. Of the 25 elderly patients with LD-SCLC identified, 12 (48%) individuals received etoposide-cisplatin chemotherapy with early concurrent twice-daily TRT. The main toxicities of this treatment regimen were hematologic, with neutropenia of Grade 4 being observed in all patients and febrile neutropenia of Grade 3 in eight patients during the first cycle of chemoradiotherapy. The toxicity of TRT was acceptable, with all patients completing the planned radiotherapy within a median of 29 days (range, 19-33). No treatment-related deaths were observed. The median progression-free survival and overall survival times were 14.2 months (95% confidence interval, 4.3-18.2) and 24.1 months (95% confidence interval, 11.3-27.2), respectively. Etoposide-cisplatin chemotherapy with early concurrent twice-daily TRT was highly myelotoxic in elderly patients with LD-SCLC, although no treatment-related deaths were observed in our cohort. Prospective studies are required to establish the optimal schedule and dose of chemotherapy and TRT in such patients.

Randomized phase 2 study of subcutaneous amifostine versus epoetin‐α given 3 times weekly during concurrent chemotherapy and hyperfractionated radiotherapy for limited‐disease small cell lung cancer

The purpose of the current study was to investigate the role of amifostine and epoetin-alpha in reducing severe toxicities during concurrent chemo-hyperfractionated radiotherapy (CCRT) for limited disease small cell lung cancer (LD-SCLC). Seventy-six patients with LD-SCLC were enrolled. The treatment schedule was consisted of two 28-day cycles of cisplatin at a dose of 30 mg/m2 (Days 1 and 8) and irinotecan at a dose of 60 mg/m2 (Days 1, 8, and 15) followed by two 21-day cycles of cisplatin at a dose of 60 mg/m2 (Day 1) and etoposide at a dose of 100 mg/m2 (Days 1-3) with concurrent twice-daily thoracic radiotherapy for a total of 45 grays. Patients were randomly assigned at registration to either amifostine at a dose of 500 mg or epoetin-alpha at a dose of 10,000 IU subcutaneously 3 times weekly (n = 36 patients and 40 patients, respectively). Fifteen of 36 patients assigned to the amifostine arm did not receive amifostine because of a lack of supply. Amifostine treatment was associated with higher febrile neutropenia (P = .003) and grade 2 or 3 nausea (according to the National Cancer Institute Common Toxicity Criteria [version 3.0]) (P = .03). It also demonstrated a trend toward higher grade 4 leukopenia (P = .05). Grade 3 esophagitis was reported in 30% of patients treated with amifostine and 9% of patients treated with epoetin-alpha (P = .059). Epoetin-alpha treatment was associated with less grade 2 or 3 anemia (P = .031) and lower decreases in hemoglobin level during CCRT (P = .016). The median survival times for both treatment arms were comparable (22.6 months in the amifostine arm vs 25.6 months in the epoetin-alpha arm; P = .447). Although amifostine administered 3 times weekly during CCRT did not significantly reduce severe toxicities, epoetin-alpha was effective in preventing severe anemia during CCRT in patients with LD-SCLC. Other radioprotective strategies to minimize severe toxicities should be investigated.

Phase II Study of Etoposide and Cisplatin With Concurrent Twice-Daily Thoracic Radiotherapy Followed by Irinotecan and Cisplatin in Patients With Limited-Disease Small-Cell Lung Cancer: West Japan Thoracic Oncology Group 9902

Phase II Study of Etoposide and Cisplatin With Concurrent Twice-Daily Thoracic Radiotherapy Followed by Irinotecan and Cisplatin in Patients With Limited-Disease Small-Cell Lung Cancer: West Japan Thoracic Oncology Group 9902

Changes in Patterns of Care for Limited-Stage Small-Cell Lung Cancer: Results of the 99-01 Patterns of Care Study—A Nationwide Survey in Japan

This study was undertaken to analyze the practice process of thoracic radiotherapy (TRT) and evaluate changes in patterns of care for patients with limited-stage small-cell lung cancer (LS-SCLC) in Japan. The Patterns of Care Study (PCS) conducted the second nationwide survey of care process for patients with LS-SCLC treated by using TRT between 1999 and 2001. The PCS collected data for 139 patients with LS-SCLC (man-woman ratio, 5:1; median age, 69 years; age > 70 years, 43%; Karnofsky Performance Status > 70, 73%; and Stage III, 88%). Median total dose was 50 Gy. Twice-daily TRT was used in 44% of patients. Median field size was 12 x 14 cm. The most commonly used photon energy was 10 MV (77%), whereas obsolete techniques using (60)Co or X-ray energy less than 6 MV comprised 12%. Three-dimensional conformal therapy was used with 12% of patients. Computed tomography simulation was performed in 40% of cases. Only 12 patients (8.6%) received prophylactic cranial irradiation (PCI). Concurrent chemotherapy and TRT (CCRT) was used for 94 patients (68%). Only 6 patients (4.4%) entered clinical trials. Compared with the previous PCS 95-97, significant increases in the use of CCRT (34-68%; p < 0.0001), twice-daily TRT (15-44%; p < 0.0001), and PCI (1.7-8.6%; p =0.0045) were observed, although the absolute number of patients receiving PCI was still extremely low. Evidence-based CCRT and twice-daily TRT has penetrated into clinical practice. However, PCI is not yet widely accepted in Japan.

Limited-Stage Small-Cell Lung Cancer: The Current Status of Combined-Modality Therapy

Limited-stage (LS) small-cell lung cancer (SCLC) remains a therapeutic challenge to medical and radiation oncologists. The treatment of LS-SCLC has evolved significantly over the last two decades with combined-modality therapy now the standard of care. The addition of thoracic radiotherapy (TRT) to standard chemotherapy has led to improvements in long-term survival in this population. However, many questions remain about the optimal way to deliver chemoradiotherapy. In a landmark trial, twice-daily TRT to a dose of 45 Gy increased 5-year survival by 10% compared with once-daily TRT administered to the same dose. This suggests that more intensive TRT regimens may lead to further survival gains, assuming they can be delivered safely in this setting. Strategies currently under investigation include higher total daily doses delivered once daily or novel concurrent boost techniques allowing more intensive treatments over shorter periods of time. Several trials and meta-analyses have evaluated the timing of TRT with chemotherapy, with the weight of evidence suggesting that early and concurrent TRT with chemotherapy is optimal. Novel cytotoxic chemotherapy combinations have failed thus far to provide an advantage over standard etoposide-cisplatin combinations. Prophylactic cranial irradiation in near or complete responders to induction chemoradiotherapy has also been shown to improve long-term survival rates. LS-SCLC has been a model cancer in terms of the potential benefit of combined chemoradiotherapy strategies in improving patient outcomes.

Results of a Phase II Study of High-Dose Thoracic Radiation Therapy With Concurrent Cisplatin and Etoposide in Limited-Stage Small-Cell Lung Cancer (NCCTG 95-20-53)

To evaluate the outcome of patients with limited-stage small-cell lung cancer (L-SCLC) treated with cisplatin and etoposide (PE), early prophylactic cranial irradiation (PCI), and high-dose twice-daily thoracic radiotherapy (bid RT). A total of 76 assessable patients were treated on this phase II trial, which included six cycles of PE. PCI (25 Gy/10 fractions) was delivered during cycle 3 to responding patients. Cycles 4 and 5 included concurrent chemotherapy and thoracic RT (30 Gy/20 bid fractions, a 2-week break, and another 30 Gy/20 bid fractions). Of the 76 assessable patients, 74 patients (97%) suffered grade 3 or greater (3+) toxicity and 61 patients (80%) had grade 4 or greater (4+) toxicity. Of these adverse events, grade 3+ hematologic toxicity occurred in 72 patients (95%), and grade 3+ nonhematologic toxicity occurred in 55 patients (72%). Only one (2%) of the 61 patients who received PCI experienced treatment failure in the brain. The 5-year survival rate of the 76 assessable patients was 24% (median, 20 months). The 5-year survival rate of the 64 patients who received thoracic RT was 29% (median, 22 months). The 5-year cumulative incidence of in-field treatment failure was 34%. This regimen included a high total dose of bid TRT, which resulted in a favorable 5-year survival rate. Local failure remains a problem that will require additional investigation. Newer technology should allow the safe administration of greater doses of RT, which should improve patient outcome. Data from eight trials were combined to demonstrate a relationship between RT dose fractionation and 5-year survival.

Phase II Study of Induction Irinotecan + Cisplatin Chemotherapy Followed by Concurrent Irinotecan + Cisplatin Plus Twice-Daily Thoracic Radiotherapy

Background: Irinotecan hydrochloride, a topoisomerase I inhibitor, is effective against small-cell lung cancer. Irinotecan also can act as a potential radiation sensitizer along with cisplatin. To evaluate efficacy and toxicity of irinotecan plus cisplatin (IP) with concurrent thoracic radiotherapy, we conducted a phase II study of IP followed by concurrent IP plus hyperfractionated thoracic radiotherapy in patients with previously untreated limited-stage small-cell lung cancer. Methods: Twenty-four patients with previously untreated small-cell lung cancer were enrolled onto the study since November 2004. Irinotecan was administered intravenously on days 1 and 8 in combination with cisplatin on day1 every 21 days. From the first day of third cycle, twice-daily thoracic irradiation (total 45 Gy) was given. Prophylactic cranial irradiation was given to the patients who showed complete remission after concurrent chemoradiotherapy. Restaging was done after second and sixth cycle with chest CT and/or bronchosocpy. Results: Up to November 2004, 19 patients were assessable. The median follow-up time was 12.5 months. A total of 99 cycles (median 5.2 cycles per patient) were administered. The actual dose intensity values were cisplatin /week and irinotecan /week. Among the 19 patients, the objective response rate was 95% (19 patients), with 9 patients (47%) having a complete response (CR). The major grade 3/4 hematological toxicities were neutropenia (35% of cycles), anemia (7% of cycles), thrombocytopenia (7% of cycles). Febrile neutropenia was 4% of cycles. The predominant grade 3/4 non-hematological toxicities was diarrhea (5% of cycles). Toxicities was not significantly different with concurrent administration of irinotecan and cisplatin with radiotherapy, except grade 3/4 radiation esophagitis (10% of patients). No treatment-related deaths were observed. The 1-year and 2-year survival rate of eligible patients was 89% (16/18) and 47% (9/18), respectively. Conclusion: Three-week schedule of irinotecan plus cisplatin followed by concurrent IP plus hyperfractionated thoracic radiotherapy is an effective treatment for limited disease small-cell lung cancer, with acceptable toxicity.

Phase II Study of Etoposide and Cisplatin With Concurrent Twice-Daily Thoracic Radiotherapy Followed by Irinotecan and Cisplatin in Patients With Limited-Disease Small-Cell Lung Cancer: West Japan Thoracic Oncology Group 9902

We initially conducted a randomized phase II study to compare irinotecan and cisplatin (IP) versus irinotecan, cisplatin, and etoposide (IPE) after etoposide and cisplatin (EP) with concurrent twice-daily thoracic radiotherapy (TRT) in limited-disease small-cell lung cancer (LD-SCLC). We amended the protocol to evaluate IP after EP with concurrent twice-daily TRT in a single-arm phase II study because of an unacceptable toxicity in IPE. Previously untreated patients with LD-SCLC were treated intravenously with etoposide 100 mg/m2 on days 1 through 3 and cisplatin 80 mg/m2 on day 1 with concurrent twice-daily TRT (1.5 Gy per fraction, a total dose of 45 Gy) beginning on day 2 followed by three cycles of irinotecan 60 mg/m2 on days 1, 8, and 15 and cisplatin 60 mg/m2 on day 1 of a 4-week cycle. Of the 51 patients enrolled, 49 patients were assessable for response and toxicity. The overall response rate and complete response rate were 88% and 41%, respectively. The median survival time for all patients was 23 months. The 2-year and 3-year survival rates were 49% and 29.7%, respectively. The median progression-free survival was 11.8 months. The major toxicities observed were neutropenia (grade 4, 84%), febrile neutropenia (grade 3, 31%), infection (grade 3 to 4, 33%), electrolytes imbalance (grade 3 to 4, 20%), and diarrhea (grade 3 to 4, 14%). EP with concurrent twice-daily TRT followed by the consolidation of IP appears to be an active regimen which deserves further phase III testing in patients with LD-SCLC.

Chemoradiotherapy for lung cancer

Chemoradiotherapy is a standard treatment for both unresectable locally advanced non-small cell lung cancer and limited-stage small cell lung cancer. Cisplatin-based chemotherapy with concurrent thoracic radiotherapy yields a 5-year survival rate of ∼ 15% for patients with unresectable locally advanced non-small cell lung cancer. The state-of-the-art treatment for limited-stage small cell lung cancer is four cycles of chemotherapy with cisplatin plus etoposide combined with early concurrent twice-daily thoracic irradiation and prophylactic cranial irradiation after complete remission. A 5-year survival rate of ∼ 25% is expected among patients treated for limited-stage small cell lung cancer. The incorporation of new agents, including target-based drugs, is one of the most promising strategies for improving the survival of patients.

Pilot Study of Concurrent Etoposide and Cisplatin Plus Accelerated Hyperfractionated Thoracic Radiotherapy Followed by Irinotecan and Cisplatin for Limited-Stage Small Cell Lung Cancer: Japan Clinical Oncology Group 9903

Irinotecan and cisplatin (IP) significantly improved survival compared with etoposide and cisplatin (EP), in patients with extensive-stage small cell lung cancer (SCLC) in a previous Japan Clinical Oncology Group (JCOG) randomized trial. JCOG9903 was conducted to evaluate the safety of sequentially given IP following concurrent EP plus twice-daily thoracic irradiation (TRT) for the treatment of limited-stage SCLC (LSCLC). Between October 1999 and July 2000, 31 patients were accrued from 10 institutions. Thirty patients were assessable for toxicity, response, and survival. Treatment consisted of etoposide 100 mg/m(2) on days 1 to 3, cisplatin 80 mg/m(2) on day 1, and concurrent twice-daily TRT of 45 Gy beginning on day 2. The IP regimen started on day 29 and consisted of irinotecan 60 mg/m(2) on days 1, 8, and 15 and cisplatin 60 mg/m(2) on day 1, with three 28-day cycles. There were no treatment-related deaths. The response rate was 97% (complete response, 37%; partial response, 60%). Median overall survival was 20.2 months; 1-, 2-, and 3-year survival rates were 76%, 41%, and 38%, respectively. Of the 24 patients who started the IP regimen, 22 received two or more cycles. Hematologic toxicities of grade 3 or 4 included neutropenia (67%), anemia (50%), and thrombocytopenia (4%). Nonhematologic toxicities of grade 3 or 4 included diarrhea (8%), vomiting (8%), and febrile neutropenia (8%). Of the 20 patients with recurrence, none had local recurrence alone and only two had both local and distant metastasis as the initial sites of disease progression. IP following concurrent EP plus twice-daily TRT is safe with acceptable toxicities. A randomized phase III trial comparing EP with IP following EP plus concurrent TRT for LSCLC is ongoing (JCOG0202).

P-768 Phase II study of irinotecan/cisplatin induction followed by concurrent twice-daily thoracic irradiation with etoposide/cisplatin chemotherapy for limited disease small cell lung cancer

P-768 Phase II study of irinotecan/cisplatin induction followed by concurrent twice-daily thoracic irradiation with etoposide/cisplatin chemotherapy for limited disease small cell lung cancer

Dose intensive chemotherapy for limited-stage (LS) small cell lung cancer (SCLC): A phase II study

7157 Background: Cisplatin plus etoposide (PE) and concurrent twice-daily (BID) thoracic radiotherapy (TRT) is a standard treatment for LS-SCLC. Dose intensive weekly regimen (CODE) with G-CSF is highly active in relapsed SCLC (J Clin Oncol 15:292,1997). Early administration of dose intensive, wide diversity regimen is an intriguing strategy for the treatment of LS-SCLC. The purpose of the phase II study was to evaluate safety and efficacy of sequential administration of CODE + G-CSF following concurrent PE and BID TRT. Methods: Treatment consisted of one induction cycle of cisplatin (C) 80 mg/m2 d 1 and Etoposide (E) 100 mg/m2 d 1–3. TRT 45 Gy was given 1.5 Gy bid 5d/week for 30 fractions concurrent with cycle 1. The CODE regimen started on week 5 and consisted of C 25 mg/m2 iv weekly for 6 wks, vincristine 1 mg/m2 iv wks 6, 8, and 10, doxorubicin 40 mg/m2 and E 80 mg/m2 X 3 days iv on wks 5, 7 and 9. 50{Unknown character “Ãé¼”}g/ m2 of G-CSF was administered sc on the days when cytotoxic drugs were not given. Each patient had to fulfill the following criteria: histologically and/or cytologically documented SCLC, LS, ECOG PS 0, 1 or 2, age 74 years or younger, no prior treatment for SCLC, measurable or evaluable lesion, adequate organ functions. Results: Between Sep. 1997 and July 2001, 44 patients were enrolled. Forty-three patients are eligible and evaluable for safety and efficacy, including 36 male and 7 female, median age; 62 (range 41–74), 17 PS 0, 25 PS 1 and 1 PS 2. Overall response rate and complete response rate were 100% and 63%, respectively. The main toxicity was hematologic as follows: Grade 3/4 leukopenia in 21%/74%, anemia in 58%/26%, thrombocytopenia in 44%/5%. Two patients were deemed treatment related deaths due to pneumonitis. Thirty-nine patients started the CODE regimen and 37 (79%) patients completed 6 cycles of CODE. Median overall survival time was 33 months. Three-year and 5-year survival rate were 48% and 35%, respectively. Conclusions: PE and concurrent BID TRT followed by CODE+G-CSF is feasible with manageable toxicity and encouraging outcome has been demonstrated. Randomized trial comparing four cycles of PE and concurrent BID RT with this regimen is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb

Phase II Study of Irinotecan Plus Cisplatin Induction Followed by Concurrent Twice-Daily Thoracic Irradiation With Etoposide Plus Cisplatin Chemotherapy for Limited-Disease Small-Cell Lung Cancer

Irinotecan plus cisplatin (IP) chemotherapy demonstrated a promising outcome with a high complete response (CR) rate in chemotherapy-naïve patients with extensive small-cell lung cancer (SCLC). We evaluated the efficacy of induction IP chemotherapy followed by concurrent etoposide plus cisplatin (EP) chemotherapy with twice-daily thoracic radiotherapy (TDTRT) in limited-disease SCLC (LD-SCLC). Between November 2001 and May 2003, 35 chemotherapy-naïve patients with LD-SCLC were enrolled. Thirty-three patients (94%) were male, and 29 (83%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. The median age was 63 years. Treatment consisted of two 21-day cycles of cisplatin 40 mg/m2 and irinotecan 80 mg/m2 intravenously (i.v.) on days 1 and 8 followed by two 21-day cycles of cisplatin 60 mg/m2 i.v. on days 43 and 64, and etoposide 100 mg/m2 i.v. on days 43 to 45 and 64 to 66, with concurrent TDTRT of total 45 Gy beginning on day 43. All 35 patients were assessable for response. The objective response rate was 97% (CR, 3; partial response [PR], 31) after induction chemotherapy and 100% (CR, 15; PR, 20) after concurrent chemoradiotherapy (CCRT). After a median follow-up of 26.5 months, the median survival was 25.0 months (95% CI, 19.0 to 30.9) with 1- and 2-year overall survival rates of 85.7% and 53.9%, respectively. Median progression-free survival (PFS) was 12.9 months with a 1- and 2-year PFS of 58.5% and 36.1%, respectively. The most common toxicities were grade 3 or 4 neutropenia in 68% of patients during induction chemotherapy and 100% during CCRT. Febrile neutropenia occurred in 20% of patients during induction chemotherapy and 60% during CCRT. IP induction chemotherapy followed by concurrent TDTRT with EP chemotherapy showed a promising activity with favorable 1- and 2-year survival rates. Based on the favorable outcome in this trial, this regimen should be evaluated in a large phase III trial.

Chemoradiotherapy for lung cancer: current status and perspectives

For many years, thoracic radiotherapy had been regarded as the standard treatment for patients with unresectable locally advanced non-small cell lung cancer. However, meta-analyses show that cisplatin-containing chemoradiotherapy is significantly superior to radiotherapy alone in terms of survival. Moreover, concurrent chemoradiotherapy yields a significantly increased response rate and enhanced survival duration when compared with the sequential approach. Cisplatin-based chemotherapy with concurrent thoracic radiotherapy yields a 5-year survival rate of approximately 15% for patients with unresectable locally advanced non-small cell lung cancer. The state-of-the-art treatment for limited-stage small cell lung cancer is considered to be four cycles of combination chemotherapy with cisplatin plus etoposide combined with early concurrent twice-daily thoracic irradiation (45 Gy). If patients achieve complete remission, prophylactic cranial irradiation should be administered. A 5-year survival rate of approximately 25% is expected with the state-of-the-art treatment for limited-stage small cell lung cancer. Chemoradiotherapy is considered to be a standard treatment for both unresectable locally advanced non-small cell lung cancer and limited-stage small cell lung cancer. Several new strategies are currently being investigated to improve the survival of these patients. The incorporation of target-based drugs such as gefitinib is considered to be the most promising strategy for unresectable locally advanced non-small cell lung cancer. The incorporation of irinotecan is also a promising strategy to improve the survival of patients with limited-stage small cell lung cancer. The Japan Clinical Oncology Group is conducting clinical trials to develop new treatment strategies for both unresectable locally advanced non-small cell lung cancer and limited-stage small cell lung cancer.

Treatment options for small cell lung cancer.

Lung cancer remains the leading cause of cancer-related death in the United States. Small cell lung cancer (SCLC) comprises 15% to 25% of all lung cancers. The leading cause of lung cancer remains smoking, and rates of smoking continue to rise in women, whereas rates in other subgroups have slowed. In this article we review recent advances in the treatment of limited-stage as well as extensive-stage small cell lung cancer. In limited-stage disease, the best survival results are observed when patients are treated with twice-daily thoracic radiotherapy given concurrently with chemotherapy. Patients who have been successful in smoking cessation during therapy for limited-stage disease may have a survival benefit over those who are unable to quit smoking during treatment. In extensive-stage disease, the most significant trial is one comparing irinotecan plus cisplatin and etoposide plus cisplatin, showing a survival advantage for the irinotecan arm. This trial may change the standard of care for patients with extensive-stage disease. A similar ongoing trial in the United States is attempting to confirm these results.

O-73 High dose, twice-daily thoracic radiotherapy (TRT) with daily chemotherapy in limited stage small cell lung cancer

O-73 High dose, twice-daily thoracic radiotherapy (TRT) with daily chemotherapy in limited stage small cell lung cancer

P-58 Phase II study of irinotecan/cisplatin (IP) induction chemotherapy followed by concurrent twice-daily thoracic radiotherapy (RT) with etoposide/cisplatin (EP) for limited disease small cell lung cancer (LD-SCLC)

P-58 Phase II study of irinotecan/cisplatin (IP) induction chemotherapy followed by concurrent twice-daily thoracic radiotherapy (RT) with etoposide/cisplatin (EP) for limited disease small cell lung cancer (LD-SCLC)

Phase I/II study of altered schedule of cisplatin and etoposide administration and concurrent accelerated hyperfractionated thoracic radiotherapy for limited-stage small-cell lung cancer

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×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.

Long-term results of induction chemotherapy followed by concurrent chemotherapy and thoracic irradiation in limited small cell lung cancer

Background: Small cell lung cancer (SCLC) is a chemoresponsive tumor but overall survival remains poor even in limited disease (LD). With the aim of eradicating chemoresistant tumor cells and reducing toxicity, we investigated in this phase II trial the feasibility and outcome of a sequential approach of induction chemotherapy (CT) followed, in responding patients with LD-SCLC, by intensified platinum-based CT and concurrent thoracic irradiation (TI). Materials and methods: We treated 55 consecutive LD-SCLC patients with three 21-day cycles of cyclophosphamide, epiadriamycin and vincristine (CEV) as induction CT. In 44 (80%) patients there was an objective response and they received treatment intensification consisting of TI and concomitant CT with carboplatin and etoposide plus recombinant granulocite colony stimulating factor. Twenty-five (57%) patients were submitted to twice-daily thoracic irradiation (TDTI; 1.5 Gy per fraction, to a total dose of 45 Gy) and 19 (43%) to once-daily thoracic irradiation (ODTI; 2 Gy per fraction, to a total dose of 50 Gy). Results: Median follow up was 75 months (range, 42–102). Of 44 patients submitted to intensification with TI plus CT, 32 (73%) had a complete and 12 (27%) a partial response. Median overall survival of all 55 patients was 17 months with actuarial survival probabilities of 2 and 5 years, 32 and 25%, respectively. Analysis of patient sub-groups showed a 5-month median survival in non-responders, 19 in TDTI and 17 in ODTI patients, respectively. Two and 5 year survival probabilities were 0% in non-responders, 40 and 35% in TDTI and 39 and 21% in ODTI patients, respectively. At present, 13 of 44 responders are still alive, of which nine (20%) have been progression-free from 45 to 93 months (median 60). Treatment failure was registered in 31 (70%) of 44 patients who received both induction and intensification treatment. One-half of patients had intrathoracic recurrence, eight of which only local and the remaining seven local and distant. Fourteen (32%) patients had brain metastases. Grade 3–4 neutropenia occurred in 24 (55%) patients with no differences between treatment groups. Grade 3 esophagitis was registered in four (9%) patients: in 3/25 (12%) and 1/19 (5%) of those who received TDTI and ODTI, respectively ( P=not significant). Acute radiation pneumonitis occurred in three (12%) patients submitted to TDTI. No clinically debilitating pulmonary fibrosis, permanent esophageal stricture or toxic death was observed. Conclusions: In LD-SCLC patients late concurrent CT plus TI is feasible and effective. Our long-term results are similar to the best reported in the literature. Despite the high incidence of complete response obtained, however, one-half of the patients had intrathoracic relapse and one-third brain metastases.