|Year : 2019 | Volume
| Issue : 3 | Page : 69-73
The influence of neoadjuvant chemoradiotherapy on muscle mass in patients with rectal cancer
Gregory Simpson, Thomas Marks, Sarah Blacker, Conor Magee, Jeremy Wilson
Division of GastroIntestinal Surgery, Wirral University Teaching Hospital, UK
|Date of Submission||31-May-2019|
|Date of Decision||23-Jul-2019|
|Date of Acceptance||15-Sep-2019|
|Date of Web Publication||24-Oct-2019|
Mr. Gregory Simpson
Division of Gastrointestinal Surgery, Wirral University Teaching Hospital
Source of Support: None, Conflict of Interest: None
Background: The psoas major muscle accurately represents overall skeletal muscle mass. The skeletal muscle mass volume is related to outcomes in multiple surgical procedures including colorectal cancer. However, neoadjuvant chemoradiotherapy for rectal cancer may adversely affect muscle mass. Objective: Assess the effect of neoadjuvant chemoradiotherapy on muscle mass in rectal cancer patients as well as on outcomes. Design: Retrospective study. Setting: A large UK District General Hospital. Patients and Methods: Analysis of all rectal cancer patients between 2014 and 2017. Psoas major was measured at the L3 level using pre- and post-neoadjuvant chemoradiotherapy images. Psoas major to L3 cross-sectional area (PML3) was calculated for each patient. Main Outcome Measures: 30-day and 90-day mortality, inpatient stay, and postoperative complications. Sample Size: One hundred and twenty-one rectal cancer patients. Results: Median age was 72 years (IQR: 64–78 years). Male:Female ratio was 82:39. 30-day mortality was 0%, and 90-day mortality was 0.83%. Sixty-one patients underwent neoadjuvant chemoradiotherapy (50.4%). Thirty-one patients underwent abdominoperineal excision of the rectum (APER) (25.6%), 1 underwent proctocolectomy (0.83%), 1 underwent completion proctectomy (0.83%), and 88 patients underwent anterior resection (72.7%). Significant muscle loss occurred during neoadjuvant therapy (median loss: 25.9%, IQR: 12.6–36.8%) (P < 0.0001). No correlation was observed between PML3 and inpatient stay. Patients with PML3 in the lowest quartile had a chest infection rate of 11.1% and a complication rate of 37.1% rather than 6.2% and 26.8%, respectively, for those in the upper quartiles. Anastomotic leak rate in the PML3 lowest quartile was 23.5% compared to 11.4% in patients in the upper quartiles. Conclusion: Patients who received neoadjuvant chemoradiotherapy had a significant reduction in muscle mass. Muscle mass loss can be overcome with a prehabilitation program that may reduce muscle loss and improve outcomes. Limitations: Due to a low event-rate of anastomotic leak, it is difficult to show statistical significance with a patient cohort of this size. Conflict of Interest: None.
Keywords: Muscle mass, neoadjuvant chemoradiotherapy, rectal cancer, sarcopenia
|How to cite this article:|
Simpson G, Marks T, Blacker S, Magee C, Wilson J. The influence of neoadjuvant chemoradiotherapy on muscle mass in patients with rectal cancer. World J Colorectal Surg 2019;8:69-73
|How to cite this URL:|
Simpson G, Marks T, Blacker S, Magee C, Wilson J. The influence of neoadjuvant chemoradiotherapy on muscle mass in patients with rectal cancer. World J Colorectal Surg [serial online] 2019 [cited 2020 Aug 5];8:69-73. Available from: http://www.wjcs.us.com/text.asp?2019/8/3/69/269880
| Introduction|| |
Colorectal cancer is a leading cause of cancer-related deaths worldwide. Moreover, the management of locally advanced rectal cancer remains a challenge. Conventionally, rectal cancer is treated using a multimodal approach involving surgery, radiotherapy, and chemotherapy; however, the timing of surgery, neoadjuvant protocols, and the surgical technique used (inter alia, open, robotic, laparoscopic, and TaTME) are still debatable.
Decisions regarding surgical units are affected by complex, older patients, and excess information regarding tumor-specific molecular biology. However, there is an increasing interest in patient-related factors that can influence the surgical outcomes, of which “prehabilitation” has shown promise in colorectal and other gastrointestinal cancers.
Sarcopenia is the age-related progressive loss of muscle mass and strength. Sarcopenia and skeletal muscle mass are related to outcome in multiple specialties, including colorectal cancer,,,, and emergency surgery, though no consensus is available regarding a cut-off value to define sarcopenia.
Sarcopenia is prevalent among elderly people diagnosed with colorectal cancer. Lower levels of skeletal muscle mass are associated with increased hospital stay and re-admission,, poorer survival, and increased rates of postoperative morbidity,,,, requiring routine preoperative sarcopenia and muscle-mass assessment. Patients who experience deterioration in muscle mass have increased morbidity and mortality.,,
The psoas muscle measured using CT is a simple and reliable measure for overall skeletal muscle mass and sarcopenia measurement.,,, There are multiple methods of muscle mass measurement including MRI, DEXA, CT, ultrasound, bioelectric impedance, anthropometric analysis, and biochemical markers;,, however, routine use of CT imaging during preoperative assessment makes this method easy to use, with no additional cost.
Rectal cancer patients undergoing neoadjuvant chemoradiotherapy have readily available pre and posttreatment CT images, making them an excellent group to investigate muscle mass.
In this study, we aim to investigate the prevalence of sarcopenia in a UK population of patients undergoing surgical intervention for rectal cancer and the impact of neoadjuvant chemotherapy on skeletal muscle mass and postoperative outcomes.
| Patients and Methods|| |
In this study, we included all patients who underwent surgical resection for rectal cancer with curative intent who were identified from a prospectively maintained database of patients diagnosed between 2014 and 2017 at a single center.
Demographic, histological, clinical, biochemical, and operative data were collected and analyzed by accessing patient clinical notes and electronic records.
Outcome measures were inpatient, 30-day, and 90-day mortality, length of stay (LOS), postoperative chest infection, anastomotic leak, and postoperative complications.
All patients underwent staging CT-imaging at the same center using the same CT scanning equipment. Because the psoas major muscle significantly predicts whole-body muscle mass,, it was utilized as a marker for whole-body muscle mass.
Psoas major and lumbar vertebral body cross-sectional area were calculated at the level of the third lumbar vertebral body inferior end plate. All patients included in this study had preoperative CT images at the level of the L3 inferior end plate analyzed. PML3 ratios were calculated preoperatively for each patient. In patients who underwent neoadjuvant chemoradiotherapy, images at the level of the L3 inferior end plate were analyzed before commencement and after completion of neoadjuvant chemoradiotherapy to assess the effect of neoadjuvant chemoradiotherapy on PML3 as a representation of muscle mass loss.
Psoas major was normalized to total body size using the cross-sectional area of the corresponding L3 vertebrae as a marker of body size.
Area of interest was marked by two trained investigators, and calculated in millimeter squared (Cerner RadNet Software, MO, USA). Psoas major to lumbar vertebral body ratio (PML3 ratio) was calculated for each patient. In addition, psoas major density was calculated using mean Hounsfield units for the cross-sectional area of the psoas major at the level of the inferior end plate of L3.
Statistical analysis was performed using GraphPad
(San Diego, Ca, USA).
Mann–Whitney U test was used to compare PML3 values in patients before commencement of neoadjuvant chemoradiotherapy with PML3 values after completion of NACRT. Spearman's rank correlation coefficient was utilized to assess correlation. Categorical data were analyzed using the Chi-square test. Analysis included comparison of those patients in the bottom quartile with respect to PML3 ratio compared to patients in the upper third quartiles.
| Results|| |
[Table 1] demonstrates the baseline characteristics of patients. One hundred and twenty-one patients (39 female and 82 male) underwent surgery for rectal cancer between 2014 and 2017. Median age was 72 years (Interquartile range, IQR: 64–78 years). The 30-day mortality rate was 0%. One patient died within 90 days postoperatively (0.83%). The median inpatient stay was 8 days (IQR: 6–11.75 days).
[Table 2] shows the operative approach. [Figure 1] shows the operative procedures performed.
See [Table 3].
Patients receiving neoadjuvant chemoradiotherapy vs. patients who received no neoadjuvant therapy
[Table 4] shows the outcomes of patients who received neoadjuvant chemoradiotherapy compared to those who did not receive it.
|Table 4: Patients receiving neoadjuvant chemoradiotherapy vs patients not receiving neoadjuvant chemoradiotherapy|
Click here to view
PML3 ratio during neoadjuvant chemoradiotherapy
The median baseline PML3 ratio for all patients was 0.61 (interquartile range IQR: 0.49–0.76).
In patients who underwent neoadjuvant chemoradiotherapy, baseline median PML3 ratio before surgical or neoadjuvant treatment was 0.66 (IQR: 0.51–0.81). However, following neoadjuvant chemoradiotherapy, PML3 ratio significantly decreased in comparison to pretreatment levels, with a median PML3 ratio of 0.48 (IQR: 0.38–0.56, P < 0.0001 MWU). [Figure 2] and [Figure 3] show the trend in PML3 ratios in patients before and after neoadjuvant chemoradiotherapy, respectively.
|Figure 2: Pre-neoadjuvant chemoradiotherapy PML3 vs. Post-Neoadjuvant chemoradiotherapy PML3|
Click here to view
|Figure 3: Box and whisker plot of PML3: pre vs. post neoadjuvant chemoradiotherapy|
Click here to view
PML3 as a predictor of outcome
Twenty-seven patients were identified with a PML3 of <0.42 (the lowest quartile).
Patients with a PML3 of <0.42 had a higher incidence of chest infection and overall complications (11% and 37%, respectively) compared to those with a PML3 >0.42 (6% and 27%, respectively), although this trend of higher complications in patients with lower PML3 values did not reach statistical significance.
For inpatients who underwent anterior resection, there was no correlation between PML3 ratio and duration of inpatient stay. Patients who underwent anterior resection with a preoperative PML3 >0.42 had a rate of anastomotic leak of 11.4% (8 of 70 patients) compared to patients with PML3 <0.42 who had a rate of anastomotic leak of 23.5% (4 of 17 patients). Similar rates of complications (PML3 <0.42 = 29.4% vs PML3 > 0.42 = 28.5%) and of chest infection (PML3 <0.42 = 5.9% vs PML3 >0.42 = 4.3%) were seen in both groups. [Table 5] demonstrates complications in this patient cohort.
In patients who underwent abdominoperineal resection of the rectum, there was no correlation between duration of inpatient stay and PML3 ratio. Additionally, no significant difference was seen in complication rates in this patient group.
PML3 Ratio and outcome after neoadjuvant chemoradiotherapy
In patients who experienced a 25% or greater reduction in PML3, the complication rate was greater than those who did not experience this decline (45.1% vs 34.6%, respectively). Rates of chest infection were similar between those who had a 25% decline in PML3 versus those who did not (6.7% vs. 11.1%, respectively), similarly median inpatient stay was similar between these two groups (9 days vs 8 days).
| Conclusion|| |
The importance of skeletal muscle mass in a surgical patient has been described in numerous surgical subspecialties.,,, However, worse outcomes have been encountered only in a sarcopenic patient. These findings have been mirrored in colorectal surgery, where sarcopenia was associated with increased morbidity, mortality, longer inpatient stay, and increased hospital re-admission rates.,,,, The psoas muscle has proven to be an accurate marker of total body muscle mass,, and it is easily quantified in a CRC population owing to the use of CT imaging as a staging modality. Multiple strategies to normalize the psoas major area to stature are described including height, body surface area, and cross-sectional area of the corresponding lumbar vertebrae; however, we used normalization to L3 cross-sectional area as it allows a simple assessment of whole-body muscle mass from a single CT image.
We found out that muscle function and strength, in addition to muscle size, were important factors. Further research will involve understanding the significance of muscle function and figuring out the best method of quantification of muscle function for patients undergoing surgery for CRC.,
Our data demonstrated higher rates of postoperative complications and anastomotic leak. However, our findings failed to achieve statistical significance. This may be due to insufficient patient numbers in our dataset. Furthermore, statistical significance is often not reached with outcomes measures, such as anastomotic leak, with a low event rate.
The principal finding in our study is that patients who undergo neoadjuvant chemoradiotherapy before surgery experience a significant reduction in skeletal muscle mass represented by a reduction in PML3 ratio. Studies among patients undergoing palliative chemotherapy have demonstrated that loss of muscle mass during oncologic treatment can be reversible. The loss of skeletal muscle mass during neoadjuvant therapy could potentially be ameliorated by a prehabilitation program that incorporates exercise programs and nutritional support. This will reduce the possibility of poor outcome associated with preoperative sarcopenia and poor muscle mass. Rectal cancer treatment provides a unique chance to enhance patients, skeletal muscle mass and combat the effects of sarcopenia due to the use of neoadjuvant chemoradiotherapy, which provides a 3- to 4-month window of opportunity.
Furthermore, we aim to work in rectal cancer and sarcopenia by implementing a prehabilitation program. The program will assess if the patients can avoid the negative effects of neoadjuvant chemoradiotherapy on skeletal muscle mass and improve outcomes of patients undergoing surgery for rectal cancer.
Research involving human participants and/or animals
For this type of study, formal consent is not required.
Institutional review board and informed consent were obtained from all individual participants included in the study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Drudi LM, Phung K, Ades M, Zuckerman J, Mullie L, Steinmetz OK, et al
. Psoas muscle area predicts all- cause mortality after endovascular and open aortic aneurysm repair. Eur J Vasc Endovascular Surg 2016;52:764-9.
Shirai H, Kaido T, Hamaguchi Y, Kobayashi A, Okumura S, Yao S, et al
. Preoperative low muscle mass and low muscle quality negatively impact on pulmonary function in patients undergoing hepatectomy for hepatocellular carcinoma. Liver Cancer 2018;7:76-89.
Benjamin AJ, Buschmann MM, Zhang SQ, Wroblewski K, Kindler HL, Roggin KK, et al
. The impact of changes in radiographic sarcopenia on overall survival in older adults undergoing different treatment pathways for pancreatic cancer. J Geriatr Oncol 2018;9:367-72.
Hawkins RB, Mehaffey JH, Charles EJ, Kern JA, Lim DS, Teman NR, et al
. Psoas muscle size predicts risk-adjusted outcomes after surgical aortic valve replacement. Ann Thorac Surg 2018;106:39-45.
Trotter J, Johnston J, Ng A, Gatt M, MacFie J, McNaught C. Is sarcopenia a useful predictor of outcome in patients after emergency laparotomy? A study using the NELA database. Ann R Coll Surg Engl 2018;27:1-5.
Simpson G, Parker A, Hopley P, Wilson J, Magee C. Pre-operative psoas major measurement compared to P-POSSUM as a prognostic indicator in over-80s undergoing emergency laparotomy. Eur J Trauma Emerg Surg 2018 Oct 13. doi: 10.1007/s00068-018-1025-5.
Broughman JR, Williams GR, Deal AM, Yu H, Nyrop KA, Alston SM, et al
. Prevalence of sarcopenia in older patients with colorectal cancer. J Geriatr Oncol 2015;6:442-5.
Fukuta A, Saito T, Murata S, Makiura D, Inoue J, Okumura M, et al
. Impact of preoperative cachexia on postoperative length of stay in elderly patients with gastrointestinal cancer. Nutrition 2018;58:65-8.
Martin L, Hopkins J, Malietzis G, Jenkins JT, Sawyer MB, Brisebois R, et al
. Assessment of computed tomography (CT)-defined muscle and adipose tissue features in relation to short-term outcomes after elective surgery for colorectal cancer: A multicenter approach. Ann Surg Oncol 2018;25:2669-80.
Cespedes Feliciano EM, Avrutin E, Caan BJ, Boroian A, Mourtzakis M. Screening for low muscularity in colorectal cancer patients: A valid, clinic-friendly approach that predicts mortality. J Cachexia Sarcopenia Muscle 2018;9:898-908.
Sun G, Li Y, Peng Y, Lu D, Zhang F, Cui X, et al
. Can sarcopenia be a predictor of prognosis for patients with non-metastatic colorectal cancer? A systematic review and meta-analysis. Int J Colorectal Dis 2018;33:1419-27.
Tamagawa H, Aoyama T, Iguchi K, Fujikawa H, Sawazaki S, Sato T, et al
. Preoperative evaluation of skeletal muscle mass in the risk assessment for the short-term outcome of elderly colorectal cancer patients undergoing colectomy. Mol Clin Oncol 2018;8:779-84.
Chen WZ, Chen XD, Ma LL, Zhang FM, Lin J, Zhuang CL, et al
. Impact of visceral obesity and sarcopenia on short-term outcomes after colorectal cancer surgery. Dig Dis Sci 2018;63:1620-30.
Kroenke CH, Prado CM, Meyerhardt JA, Weltzien EK, Xiao J, Cespedes Feliciano EM, et al
. Muscle radiodensity and mortality in patients with colorectal cancer. Cancer 2018;124:3008-15.
Brown JC, Caan BJ, Meyerhardt JA, Weltzien E, Xiao J, Cespedes Feliciano EM, et al
. The deterioration of muscle mass and radiodensity is prognostic of poor survival in stage I-III colorectal cancer: A population-based cohort study (C-SCANS). J Cachexia Sarcopenia Muscle 2018;9:664-72.
Motoori M, Fujitani K, Sugimura K Miyata H, Nakatsuka R, Nishizawa Y, et al
. Skeletal muscle loss during neoadjuvant chemotherapy is an independent risk factor for postoperative infectious complications in patients with advanced esophageal cancer. Oncology 2018;95:281-7.
Sandini M, Patino M, Ferrone CR, Alvarez-Pérez CA, Honselmann KC, Paiella S, et al
. Association between changes in body composition and neoadjuvant treatment for pancreatic cancer. JAMA Surg 2018;153:809-15.
Nyers ES, Brothers TE. Perioperative psoas to lumbar vertebral index does not successfully predict amputation-free survival after lower extremity revascularization. J Vasc Surg 2017;66:1820-5.
Paknikar R, Friedman J, Cron D, Deeb GM, Chetcuti S, Grossman PM, et al
. Psoas muscle size as a frailty measure for open and transcatheter aortic valve replacement. J Thorac Cardiovasc Surg 2016;151:745-51.
Jones KI, Doleman B, Scott S, Lund JN, Williams JP. Simple psoas cross-sectional area measurement is a quick and easy method to assess sarcopenia and predicts major surgical complications. Colorectal Dis 2015;1:O20-6.
Heymsfield SB, Gonzalez MC, Lu J, Jia G, Zheng J. Skeletal muscle mass and quality: Evolution of modern measurement concepts in the context of sarcopenia. Proc Nutr Soc 2015;74:355-66.
Lippi G, Sanchis-Gomar F, Montagnana M. Biological markers in older people at risk of mobility limitations. Curr Pharm Des 2014;20:3222-44.
Rutten IJ, Ubachs J, Kruitwagen RF, van Dijk DP, Beets-Tan RG, Mssuger LF, et al
. The influence of sarcopenia on survival and surgical complications in ovarian cancer patients undergoing primary debulking surgery. Eur J Surg Oncol 2017;43:717-24.
Mourtzakis M, Prado CM, Lieffers JR, Reiman T, McCargar LJ, Baracos VE. A practical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care. Appl Physiol Nutr Metab 2008;33:997-1006.
Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al
. Definition and classification of cancer cachexia: An international consensus. Lancet Oncol 2011;12:489-95.
Cao Q, Xiong Y, Zhong Z, Ye Q. Computed tomography-assessed sarcopenia indexes predict major complications following surgery for hepatopancreatobiliary malignancy: A meta-analysis. Ann Nutr Metab 2018;74:24-34.
Deng HY, Hou L, Zha P, Huang KL, Peng L. Sarcopenia is an independent unfavorable prognostic factor of non-small cell lung cancer after surgical resection: A comprehensive systematic review and meta-analysis. Eur J Surg Oncol 2018;45:728-35.
Ratnayake CB, Loveday BP, Shrikhande SV, Windsor JA, Pandanaboyana S. Impact of preoperative sarcopenia on postoperative outcomes following pancreatic resection: A systematic review and meta-analysis. Pancreatology 2018;18:996-1004.
Sandini M, Pinotti E, Persico I, Picone D, Bellelli G, Gianotti L. Systematic review and meta-analysis of frailty as a predictor of morbidity and mortality after major abdominal surgery. BJS Open 2017;1:128-37.
Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyère O, Cederholm T, et al
. Sarcopenia: Revised European consensus on definition and diagnosis. Age Ageing 2019;48:16-31.
Fielding RA, Vellas B, Evans WJ, Bhasin S, Morley JE, Newman AB, et al
. Sarcopenia: An undiagnosed condition in older adults. Current consensus definition: Prevalence, etiology, and consequences. International working group on sarcopenia. J Am Med Dir Assoc 2011;12:249-56.
Chen LK, Liu LK, Woo J, Assantachai P, Auyeung TW, Bahyah KS, et al
. Sarcopenia in Asia: Consensus report of the Asian working group for sarcopenia. J Am Med Dir Assoc 2014;15:95-101.
Kurk SA, Peeters PHM, Dorresteijn B, de Jong PA, Jourdan M, Kuijf HJ, et al
. Impact of different palliative systemic treatments on skeletal muscle mass in metastatic colorectal cancer patients. J Cachexia Sarcopenia Muscle 2018;9:909-19.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]