Phase I trial of escalating-dose irinotecan given weekly with cisplatin and concurrent radiotherapy in locally advanced esophageal cancer.

PURPOSE: To identify the maximum-tolerated dose and dose-limiting toxicity (DLT) of weekly irinotecan combined with cisplatin and radiation in esophageal cancer. PATIENTS AND METHODS: Nineteen patients with clinical stage II to III esophageal squamous cell or adenocarcinoma were treated on this phase I trial. Induction chemotherapy with weekly cisplatin 30 mg/m2 and irinotecan 65 mg/m2 was administered for four treatments during weeks 1 to 5. Radiotherapy was delivered weeks 8 to 13 in 1.8-Gy daily fractions to a dose of 50.4 Gy. Cisplatin 30 mg/m2 and escalating-dose irinotecan (40, 50, 65, and 80 mg/m2) were administered on days 1, 8, 22, and 29 of radiotherapy. DLT was defined as a 2-week delay in radiotherapy for grade 3 to 4 toxicity. RESULTS: Minimal toxicity was observed during chemoradiotherapy, with no grade 3 or 4 esophagitis, diarrhea, or stomatitis. DLT caused by myelosuppression was seen in two of six patients treated at the 80-mg/m2 dose level, thus irinotecan 65 mg/m2 was defined as the recommended phase II dose. Dysphagia improved or resolved after induction chemotherapy in 13 (81%) of 16 patients who reported dysphagia before therapy. Only one patient (5%) required a feeding tube. Six complete responses (32%) were observed, including four pathologic complete responses in 15 patients selected to undergo surgery (27%). CONCLUSION: Cisplatin, irinotecan, and concurrent radiotherapy can be administered on a convenient schedule with relatively minimal toxicity and an acceptable rate of complete response in esophageal cancer. Further phase II evaluation of this regimen is ongoing. A phase III comparison to fluorouracil or taxane-containing chemoradiotherapy should be considered.     

Phase II study of irinotecan plus cisplatin with concurrent radiotherapy for the patients with limited-disease small-cell lung cancer

BACKGROUND: A recently conducted randomized, phase III study that compared irinotecan plus cisplatin (IP) with etoposide plus cisplatin for the patients with extensive disease SCLC revealed a superior median survival rate and a superior 2-year survival rate for the IP combination therapy. Yet there have been few such reports on the patients suffering with limited disease SCLC (LD-SCLC). We conducted a phase II trial to evaluate the efficacy and toxicity of administering IP with concurrent radiotherapy for the patients with LD-SCLC. PATIENTS AND METHODS: Twenty chemotherapy-na?ve patients with LD-SCLC were enrolled in our study. The patients were treated with 40 mg/m(2) irinotecan on days 1, 8 and 15 and with 60 mg/m(2) cisplatin on day 1 every 4 weeks until a maximum of six cycles was delivered. Once-daily radiotherapy included the administration of 50.4 Gy in 28 fractions. After completion of the radiation therapy, the dose of irinotecan was increased to 60 mg/m(2). RESULTS: The response rate was 85% (CR: 6; partial response, PR: 11). The median survival was 20.0 months (95% CI: 15.6-24.4 months) with 1-year and 2-year overall survival rates of 85 and 35%, respectively. The median progression free survival (PFS) was 12 months (95% CI: 6.2-18.1 months) with a 1-year PFS of 36%. The major hematologic toxicities of this regimen were neutropenia (60%), leukopenia (55%), anemia (20%) and thrombocytopenia (10%). The non-hematologic toxicities were nausea/vomiting (55%), diarrhea (35%) and dysphagia (15%). CONCLUSIONS: Our data show that IP with concurrent radiotherapy is an effective and tolerable regimen for the treatment of LD-SCLC and these findings warrant further investigation.     

Phase II study of irinotecan and cisplatin with concurrent split-course radiotherapy in limited-disease small cell lung cancer

Background

Irinotecan and cisplatin are one of active regimens for patients with extensive-stage small cell lung cancer (SCLC). To determine the efficacy and toxicity of irinotecan and cisplatin with concurrent split-course thoracic radiotherapy in limited-disease (LD) SCLC, we conducted a phase II study.

Patients and methods

Thirty-four patients fulfilling the following eligibility criteria were enrolled: chemotherapy-na?ve, good performance status (PS 0–1), age ≤75, LD-SCLC, and adequate organ function. The patients received irinotecan 40?mg/m² i.v. on days 1, 8, and 15, and cisplatin 60?mg/m² i.v. on day 1. Four cycles of chemotherapy were repeated every 4?weeks. Split-course thoracic radiotherapy of once-daily 2?Gy/day commenced on day 2 of each chemotherapy cycle, with 26 and 24?Gy administered in the first and second cycles, respectively.

Results

Thirty-four patients were eligible and assessable for response, toxicity, and survival. Patients’ characteristics were as follows: male/female?=?29/5; PS 0/1?=?18/16; median age (range)?=?67 (50–73); and stage IB/IIA/IIB/IIIA/IIIB?=?2/2/3/16/11. The overall response was 100?% (CR 8, PR 26). Grade 4 leukopenia, neutropenia, grade 3–5 pneumonitis, diarrhea, and esophagitis occurred in 24, 38, 6, 3, and 0?%, respectively. There were 2 treatment-related deaths from pneumonitis. The median time to tumor progression was 14.3?months. The median overall survival time and the 2- and 5-year survival rates were 44.5?months, 66.7 and 46.1?%, respectively. No tumor progression was observed in patients with CR.

Conclusion

Irinotecan plus cisplatin with concurrent split-course thoracic radiotherapy was effective and tolerable in untreated LD-SCLC.     

Sequential chemo- and radiochemotherapy with weekly paclitaxel (Taxol) and 3D-conformal radiotherapy of stage III inoperable non-small cell lung cancer. Results of a dose escalation study

The purpose of this study was the determination of the maximum tolerable dose (MTD) of weekly paclitaxel (PX) in combination with 3D-conformal radiotherapy in non-small cell lung cancer (NSCLC) and the evaluation of side effects, patient outcome and tumor response. Thirty-eight patients with inoperable NSCLC, UICC-stage IIIA (n=14)/IIIB (n=24) received two cycles of induction chemotherapy with PX/carboplatin followed by combined radiochemotherapy (60 Gy/6 weeks) with weekly PX which was escalated in cohorts of four patients until dose limiting toxicity (DLT) was reached. Starting level was 40 mg/m(2). 3D-conformal radiotherapy was applied in all patients. Toxicity was determined by WHO criteria. Patients were followed-up 3-monthly. Thirty eight patients have entered the study, 34 patients are evaluable. DLT was esophagitis III degrees, requiring interruption of radiotherapy and was reached at the PX 70 mg/m(2). Two hypersensitivity reactions (50 mg/m(2)) and one leucopenia III degrees (60 mg/m(2)) were observed. Only one patient (60 mg/m(2), 50 Gy) completely aborted treatment. The pneumonitis rate was between 21 and 36% but showed no clear correlation with PX dose. Tumor response (PR and CR) defined by CT-scan 6 weeks following radiotherapy was 88% (30/34). The 1- and 2-year survival rate is 73% and 34%. We conclude that the MTD of weekly PX with 60 Gy normofractionated radiotherapy is 60 mg/m(2). The DLT is esophagitis. Response and survival data of this sequential/combined approach are promising. A minor increase of pulmonary toxicity of irradiation is suspected.     

早期鼻咽癌希罗达增敏放疗的临床Ⅰ期研究

目的　探讨希罗达对鼻咽癌增敏放疗的剂量限制毒性 (DLT)和最大耐受剂量 (MTD) ,同时观察疗效。方法　自 2 0 0 2年 8月至 2 0 0 3年 6月 ,临床分期为T2 N1M0 的Ⅱ期鼻咽癌患者 30例 ,中位年龄 4 3岁 (32～ 6 3岁 ) ,全身功能状态评分≤ 2。放射治疗为鼻咽原发病灶 6 8～ 72Gy·34～ 36次 -1·7周 -1,颈部淋巴结阳性区 6 4～ 70Gy·32～ 35次 -1·6 .5～ 7周 -1。希罗达分为 5 0 0 ,75 0 ,10 0 0 ,12 5 0mg/m2 等 4个剂量组 ,于放疗第 1天开始 ,2次 /d ,共 14d ,每 3周为 1个疗程 ,共两个疗程。每个剂量组至少 6例患者 ,6例全部完成两个疗程化疗并进行毒性反应评价后 ,才进行剂量升级。结果　全组有 2 8例可评价疗效和毒性反应。希罗达治疗结束时 ,CR 12例 (42 .9% ) ,PR 13例 (46 .4 % ) ,SD 3例(10 .7% ) ,总有效率 (CR PR)为 89.3%。单纯颈部淋巴结CR率为 5 0 .0 % (14 / 2 8) ,单纯鼻咽肿瘤CR率为 4 6 .4 % (13/ 2 8)。放射治疗结束时CR率为 96 .4 % (2 7/ 2 8)。希罗达 5 0 0mg/m2 和 75 0mg/m2剂量组未出现任何严重DLT ;在 10 0 0mg/m2 剂量组 ,有 3例 (3/ 9)出现Ⅲ级口腔黏膜DLT ;在 12 5 0mg/m2 剂量组 ,有 4例出现DLT ,其中Ⅲ度口腔黏膜反应 4例 (4/ 6 ) ,Ⅲ度腹泻并中性粒细胞减少性发热1例     

Irinotecan and cisplatin with concurrent split-course radiotherapy in locally advanced nonsmall-cell lung cancer: a multiinstitutional phase 2 study

BACKGROUND: The purpose was to determine the efficacy and toxicity of irinotecan and cisplatin with concurrent split-course thoracic radiotherapy (TRT) in locally advanced nonsmall-cell lung cancer. METHODS: Fifty patients fulfilling the following eligibility criteria were enrolled: chemotherapy-naive, good performance status (PS, 0-2), age <75, stage III, and adequate organ function. The patients received irinotecan 60 mg/m(2) intravenously on Days 1, 8, and 15, and cisplatin 80 mg/m(2) intravenously on Day 1 in the first group. The doses were reduced to 50 and 60 mg/m(2), respectively, in the second group. Two cycles of chemotherapy were repeated every 4 weeks. Split-course thoracic radiotherapy of 2 Gy/day commenced on Day 2 of each chemotherapy cycle, with 28 and 32 Gy administered in the first and second cycles, respectively. RESULTS: Fifty patients were eligible and 48 (16 in the first, 32 in the second group) patients were assessable for response, toxicity, and survival. The overall response was 83% (95% confidence interval [CI], 70%-93%). Grade 4 leukopenia, neutropenia, grade 3 or 4 diarrhea, pneumonitis, esophagitis, and fatigue occurred in 21%, 48%, 19%, 10%, and 19%, respectively. The median time to progression was 8.2 months. The median overall survival time and the 2- and 5-year survival rates were 20.1 months, 47.1%, and 17.1%, respectively. In subgroup analysis, grade 4 neutropenia, grade 3 or 4 diarrhea, the overall response, and the median survival times of the first/second groups were 63%/41%, 19%/19%, 75%/88%, and 13.1/33.4 months, respectively. CONCLUSIONS: This combined modality of irinotecan and cisplatin with concurrent TRT is active and further investigations are warranted at the second group dose level.     

Dose-Escalation Study of Thoracic Radiotherapy in Combination With Pemetrexed Plus Cisplatin Followed by Pemetrexed Consolidation Therapy in Japanese Patients With Locally Advanced Nonsquamous Non–Small-Cell Lung Cancer

BackgroundPemetrexed has radiosensitizing potential when evaluated in vitro in combination with platinum-containing compounds and radiation. We determined the recommended dose (RD) of thoracic radiotherapy (TRT) with a concurrent chemotherapy combination of pemetrexed and cisplatin in Japanese patients with nonsquamous non–small-cell lung cancer (NSCLC).Patients and MethodsEligible patients were histologically confirmed as having locally advanced nonsquamous NSCLC. Study treatment consisted of 2 phases: concurrent chemoradiation and consolidation. In the concurrent chemoradiation phase, all patients received pemetrexed 500 mg/m² plus cisplatin 75 mg/m² on day 1 of a 21-day interval for 3 cycles. The first 6 patients were given 60 Gy concurrently at level 1 dose (L1D). If dose-limiting toxicity (DLT) occurred in < 2 patients at L1D, radiation was escalated to 66 Gy (level 2 dose [L2D]).ResultsEighteen patients were treated and completed chemoradiotherapy; 12 completed the consolidation phase. In the concurrent chemoradiation phase, 1 patient experienced 2 DLTs [grade 3 anorexia and diarrhea] at L1D. Because no DLT was observed at L2D, it was determined to be the RD. Common toxicities ≥grade 3 were neutropenia and leukopenia. At L1D, 1 patient each experienced grade 2 and grade 3 pneumonitis, and 2 patients experienced grade 2 esophagitis. Six patients experienced grade 2 pneumonitis and 3 patients experienced grade 2 esophagitis at L2D. Fifteen patients achieved partial response (PR), 2 had stable disease (SD), and 1 had progressive disease (PD).ConclusionExpected toxicities from concurrent chemoradiation were not worsened with concurrent TRT at a total dose of 66 Gy combined with pemetrexed in Japanese patients with locally advanced (LA) nonsquamous NSCLC.     

Phase I study of irinotecan and cisplatin with concurrent split-course radiotherapy in limited-disease small-cell lung cancer

We conducted a phase I study of irinotecan (CPT-11) and cisplatin with concurrent split-course radiotherapy in limited-disease small-cell lung cancer (LD-SCLC). This study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of this therapy. Four chemotherapy cycles of CPT-11 (days 1, 8 and 15) and cisplatin (day 1) were repeated every 28 days. Radiotherapy of 2 Gy/day commenced on day 2 of each chemotherapy cycle with 20 Gy administered from the first to the third cycles (a total of 60 Gy). 17 patients were enrolled at three dose levels (CPT-11/cisplatin: 40/60, 50/60 and 60/60 mg/m(2)), and 16 were evaluable for toxicity and outcome. 2 of 4 patients at 60/60 mg/m(2) refused continuation of therapy because of general fatigue, and the relative dose intensity of CPT-11 at 50/60 mg/m(2) was approximately 50%. These levels were considered as the MTD. Tumour responses included four complete responses (CR), 11 partial responses (PR) and one no change (NC), and the overall response rate was 93.8% (95% confidence interval: (CI) 71.7-98.9%). This combined modality is tolerable, and CPT-11/cisplatin of 40/60 mg/m(2) in this modality is recommended for phase II study.     

Phase II trial of irinotecan and cisplatin with early concurrent radiotherapy in limited-disease small-cell lung cancer

BACKGROUND: A Phase II trial of irinotecan and cisplatin (IP) with early concurrent radiotherapy was performed in limited-disease small-cell lung cancer (LD-SCLC) to evaluate the efficacy and toxicity. METHODS: For untreated LD-SCLC patients, irinotecan (60 mg/m2, Days 1, 8, and 15) and cisplatin (40 mg/m2, Days 1 and 8) were repeated every 4 weeks for a maximum of 6 cycles. Thoracic radiotherapy of 1.8 Gy/day was begun on Day 1 of the second chemotherapy cycle, up to a total of 45 to 54 Gy. Prophylactic cranial irradiation (30 Gy in 10 fractions) was performed on patients with a complete response (CR). RESULTS: Thirty-three LD-SCLC patients were enrolled. The median age was 60 years and 31 patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Twelve (36.4%) patients had N3 disease. The response rate was 87.9%, with a CR rate of 45.5%. At a median follow-up period of 27 months the median progression-free survival (PFS) and overall survival (OS) were 14.4 and 26.1 months, respectively, with 2-year PFS and OS rates of 26.8% and 54.9%. The dominating toxicity was neutropenia, with grade 3-5 of 81.8%. The most common grade 3-5 nonhematologic toxicities were diarrhea (21.2%), anorexia (21.2%), and fatigue (21.2%). Grade 3-5 radiation esophagitis and pneumonitis occurred in 18.2% and 9.1% of patients, respectively. There were 2 treatment-related deaths from sepsis and radiation pneumonitis. CONCLUSIONS: IP with early concurrent radiotherapy was effective and tolerable in untreated LD-SCLC.     

Oral vinorelbine and cisplatin with concomitant radiotherapy in stage III non-small cell lung cancer (NSCLC): a feasibility study

BACKGROUND: Concurrent chemoradiotherapy has improved survival in inoperable stage III non-small cell lung cancer (NSCLC). This phase I trial was performed in order to establish a dose recommendation for oral vinorelbine in combination with cisplatin and simultaneous radiotherapy. PATIENTS AND METHODS: Previously untreated patients with stage IIIB NSCLC received concurrent chemoradiotherapy with 66 Gy and 2 cycles of cisplatin and oral vinorelbine which was administered at 3 different levels (40, 50 and 60 mg/m2). This was to be followed by 2 cycles of cisplatin/ vinorelbine oral consolidation chemotherapy. The study goal was to determine the maximal recommended dose of oral vinorelbine during concurrent treatment. RESULTS: 11 stage IIIB patients were entered into the study. The median radiotherapy dose was 66 Gy. Grade 3-4 toxicity included neutropenia, esophagitis, gastritis and febrile neutropenia. The dose-limiting toxicity for concurrent chemoradiotherapy was esophagitis. 9 patients received consolidation chemotherapy, with neutropenia and anemia/thrombocytopenia grade 3 being the only toxicities. The overall response was 73%. CONCLUSION: Oral vinorelbine 50 mg/m2 (days 1, 8, 15 over 4 weeks) in combination with cisplatin 20 mg/m2 (days 1-4) is the recommended dose in combination with radiotherapy (66 Gy) and will be used for concurrent chemoradiotherapy in a forthcoming phase III trial testing the efficacy of consolidation chemotherapy in patients not progressing after chemoradiotherapy.     

Phase I dose escalation study of carboplatin to a fixed dose of irinotecan as first-line treatment of small cell lung cancer

BACKGROUND: Superiority of irinotecan (CPT-11) plus cisplatin over etoposide plus cisplatin in small cell lung cancer (SCLC) has recently been demonstrated. This study determines dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of escalating doses of carboplatin to a fixed dose of irinotecan in Caucasians with small cell lung cancer. PATIENTS AND METHODS: Patients with extensive small cell lung cancer received 50 mg/m(2) irinotecan on day 1, 8, and 15. Dose escalation of carboplatin on day 1 started in dose level 1 at an AUC of 5 mg x min/ml and was escalated to AUC 6 in level 2. Cycles were repeated on day 29. Dose escalation was evaluated after 3 consecutive patients. If no grade IV neutropenia lasting for > or =7 days or thrombopenia or non-hematologic toxicity > or = grade III occurred, treatment was continued in the next dose level. RESULTS: 16 patients were treated. DLT was reached in dose level 2 with 2 grade IV neutropenias and 1 grade IV thrombopenia and diarrhea. Toxicity was further investigated at dose level 1 in a total of 10 patients, which revealed 2 grade III neutropenias and 1 grade III diarrhea. Of 15 evaluable patients, 10 had a partial response, 3 had disease stabilization and 2 progressed. CONCLUSION: Dose level 1 was found to be MTD, this dose is currently compared to the combination of etoposide plus carboplatin within a randomised phase II/III trial.     

Irinotecan and cisplatin with concurrent thoracic radiotherapy in a once-every-three-weeks schedule in patients with limited-disease small-cell lung cancer: a phase I study

BACKGROUND: Irinotecan and cisplatin with concurrent radiotherapy is a powerful treatment combination for patients with limited-disease small-cell lung cancer (LD-SCLC). The objective was to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of irinotecan and cisplatin with concurrent thoracic radiotherapy (TRT) as a once-every-three-weeks schedule. PATIENTS AND METHODS: Patients with LD-SCLC received a fixed-dose of irinotecan (340 mg) and cisplatin (135mg) at day 1 in cycles 1 and 4. During cycles 2 and 3, irinotecan and cisplatin were given in a dose-escalation schedule with concurrent TRT (once daily, total dose 45Gray). RESULTS: No DLT was observed at first two levels (irinotecan 100mg or 120 mg and cisplatin 100mg at day 1 of cycles 2 and 3). In the first five patients, four episodes of grade III diarrhoea/dehydration were observed at cycles 1 and 4. Therefore, from the sixth patient on, fixed-dose irinotecan at cycles 1 and 4 was reduced to 250 mg. At the subsequent level of irinotecan 140 mg and cisplatin 100mg in cycles 2 and 3, two DLTs (severe oesophagitis and late vertebral radiation toxicity) were observed in one patient. CONCLUSION: Irinotecan 140 mg and cisplatin 100mg with concurrent TRT was considered the MTD. Irinotecan and cisplatin in a once-every-three-weeks schedule is not recommended due to severe toxicity. Irinotecan may be more suited for intermittent weekly administration.     

Ⅱ期和(或)Ⅲ期直肠癌术后希罗达同步放化疗的研究

目的 探讨Ⅱ期和（或）Ⅲ期直肠癌患者根治术后,采用希罗达同步放化疗的剂量限制性毒性反应（DLT）和最大耐受剂量（MTD）。方法24例直肠癌患者,年龄为18～75岁,KPS评分≥70分,根治性手术后病理证实为Ⅱ期和（或）Ⅲ期。希罗达从放射治疗第1天开始服用,间隔12h,连续服用14d,休息7d,为1个周期。共治疗2个周期。同步进行的盆腔放射治疗5周,共25次,总剂量为50Gy。≥3度的血液学或非血液学毒性反应为希罗达DLT。结果24例患者分别入希罗达每天1000mg/m^2组（3例）、1200mg／m^2组（3例）、1400mg／m^2组（3例）、1500mg／m^2组（3例）、1600mg／m^2组（6例）和1700mg／m^2组（6例）。1600mg／m^2组出现1例DLT（1例3度腹泻）,补充3例后,未出现DLT,继而进入每天1700mg／m^2组。1700mg／m^2组相继出现2例DLT（3度和4度腹泻各1例）。结论Ⅱ期和（或）Ⅲ期直肠癌根治术后希罗达同步放化疗是安全、可行的。希罗达的最大耐受剂量为每天1600mg／m^2,限制性毒性反应为腹泻。     

Phase I study of weekly CPT-11 (irinotecan)/docetaxel in patients with advanced solid tumors

Based on the synergistic cytotoxicity demonstrated in vitro by topoisomerase I inhibitors followed by docetaxel and the feasibility of giving both drugs on a weekly schedule avoiding overlapping toxicities, we designed a phase I trial of weekly CPT-11 (irinotecan)/docetaxel to determine the dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) of this combination. Eighteen patients with advanced solid tumors treated with at least one prior chemotherapy regimen were included in this trial. CPT-11 was administered as a 90-min (intravenous) IV infusion followed immediately by docetaxel as a 30-min IV infusion. Both drugs were given on days 1, 8 and 15 in 4-week cycles. Four escalating dose levels of CPT-11/docetaxel (level I: 60/20 mg/m(2), level II: 60/25 mg/m(2), level III: 70/25 mg/m(2), and level IV: 70/30 mg/m(2)) were studied. Forty-seven cycles were administered (range, 1-5 courses) with a median number of 2.6 cycles per patient. Grade 4 leukopenia was the DLT reached at dose-level IV (CPT-11/docetaxel 70/30 mg/m(2)). Four patients had grade 3 anemia at dose levels III (two patients) and IV (two patients), while grade 3/4 thrombocytopenia was not seen. Grade 3/4 non-hematologic toxicities included grade 3 diarrhea in two patients (dose levels II and IV), grade 3 asthenia in one patient (dose level II) and grade 3 stomatitis in one patient (dose level I). The recommended dose of this weekly schedule is CPT-11 70 mg/m(2) and docetaxel 25 mg/m(2). DLT of this regimen is leukopenia, although toxicity is manageable at the recommended dose level. The activity of this regimen is being evaluated in a phase II study in previously treated patients with advanced non-small cell lung cancer.     

Combination chemotherapy with irinotecan and cisplatin as second-line treatment for small cell lung cancer

Objective: To evaluate the efficacy and safety of irinotecan (CPT-11) plus cisplatin (DDP) in patients with small call lung cancer (SCLC) as second-line chemotherapy.Methods: Patients received irinotecan 60 mg/m2 on days 1, 8, 15,and cisplatin 25 mg/m2 on days 1-3, every 28 days one cycle.Response was evaluated every two cycles and patients were follow-up for two years or until death.Results: Among the 28 evaluable patients, there were 1 CR, 7 PR, 8 SD and 12 PD.The response rate was 28.6% (8/28).Median time to progression (TTP) was 3.2 (0.8-5.6) months.Median survival aftersecond-line treatment was 7.5 (1.5-31) months and overall survival was 15 (2.3-43.5) months.The most common adverseeffect was hematological toxicity with 36.7% (11/30), grades Ⅲ-Ⅳ neutroperia.Hepatic toxicity was another major side effect.Only one patient developed grade Ⅲ diarrhea.Conclusion: The combination of irinotecan and cisplatin is feasible, effective,and safe for SCLC as second-line treatment.     

Chemotherapy with concurrent brain and thoracic radiotherapy in brain-only metastases of treatment naive small-cell lung cancer: a phase II study

To study the treatment outcomes of brain-only metastases from small-cell lung cancer (SCLC) at initial diagnose treated by chemotherapy with concurrent brain and thoracic radiotherapy (RT). From Jan 2004 to Jan 2009, 36 treatment-na?ve SCLC patients with brain-only metastases in Sun yat-sen University were enrolled. Treatment contained initial EP chemotherapy with concurrent whole-brain radiotherapy (WBRT). EP regimen consisted of etoposide 100 mg/m(2) IV d1-3, cisplatin 80 mg/m(2) IV d1, repeated every 3 weeks. WBRT with total dose of 30 Gy in 10 fractions was started within 1 week from the beginning of chemotherapy followed by thoracic RT including 2 Gy once daily to a total dose of 60 Gy. Treatment responses were evaluated after 3 cycles of chemotherapy. EP regimen was given totally 6 cycles for no tumor progression. Thirty-four patients were evaluable. All of the 20 CNS symptomatic patients experienced symptoms relief. Objective responses in the brain and primary thoracic lesions were observed in 26 (76.5%, 16CR + 10PR) and 29 (85.3%, 23CR + 6PR) patients, respectively. The median survival time (MST) was 19.2 months, and the 1-and 2-year overall survival rates (OS) were 70.6 and 29.4%, respectively, in all patients. Patients with CR response had the longest MST of 21.9 months and 1-and 2-year OS of 93.8 and 43.8%, respectively. Treatment toxicity profiles were acceptable. The treatment strategy of concurrent chemotherapy with brain and thoracic RT might achieve promising survival outcomes comparable to limited-stage SCLC in initially diagnosed SCLC with brain-only metastases.     

Phase I study of weekly alternating therapy with irinotecan/cisplatin and etoposide/cisplatin for patients with small-cell lung cancer

The combination of IP (irinotecan/cisplatin) has been shown to confer a survival benefit compared with EP (etoposide/cisplatin) in patients with extensive-stage small-cell lung cancer (SCLC). Based on this and potential synergy from sequential inhibition of topoisomerases I and II, we conducted a phase I study to assess the feasibility of weekly therapy alternating IP and EP. The doses of EP were fixed (etoposide 60 mg/m2 on days 1-3 and cisplatin 20 mg/m2 on day 1). The dose of irinotecan was escalated in serial cohorts at 3 dose levels: 80, 90, and 100 mg/m2 on day 1. Granulocyte colony-stimulating factor was given on days 2-5 and days 4-7 after IP and EP, respectively. Patients with limited-stage SCLC received chemoradiation during weeks 4-6 with etoposide 120 mg/m2 on days 1-3, cisplatin 60 mg/m2 on day 1, and thoracic radiation 1.5 Gy twice daily in 30 fractions. Patients received 12 weeks of therapy. To evaluate dose escalation in subsequent cohorts, dose-limiting toxicity (DLT) was initially assessed during weeks 1-3 of treatment. Characteristics of the 18 patients accrued are as follows: performance status 0/1, n = 9; female sex, n = 9; extended-stage SCLC, n = 16; and median age, 53 years. Four patients treated at irinotecan dose level 1 (80 mg/m2), 6 patients at dose level 2 (90 mg/m2), and 6 patients at dose level 3 (100 mg/m2) did not experience DLT in weeks 1-4 and completed therapy without major incident. The only 2 patients to experience DLT during weeks 1-4 were treated at dose level 2. Both were hospitalized during week 4 and subsequently died. However, patients had already been accrued at dose level 3 and tolerated therapy well. Therefore, the trial design was modified to assess DLT during weeks 1-4, and additional patients were cautiously added to the dose level 2 and 3 cohorts. Analysis of summary toxicity data resulted in a recommendation that dose level 3 be used in phase II based on the probability of DLT of 16% (95% CI, 3%-29%). Responses in 16 evaluable patients include complete response in 1 patient, partial response in 14 patients, and minor response in 1 patient. With the exception of the 2 deaths, the therapy was well tolerated and active. Phase II evaluation of the regimen in patients with extensive-stage SCLC is ongoing.     

Phase I study of concurrent chemoradiation with pemetrexed and cisplatin followed by consolidation pemetrexed for patients with unresectable stage III non-small cell lung cancer

Purpose

Although concurrent chemotherapy and radiation is the standard approach for good risk unresectable stage III non-small cell lung cancer (NSCLC) patients, there is no optimal concurrent chemotherapy regimen. Administration of chemotherapy at full dose with maximal activity against local and micrometastatic disease is highly desirable. This study tested the feasibility of 3 cycles of full dose cisplatin and pemetrexed concurrent with definitive thoracic radiotherapy followed by consolidation pemetrexed, without the dose-limiting toxicity (DLT) exceeding 33% of the patients.

Methods

Patients with unresectable stage III NSCLC, good performance status and no serious comorbidity were eligible. Patients received thoracic radiation to a dose of 66 Gy concurrently with three 21-day cycles of pemetrexed 500 mg/m², and cisplatin at escalating doses from 60 to 75 mg/m². Consolidation chemotherapy of pemetrexed 500 mg/m² was provided for 3 more 21-day cycles. Cisplatin doses were escalated as far as no more than 1/3 of the patients in a level developing dose limiting toxicities (DLT).

Results

Fifteen eligible patients were enrolled: nine in the first dose level and 3 in the second and third dose levels respectively. Two out of 9 patients in the first dose level experienced DLT (grade 3 esophagitis resulting in delay in treatment administration). The major serious acute toxicities were esophagitis (40%) and febrile neutropenia (20%). With a median follow up time of 22 months, median time to progression and overall survival has not been reached. The rate of survival at 24 months was 57.5% (95% CI: 27.5–87.4%) of the patients.

Conclusions

Three systemic dose levels of pemetrexed and cisplatin could be administered concurrently with radiotherapy. The rate of survival at 24 months was encouraging.     

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.     

Phase I study of weekly docetaxel infusion and concurrent radiation therapy for head and neck cancer

OBJECTIVE: This study was designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of weekly docetaxel in combination with concurrent radiotherapy for treating head and neck cancer. METHODS: Twelve patients with unresectable or postoperative head and neck cancers were enrolled in a dose-escalating phase I study. Eleven of the 12 patients were postoperative patients with intermediate or high pathological risk features. Radiotherapy was delivered as a standard fractionation regimen (2 Gy/day, 5 fractions/week) to a total dose of 60-70 Gy. The starting dose of docetaxel was 10 mg/m(2) (once per week) with a subsequent dose escalation of 5 mg/m(2) in cohorts of three patients. In 2001 and 2002, 12 patients completing three dose levels were included in the study. RESULTS: The MTD of docetaxel was 20 mg/m(2). With the third dose level (20 mg/m(2)), DLT was observed in two of three patients. One experienced grade IV mucositis and another suffered from prolonged grade III mucositis-enforced treatment delay for 13 days. Hematological toxicity was minimal. Mucositis was the DLT of concurrent chemoradiotherapy using weekly docetaxel administration for head and neck cancer. CONCLUSIONS: We identified the recommended phase II dose of docetaxel as 15 mg/m(2) administered weekly with concurrent radiotherapy for head and neck cancers.