Diseases of the Esophagus (2015) 28, 453–459 DOI: 10.1111/dote.12215
Original article
Definitive chemoradiation for patients with inoperable and/or unresectable esophageal cancer: locoregional recurrence pattern E. Versteijne,1 H. W. M. van Laarhoven,2 J. E. van Hooft,3 R. M. van Os,1 E. D. Geijsen,1 M. I. van Berge Henegouwen,4 M. C. C. M. Hulshof1 Departments of 1Radiotherapy, 2Medical Oncology, 3Gastroenterology and 4Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
SUMMARY. A locoregional recurrence after definitive chemoradiation (dCRT) for patients with inoperable or unresectable esophageal cancer occurs in about 50% of the patients and is a major cause of failure with a poor prognosis. The aim of this study was to determine the pattern of locoregional recurrence and its prognostic factors after dCRT in order to search for improvements in radiation treatment. We retrospectively reviewed 184 patients treated with external beam radiotherapy (50.4 Gray/28 fractions), combined with weekly concurrent paclitaxel and carboplatin. Locoregional recurrences were defined by clinical signs of recurrent or progressive disease, combined with progression on computed tomography/positron emission tomography-computed tomography scan, or suspicious endoscopic findings and/or histological proof of recurrence. The site of locoregional recurrence was analyzed with respect to the borders of the radiation fields. After a mean follow up of 22.8 months, 76 patients (41%) had evidence of locoregional recurrence. The 3-years locoregional recurrence-free rate was 45%. The majority of locoregional recurrences occurred within 12 months, nearly all within 24 months. The majority of these patients failed at the site of the primary tumor (86%). Infield locoregional recurrences at the site of the lymph nodes only occurred in 1% compared with 57% at the site of the primary tumor only. Outfield locoregional lymph node recurrences occurred in 22%, without infield recurrence occurred in only 4% of all patients. The 1-, 3-, and 5-year overall survival was 65%, 28%, and 21%, respectively. The current analysis demonstrates that a locoregional recurrence after dCRT occurs in 41% of the patients, the majority at the site of the primary tumor. These data suggest a benefit of dose intensification of the primary tumor, but not at the site of the lymph nodes. Higher radiation doses should be assessed with prospective trials. KEY WORDS:
definitive chemoradiation, esophageal cancer, locoregional recurrence.
INTRODUCTION Worldwide esophageal cancer is the sixth cause of death, with over 400 000 deaths in 2008.1 The incidence rises worldwide, with a threefold increase of esophageal adenocarcinoma (AC) in males over the last two decades in the Netherlands (1989–2008). The incidence of esophageal squamous cell carcinoma (SCC) is slightly increasing in females, attributed to increasing smoking habits.2 Surgery is the mainstay standard approach for most localized esophageal cancers. Preoperative chemoradiation (CRT) followed by surgery showed Address correspondence to: Ms Eva Versteijne, MD, Department of Radiotherapy, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands. Email: [email protected] Conflicts of interest: None. © 2014 International Society for Diseases of the Esophagus
an improved survival compared with treatment with surgery alone.3 Patients not suitable for surgery, either because of locally advanced disease, co-morbidity, or high cervical location, are referred for definitive chemoradiation (dCRT). dCRT is an effective and well-tolerated treatment, with survival rates in resectable patients similar to those in surgical series without preoperative CRT.4,5 Nevertheless, the prognosis and survival of inoperable or unresectable esophageal cancer remains poor, with a 5-year survival of about 20%.4,6 After dCRT, almost 50% of patients develop a locoregional recurrence, and recurrence patterns differ from the pattern of recurrence after surgery.4,7–10 Previously identified prognostic factors for locoregional recurrence include T3/T4 tumors and tumor length >8 cm.7,9–11 However, these data are confined to local failure risk after radiation combined 453
454
Diseases of the Esophagus
with cisplatin and 5-fluorouracil (5-FU). In the current study, chemotherapy within the dCRT regime consisted of carboplatin and paclitaxel. Two previous retrospective studies and a phase II study describes concurrent CRT with carboplatin and paclitaxel as a well-tolerated treatment, and suggest superior overall survival (OS) compared with cisplatin/5-FU.12–14 The aim of this study was to analyze the recurrence pattern – specifically in relation to the radiation field and clinical factors predicting locoregional failure and OS. These results lead to recommendations for improvement of radiation treatment of patients with inoperable and unresectable esophageal cancer.
MATERIALS AND METHODS Patients We identified 184 patients with inoperable or unresectable esophageal cancer, treated at the Academic Medical Center Amsterdam, from May 2003 to August 2011, with a minimal follow up of 1 year. All patients had histological confirmed esophageal cancer, and were treated with dCRT with curative intent. Data regarding treatment and disease of all patients were retrospectively recorded in an electronic database. Inclusion criteria Patients were defined as unresectable when they had extended disease (T4), technical unresectable tumor (high cervical localization), and a locoregional recurrence after previous curative treatment or M1a/M1b disease (6th edition of TNM classification of the Union International Contre le Cancer [TNM UICC]). Patients were defined inoperable when co-morbidity excluded them from surgery.
current paclitaxel (50 mg/m2) and carboplatin (area under the curve [AUC] = 2). For treatment simulation and planning purposes, all patients had undergone 3-dimensional CT or PET/CT scanning with oral contrast. Treatment position was supine, with the arms raised above the head. The gross tumor volume (GTV) was contoured on the planning CT scan by the radiation oncologist, using data from PET/CT fusion scans when available, endoscopic ultrasound images and diagnostic CT images. The conformal clinical target volume (CTV) consisted of GTV plus at least the peri-esophageal lymph node area extended in cranio-caudal direction by a 3.5 cm margin – because of old field margins of 5 cm (minus 0.5 cm toward the 95% isodose and minus 1.0 cm for CTV-planning target volume [PTV]) with limitation of the margin into the cardia up to 2.3 cm because of toxicity and based on the guidelines of the CROSS study.3 The PTV consisted of the CTV expanded with 1.0 cm in all directions (Fig. 1). Treatment modifications in radiotherapy techniques did not occur during the study period. Radiation has been delivered as a four field conformal beam arrangement, with the following normal tissue constraints of critical organs:
Original article
Definitive chemoradiation for patients with inoperable and/or unresectable esophageal cancer: locoregional recurrence pattern E. Versteijne,1 H. W. M. van Laarhoven,2 J. E. van Hooft,3 R. M. van Os,1 E. D. Geijsen,1 M. I. van Berge Henegouwen,4 M. C. C. M. Hulshof1 Departments of 1Radiotherapy, 2Medical Oncology, 3Gastroenterology and 4Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
SUMMARY. A locoregional recurrence after definitive chemoradiation (dCRT) for patients with inoperable or unresectable esophageal cancer occurs in about 50% of the patients and is a major cause of failure with a poor prognosis. The aim of this study was to determine the pattern of locoregional recurrence and its prognostic factors after dCRT in order to search for improvements in radiation treatment. We retrospectively reviewed 184 patients treated with external beam radiotherapy (50.4 Gray/28 fractions), combined with weekly concurrent paclitaxel and carboplatin. Locoregional recurrences were defined by clinical signs of recurrent or progressive disease, combined with progression on computed tomography/positron emission tomography-computed tomography scan, or suspicious endoscopic findings and/or histological proof of recurrence. The site of locoregional recurrence was analyzed with respect to the borders of the radiation fields. After a mean follow up of 22.8 months, 76 patients (41%) had evidence of locoregional recurrence. The 3-years locoregional recurrence-free rate was 45%. The majority of locoregional recurrences occurred within 12 months, nearly all within 24 months. The majority of these patients failed at the site of the primary tumor (86%). Infield locoregional recurrences at the site of the lymph nodes only occurred in 1% compared with 57% at the site of the primary tumor only. Outfield locoregional lymph node recurrences occurred in 22%, without infield recurrence occurred in only 4% of all patients. The 1-, 3-, and 5-year overall survival was 65%, 28%, and 21%, respectively. The current analysis demonstrates that a locoregional recurrence after dCRT occurs in 41% of the patients, the majority at the site of the primary tumor. These data suggest a benefit of dose intensification of the primary tumor, but not at the site of the lymph nodes. Higher radiation doses should be assessed with prospective trials. KEY WORDS:
definitive chemoradiation, esophageal cancer, locoregional recurrence.
INTRODUCTION Worldwide esophageal cancer is the sixth cause of death, with over 400 000 deaths in 2008.1 The incidence rises worldwide, with a threefold increase of esophageal adenocarcinoma (AC) in males over the last two decades in the Netherlands (1989–2008). The incidence of esophageal squamous cell carcinoma (SCC) is slightly increasing in females, attributed to increasing smoking habits.2 Surgery is the mainstay standard approach for most localized esophageal cancers. Preoperative chemoradiation (CRT) followed by surgery showed Address correspondence to: Ms Eva Versteijne, MD, Department of Radiotherapy, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands. Email: [email protected] Conflicts of interest: None. © 2014 International Society for Diseases of the Esophagus
an improved survival compared with treatment with surgery alone.3 Patients not suitable for surgery, either because of locally advanced disease, co-morbidity, or high cervical location, are referred for definitive chemoradiation (dCRT). dCRT is an effective and well-tolerated treatment, with survival rates in resectable patients similar to those in surgical series without preoperative CRT.4,5 Nevertheless, the prognosis and survival of inoperable or unresectable esophageal cancer remains poor, with a 5-year survival of about 20%.4,6 After dCRT, almost 50% of patients develop a locoregional recurrence, and recurrence patterns differ from the pattern of recurrence after surgery.4,7–10 Previously identified prognostic factors for locoregional recurrence include T3/T4 tumors and tumor length >8 cm.7,9–11 However, these data are confined to local failure risk after radiation combined 453
454
Diseases of the Esophagus
with cisplatin and 5-fluorouracil (5-FU). In the current study, chemotherapy within the dCRT regime consisted of carboplatin and paclitaxel. Two previous retrospective studies and a phase II study describes concurrent CRT with carboplatin and paclitaxel as a well-tolerated treatment, and suggest superior overall survival (OS) compared with cisplatin/5-FU.12–14 The aim of this study was to analyze the recurrence pattern – specifically in relation to the radiation field and clinical factors predicting locoregional failure and OS. These results lead to recommendations for improvement of radiation treatment of patients with inoperable and unresectable esophageal cancer.
MATERIALS AND METHODS Patients We identified 184 patients with inoperable or unresectable esophageal cancer, treated at the Academic Medical Center Amsterdam, from May 2003 to August 2011, with a minimal follow up of 1 year. All patients had histological confirmed esophageal cancer, and were treated with dCRT with curative intent. Data regarding treatment and disease of all patients were retrospectively recorded in an electronic database. Inclusion criteria Patients were defined as unresectable when they had extended disease (T4), technical unresectable tumor (high cervical localization), and a locoregional recurrence after previous curative treatment or M1a/M1b disease (6th edition of TNM classification of the Union International Contre le Cancer [TNM UICC]). Patients were defined inoperable when co-morbidity excluded them from surgery.
current paclitaxel (50 mg/m2) and carboplatin (area under the curve [AUC] = 2). For treatment simulation and planning purposes, all patients had undergone 3-dimensional CT or PET/CT scanning with oral contrast. Treatment position was supine, with the arms raised above the head. The gross tumor volume (GTV) was contoured on the planning CT scan by the radiation oncologist, using data from PET/CT fusion scans when available, endoscopic ultrasound images and diagnostic CT images. The conformal clinical target volume (CTV) consisted of GTV plus at least the peri-esophageal lymph node area extended in cranio-caudal direction by a 3.5 cm margin – because of old field margins of 5 cm (minus 0.5 cm toward the 95% isodose and minus 1.0 cm for CTV-planning target volume [PTV]) with limitation of the margin into the cardia up to 2.3 cm because of toxicity and based on the guidelines of the CROSS study.3 The PTV consisted of the CTV expanded with 1.0 cm in all directions (Fig. 1). Treatment modifications in radiotherapy techniques did not occur during the study period. Radiation has been delivered as a four field conformal beam arrangement, with the following normal tissue constraints of critical organs:
