- Email: [email protected]
Treatment of oesophageal cancer – Stressing the patient perspective
European Journal of Cancer 84 (2017) 360e362
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
Editorial
Treatment of oesophageal cancer e Stressing the patient perspective Being the sixth most common cause of cancer-related death worldwide, oesophageal cancer is a global health challenge. The two major subtypes are oesophageal squamous cell carcinoma (OSCC) and oesophageal adenocarcinoma (OAC) [1]. As OSCC and OAC are epidemiologically and biologically distinct [2], the European Society of Medical Oncology (ESMO) guidelines recommend different treatment algorithms for both subtypes [3]. Combined chemoradiotherapy (CRT) has an established role in the treatment of oesophageal cancer, especially in the OSCC subtype, where it is applied as neoadjuvant (pre-operative) or definitive (non-operative) treatment. Discussion is ongoing about radiation doses, optimal radiation volumes, and concurrent medical treatment. Cisplatin and 5-fluorouracil (CF) is the most established drug regimen for CRT of OSCC but is felt to be suboptimal, as the efficacy of CF-based CRT is limited and side-effects are common. The recent prospective randomized PRODIGE5/ ACCORD17 trial conducted in a French academic network, did not reveal significant differences in survival outcomes between two CRT regimens, CF four cycles or FOLFOX (oxaliplatin/5-fluorouracil/folinic acid) six cycles, given with 50 Gy of radiotherapy in 25 fractions [4]. A secondary analysis, published in this issue of the European Journal of Cancer [5] aimed to describe the impact of CRT on health-related quality of life (HRQOL), physical functioning, and disease-related symptoms, and to evaluate whether baseline HRQOL domains can predict overall survival in patients with non-metastatic oesophageal cancer, 86% of which had an OSCC subtype. HRQOL was prospectively assessed
DOI of original article: http://dx.doi.org/10.1016/j.ejca.2017.07. 038.
http://dx.doi.org/10.1016/j.ejca.2017.08.021 0959-8049/ª 2017 Elsevier Ltd. All rights reserved.
using the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire version 3.0 with the oesophageal cancer module (QLQ-OES18). Authors report that in both groups CRT significantly worsened social and physical functions and increased fatigue occurred during treatment, with subsequent recovery within 24 weeks. During follow-up, HRQOL scores revealed no significant differences between chemotherapy regimens and also time until definitive deterioration analysis showed no significant differences in global HRQOL, functional or main symptom domains. The patient perspective gets increasing importance in cancer care and research. In this randomized controlled trial it is depicted by a comprehensive assessment of several HRQOL domains. The authors should be congratulated for their achievement to collect valuable patient-reported quality of life data, even if some shortcomings in the trial design and conduct of the study occurred. The validity of the HRQOL assessment in this study is to a certain extent hampered by the amount of missing data. In contrast to a high compliance of filling out the questionnaires at baseline, followup data after 6 months were obtained in only 41% of patients. Better mechanisms for a stringent HRQOL assessment should be implemented in future studies. This will require new logistics like electronic alerts and reporting devices and will certainly cost money. Public funding authorities should be prepared that conducting high-quality and independent academic research comes at a price and we should not leave it to the pharmaceutical industry and the agencies alone to dictate us clinical study designs and clinical outcome parameters. Apart from the missing data issue, differences between the two chemotherapy schedules (3-weekly CF versus 2weekly FOLFOX) may have caused unbalanced side-
Editorial
effect and symptom reporting, leading to overoptimistic results in the CF arm regarding some symptom domains. As a secondary analysis, the authors determined the prognostic value of baseline EORTC questionnaire scores with respect to survival outcomes. Stage at diagnosis was the only independent significant prognostic factor for progression free survival and overall survival (OS) while only the EORTC HRQOL eating domain approached the statistical significance for OS. Over the last two decades, methodologically robust studies have shown that pretreatment HRQOL scores are superior to traditionally used variables in predicting OS in patients with OSCC. In a study involving 110 patients treated with radiation, baseline physical functioning was the most significant survival predictor. In addition, of the QOL scores assessed 2 months after radiation, the dysphagia symptom scale was the most significant indicator for OS [6]. These data provided evidence to support the correlation of patient-reported QOL scores with survival. Pretreatment physical functioning might be a surrogate marker of an unrecognized biologic prognostic factor. The poor survival outcome for patients with persistent dysphagia after treatment implied that local control remains the main issue to overcome in treating oesophageal cancer with radiation. Comparable findings were published from a surgically treated Swedish cohort. In 401 oesophageal cancer patients who survived at least 6 months postoperatively, poor global HRQOL, physical function, social function, fatigue, pain, dyspnoea, appetite loss, dysphagia and pain scores were associated with an increased hazard ratio for death [7]. Unfortunately, PRODIGE5/ACCORD17 leaves the question unanswered which chemotherapy regimen should be combined with radiation when patients with OSCC undergo definitive CRT. Neither survival outcomes, nor toxicity and HRQOL assessment showed any clinically meaningful advantage for either of the regimens, CF and FOLFOX. Combining weekly carboplatin and paclitaxel with radiation had high efficacy in the OSCC subgroup of patients recruited in the Preoperative chemoradiotherapy for oesophageal or junctional cancer (CROSS) trial [8]. Carboplatin/paclitaxel has also been investigated as definitive CRT in oesophageal cancer patients in a non-randomised retrospective study and showed comparable outcomes in terms of disease-free and overall survival compared with CF. Interestingly, toxicity rates were lower in the carboplatin/paclitaxel group and treatment compliance was higher. The investigators concluded that carboplatin/ paclitaxel would be a good candidate regimen for further evaluation [9]. Good CRT regimens are needed for integration of novel treatment options. While in view of the high complexity of genetic alterations in OSCC [2] a precision medicine approach has not been achieved thus far and
361
prospective randomized controlled trials assessing biologically targeted agents including anti-EGFR-directed treatment have failed [1], immunotherapy is at the horizon. A first study investigating the programmed death receptor-1 (PD-1) inhibitor nivolumab in metastatic OSCC has been reported recently and shows promising anti-tumour activity [10]. Combining PD-1 inhibitors with definitive or neoadjuvant CRT are underway. Christophe Mariette, who we now miss so strongly in our community, has established the concept of salvage oesophagectomy for patients who fail definitive CRT [11]. He has also established hybrid-minimally invasive oesophagectomy [12] as a safer and more effective surgical standard-of-care in his strong French network. We admire him for his life work which is unequalled and unique. As the efficacy of definitive CRT for OSCC may increase with integration of novel therapeutics like immune checkpoint inhibitors, the need for patients to undergo oesophagectomy will hopefully decline. Assessment of HRQOL outcomes should be an integral part of studies investigating novel treatment approaches in oesophageal cancer patients. I share Christophe Mariette’s vision of future treatment of oesophageal cancer which seeks to overcome drug and radiation resistance, and to reserve oesophagectomy to the patients who cannot be cured with CRT. Everyone who worked with Christophe Mariette knows how important the patient perspective was in his daily practice and in his research. We should follow his idea and have a strong interest in the assessment of the patient perspective. We should provide our patients with all support they need when undergoing the complex and demanding treatment for oesophageal cancer.
Conflict of interest statement Received research support from BMS and Roche Diagnostics; worked as an advisor for Astellas, Biontech, Elsevier, Ganymed; received honoraria for educational lectures from Astra Zeneca, Amgen, BMS, E.Cancer, Eli Lilly, Excerpta Medica, Medscape, MSD and Servier.
References [1] Smyth EC, Lagergren J, Fitzgerald RC, et al. Nat Rev Dis Prim 2017;3:17048. [2] Cancer Genome Atlas Research Network, Analysis Working Group. Integrated genomic characterization of oesophageal carcinoma. Nature 2017;541:169e75. [3] Lordick F, Mariette C, Haustermans K, et al. Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016;27(Suppl. 5):v50e7. [4] Conroy T, Galais MP, Raoul JL, et al. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol 2014; 15:305e14. [5] Bascoul-Mollevi C, Gourgou S, Galais MP, et al. Health-Related Quality of Life results from the PRODIGE 5/ACCORD 17
362
[6]
[7]
[8]
[9]
[10]
Editorial randomized trial of FOLFOX vs fluorouracil-cisplatin regimen in esophageal cancer. Eur J Cancer 2017;84:239e49. Fang FM, Tsai WL, Chiu HC, et al. Quality of life as a survival predictor for esophageal squamous cell carcinoma treated with radiotherapy. Int J Radiat Oncol Biol Phys 2004;58:1394e404. Dja¨rv T, Lagergren P. Six-month postoperative quality of life predicts long-term survival after oesophageal cancer surgery. Eur J Cancer 2011;47:530e5. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2012;366:2074e84. Honing J, Smit JK, Muijs CT, et al. A comparison of carboplatin and paclitaxel with cisplatinum and 5-fluorouracil in definitive chemoradiation in esophageal cancer patients. Ann Oncol 2014; 25:638e43. Kudo T, Hamamoto Y, Kato K, et al. Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial. Lancet Oncol 2017;18:631e9.
[11] Markar S, Gronnier C, Duhamel A, et al. Salvage surgery after chemoradiotherapy in the management of esophageal cancer: is it a viable therapeutic option? J Clin Oncol 2015;33:3866e73. [12] Mariette C, Markar S, Dabakuyo-Y TS, et al. Hybrid Minimally Invasive vs. Open Esophagectomy for patients with Esophageal Cancer: Long-term outcomes of a multicentre, open-label, randomized phase III controlled trial, the MIRO trial. Annals of Oncology 2017;28(suppl_5):v605e49.
Florian Lordick, MD, PhD Professor of Oncology, Director of the University Cancer Center Leipzig, University Medicine Leipzig, Germany, Liebigstr. 20, D e 04103 Leipzig, Germany E-mail address: [email protected]
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
Editorial
Treatment of oesophageal cancer e Stressing the patient perspective Being the sixth most common cause of cancer-related death worldwide, oesophageal cancer is a global health challenge. The two major subtypes are oesophageal squamous cell carcinoma (OSCC) and oesophageal adenocarcinoma (OAC) [1]. As OSCC and OAC are epidemiologically and biologically distinct [2], the European Society of Medical Oncology (ESMO) guidelines recommend different treatment algorithms for both subtypes [3]. Combined chemoradiotherapy (CRT) has an established role in the treatment of oesophageal cancer, especially in the OSCC subtype, where it is applied as neoadjuvant (pre-operative) or definitive (non-operative) treatment. Discussion is ongoing about radiation doses, optimal radiation volumes, and concurrent medical treatment. Cisplatin and 5-fluorouracil (CF) is the most established drug regimen for CRT of OSCC but is felt to be suboptimal, as the efficacy of CF-based CRT is limited and side-effects are common. The recent prospective randomized PRODIGE5/ ACCORD17 trial conducted in a French academic network, did not reveal significant differences in survival outcomes between two CRT regimens, CF four cycles or FOLFOX (oxaliplatin/5-fluorouracil/folinic acid) six cycles, given with 50 Gy of radiotherapy in 25 fractions [4]. A secondary analysis, published in this issue of the European Journal of Cancer [5] aimed to describe the impact of CRT on health-related quality of life (HRQOL), physical functioning, and disease-related symptoms, and to evaluate whether baseline HRQOL domains can predict overall survival in patients with non-metastatic oesophageal cancer, 86% of which had an OSCC subtype. HRQOL was prospectively assessed
DOI of original article: http://dx.doi.org/10.1016/j.ejca.2017.07. 038.
http://dx.doi.org/10.1016/j.ejca.2017.08.021 0959-8049/ª 2017 Elsevier Ltd. All rights reserved.
using the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire version 3.0 with the oesophageal cancer module (QLQ-OES18). Authors report that in both groups CRT significantly worsened social and physical functions and increased fatigue occurred during treatment, with subsequent recovery within 24 weeks. During follow-up, HRQOL scores revealed no significant differences between chemotherapy regimens and also time until definitive deterioration analysis showed no significant differences in global HRQOL, functional or main symptom domains. The patient perspective gets increasing importance in cancer care and research. In this randomized controlled trial it is depicted by a comprehensive assessment of several HRQOL domains. The authors should be congratulated for their achievement to collect valuable patient-reported quality of life data, even if some shortcomings in the trial design and conduct of the study occurred. The validity of the HRQOL assessment in this study is to a certain extent hampered by the amount of missing data. In contrast to a high compliance of filling out the questionnaires at baseline, followup data after 6 months were obtained in only 41% of patients. Better mechanisms for a stringent HRQOL assessment should be implemented in future studies. This will require new logistics like electronic alerts and reporting devices and will certainly cost money. Public funding authorities should be prepared that conducting high-quality and independent academic research comes at a price and we should not leave it to the pharmaceutical industry and the agencies alone to dictate us clinical study designs and clinical outcome parameters. Apart from the missing data issue, differences between the two chemotherapy schedules (3-weekly CF versus 2weekly FOLFOX) may have caused unbalanced side-
Editorial
effect and symptom reporting, leading to overoptimistic results in the CF arm regarding some symptom domains. As a secondary analysis, the authors determined the prognostic value of baseline EORTC questionnaire scores with respect to survival outcomes. Stage at diagnosis was the only independent significant prognostic factor for progression free survival and overall survival (OS) while only the EORTC HRQOL eating domain approached the statistical significance for OS. Over the last two decades, methodologically robust studies have shown that pretreatment HRQOL scores are superior to traditionally used variables in predicting OS in patients with OSCC. In a study involving 110 patients treated with radiation, baseline physical functioning was the most significant survival predictor. In addition, of the QOL scores assessed 2 months after radiation, the dysphagia symptom scale was the most significant indicator for OS [6]. These data provided evidence to support the correlation of patient-reported QOL scores with survival. Pretreatment physical functioning might be a surrogate marker of an unrecognized biologic prognostic factor. The poor survival outcome for patients with persistent dysphagia after treatment implied that local control remains the main issue to overcome in treating oesophageal cancer with radiation. Comparable findings were published from a surgically treated Swedish cohort. In 401 oesophageal cancer patients who survived at least 6 months postoperatively, poor global HRQOL, physical function, social function, fatigue, pain, dyspnoea, appetite loss, dysphagia and pain scores were associated with an increased hazard ratio for death [7]. Unfortunately, PRODIGE5/ACCORD17 leaves the question unanswered which chemotherapy regimen should be combined with radiation when patients with OSCC undergo definitive CRT. Neither survival outcomes, nor toxicity and HRQOL assessment showed any clinically meaningful advantage for either of the regimens, CF and FOLFOX. Combining weekly carboplatin and paclitaxel with radiation had high efficacy in the OSCC subgroup of patients recruited in the Preoperative chemoradiotherapy for oesophageal or junctional cancer (CROSS) trial [8]. Carboplatin/paclitaxel has also been investigated as definitive CRT in oesophageal cancer patients in a non-randomised retrospective study and showed comparable outcomes in terms of disease-free and overall survival compared with CF. Interestingly, toxicity rates were lower in the carboplatin/paclitaxel group and treatment compliance was higher. The investigators concluded that carboplatin/ paclitaxel would be a good candidate regimen for further evaluation [9]. Good CRT regimens are needed for integration of novel treatment options. While in view of the high complexity of genetic alterations in OSCC [2] a precision medicine approach has not been achieved thus far and
361
prospective randomized controlled trials assessing biologically targeted agents including anti-EGFR-directed treatment have failed [1], immunotherapy is at the horizon. A first study investigating the programmed death receptor-1 (PD-1) inhibitor nivolumab in metastatic OSCC has been reported recently and shows promising anti-tumour activity [10]. Combining PD-1 inhibitors with definitive or neoadjuvant CRT are underway. Christophe Mariette, who we now miss so strongly in our community, has established the concept of salvage oesophagectomy for patients who fail definitive CRT [11]. He has also established hybrid-minimally invasive oesophagectomy [12] as a safer and more effective surgical standard-of-care in his strong French network. We admire him for his life work which is unequalled and unique. As the efficacy of definitive CRT for OSCC may increase with integration of novel therapeutics like immune checkpoint inhibitors, the need for patients to undergo oesophagectomy will hopefully decline. Assessment of HRQOL outcomes should be an integral part of studies investigating novel treatment approaches in oesophageal cancer patients. I share Christophe Mariette’s vision of future treatment of oesophageal cancer which seeks to overcome drug and radiation resistance, and to reserve oesophagectomy to the patients who cannot be cured with CRT. Everyone who worked with Christophe Mariette knows how important the patient perspective was in his daily practice and in his research. We should follow his idea and have a strong interest in the assessment of the patient perspective. We should provide our patients with all support they need when undergoing the complex and demanding treatment for oesophageal cancer.
Conflict of interest statement Received research support from BMS and Roche Diagnostics; worked as an advisor for Astellas, Biontech, Elsevier, Ganymed; received honoraria for educational lectures from Astra Zeneca, Amgen, BMS, E.Cancer, Eli Lilly, Excerpta Medica, Medscape, MSD and Servier.
References [1] Smyth EC, Lagergren J, Fitzgerald RC, et al. Nat Rev Dis Prim 2017;3:17048. [2] Cancer Genome Atlas Research Network, Analysis Working Group. Integrated genomic characterization of oesophageal carcinoma. Nature 2017;541:169e75. [3] Lordick F, Mariette C, Haustermans K, et al. Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016;27(Suppl. 5):v50e7. [4] Conroy T, Galais MP, Raoul JL, et al. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol 2014; 15:305e14. [5] Bascoul-Mollevi C, Gourgou S, Galais MP, et al. Health-Related Quality of Life results from the PRODIGE 5/ACCORD 17
362
[6]
[7]
[8]
[9]
[10]
Editorial randomized trial of FOLFOX vs fluorouracil-cisplatin regimen in esophageal cancer. Eur J Cancer 2017;84:239e49. Fang FM, Tsai WL, Chiu HC, et al. Quality of life as a survival predictor for esophageal squamous cell carcinoma treated with radiotherapy. Int J Radiat Oncol Biol Phys 2004;58:1394e404. Dja¨rv T, Lagergren P. Six-month postoperative quality of life predicts long-term survival after oesophageal cancer surgery. Eur J Cancer 2011;47:530e5. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2012;366:2074e84. Honing J, Smit JK, Muijs CT, et al. A comparison of carboplatin and paclitaxel with cisplatinum and 5-fluorouracil in definitive chemoradiation in esophageal cancer patients. Ann Oncol 2014; 25:638e43. Kudo T, Hamamoto Y, Kato K, et al. Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial. Lancet Oncol 2017;18:631e9.
[11] Markar S, Gronnier C, Duhamel A, et al. Salvage surgery after chemoradiotherapy in the management of esophageal cancer: is it a viable therapeutic option? J Clin Oncol 2015;33:3866e73. [12] Mariette C, Markar S, Dabakuyo-Y TS, et al. Hybrid Minimally Invasive vs. Open Esophagectomy for patients with Esophageal Cancer: Long-term outcomes of a multicentre, open-label, randomized phase III controlled trial, the MIRO trial. Annals of Oncology 2017;28(suppl_5):v605e49.
Florian Lordick, MD, PhD Professor of Oncology, Director of the University Cancer Center Leipzig, University Medicine Leipzig, Germany, Liebigstr. 20, D e 04103 Leipzig, Germany E-mail address: [email protected]