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Concurrent chemotherapy and radiotherapy in the treatment of unresectable stage III non-small cell lung cancer
110
Combined Modality Therapy
results of a Radiation Therapy Oncology I3-6-• Preliminary Group trial (RTOG) 9705, a phase II study of postoperative adjuvant therapy in patients with completely resacted stage II and stage Ilia non-small cell lung cancer M. Graham 1, R. Paulus2, T. Wasserman 1, M.V. Pilepich 3, M. Machtay4, R. Komaki5, J.N. Akins 6, W. Curran 7. rwashington
University; ZRTOG Statistical Headquarters; 3University of Michigan; 4University of Pennsylvania; 5University of Texas - MD Anderson; 6Southeastern CCOP; 7 Thomas Jefferson University, USA Purpose: To determine the progression-free and overall survival of patients with completely resected stage li-IIIA NSCLC treated with postoperative concurrent paclitaxel/carboplatin chemotherapy and thoracic radiation therapy. To determine toxicity from this approach. Methods and Materials: This study accrued 93 patients from July, 1997 to June 1998. Four patient were ineligible. Patients received postoperative chemotherapy with carboplatin AUC = 5 mg/m2/min over 30-60 minutes IV, days, 1, 22 (cycles 1 and 2), AUC = 6 mg/m2/min over 30-60 minutes IV days 43, 64 (cycles 3 and 4) and paclitaxel 3 hr infusion days 1, 22, 43, 64 (135 mg/m2 with XRT cycles 1 and 2), 225 mg/m2 (cycles 3 and 4) concurrently with thoracic XRT (50.4 Gy/28 fractions/6 weeks with boost only to patients with extracapsular extension of nodal metastasis. 82% of patients had an initial KPS of 90-100, 76% had minimal weight loss, 54% were postoperatively staged IliA. 63% of patients had Iobectomy, and all had complete resection. 88% of patients completed their chemotherapy per protocol. Results: The median survival was 38.6 months. Median progression-free survival has not been reached; only 25 of 88 patients have died or experienced progression. One patient died of acute toxicity (sepsis), and three patients had a grade 4 non-hematologic toxicity (respiratory-I, nausea and vomiting-2, esophageal-I). Acute grade 3 esophagitis was present 16%. There were 2 cases of late grade 4 non-hematologic toxicity (respiratory-I, esophageal-I). Conclusions: The initial survival results of this phase II trial are not significantly improved compared to other trials using postoperative thoracic radiation therapy alone. Based upon these preliminary results, the concurrent combination of chemotherapy and thoracic radiation therapy for postoperative therapy of resected NSCLC is not justified based on the added toxicity and the lack of apparent survival benefit. Longer follow up is desirable to see if any delayed benefit will be realized.
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Concurrent chemotherapy and radiotherapy in the treatment of unresectable stage III non-small cell lung cancer S.S. Leong, Y.K. Ong, K.W. Fong, K.M. Lee, J. Wee, K.F. Foo, P. Ang, M.H. Tay, H.T. See, Z.W. Wong, E.H. Tan. National Cancer Centre, Singapore Multi-modality treatment for the management of stage III non-small cell lung cancer (NSCLC) is now widely accepted as the state-ofan treatment for this group of patients. However, there is as yet no 'standard' recommendation as to the best sequence for combining the different therapies. We aimed to evaluate the efficacy and toxicities of a treatment regime comprising of induction chemotherapy followed by concurrent chemo-irradiation. Fifty-six patients (44 males and 12 females) were accrued from August 1997 to November 1999. The median age of patients accrued was 65, with a range of 33 to 77. Fiftyfive out of 56 patients were of performance status ECOG (Eastern Co-operative Oncology Group) 0 or 1. Thirteen patients (23%) had stage IliA disease and 43 (77%) had stage IlIB disease. Histology was that of squamous cell in 20, large cell in 15, adenocarcinoma in 12, and unspecified in 9. Planned treatment consisted of two cycles of paclitaxel at 175 mg/m2 and carboplatin at AUC (area under curve) of 6, given at 3-weekly intervals, followed by thoracic radiotherapy to 64 Gy at 2 Gy daily fractions together with weekly paclitaxel at 60 mg/m2. Forty-two patients completed 2 cycles of induction chemotherapy and are evaluable for response. Two patients had clinical complete response (CR) after the 2 cycles of chemotherapy, 27 patients had partial
response (PR) giving an overall response rate of 71%, 10 patients had stable disease (SD) and 3 patients had progressive disease (PD). Twenty-nine patients have received at least 50 Gy of radiotherapy together with concurrent chemotherapy and are evaluable for response at this time. There were 4 CR, 19 PR (overall response of 65%), 6 PD. The treatment regime is tolerable with the main toxicity being a nadir neutrophil count of <1000 in 47% of all patients treated. Grade 3 fatigue was experienced in 28% of patients at some point during the treatment. Odynophagia is the commonest complaint during the concurrent phase of treatment and was experienced in 63% but was only severe in 13% of patients. This treatment regime is tolerable and has demonstrated promising efficacy The time to progression and the median survival will better define the appropriateness of this regime.
I-3-6~An effective treatment of lung cancer associated with malignant pleural effusion by intrapleural and intravenous chemotherapy plus pulmonary irradiadion W, Su, W. Lai, H. Chen, G. Huang, T. Hsiue, C. Chen, C. Tsao, N. Wang. National Cheng Kung University Hospital, College of
Medicine, National Cheng Kung University, Tainan, Taiwan To improve the survival of patients with lung cancer associated with malignant pleural effusion, we designed a combined modality treatment. From 4•98 to 11/99, a total of 22 patents were enrolled in the study. Patient characteristics were: Men 9, Women 13; median age 60 years (44-72); stage IIIB 6, stage IV 16; median PS ECOG 2 (0-2). Phase I chemotherapy (cisplatin 60 mg/m2 intrapleurally on dl and gemcitabine 1000 mg/m2 IV on dl, 8, 15, q4w × 3) was started after surgical implantation of intrapleural and intravenous port-A, followed with radiotherapy (7000 cGy/35 fr) and then phase II chemotherapy (docetaxel 60-75 mg/m2q3w x 3-6). The clinical response after plase I CT was: 13 PR (59%), 4 SD (18%) and 5 PD (23%). The main toxicities (Gr2/3) were nausea/vomiting 36%, and chest pain 14%. The RR after phase II CT was: 8 PR (67%), 2 SD (17%), 2 PD (17%). The main toxicities were leukopenia (Gr3/4) 42%, alopecia (Gr2) 75%, and neurosensory (Gr2/3) 25%. None of the 22 patients had recurrence of pleural effusion. Sixteen patients (73%) are still alive at a median follow up of 10 months (3-19 m). The median survival is not reached. The combined modality treatment was well tolerated and achieved promising disease control.
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phase II trial of individualized response-based induction chemotherapy (IC) of mitomycin-C, vindesine, cisplatin (MVP) followed by thoracic radiotherapy (TRT) with daily low-dose carboplatin (CBDCA) for the treatment of unresectable stage III non-small-cell lung cancer (NSCLC)
T. Shinbo, M. Makino, H. Tsukada, A. Yokoyama, M. Saitou, Y. Kurita.
Niigata Cancer Center Hospital, Niigata, Japan Chemoradiotherapy is a standard treatment for selected patients (Pts) with locally advanced NSCLC. At present however there is no conclusive data on optimal timing of TRT with respect to chemotherapy. With broad spectrum of responses to chemotherapy in each patients, we planned a phase II trial of individualized chemoradiotherapy. To increase total therapeutic intensity, timing of TRT was adjusted according to response to induction chemotherapy. Between 11/96 and 12/99, 29 Pts were entered in this institutional trial. The median age was 64 years (range 45-70). Thirteen had stage IliA and 16 stage IIIB disease. Twenty-six were male and 9 had an ECOG-PS of 0, and 20 had PS 1. Eligibility criteria included measurable disease, adequate organ function, and signed informed consent. IC consisted of 80 mg/m2 cisplatin (day 1), 8 mg/m2 mitomycin-C (day 1), 3 mg/m 2 vindesine (day 1, 8). Patients who responded to iC (MR or PR) received 2 cycles of chemotherapy, and those refractory to iC (SD or PD) received no more IC. After IC, TRT to post-IC tumor volume with standard fraction to a total dose of 60 Gy in 6 wks was done. Daily CBDCA (25 mg/m2) was delivered in the 1, 2, 4, and 5th week concurrently. Twenty-two
Combined Modality Therapy
results of a Radiation Therapy Oncology I3-6-• Preliminary Group trial (RTOG) 9705, a phase II study of postoperative adjuvant therapy in patients with completely resacted stage II and stage Ilia non-small cell lung cancer M. Graham 1, R. Paulus2, T. Wasserman 1, M.V. Pilepich 3, M. Machtay4, R. Komaki5, J.N. Akins 6, W. Curran 7. rwashington
University; ZRTOG Statistical Headquarters; 3University of Michigan; 4University of Pennsylvania; 5University of Texas - MD Anderson; 6Southeastern CCOP; 7 Thomas Jefferson University, USA Purpose: To determine the progression-free and overall survival of patients with completely resected stage li-IIIA NSCLC treated with postoperative concurrent paclitaxel/carboplatin chemotherapy and thoracic radiation therapy. To determine toxicity from this approach. Methods and Materials: This study accrued 93 patients from July, 1997 to June 1998. Four patient were ineligible. Patients received postoperative chemotherapy with carboplatin AUC = 5 mg/m2/min over 30-60 minutes IV, days, 1, 22 (cycles 1 and 2), AUC = 6 mg/m2/min over 30-60 minutes IV days 43, 64 (cycles 3 and 4) and paclitaxel 3 hr infusion days 1, 22, 43, 64 (135 mg/m2 with XRT cycles 1 and 2), 225 mg/m2 (cycles 3 and 4) concurrently with thoracic XRT (50.4 Gy/28 fractions/6 weeks with boost only to patients with extracapsular extension of nodal metastasis. 82% of patients had an initial KPS of 90-100, 76% had minimal weight loss, 54% were postoperatively staged IliA. 63% of patients had Iobectomy, and all had complete resection. 88% of patients completed their chemotherapy per protocol. Results: The median survival was 38.6 months. Median progression-free survival has not been reached; only 25 of 88 patients have died or experienced progression. One patient died of acute toxicity (sepsis), and three patients had a grade 4 non-hematologic toxicity (respiratory-I, nausea and vomiting-2, esophageal-I). Acute grade 3 esophagitis was present 16%. There were 2 cases of late grade 4 non-hematologic toxicity (respiratory-I, esophageal-I). Conclusions: The initial survival results of this phase II trial are not significantly improved compared to other trials using postoperative thoracic radiation therapy alone. Based upon these preliminary results, the concurrent combination of chemotherapy and thoracic radiation therapy for postoperative therapy of resected NSCLC is not justified based on the added toxicity and the lack of apparent survival benefit. Longer follow up is desirable to see if any delayed benefit will be realized.
•6-•
Concurrent chemotherapy and radiotherapy in the treatment of unresectable stage III non-small cell lung cancer S.S. Leong, Y.K. Ong, K.W. Fong, K.M. Lee, J. Wee, K.F. Foo, P. Ang, M.H. Tay, H.T. See, Z.W. Wong, E.H. Tan. National Cancer Centre, Singapore Multi-modality treatment for the management of stage III non-small cell lung cancer (NSCLC) is now widely accepted as the state-ofan treatment for this group of patients. However, there is as yet no 'standard' recommendation as to the best sequence for combining the different therapies. We aimed to evaluate the efficacy and toxicities of a treatment regime comprising of induction chemotherapy followed by concurrent chemo-irradiation. Fifty-six patients (44 males and 12 females) were accrued from August 1997 to November 1999. The median age of patients accrued was 65, with a range of 33 to 77. Fiftyfive out of 56 patients were of performance status ECOG (Eastern Co-operative Oncology Group) 0 or 1. Thirteen patients (23%) had stage IliA disease and 43 (77%) had stage IlIB disease. Histology was that of squamous cell in 20, large cell in 15, adenocarcinoma in 12, and unspecified in 9. Planned treatment consisted of two cycles of paclitaxel at 175 mg/m2 and carboplatin at AUC (area under curve) of 6, given at 3-weekly intervals, followed by thoracic radiotherapy to 64 Gy at 2 Gy daily fractions together with weekly paclitaxel at 60 mg/m2. Forty-two patients completed 2 cycles of induction chemotherapy and are evaluable for response. Two patients had clinical complete response (CR) after the 2 cycles of chemotherapy, 27 patients had partial
response (PR) giving an overall response rate of 71%, 10 patients had stable disease (SD) and 3 patients had progressive disease (PD). Twenty-nine patients have received at least 50 Gy of radiotherapy together with concurrent chemotherapy and are evaluable for response at this time. There were 4 CR, 19 PR (overall response of 65%), 6 PD. The treatment regime is tolerable with the main toxicity being a nadir neutrophil count of <1000 in 47% of all patients treated. Grade 3 fatigue was experienced in 28% of patients at some point during the treatment. Odynophagia is the commonest complaint during the concurrent phase of treatment and was experienced in 63% but was only severe in 13% of patients. This treatment regime is tolerable and has demonstrated promising efficacy The time to progression and the median survival will better define the appropriateness of this regime.
I-3-6~An effective treatment of lung cancer associated with malignant pleural effusion by intrapleural and intravenous chemotherapy plus pulmonary irradiadion W, Su, W. Lai, H. Chen, G. Huang, T. Hsiue, C. Chen, C. Tsao, N. Wang. National Cheng Kung University Hospital, College of
Medicine, National Cheng Kung University, Tainan, Taiwan To improve the survival of patients with lung cancer associated with malignant pleural effusion, we designed a combined modality treatment. From 4•98 to 11/99, a total of 22 patents were enrolled in the study. Patient characteristics were: Men 9, Women 13; median age 60 years (44-72); stage IIIB 6, stage IV 16; median PS ECOG 2 (0-2). Phase I chemotherapy (cisplatin 60 mg/m2 intrapleurally on dl and gemcitabine 1000 mg/m2 IV on dl, 8, 15, q4w × 3) was started after surgical implantation of intrapleural and intravenous port-A, followed with radiotherapy (7000 cGy/35 fr) and then phase II chemotherapy (docetaxel 60-75 mg/m2q3w x 3-6). The clinical response after plase I CT was: 13 PR (59%), 4 SD (18%) and 5 PD (23%). The main toxicities (Gr2/3) were nausea/vomiting 36%, and chest pain 14%. The RR after phase II CT was: 8 PR (67%), 2 SD (17%), 2 PD (17%). The main toxicities were leukopenia (Gr3/4) 42%, alopecia (Gr2) 75%, and neurosensory (Gr2/3) 25%. None of the 22 patients had recurrence of pleural effusion. Sixteen patients (73%) are still alive at a median follow up of 10 months (3-19 m). The median survival is not reached. The combined modality treatment was well tolerated and achieved promising disease control.
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6
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•
A
phase II trial of individualized response-based induction chemotherapy (IC) of mitomycin-C, vindesine, cisplatin (MVP) followed by thoracic radiotherapy (TRT) with daily low-dose carboplatin (CBDCA) for the treatment of unresectable stage III non-small-cell lung cancer (NSCLC)
T. Shinbo, M. Makino, H. Tsukada, A. Yokoyama, M. Saitou, Y. Kurita.
Niigata Cancer Center Hospital, Niigata, Japan Chemoradiotherapy is a standard treatment for selected patients (Pts) with locally advanced NSCLC. At present however there is no conclusive data on optimal timing of TRT with respect to chemotherapy. With broad spectrum of responses to chemotherapy in each patients, we planned a phase II trial of individualized chemoradiotherapy. To increase total therapeutic intensity, timing of TRT was adjusted according to response to induction chemotherapy. Between 11/96 and 12/99, 29 Pts were entered in this institutional trial. The median age was 64 years (range 45-70). Thirteen had stage IliA and 16 stage IIIB disease. Twenty-six were male and 9 had an ECOG-PS of 0, and 20 had PS 1. Eligibility criteria included measurable disease, adequate organ function, and signed informed consent. IC consisted of 80 mg/m2 cisplatin (day 1), 8 mg/m2 mitomycin-C (day 1), 3 mg/m 2 vindesine (day 1, 8). Patients who responded to iC (MR or PR) received 2 cycles of chemotherapy, and those refractory to iC (SD or PD) received no more IC. After IC, TRT to post-IC tumor volume with standard fraction to a total dose of 60 Gy in 6 wks was done. Daily CBDCA (25 mg/m2) was delivered in the 1, 2, 4, and 5th week concurrently. Twenty-two