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Is Weight Loss a Loss of Chance in Patients Receiving Chemoradiotherapy?
EDITORIAL
Is Weight Loss a Loss of Chance in Patients Receiving Chemoradiotherapy? Jean-Louis Pujol, MD, PhD* Weight loss during the 6 months preceding diagnosis of lung cancer is considered as an important prognostic feature. When it occurs during chemotherapy, loss of body weight indicates a poor therapeutic index and jeopardizes chances for a complete and successful treatment program. But weight loss of more than 5% (or more than 2% with a body mass index >20 kg/m2) is only one of the criteria for defining cancer cachexia.1,2 The latter is a critical adverse event of cancer. The main feature of cancer cachexia is sarcopenia (muscle mass wasting, loss of lean body weight), which is associated with fatigue, ongoing catabolism, poor tolerance of treatment, and an unfavorable prognosis.1 In this issue of the Journal of Thoracic Oncology, Sanders et al. have reported a study aimed at determining whether weight loss occurring at the beginning of chemoradiotherapy is a prognostic determinant in patients with stage IIIA or IIIB non–small cell lung cancer.3 Various platinum-based doublets were used as the backbone of the chemoradiotherapy part of therapy that started only after two induction cycles of chemotherapy. Patients who were without cachexia at the time of diagnosis and who completed the complete protocol were retrospectively analyzed. Among them, patients who lost more than 5% of their body weight had a shorter survival than did patients whose body weight remained stable. The authors must be commended for adding an interesting clue to the corpus of data suggesting that cancer cachexia is part of prognostic evaluation and treatment monitoring of a patient with lung cancer who is undergoing multimodality treatment, including modern intensity-modulated radiotherapy. At that point, a provocative question would be Is this symptom measured using low technology (a calibrated weighing machine) sufficient to assess all aspects of cancer cachexia? Even if weight loss and body mass index are both criteria defining cancer cachexia, they are considered screening tools only. Characterizing cancer cachexia requires identifying all features of cachexia, above all, sarcopenia. Different methods have been proposed to evaluate muscle wasting in oncology. Muscle mass area as measured on a computed tomography cross-sectional image at the L3 level is the preferred method.4 Muscle strength is the other important variable of this
evaluation. Other criteria are anorexia, food intake, and impact of weight loss on quality of life and psychosocial status. Finally, inflammatory serum proteins (e.g., C-reactive protein) and catabolic drive markers are frequently increased in cancer cachexia; they are part of the cachexia evaluation. Consequently, loss of body weight is only a marker of cachexia. In addition, some patients might experience sarcopenia without apparent change in body weight. This is the case in sarcopenic obesity5: skeletal muscle loss might be hidden by alteration of body mass composition (e.g., an increase in extracellular fluid or in tumor burden). Change in skeletal muscle mass has been observed in patients with lung cancer who are treated with either radiotherapy or chemotherapy.6,7 Therefore, the observation that patients who experience early weight loss during chemoradiotherapy are at higher risk of death, even if they have completed planned therapy, is a novel insight into the relationship between cachexia and prognosis. In the study by Sanders et al., body mass decreases before onset of esophagitis. One can hypothesize that this weight loss is related to the disease itself. Of note, cancer cachexia is not a simple binary feature. It is a continuum from precachexia to refractory cachexia, with all the subtle degrees in between.1,2 It is therefore possible that some patients had sarcopenia at diagnosis even though no major change in body weight was observed insofar as alteration in body weight composition was at its beginning. In the present study, one can speculate that precachexia might have preceded induction therapy and that weight loss is unmasked thereafter.
*Corresponding author. Montpellier Academic Hospital, Hôpital Arnaud de Villeneuve, Montpellier, France. INSERM U 1194, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France. Disclosure: The author declares no conflict of interest. Address for correspondence: Jean-Louis Pujol, MD, PhD, Institut de Recherche en Cancérologie de Montpellier, Thoracic Oncology, Due de la Cardonille, Montpellier, Cedex 34294, France. E-mail: jl-pujol@ chu-montpellier.fr ª 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. ISSN: 1556-0864 http://dx.doi.org/10.1016/j.jtho.2016.04.010
Journal of Thoracic Oncology
Vol. 11 No. 6: 787-788
788 Pujol
Treatment-induced cachexia is another interpretation of the observation by Sanders et al. As already mentioned, patients in their study received two cycles of induction chemotherapy before entering chemoradiotherapy. Platinum-based regimens (particularly cisplatin) are known to induce anorexia, nausea, and vomiting, leading to reduced food intake. This is in accordance with recent studies performed in cancer of the lung or other organs, such as pancreatic8 and esophageal cancer.9 Awad et al. have observed that patients with esophageal cancer had a high incidence of sarcopenia and that during initiation of neoadjuvant chemotherapy, skeletal muscle mass further decreased together with a concomitant reduction of lean body mass.9 A similar phenomenon could have occurred in the study by Sanders et al. during the induction chemotherapy as given before chemoradiotherapy. In addition to cisplatin-induced anorexia, a direct effect of the platinum compound on muscle has been demonstrated. In a murine model, the combination of cisplatin and dietary restriction induces a significant increase in messenger RNA expression of muscle atrophy F-box gene (MAFbx), and muscle RING finger-1 gene (MuRF1), two genes involved in the ubiquitin-proteasome pathway, which is the primary pathway involved in intracellular protein degradation in skeletal muscle.10 This could be a third interpretation of the weight loss observed in this study. The relationship between weight loss and prognosis as observed by Sanders et al. deserves further studies aimed at determining whether an early intervention designed to reverse or slow down cachexia might improve a patient’s outcome. In the past, studies evaluating progestational drugs or corticosteroids have failed to correct cancer cachexia, although these classical drugs might alleviate anorexia and increase weight. There was actually no correction of cancer cachexia insofar as these drugs alter body composition instead of increasing lean body weight (i.e., increased fluid retention but decreased muscle mass). Recently, Temel et al. reported two simultaneous phase 3 studies comparing anamorelin versus placebo in lung cancer patients with cachexia.11 Anamorelin is a high-affinity, selective ghrelin-receptor agonist (ghrelin is a ligand for the G-protein–coupled ghrelin receptor acting through the insulin-like growth factor pathway). The studies demonstrated that this agonist significantly increased lean body weight (as assessed at weeks 6 and 12 by dual-energy x-ray absorptiometry) but failed to modify muscle strength, a coprimary end point. Survival did not differ significantly between anamorelin and placebo, but various treatments were delivered in these large studies and a significant proportion of patients received best supportive care only. Temel et al. considered that there is therefore no
Journal of Thoracic Oncology
Vol. 11 No. 6
detrimental effect of the drug. Hitherto, it is not possible to determine whether an anamorelin-induced positive change in body composition is sufficient to modify functional muscle activity and to reduce cachexia consequences in lung cancer. Cancer cachexia in patients undergoing multimodality treatment for stage III lung cancer might be important to consider in further studies aimed at demonstrating that limiting anorexia and sarcopenia also reduce the risks for disease progression and death.
Acknowledgments The authors thank Mrs. Valérie Macioce for careful editing of the manuscript.
References 1. Fearon K, Strasser F, Anker SD, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011;12:489–495. 2. Blum D, Stene GB, Solheim TS, et al. Validation of the consensus-definition for cancer cachexia and evaluation of a classification model—a study based on data from an international multicentre project (EPCRC-CSA). Ann Oncol. 2014;25:1635–1642. 3. Sanders KJC, Hendriks LE, Troost EGC, et al. Early weight loss during chemoradiotherapy has a detrimental impact on outcome in NSCLC. J Thorac Oncol. 2016;11:873–879. 4. Shen W, Punyanitya M, Wang Z, et al. Total body skeletal muscle and adipose tissue volumes: estimation from a single abdominal cross-sectional image. J Appl Physiol (1985). 2004;97:2333–2338. 5. Martin L, Birdsell L, Macdonald N, et al. Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index. J Clin Oncol. 2013;31:1539–1547. 6. Stene GB, Helbostad JL, Amundsen T, et al. Changes in skeletal muscle mass during palliative chemotherapy in patients with advanced lung cancer. Acta Oncol. 2015;54:340–348. 7. Jafri SH, Previgliano C, Khandelwal K, Shi R. Cachexia index in advanced non-small-cell lung cancer patients. Clin Med Insights Oncol. 2015;9:87–93. 8. Dalal S, Hui D, Bidaut L, et al. Relationships among body mass index, longitudinal body composition alterations, and survival in patients with locally advanced pancreatic cancer receiving chemoradiation: a pilot study. J Pain Symptom Manage. 2012;44:181–191. 9. Awad S, Tan BH, Cui H, et al. Marked changes in body composition following neoadjuvant chemotherapy for oesophagogastric cancer. Clin Nutr. 2012;31:74–77. 10. Sakai H, Sagara A, Arakawa K, et al. Mechanisms of cisplatin-induced muscle atrophy. Toxicol Appl Pharmacol. 2014;278:190–199. 11. Temel JS, Abernethy AP, Currow DC, et al. Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials. Lancet Oncol. 2016;17:519–531.
Is Weight Loss a Loss of Chance in Patients Receiving Chemoradiotherapy? Jean-Louis Pujol, MD, PhD* Weight loss during the 6 months preceding diagnosis of lung cancer is considered as an important prognostic feature. When it occurs during chemotherapy, loss of body weight indicates a poor therapeutic index and jeopardizes chances for a complete and successful treatment program. But weight loss of more than 5% (or more than 2% with a body mass index >20 kg/m2) is only one of the criteria for defining cancer cachexia.1,2 The latter is a critical adverse event of cancer. The main feature of cancer cachexia is sarcopenia (muscle mass wasting, loss of lean body weight), which is associated with fatigue, ongoing catabolism, poor tolerance of treatment, and an unfavorable prognosis.1 In this issue of the Journal of Thoracic Oncology, Sanders et al. have reported a study aimed at determining whether weight loss occurring at the beginning of chemoradiotherapy is a prognostic determinant in patients with stage IIIA or IIIB non–small cell lung cancer.3 Various platinum-based doublets were used as the backbone of the chemoradiotherapy part of therapy that started only after two induction cycles of chemotherapy. Patients who were without cachexia at the time of diagnosis and who completed the complete protocol were retrospectively analyzed. Among them, patients who lost more than 5% of their body weight had a shorter survival than did patients whose body weight remained stable. The authors must be commended for adding an interesting clue to the corpus of data suggesting that cancer cachexia is part of prognostic evaluation and treatment monitoring of a patient with lung cancer who is undergoing multimodality treatment, including modern intensity-modulated radiotherapy. At that point, a provocative question would be Is this symptom measured using low technology (a calibrated weighing machine) sufficient to assess all aspects of cancer cachexia? Even if weight loss and body mass index are both criteria defining cancer cachexia, they are considered screening tools only. Characterizing cancer cachexia requires identifying all features of cachexia, above all, sarcopenia. Different methods have been proposed to evaluate muscle wasting in oncology. Muscle mass area as measured on a computed tomography cross-sectional image at the L3 level is the preferred method.4 Muscle strength is the other important variable of this
evaluation. Other criteria are anorexia, food intake, and impact of weight loss on quality of life and psychosocial status. Finally, inflammatory serum proteins (e.g., C-reactive protein) and catabolic drive markers are frequently increased in cancer cachexia; they are part of the cachexia evaluation. Consequently, loss of body weight is only a marker of cachexia. In addition, some patients might experience sarcopenia without apparent change in body weight. This is the case in sarcopenic obesity5: skeletal muscle loss might be hidden by alteration of body mass composition (e.g., an increase in extracellular fluid or in tumor burden). Change in skeletal muscle mass has been observed in patients with lung cancer who are treated with either radiotherapy or chemotherapy.6,7 Therefore, the observation that patients who experience early weight loss during chemoradiotherapy are at higher risk of death, even if they have completed planned therapy, is a novel insight into the relationship between cachexia and prognosis. In the study by Sanders et al., body mass decreases before onset of esophagitis. One can hypothesize that this weight loss is related to the disease itself. Of note, cancer cachexia is not a simple binary feature. It is a continuum from precachexia to refractory cachexia, with all the subtle degrees in between.1,2 It is therefore possible that some patients had sarcopenia at diagnosis even though no major change in body weight was observed insofar as alteration in body weight composition was at its beginning. In the present study, one can speculate that precachexia might have preceded induction therapy and that weight loss is unmasked thereafter.
*Corresponding author. Montpellier Academic Hospital, Hôpital Arnaud de Villeneuve, Montpellier, France. INSERM U 1194, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France. Disclosure: The author declares no conflict of interest. Address for correspondence: Jean-Louis Pujol, MD, PhD, Institut de Recherche en Cancérologie de Montpellier, Thoracic Oncology, Due de la Cardonille, Montpellier, Cedex 34294, France. E-mail: jl-pujol@ chu-montpellier.fr ª 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. ISSN: 1556-0864 http://dx.doi.org/10.1016/j.jtho.2016.04.010
Journal of Thoracic Oncology
Vol. 11 No. 6: 787-788
788 Pujol
Treatment-induced cachexia is another interpretation of the observation by Sanders et al. As already mentioned, patients in their study received two cycles of induction chemotherapy before entering chemoradiotherapy. Platinum-based regimens (particularly cisplatin) are known to induce anorexia, nausea, and vomiting, leading to reduced food intake. This is in accordance with recent studies performed in cancer of the lung or other organs, such as pancreatic8 and esophageal cancer.9 Awad et al. have observed that patients with esophageal cancer had a high incidence of sarcopenia and that during initiation of neoadjuvant chemotherapy, skeletal muscle mass further decreased together with a concomitant reduction of lean body mass.9 A similar phenomenon could have occurred in the study by Sanders et al. during the induction chemotherapy as given before chemoradiotherapy. In addition to cisplatin-induced anorexia, a direct effect of the platinum compound on muscle has been demonstrated. In a murine model, the combination of cisplatin and dietary restriction induces a significant increase in messenger RNA expression of muscle atrophy F-box gene (MAFbx), and muscle RING finger-1 gene (MuRF1), two genes involved in the ubiquitin-proteasome pathway, which is the primary pathway involved in intracellular protein degradation in skeletal muscle.10 This could be a third interpretation of the weight loss observed in this study. The relationship between weight loss and prognosis as observed by Sanders et al. deserves further studies aimed at determining whether an early intervention designed to reverse or slow down cachexia might improve a patient’s outcome. In the past, studies evaluating progestational drugs or corticosteroids have failed to correct cancer cachexia, although these classical drugs might alleviate anorexia and increase weight. There was actually no correction of cancer cachexia insofar as these drugs alter body composition instead of increasing lean body weight (i.e., increased fluid retention but decreased muscle mass). Recently, Temel et al. reported two simultaneous phase 3 studies comparing anamorelin versus placebo in lung cancer patients with cachexia.11 Anamorelin is a high-affinity, selective ghrelin-receptor agonist (ghrelin is a ligand for the G-protein–coupled ghrelin receptor acting through the insulin-like growth factor pathway). The studies demonstrated that this agonist significantly increased lean body weight (as assessed at weeks 6 and 12 by dual-energy x-ray absorptiometry) but failed to modify muscle strength, a coprimary end point. Survival did not differ significantly between anamorelin and placebo, but various treatments were delivered in these large studies and a significant proportion of patients received best supportive care only. Temel et al. considered that there is therefore no
Journal of Thoracic Oncology
Vol. 11 No. 6
detrimental effect of the drug. Hitherto, it is not possible to determine whether an anamorelin-induced positive change in body composition is sufficient to modify functional muscle activity and to reduce cachexia consequences in lung cancer. Cancer cachexia in patients undergoing multimodality treatment for stage III lung cancer might be important to consider in further studies aimed at demonstrating that limiting anorexia and sarcopenia also reduce the risks for disease progression and death.
Acknowledgments The authors thank Mrs. Valérie Macioce for careful editing of the manuscript.
References 1. Fearon K, Strasser F, Anker SD, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011;12:489–495. 2. Blum D, Stene GB, Solheim TS, et al. Validation of the consensus-definition for cancer cachexia and evaluation of a classification model—a study based on data from an international multicentre project (EPCRC-CSA). Ann Oncol. 2014;25:1635–1642. 3. Sanders KJC, Hendriks LE, Troost EGC, et al. Early weight loss during chemoradiotherapy has a detrimental impact on outcome in NSCLC. J Thorac Oncol. 2016;11:873–879. 4. Shen W, Punyanitya M, Wang Z, et al. Total body skeletal muscle and adipose tissue volumes: estimation from a single abdominal cross-sectional image. J Appl Physiol (1985). 2004;97:2333–2338. 5. Martin L, Birdsell L, Macdonald N, et al. Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index. J Clin Oncol. 2013;31:1539–1547. 6. Stene GB, Helbostad JL, Amundsen T, et al. Changes in skeletal muscle mass during palliative chemotherapy in patients with advanced lung cancer. Acta Oncol. 2015;54:340–348. 7. Jafri SH, Previgliano C, Khandelwal K, Shi R. Cachexia index in advanced non-small-cell lung cancer patients. Clin Med Insights Oncol. 2015;9:87–93. 8. Dalal S, Hui D, Bidaut L, et al. Relationships among body mass index, longitudinal body composition alterations, and survival in patients with locally advanced pancreatic cancer receiving chemoradiation: a pilot study. J Pain Symptom Manage. 2012;44:181–191. 9. Awad S, Tan BH, Cui H, et al. Marked changes in body composition following neoadjuvant chemotherapy for oesophagogastric cancer. Clin Nutr. 2012;31:74–77. 10. Sakai H, Sagara A, Arakawa K, et al. Mechanisms of cisplatin-induced muscle atrophy. Toxicol Appl Pharmacol. 2014;278:190–199. 11. Temel JS, Abernethy AP, Currow DC, et al. Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials. Lancet Oncol. 2016;17:519–531.