HHS Public Access Author manuscript Author Manuscript
J Thorac Oncol. Author manuscript; available in PMC 2017 July 06. Published in final edited form as: J Thorac Oncol. 2017 June ; 12(6): 993–1000. doi:10.1016/j.jtho.2017.02.026.
Improved Outcomes with Modern Lung-Sparing Trimodality Therapy in Patients with Malignant Pleural Mesothelioma Fauzia Shaikh, M.D.*, Marjorie G. Zauderer, M.D.‖, Donata von Reibnitz*, Abraham J. Wu, M.D.*, Ellen D. Yorke, Ph.D.†, Amanda Foster, M.S.*, Weiji Shi, M.S.‡, Zhigang Zhang, Ph.D.‡, Prasad S. Adusumilli, M.D.¶, Kenneth E. Rosenzweig, M.D.§, Lee M. Krug, M.D.‖,#, Valerie W. Rusch, M.D.¶, and Andreas Rimner, M.D.*
Author Manuscript
*Department
of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New
York †Department
of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York
‡Department
of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
§Current
address: Department of Radiation Oncology, Mount Sinai Medical Center, New York, New York
‖Department
of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York
¶Department
of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
Author Manuscript
#Current
address: Bristol Myers Squibb, Head of Immuno-Oncology for Lung and Head & NeckMalignancies
Abstract Introduction—Higher target conformity and better sparing of organs at risk with modern radiotherapy (RT) may result in higher tumor control and less toxicities. In this study, we compare our institutional multimodality therapy experience of adjuvant chemotherapy and hemithoracic intensity-modulated pleural RT (IMPRINT) to previously used adjuvant conventional RT (CONV) in patients with malignant pleural mesothelioma (MPM) treated with lung-sparing pleurectomy/ decortication (P/D).
Author Manuscript
Methods—We analyzed 209 patients who underwent P/D and adjuvant RT (n[CONV]=131, n[IMPRINT]=78) for MPM between 1974 and 2015. The primary endpoint was overall survival (OS). The Kaplan-Meier method and Cox proportional hazards model were used to calculate OS;
Reprint requests to: Andreas Rimner, MD, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, Box 22, New York, New York 10065; Tel (212) 639-6025; Fax (212) 639-2417; [email protected]. This work was presented at the 2014 International Mesothelioma Interest Group Meeting, but has not been submitted for publication elsewhere. Conflicts of Interest and Source of Funding: No relevant conflicts of interest were declared. This research was supported in part by an NIH Core Grant P30 CA008748 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Shaikh et al.
Page 2
Author Manuscript
competing ri sks analysis was performed for local failure-free (LFFS) and progression-free survival (PFS). Univariate (UVA) and multivariate analysis (MVA) was performed with relevant clinical and treatment factors. Results—The median age was 64 years, 80% were male. Patients receiving IMPRINT had significantly higher rates of epithelial histology, advanced pStage and chemotherapy treatment. OS was significantly higher after IMPRINT (median 20.2 vs 12.3 months, p=0.001). Higher Karnofsky performance score (KPS), epithelioid histology, macroscopically complete resection (MCR), and use of chemotherapy/IMPRINT were found to be significant factors for longer OS upon MVA. No significant predictive factors were identified for local failure or progression. Fewer patients developed grade ≥2 esophagitis after IMPRINT compared to CONV (23% vs 47%).
Author Manuscript
Conclusions—Trimodality therapy including adjuvant hemithoracic IMPRINT, chemotherapy, and P/D is associated with promising OS rates and decreased toxicities in patients with MPM. Dose constraints should be applied vigilantly to minimize serious adverse events. Keywords Malignant Pleural Mesothelioma; Intensity-Modulated Pleural Radiation Therapy (IMPRINT); conventional RT; Pleurectomy/Decortication
Introduction
Author Manuscript
Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy affecting the pleura and commonly associated with previous asbestos exposure. While some advances have been made in the various therapeutic approaches including lung-sparing surgical technique, chemotherapy drug types and doses and radiation therapy techniques, their impact on patient outcomes in a multimodality context remains unclear.
Author Manuscript
For patients with favorable histology and resectable disease, cytoreductive surgery with the goal of a macroscopically complete resection (MCR) has been the centerpiece of multimodality management at our institution. The debate about the optimal surgical procedure in MPM is ongoing. When compared retrospectively, patients undergoing lungsparing techniques with complete resection (P/D and extended P/D (EPD)) as opposed to patients having an extrapleural pneumonectomy (EPP) were found to have at least equivalent overall survival with less postoperative morbidity and mortality than after EPP. 1-5 This observation has led to a shift in surgical approach from predominantly EPPs to a more frequent use of lung-sparing approaches such as P/D and EPD. To exclude confounding by surgical approach, this study includes only patients who underwent lung-sparing surgery. We used the International Association of the Study of Lung Cancer (IASLC) Mesothelioma Domain and the International Mesothelioma Interest Group (IMIG) definitions of P/D in this study.6 Platinum/pemetrexed chemotherapy has been established as the standard of care for systemic therapy in patients with MPM, since it was shown to significantly improve overall survival compared to platinum chemotherapy alone in a phase III trial (12.1 vs 9.3 months) (Vogelzang et al.) and confirmed by a similar study using ralitrexed (van Meerbeeck et
J Thorac Oncol. Author manuscript; available in PMC 2017 July 06.
Shaikh et al.
Page 3
Author Manuscript
al.).7, 8 Typically four cycles are administered in the setting of multimodality therapy, delivered either as neoadjuvant or adjuvant therapy. Adjuvant hemithoracic radiation therapy has been explored as part of multimodality treatment to reduce the risk of local and regional failure, especially after lung-sparing surgery given the high risk of microscopic residual disease. While 2D combined photon/ electron conventional RT had historically been the standard technique available at the time, the development of intensity-modulated pleural radiation therapy (IMPRINT) in the past decade has made a more precise application of hemithoracic RT possible, reducing areas of dose uncertainty and doses to underlying organs at risk, in particular the lungs, but also the heart, liver, stomach, kidneys and bowels. 9-18
Author Manuscript
In a recent prospective phase II trial we demonstrated the safety of hemithoracic IMPRINT after chemotherapy and P/D for patients with MPM.19 In this study, we analyzed our institutional database to compare outcomes and toxicities of patients with MPM treated with lung-sparing surgery followed by either adjuvant conventional RT or IMPRINT.
Methods and Materials Study design and patients For this study, data of patients with MPM treated at our institution between 1974 and 2015 were collected from the institutional database. Patients were included if they had lungsparing surgery as well as adjuvant radiation therapy (RT).
Author Manuscript
Tumor information, treatment details and follow-up data were retrieved from the patients' medical records. Toxicity was scored per NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Given the uncertainty about categorizing radiation pneumonitis we defined grade 2 pneumonitis as patients requiring systemic prednisone, and grade 3 pneumonitis as patients requiring continuous oxygen or need for hospitalization. Treatment characteristics
Author Manuscript
All patients underwent one of three lung-sparing types of surgical procedure, namely extended pleurectomy/decortication (EPD), pleurectomy/decortication (P/D), or partial pleurectomy (PP). Only 15 patients (11%) in the CONV group received chemotherapy, but 90% of patients in the IMPRINT group were treated with neoadjuvant or adjuvant chemotherapy. With the exeption of two cases, all patients in the IMPRINT group received a platinum/pemetrexed doublet. The technique of conventional RT performed at our institution has been previously described by Kutcher et al.20 and Gupta et al.21 Patients were immobilized with their arms raised above their head in supine position. The field borders were the top of T1 superiorly, the bottom of L2/base of diaphragm inferiorly, the ribcage including the skin laterally and the contralateral border of the vertebral bodies medially. A 1.5 to 2.0cm margin was added medially if mediastinal nodes were involved. Patients were simulated using fluoroscopy or
J Thorac Oncol. Author manuscript; available in PMC 2017 July 06.
Shaikh et al.
Page 4
Author Manuscript
CT, and the planning target volume (PTV) was defined as the pleura and diaphragm with a 1cm margin. Blocks were placed anteriorly and posteriorly over abdomen and lung, and starting at 1980 cGy - over the heart in the case of left-sided tumors. There was a 15% scatter under the blocks from the photon fields, therefore a supplemental daily electron dose of 153 cGy was prescribed. The spinal cord was excluded from the treatment field for the final 2 fractions to avoid overdosing. Radiation treatments were delivered in 180 cGy fractions with 6 MV photon beams using linear accelerators.
Author Manuscript
Since 2004 we have developed a hemithoracic pleural IMRT technique for MPM patients that was previously described.15, 16, 19 Patients were immobilized with their arms raised above their head in supine position. The initial PTV was defined using the planning CT scan and encompassed the hemithoracic pleura and chest wall reaching from the thoracic inlet until the insertion of the diaphragm at the L1/L2 vertebral body. A PET-CT scan and respiratory correlated 4D-CT scan (available since 2008) were used to further refine the target volume. Radiation treatments were delivered in 180 cGy fractions with 6 MV photon beams using Varian linear accelerators with a dynamic multileaf collimator. Statistical methods and design
Author Manuscript
The primary endpoint of the analysis was overall survival (OS). Local failure free survival (LFFS) and progression free survival (PFS) were determined as well. All endpoints were measured beginning at the start of radiation therapy until the date of event (death, local failure or progression, respectively) or until the last follow-up date. The Kaplan-Meier method was used for calculating overall survival rates, Cox proportional hazards regression model was used for OS analysis, and a Fine and Gray competing risks analysis was performed for LFFS and PFS. Univariate analysis (UVA) was performed for the following factors: age at diagnosis, sex, Karnofsky performance score (KPS), histology, laterality of tumor, clinical and pathological stage, macroscopically complete resection (MCR), chemotherapy, RT technique and RT dose. Factors with a p-value ≤ 0.15 were considered candidates for stepwise multivariate analysis (MVA) to evaluate the association of RT technique with each endpoint. Forward and backward selection procedures were implemented to confirm results. Incidence of significant (≥ grade 2) toxicities were compared between RT techniques using Fisher's exact test. These results were adjusted for multiple comparisons using the Bonferroni method. Statistical analysis was conducted with the software SAS version 9.4 (SAS Institute Inc. Cary, NC), and R version 3.1.2 package cmprsk.
Results Author Manuscript
Patient characteristics We analyzed 209 patients with MPM who met the inclusion criteria. The median age of patients was 64 (range: 34 to 84), male to female ratio was 4:1 and median KPS was 80 (range: 60 to 100). 131 patients (63%) received conventional external beam radiation therapy (CONV) and 78 (37%) intensity-modulated pleural radiation therapy (IMPRINT). All patients treated since March 2005 received IMPRINT. Eighty-five patients (41%) received chemotherapy (70 IMPRINT and 15 CONV patients). Significant differences between the
J Thorac Oncol. Author manuscript; available in PMC 2017 July 06.
Shaikh et al.
Page 5
Author Manuscript
CONV and IMPRINT group were noted in age (> 64 years: 45% and 65% respectively, p=0.006), KPS (>80: 31% and 50% respectively, p=0.008), histology (epithelioid: 59% and 86% respectively, p4500 cGy (HR 0.70, 95% CI 0.50-0.96, p=0.03). On MVA, KPS > 80% (p=0.01), epithelioid histology (p=0.003), MCR (p=0.01) and IMPRINT (p=0.02) were significantly associated with longer OS. [Table 2]
Author Manuscript
Although chemotherapy was associated with improved survival in the UVA (vs. no chemotherapy, HR 0.63, 95%CI 0.46-0.86, p=0.004), it did not enter into the stepwise Cox proportional hazards MVA final model as it was highly correlated with RT technique. Seventy patients (90%) receiving IMPRINT also underwent chemotherapy, while only 15 patients (11%) in the CONV cohort received chemotherapy (p
J Thorac Oncol. Author manuscript; available in PMC 2017 July 06. Published in final edited form as: J Thorac Oncol. 2017 June ; 12(6): 993–1000. doi:10.1016/j.jtho.2017.02.026.
Improved Outcomes with Modern Lung-Sparing Trimodality Therapy in Patients with Malignant Pleural Mesothelioma Fauzia Shaikh, M.D.*, Marjorie G. Zauderer, M.D.‖, Donata von Reibnitz*, Abraham J. Wu, M.D.*, Ellen D. Yorke, Ph.D.†, Amanda Foster, M.S.*, Weiji Shi, M.S.‡, Zhigang Zhang, Ph.D.‡, Prasad S. Adusumilli, M.D.¶, Kenneth E. Rosenzweig, M.D.§, Lee M. Krug, M.D.‖,#, Valerie W. Rusch, M.D.¶, and Andreas Rimner, M.D.*
Author Manuscript
*Department
of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New
York †Department
of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York
‡Department
of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
§Current
address: Department of Radiation Oncology, Mount Sinai Medical Center, New York, New York
‖Department
of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York
¶Department
of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
Author Manuscript
#Current
address: Bristol Myers Squibb, Head of Immuno-Oncology for Lung and Head & NeckMalignancies
Abstract Introduction—Higher target conformity and better sparing of organs at risk with modern radiotherapy (RT) may result in higher tumor control and less toxicities. In this study, we compare our institutional multimodality therapy experience of adjuvant chemotherapy and hemithoracic intensity-modulated pleural RT (IMPRINT) to previously used adjuvant conventional RT (CONV) in patients with malignant pleural mesothelioma (MPM) treated with lung-sparing pleurectomy/ decortication (P/D).
Author Manuscript
Methods—We analyzed 209 patients who underwent P/D and adjuvant RT (n[CONV]=131, n[IMPRINT]=78) for MPM between 1974 and 2015. The primary endpoint was overall survival (OS). The Kaplan-Meier method and Cox proportional hazards model were used to calculate OS;
Reprint requests to: Andreas Rimner, MD, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, Box 22, New York, New York 10065; Tel (212) 639-6025; Fax (212) 639-2417; [email protected]. This work was presented at the 2014 International Mesothelioma Interest Group Meeting, but has not been submitted for publication elsewhere. Conflicts of Interest and Source of Funding: No relevant conflicts of interest were declared. This research was supported in part by an NIH Core Grant P30 CA008748 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Shaikh et al.
Page 2
Author Manuscript
competing ri sks analysis was performed for local failure-free (LFFS) and progression-free survival (PFS). Univariate (UVA) and multivariate analysis (MVA) was performed with relevant clinical and treatment factors. Results—The median age was 64 years, 80% were male. Patients receiving IMPRINT had significantly higher rates of epithelial histology, advanced pStage and chemotherapy treatment. OS was significantly higher after IMPRINT (median 20.2 vs 12.3 months, p=0.001). Higher Karnofsky performance score (KPS), epithelioid histology, macroscopically complete resection (MCR), and use of chemotherapy/IMPRINT were found to be significant factors for longer OS upon MVA. No significant predictive factors were identified for local failure or progression. Fewer patients developed grade ≥2 esophagitis after IMPRINT compared to CONV (23% vs 47%).
Author Manuscript
Conclusions—Trimodality therapy including adjuvant hemithoracic IMPRINT, chemotherapy, and P/D is associated with promising OS rates and decreased toxicities in patients with MPM. Dose constraints should be applied vigilantly to minimize serious adverse events. Keywords Malignant Pleural Mesothelioma; Intensity-Modulated Pleural Radiation Therapy (IMPRINT); conventional RT; Pleurectomy/Decortication
Introduction
Author Manuscript
Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy affecting the pleura and commonly associated with previous asbestos exposure. While some advances have been made in the various therapeutic approaches including lung-sparing surgical technique, chemotherapy drug types and doses and radiation therapy techniques, their impact on patient outcomes in a multimodality context remains unclear.
Author Manuscript
For patients with favorable histology and resectable disease, cytoreductive surgery with the goal of a macroscopically complete resection (MCR) has been the centerpiece of multimodality management at our institution. The debate about the optimal surgical procedure in MPM is ongoing. When compared retrospectively, patients undergoing lungsparing techniques with complete resection (P/D and extended P/D (EPD)) as opposed to patients having an extrapleural pneumonectomy (EPP) were found to have at least equivalent overall survival with less postoperative morbidity and mortality than after EPP. 1-5 This observation has led to a shift in surgical approach from predominantly EPPs to a more frequent use of lung-sparing approaches such as P/D and EPD. To exclude confounding by surgical approach, this study includes only patients who underwent lung-sparing surgery. We used the International Association of the Study of Lung Cancer (IASLC) Mesothelioma Domain and the International Mesothelioma Interest Group (IMIG) definitions of P/D in this study.6 Platinum/pemetrexed chemotherapy has been established as the standard of care for systemic therapy in patients with MPM, since it was shown to significantly improve overall survival compared to platinum chemotherapy alone in a phase III trial (12.1 vs 9.3 months) (Vogelzang et al.) and confirmed by a similar study using ralitrexed (van Meerbeeck et
J Thorac Oncol. Author manuscript; available in PMC 2017 July 06.
Shaikh et al.
Page 3
Author Manuscript
al.).7, 8 Typically four cycles are administered in the setting of multimodality therapy, delivered either as neoadjuvant or adjuvant therapy. Adjuvant hemithoracic radiation therapy has been explored as part of multimodality treatment to reduce the risk of local and regional failure, especially after lung-sparing surgery given the high risk of microscopic residual disease. While 2D combined photon/ electron conventional RT had historically been the standard technique available at the time, the development of intensity-modulated pleural radiation therapy (IMPRINT) in the past decade has made a more precise application of hemithoracic RT possible, reducing areas of dose uncertainty and doses to underlying organs at risk, in particular the lungs, but also the heart, liver, stomach, kidneys and bowels. 9-18
Author Manuscript
In a recent prospective phase II trial we demonstrated the safety of hemithoracic IMPRINT after chemotherapy and P/D for patients with MPM.19 In this study, we analyzed our institutional database to compare outcomes and toxicities of patients with MPM treated with lung-sparing surgery followed by either adjuvant conventional RT or IMPRINT.
Methods and Materials Study design and patients For this study, data of patients with MPM treated at our institution between 1974 and 2015 were collected from the institutional database. Patients were included if they had lungsparing surgery as well as adjuvant radiation therapy (RT).
Author Manuscript
Tumor information, treatment details and follow-up data were retrieved from the patients' medical records. Toxicity was scored per NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Given the uncertainty about categorizing radiation pneumonitis we defined grade 2 pneumonitis as patients requiring systemic prednisone, and grade 3 pneumonitis as patients requiring continuous oxygen or need for hospitalization. Treatment characteristics
Author Manuscript
All patients underwent one of three lung-sparing types of surgical procedure, namely extended pleurectomy/decortication (EPD), pleurectomy/decortication (P/D), or partial pleurectomy (PP). Only 15 patients (11%) in the CONV group received chemotherapy, but 90% of patients in the IMPRINT group were treated with neoadjuvant or adjuvant chemotherapy. With the exeption of two cases, all patients in the IMPRINT group received a platinum/pemetrexed doublet. The technique of conventional RT performed at our institution has been previously described by Kutcher et al.20 and Gupta et al.21 Patients were immobilized with their arms raised above their head in supine position. The field borders were the top of T1 superiorly, the bottom of L2/base of diaphragm inferiorly, the ribcage including the skin laterally and the contralateral border of the vertebral bodies medially. A 1.5 to 2.0cm margin was added medially if mediastinal nodes were involved. Patients were simulated using fluoroscopy or
J Thorac Oncol. Author manuscript; available in PMC 2017 July 06.
Shaikh et al.
Page 4
Author Manuscript
CT, and the planning target volume (PTV) was defined as the pleura and diaphragm with a 1cm margin. Blocks were placed anteriorly and posteriorly over abdomen and lung, and starting at 1980 cGy - over the heart in the case of left-sided tumors. There was a 15% scatter under the blocks from the photon fields, therefore a supplemental daily electron dose of 153 cGy was prescribed. The spinal cord was excluded from the treatment field for the final 2 fractions to avoid overdosing. Radiation treatments were delivered in 180 cGy fractions with 6 MV photon beams using linear accelerators.
Author Manuscript
Since 2004 we have developed a hemithoracic pleural IMRT technique for MPM patients that was previously described.15, 16, 19 Patients were immobilized with their arms raised above their head in supine position. The initial PTV was defined using the planning CT scan and encompassed the hemithoracic pleura and chest wall reaching from the thoracic inlet until the insertion of the diaphragm at the L1/L2 vertebral body. A PET-CT scan and respiratory correlated 4D-CT scan (available since 2008) were used to further refine the target volume. Radiation treatments were delivered in 180 cGy fractions with 6 MV photon beams using Varian linear accelerators with a dynamic multileaf collimator. Statistical methods and design
Author Manuscript
The primary endpoint of the analysis was overall survival (OS). Local failure free survival (LFFS) and progression free survival (PFS) were determined as well. All endpoints were measured beginning at the start of radiation therapy until the date of event (death, local failure or progression, respectively) or until the last follow-up date. The Kaplan-Meier method was used for calculating overall survival rates, Cox proportional hazards regression model was used for OS analysis, and a Fine and Gray competing risks analysis was performed for LFFS and PFS. Univariate analysis (UVA) was performed for the following factors: age at diagnosis, sex, Karnofsky performance score (KPS), histology, laterality of tumor, clinical and pathological stage, macroscopically complete resection (MCR), chemotherapy, RT technique and RT dose. Factors with a p-value ≤ 0.15 were considered candidates for stepwise multivariate analysis (MVA) to evaluate the association of RT technique with each endpoint. Forward and backward selection procedures were implemented to confirm results. Incidence of significant (≥ grade 2) toxicities were compared between RT techniques using Fisher's exact test. These results were adjusted for multiple comparisons using the Bonferroni method. Statistical analysis was conducted with the software SAS version 9.4 (SAS Institute Inc. Cary, NC), and R version 3.1.2 package cmprsk.
Results Author Manuscript
Patient characteristics We analyzed 209 patients with MPM who met the inclusion criteria. The median age of patients was 64 (range: 34 to 84), male to female ratio was 4:1 and median KPS was 80 (range: 60 to 100). 131 patients (63%) received conventional external beam radiation therapy (CONV) and 78 (37%) intensity-modulated pleural radiation therapy (IMPRINT). All patients treated since March 2005 received IMPRINT. Eighty-five patients (41%) received chemotherapy (70 IMPRINT and 15 CONV patients). Significant differences between the
J Thorac Oncol. Author manuscript; available in PMC 2017 July 06.
Shaikh et al.
Page 5
Author Manuscript
CONV and IMPRINT group were noted in age (> 64 years: 45% and 65% respectively, p=0.006), KPS (>80: 31% and 50% respectively, p=0.008), histology (epithelioid: 59% and 86% respectively, p4500 cGy (HR 0.70, 95% CI 0.50-0.96, p=0.03). On MVA, KPS > 80% (p=0.01), epithelioid histology (p=0.003), MCR (p=0.01) and IMPRINT (p=0.02) were significantly associated with longer OS. [Table 2]
Author Manuscript
Although chemotherapy was associated with improved survival in the UVA (vs. no chemotherapy, HR 0.63, 95%CI 0.46-0.86, p=0.004), it did not enter into the stepwise Cox proportional hazards MVA final model as it was highly correlated with RT technique. Seventy patients (90%) receiving IMPRINT also underwent chemotherapy, while only 15 patients (11%) in the CONV cohort received chemotherapy (p
