Lung Cancer 83 (2014) 67–72
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Phase II study of low-dose paclitaxel with timed thoracic radiotherapy followed by adjuvant gemcitabine and carboplatin in unresectable stage III non-small cell lung cancer夽 Jun Zhang a,d , Hiram A. Gay b , Suzanne Russo c , Teresa Parent a , Raid Aljumaily a , Paul R. Walker a,∗ a Leo Jenkins Cancer Center, Division of Hematology Oncology, Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United States b Department of Radiation Oncology, Washington University, School of Medicine, Saint Louis, MO, United States c Department of Radiation Oncology, Mitchell Cancer Institute, University of South Alabama, United States d Department of Medicine, Section of Hematology Oncology, Baylor College of Medicine, Houston, TX, United States
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Article history: Received 16 May 2013 Received in revised form 4 September 2013 Accepted 13 September 2013 Keywords: Unresectable Non-small cell lung cancer Chemoradiotherapy Timed thoracic radiation Gemcitibine/carboplatin
a b s t r a c t Objectives: The purpose of the proposed study is to evaluate the effectiveness and safety of low-dose paclitaxel with timed thoracic radiotherapy (TTR) for local control by inducing maximum radiosensitization through G2-M phase cell cycle arrest, followed by full dose adjuvant chemotherapy with gemcitabine and carboplatin for eradication of possible micrometastasis in unresectable stage III non-small cell lung cancer (NSCLC). Materials and methods: This is a single-center, non-randomized prospective phase II study. Patients with unresectable stage III NSCLC were treated with paclitaxel 15 mg/m2 IV, followed by TTR 6 h later on Monday/Wednesday/Friday, and TTR only on Tuesday/Thursday mornings (total 55 Gy). Full dose adjuvant chemotherapy consisted of intravenous carboplatin (AUC 5) on day 1, gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days for 4 cycles. The primary endpoint was overall survival (OS). Secondary endpoints were overall response rate (ORR), and toxicities. Results: Twenty-seven patients were eligible for the study. Patient characteristics were: 19 males (70%); median age 67 years (range 39–82); 15 (56%) stage IIIB; 89% with ECOG performance status ≥1. Three-year OS was 16.7% in all patients, and 27.3% in patients received three or more cycles of adjuvant chemotherapy, respectively. ORR was 63%. Grade 3 toxicities during paclitaxel plus concurrent TTR phase were radiation esophagitis (11%) and radiation pneumonitis (4%), no grade 4 toxicities occurred. One grade 5 hemoptysis. Grade 3/4 toxicities during adjuvant gemcitabine/carboplatin were pneumonitis (22%), anemia (30%), neutropenia (22%), and thrombocytopenia (33%), one grade 5 neutropenic fever. Conclusion: Low-dose paclitaxel with concurrent TTR is an effective chemoradiotherapy regimen in unresectable stage III NSCLC. Improved survival benefit was observed in patients who have received three or more cycles of full dose adjuvant chemotherapy, yet, gemcitabine related radiation pneumonitis and hematological toxicities limited adjuvant chemotherapy delivery. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung cancer is the leading cause of cancer related death worldwide. In 2013, it is estimated 228,190 new diagnosis and 159,480
夽 Clinical trial registration number: NCT00449657. ∗ Corresponding author at: 600 Moye Blvd, Suite 3E127, Division of Hematology Oncology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States. Tel.: +1 252 744 1775; fax: +1 252 744 3418. E-mail address: [email protected] (P.R. Walker). 0169-5002/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2013.09.007
deaths from lung cancer in the United States [1]. Approximately one third of patients present with locally advanced nonmetastatic disease, many of whom are surgically unresectable due to the extent of disease or medically inoperable because of pulmonary and/or other co-morbidities. The result of phase III trial CALGB 8433 established that chemotherapy induction followed by radiotherapy is superior to radiotherapy alone in treating stage III NSCLC [2,3]. The result was further confirmed in a large intergroup trial in North America [4]. Over the past two decades, multiple randomized phase II/III trials have been conducted comparing concurrent chemoradiotherapy with sequential chemotherapy followed by radiotherapy in
68
J. Zhang et al. / Lung Cancer 83 (2014) 67–72
unresectable stage III NSCLC [5–11]. A meta-analysis concluded a 5.7% absolute survival benefit at 3 years for patients receiving concurrent platinum-based chemoradiotherapy as compared to sequential chemotherapy and radiation [12]. Therefore, the contemporary standard of care for unresectable stage III NSCLC is concurrent chemoradiotherapy. Despite decades of efforts from different oncology groups in treating unresectable NSCLC, the progress has been slow. With the best available treatment modalities, the median survival time (MST) is less than 18 months and 5 year survival less than 15% for surgically unresectable stage III lung cancer [12]. Chen et al. observed that in vitro low dose paclitaxel resulted in a G2-M phase cell cycle arrest peak at 4 h and again at 24 h post-treatment [13]. Furthermore, in their phase I/II clinical trial, paclitaxel was delivered at three different dose levels: 15, 20, or 25 mg/m2 , followed by at least 5-h-delayed thoracic radiation (TRT) on Monday/Wednesday/Friday, and 24-h-delayed TRT on Tuesday and Thursday. The in-field tumor control rate was 97.6% with a 3-year survival rate of 18% [13–15]. Post-surgical adjuvant chemotherapy with four cycles platinum-based chemotherapy has consistently shown an enhanced survival benefit in NSCLC [16–18]. In patients with advanced NSCLC, the combination of gemcitabine and cisplatin resulted in a response rate ≥50% [19,20]. A randomized phase III trial demonstrated that the combination of gemcitabine/carboplatin has comparable efficacy, but less toxicities, compared with gemcitabine/cisplatin in stage IIIB and stage IV NSCLC [21]. The present study was designed before the era of histology based chemotherapy in NSCLC. Gemcitabine/carboplatin combination was chosen as the adjuvant full dose chemotherapy doublet because of its favorable toxicity profile. In an attempt to achieve high local control while eradicating micrometastasis in unresectable stage III NSCLC, we conducted a single institutional phase II study combining low-dose paclitaxel with timed thoracic radiotherapy (TTR), followed by adjuvant full dose chemotherapy with gemcitabine/carboplatin. We limited the total radiation dose to 5500 cGy for reduction of radiation related toxicities.
2. Materials and methods 2.1. Eligibility criteria Eligibility criteria included untreated pathologically confirmed NSCLC with surgically unresectable or medically inoperable stage IIIA or IIIB (TNM 6th edition) by radiographic or pathological staging, age >18 years, ECOG performance status (PS) ≤ 2, and adequate organ function (absolute neutrophil count >1500/l, platelet count 100,000/l, serum creatinine ≤2.0 mg/l, bilirubin ≤1.5 × upper limit of normal (ULN), and ALT and AST ≤3 × ULN). Exclusion criteria included: superior sulcus or resectable tumors, other active malignancies, serious concomitant systemic disorders, a life expectancy less than 12 weeks, or any contraindication to gemcitabine, carboplatin, or paclitaxel. Informed consent were obtained from eligible patients before enrollment. This protocol (NCT00449657) was approved by the institutional review board of the Brody School of Medicine at East Carolina University. 2.2. Study design and treatment modifications This was a single-center, nonrandomized, prospective phase II study. Treatment consisted of low-dose paclitaxel with concurrent TTR, followed by full dose gemcitabine/carboplatin for four cycles. The study schema is shown in Fig. 1. All patients had three-dimensional CT-based treatment planning with heterogeneity correction. Image guided radiation therapy (IGRT) was mandatory. Intensity modulated radiation therapy (IMRT) was not allowed. The lymph node gross tumor volume (GTVN) was defined as lymph nodes pathologically involved, hypermetabolic on PET/CT, or >1 cm in short axis on CT. The lymph node clinical tumor volume (CTVN) consisted of the GTVN with a 1 cm expansion. Station VII/subcarinal lymph nodes were treated but elective nodal irradiation was not undertaken. The primary tumor gross tumor volume (GTVP) was defined by imaging. The primary clinical tumor volume (CTVP) consisted of the GTVP + 0.5 cm for squamous or +0.8 cm for adenocarcinoma. The planning tumor volume (PTV) consisted of the CTVP + CTVN + 4 mm
Fig. 1. Treatment schema.
J. Zhang et al. / Lung Cancer 83 (2014) 67–72
for setup uncertainties and up to 1.5 cm to account for tumor motion, and was covered by at least the 95% isodose. Normal tissue dose constraints included: a V20 of
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Phase II study of low-dose paclitaxel with timed thoracic radiotherapy followed by adjuvant gemcitabine and carboplatin in unresectable stage III non-small cell lung cancer夽 Jun Zhang a,d , Hiram A. Gay b , Suzanne Russo c , Teresa Parent a , Raid Aljumaily a , Paul R. Walker a,∗ a Leo Jenkins Cancer Center, Division of Hematology Oncology, Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United States b Department of Radiation Oncology, Washington University, School of Medicine, Saint Louis, MO, United States c Department of Radiation Oncology, Mitchell Cancer Institute, University of South Alabama, United States d Department of Medicine, Section of Hematology Oncology, Baylor College of Medicine, Houston, TX, United States
a r t i c l e
i n f o
Article history: Received 16 May 2013 Received in revised form 4 September 2013 Accepted 13 September 2013 Keywords: Unresectable Non-small cell lung cancer Chemoradiotherapy Timed thoracic radiation Gemcitibine/carboplatin
a b s t r a c t Objectives: The purpose of the proposed study is to evaluate the effectiveness and safety of low-dose paclitaxel with timed thoracic radiotherapy (TTR) for local control by inducing maximum radiosensitization through G2-M phase cell cycle arrest, followed by full dose adjuvant chemotherapy with gemcitabine and carboplatin for eradication of possible micrometastasis in unresectable stage III non-small cell lung cancer (NSCLC). Materials and methods: This is a single-center, non-randomized prospective phase II study. Patients with unresectable stage III NSCLC were treated with paclitaxel 15 mg/m2 IV, followed by TTR 6 h later on Monday/Wednesday/Friday, and TTR only on Tuesday/Thursday mornings (total 55 Gy). Full dose adjuvant chemotherapy consisted of intravenous carboplatin (AUC 5) on day 1, gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days for 4 cycles. The primary endpoint was overall survival (OS). Secondary endpoints were overall response rate (ORR), and toxicities. Results: Twenty-seven patients were eligible for the study. Patient characteristics were: 19 males (70%); median age 67 years (range 39–82); 15 (56%) stage IIIB; 89% with ECOG performance status ≥1. Three-year OS was 16.7% in all patients, and 27.3% in patients received three or more cycles of adjuvant chemotherapy, respectively. ORR was 63%. Grade 3 toxicities during paclitaxel plus concurrent TTR phase were radiation esophagitis (11%) and radiation pneumonitis (4%), no grade 4 toxicities occurred. One grade 5 hemoptysis. Grade 3/4 toxicities during adjuvant gemcitabine/carboplatin were pneumonitis (22%), anemia (30%), neutropenia (22%), and thrombocytopenia (33%), one grade 5 neutropenic fever. Conclusion: Low-dose paclitaxel with concurrent TTR is an effective chemoradiotherapy regimen in unresectable stage III NSCLC. Improved survival benefit was observed in patients who have received three or more cycles of full dose adjuvant chemotherapy, yet, gemcitabine related radiation pneumonitis and hematological toxicities limited adjuvant chemotherapy delivery. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung cancer is the leading cause of cancer related death worldwide. In 2013, it is estimated 228,190 new diagnosis and 159,480
夽 Clinical trial registration number: NCT00449657. ∗ Corresponding author at: 600 Moye Blvd, Suite 3E127, Division of Hematology Oncology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States. Tel.: +1 252 744 1775; fax: +1 252 744 3418. E-mail address: [email protected] (P.R. Walker). 0169-5002/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2013.09.007
deaths from lung cancer in the United States [1]. Approximately one third of patients present with locally advanced nonmetastatic disease, many of whom are surgically unresectable due to the extent of disease or medically inoperable because of pulmonary and/or other co-morbidities. The result of phase III trial CALGB 8433 established that chemotherapy induction followed by radiotherapy is superior to radiotherapy alone in treating stage III NSCLC [2,3]. The result was further confirmed in a large intergroup trial in North America [4]. Over the past two decades, multiple randomized phase II/III trials have been conducted comparing concurrent chemoradiotherapy with sequential chemotherapy followed by radiotherapy in
68
J. Zhang et al. / Lung Cancer 83 (2014) 67–72
unresectable stage III NSCLC [5–11]. A meta-analysis concluded a 5.7% absolute survival benefit at 3 years for patients receiving concurrent platinum-based chemoradiotherapy as compared to sequential chemotherapy and radiation [12]. Therefore, the contemporary standard of care for unresectable stage III NSCLC is concurrent chemoradiotherapy. Despite decades of efforts from different oncology groups in treating unresectable NSCLC, the progress has been slow. With the best available treatment modalities, the median survival time (MST) is less than 18 months and 5 year survival less than 15% for surgically unresectable stage III lung cancer [12]. Chen et al. observed that in vitro low dose paclitaxel resulted in a G2-M phase cell cycle arrest peak at 4 h and again at 24 h post-treatment [13]. Furthermore, in their phase I/II clinical trial, paclitaxel was delivered at three different dose levels: 15, 20, or 25 mg/m2 , followed by at least 5-h-delayed thoracic radiation (TRT) on Monday/Wednesday/Friday, and 24-h-delayed TRT on Tuesday and Thursday. The in-field tumor control rate was 97.6% with a 3-year survival rate of 18% [13–15]. Post-surgical adjuvant chemotherapy with four cycles platinum-based chemotherapy has consistently shown an enhanced survival benefit in NSCLC [16–18]. In patients with advanced NSCLC, the combination of gemcitabine and cisplatin resulted in a response rate ≥50% [19,20]. A randomized phase III trial demonstrated that the combination of gemcitabine/carboplatin has comparable efficacy, but less toxicities, compared with gemcitabine/cisplatin in stage IIIB and stage IV NSCLC [21]. The present study was designed before the era of histology based chemotherapy in NSCLC. Gemcitabine/carboplatin combination was chosen as the adjuvant full dose chemotherapy doublet because of its favorable toxicity profile. In an attempt to achieve high local control while eradicating micrometastasis in unresectable stage III NSCLC, we conducted a single institutional phase II study combining low-dose paclitaxel with timed thoracic radiotherapy (TTR), followed by adjuvant full dose chemotherapy with gemcitabine/carboplatin. We limited the total radiation dose to 5500 cGy for reduction of radiation related toxicities.
2. Materials and methods 2.1. Eligibility criteria Eligibility criteria included untreated pathologically confirmed NSCLC with surgically unresectable or medically inoperable stage IIIA or IIIB (TNM 6th edition) by radiographic or pathological staging, age >18 years, ECOG performance status (PS) ≤ 2, and adequate organ function (absolute neutrophil count >1500/l, platelet count 100,000/l, serum creatinine ≤2.0 mg/l, bilirubin ≤1.5 × upper limit of normal (ULN), and ALT and AST ≤3 × ULN). Exclusion criteria included: superior sulcus or resectable tumors, other active malignancies, serious concomitant systemic disorders, a life expectancy less than 12 weeks, or any contraindication to gemcitabine, carboplatin, or paclitaxel. Informed consent were obtained from eligible patients before enrollment. This protocol (NCT00449657) was approved by the institutional review board of the Brody School of Medicine at East Carolina University. 2.2. Study design and treatment modifications This was a single-center, nonrandomized, prospective phase II study. Treatment consisted of low-dose paclitaxel with concurrent TTR, followed by full dose gemcitabine/carboplatin for four cycles. The study schema is shown in Fig. 1. All patients had three-dimensional CT-based treatment planning with heterogeneity correction. Image guided radiation therapy (IGRT) was mandatory. Intensity modulated radiation therapy (IMRT) was not allowed. The lymph node gross tumor volume (GTVN) was defined as lymph nodes pathologically involved, hypermetabolic on PET/CT, or >1 cm in short axis on CT. The lymph node clinical tumor volume (CTVN) consisted of the GTVN with a 1 cm expansion. Station VII/subcarinal lymph nodes were treated but elective nodal irradiation was not undertaken. The primary tumor gross tumor volume (GTVP) was defined by imaging. The primary clinical tumor volume (CTVP) consisted of the GTVP + 0.5 cm for squamous or +0.8 cm for adenocarcinoma. The planning tumor volume (PTV) consisted of the CTVP + CTVN + 4 mm
Fig. 1. Treatment schema.
J. Zhang et al. / Lung Cancer 83 (2014) 67–72
for setup uncertainties and up to 1.5 cm to account for tumor motion, and was covered by at least the 95% isodose. Normal tissue dose constraints included: a V20 of
