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ORIGINAL ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 6  |  Page : 1525-1529

Correlation of skeletal muscle depletion with acute toxicities for cervical cancer patients undergoing concurrent chemoradiation: A prospective study


1 Department of Radiation Oncology, MS Ramaiah Medical College and Hospital, Bengaluru, Karnataka, India
2 Department of Radio Diagnosis, MS Ramaiah Medical College and Hospital, Bengaluru, Karnataka, India

Date of Submission14-Sep-2020
Date of Decision08-Jul-2021
Date of Acceptance15-Oct-2021
Date of Web Publication19-Jul-2022

Correspondence Address:
Manur Janaki Gururajachar
Department of Radiation Oncology, MS Ramaiah Medical College and Hospital, Bengaluru - 560 054, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1353_20

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 > Abstract 


Context: Pelvic radiation with concurrent chemotherapy is associated with toxicities that worsen the cachectic state of the patient.
Aims: The aim of this study is to quantify skeletal muscle changes on computed tomography (CT) images helps in assessing the same which could be correlated with the toxicities.
Settings and Design: The study design was s prospective study.
Subjects and Methods: Forty-one patients were treated with chemoradiation followed by brachytherapy (BT) for cervical cancer. Preexternal beam and preBT CT scans were used to assess skeletal muscle index (SMI). The changes in the SMI were correlated with enteritis, dyselectrolytemia, and hematological toxicities.
Statistical Analysis Used: Paired t-test was used to compare pre- and post-treatment SMI. Chi-square test would be used to study the association between toxicity and SMI change.
Results: The mean SMI was 57.41 cm2/m2 (42.5–73) in the preexternal beam radiotherapy (EBRT) scans and 54.5 cm2/m2 (40.9–71.07) in the post-EBRT scans. Twenty-two patients (53.7%), 14 patients (34.1%), and five patients (12.2%) belonged to <5%, 5%–10%, and >10% loss in SMI groups, respectively. Grade III enteritis was seen in 31.7% of the patients, hyponatremia in 26.8% of the patients in the 4th week, and leukopenia and neutropenia were seen in 26.8% of cases in the 5th week. Enteritis correlated significantly with the change in SMI (P = 0.047).
Conclusion: Patients with cancer cachexia are at higher risk for radiation enteritis during chemoradiation for cervical cancer.

Keywords: Cervical cancer, chemoradiation, skeletal muscle depletion


How to cite this article:
Kumar SA, Gururajachar MJ, Martin VP. Correlation of skeletal muscle depletion with acute toxicities for cervical cancer patients undergoing concurrent chemoradiation: A prospective study. J Can Res Ther 2022;18:1525-9

How to cite this URL:
Kumar SA, Gururajachar MJ, Martin VP. Correlation of skeletal muscle depletion with acute toxicities for cervical cancer patients undergoing concurrent chemoradiation: A prospective study. J Can Res Ther [serial online] 2022 [cited 2022 Dec 2];18:1525-9. Available from: https://www.cancerjournal.net/text.asp?2022/18/6/0/351393




 > Introduction Top


Concurrent chemoradiation (CCRT) is the gold standard treatment for locally advanced cervical cancer with Cochrane meta-analysis showing an overall and disease-free survival (DFS) benefit of 10 and 13%, respectively, at 5 years.[1] Pelvic radiation causes varying grades of acute enteritis that lead to dehydration, electrolyte imbalance, and cisplatin increases these toxicities. Most nonhematological acute Grade III and four toxicities are considerably more common with CCRT than radiotherapy alone (28% vs. 1.5%). Gastrointestinal (GI) toxicity is twice common (8% vs. 4%) with 8% of the patients in the CCRT group suffering severe or life-threatening adverse events.[2] These well-documented toxicities and their management have been standardized in the present-day scenario.

Cancer cachexia is defined as a multifactorial syndrome characterized by an ongoing loss of skeletal muscle (SM) mass. Once cachexia sets in, the body tries to compensate by utilizing other sources of energy such as SM and adipose tissue. Sarcopenia is muscle mass depletion that happens due to physiological changes in the SM mass due to tumor growth[3] which worsens due to cancer treatment to varying degrees. Anticancer drugs cause muscle wasting directly through activation of the nuclear factor kappa B (NF-kB) pathway or indirectly through production of proinflammatory cytokines such as interleukin (IL)-1b, IL-6, and tumor necrosis factor or by inducing oxidative stress and tissue injury.[4]

On computed tomography (CT), each tissue has a specific radiation attenuation which is measured in absolute numbers in Hounsfield Units (HU). There are different ranges used by various authors, but most common values for nonvisceral intramuscular fat ranges from −190 to −30 and muscle ranges from −29 to +150. Thus, the differentiation of fat and muscle is possible.[5] Sarcopenia can be detected on CT scans and has been studied as a biomarker of cachexia in cancers of ovary by Aust,[6] head and neck by Grossberg et al.,[7] pancreas by Choi et al.,[8] rectum by Choi et al.,[9] and cervix by Kiyotoki et al.[10] Grossberg et al. in their study on head-and-neck cancer patients receiving chemoradiation found that the sarcopenia almost doubled at 68 months of treatment with those who were sarcopenic at the beginning were older and had shorter survival.

CT scans not only have a place in staging of cervical cancer but also are routinely used during teletherapy as well as brachytherapy (BT) planning. Modern image-based estimations of the total SM cross-sectional area in abdominal cross-sectional CT images at the L3 level can be used to measure and when normalized to the height of the patient will provide the SM index (SMI) which is more an accurate measure of sarcopenia than loss of weight alone.[11]

Kiyotoki et al. have used the same principle and observed that >15% change in SMI is an important poor prognostic factor in patients with cervical cancer undergoing CCRT.[10]

The present study was designed to look into the changes in the SM mass with CTRT. In addition, we tried to correlate the change in SMI with acute toxicities.


 > Subjects and Methods Top


Biopsy-proven nonmetastatic locally advanced cases of cervical cancer treated between January 2018 and December 2019 were included in the study after getting institutional ethical clearance SS-1/EC/071/2017 and informed consent. Sample size estimation was based on the work by Aust et al. who studied SM mass loss as a prognostic factor. Expecting a change of 7.5% after treatment and with a 95% confidence level, 80% power, with 0.46 effect size, the study required a minimum of 39 participants. Considering 5% loss to follow-up, we accrued 41 participants.[6]

All patients underwent clinical examination and FIGO staging with a punch biopsy from the cervical growth followed by contrast-enhanced CT scan of thorax, abdomen, and pelvis. All patients underwent CT simulation before external beam radiotherapy (pre-EBRT) and were treated with three-dimensional (3D) conformal technique to dose of 45 Gy/25 Fr with concurrent weekly cisplatin at 40 mg/m2. Gross nodal disease was boosted up to 54 Gy using simultaneous integrated boost with field in field plans. This was followed 10–15 days later by CT-guided remote high dose rate BEBIG after loading cobalt-based BT. Four fractions of 6.5 Gy each were given over 2 days in a single application with 6 h gap between 2 Fr and 2 Fr per day. The dose was prescribed to high-risk clinical target volume including the entire cervix and additional disease at the time of BT. On examination under anesthesia at the time of BT, those who had disease confined to cervix, medial one-third of parametrium and upper one-third of vagina received intracavitary while disease beyond were treated with interstitial BT.

Weekly monitoring of toxicities such as enteritis, dyselectrolytemia, and hematological toxicities were done as per the Common Toxicity Criteria of Adverse Events 4.03 and the maximum grade for the week was documented. Patients developing Grade III or above toxicities were managed conservatively and based on physician discretion, a gap in radiation schedule or postponement of the scheduled chemotherapy were considered.

Using OSIRIX application, the following muscles were marked on a single axial cross-sectional preEBRT image at the L3 level for cross-sectional area calculation: Rectus abdominus, abdominal (lateral and oblique), psoas, and paraspinal (quadratus lumborum, erector spinae) in the abdominal window. A predefined HU ranging from −190 to −30 HU is used to demarcate intermuscular adipose tissue and −29 HU to 150 HU for muscle tissue. Total cross-sectional muscle area (cm2) was determined for the identified muscles and the area identified as fat was highlighted and subtracted from it on the CT slices as depicted in [Figure 1]. The muscle area was normalized for height and reported as lumbar SMI (cm2/m2). The same was repeated on the preBT images and the change in SMI was documented. Patients with an SMI of < 39 cm2/m2 were labeled sarcopenic and the change in SMI was quantified as < 5%, 5%–10%, and more than 10%, which was correlated with toxicities during the treatment course.
Figure 1: Contoured abdominal muscles and the fat as shaded areas at L3 in the pre-EBRT CT scan and pre-BT CT scan. EBRT = External beam radiotherapy, CT = Computed tomography, BT = Brachytherapy

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Statistical analysis

Descriptive statistics of SMI were analyzed and summarized in terms of mean with standard variation. Microsoft Excel was used to generate the graphs and tables. Analysis was performed using the SPSS software version 20.0 (IBM Corp., Armonk, NY, USA). A P < 0.05 was considered statistically significant. Paired t-test was used to compare pre-and post-treatment SMI. Pearson's correlation test was used to study the association between toxicity and SMI change.


 > Results Top


Forty-one patients were the participants of this prospective study. The patient and tumor characteristics are as shown in the [Table 1]. All our patients had normal albumin at preEBRT and preBT assessment. All patients completed radiation schedule as planned. Out of the planned five weekly cisplatin chemotherapy, 19 (46.3%) received the entire course of five weekly doses, 22 (53.7%) patients received four cycles of weekly cisplatin, and all patients received minimum of three cycles. Fifth cycle was avoided in seven patients due to Grade III hematology toxicities and three patients due to Grade III enteritis. The remaining patients did not complete all five cycles due to logistic issues.
Table 1: Patient characteristics

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The mean overall treatment time in our group of patients was 49.22 days (ranging between 43 and 56 days). The mean treatment duration for EBRT was 37 days (32-44). Two patients were given a gap of 2 days in view of Grade III enteritis. Five patients had pelvic lymphadenopathy of maximum size 2 cm on CT scan. The nodes were treated up to 54 Gy. None of the patients had paraaortic lymphadenopathy and no patients were treated with elective nodal irradiation.

The mean body mass index (BMI) was 23.48 kg/m2 (range 15.03–31.0) in the pre-EBRT assessment and 22.55 kg/m2 (range 14.68–30.86) in the preBT assessment. Three patients were classified as obese (>30 kg/m2) in the pre-EBRT as well as during the preBT assessment out of whom one patient had an increase in BMI (30.86 vs. 30.09). These patients showed an 8% change in SMI but the change in BMI for obese patients was almost nil in two cases and it had increased in one patient.

The mean SMI was 57.41 cm2/m2 (42.5–73) in the pre-EBRT scan and 54.5 cm2/m2 (40.9–71.07) in the pre-BT scan. None of our patients were sarcopenic at presentation. Twenty-two patients (53.7%), 14 patients (34.1%), and five patients (12.2%) belonged to 5%, 5%–10%, and >10% loss in SMI, respectively.

There were 11 patients who were above the age of 60 years. The mean SMI was 53.83 cm2/m2 (42.5–69.5) and 58.73 cm2/m2 (46.5–72.9) in the pre-EBRT scan and the mean SMI in the pre-BT scan in them. The same for patients <60 years was 52.11 cm2/m2 (40.9–67.03) and 55.26 cm2/m2 (43.02–71.1), respectively. When age was correlated with the change in SMI, the age group of more than 60 years had a significant SMI loss with a P = 0.042. For patients <60 years the correlation was not significant with a P = 0.554.

Toxicities

Thirteen patients (31.70%) were found to have Grade III or above enteritis at 4th week and seven (17.07%) patients at 5th week, respectively, with the maximum number of patients showing at week 4.

Maximum grade of hyponatremia was Grade III and seen during 4th week of treatment in 11 (26.8%) of patients. None of the patients had a Grade III hypokalemia. Weekly assessment of patients during EBRT with complete blood counts revealed none of the patients as having a hemoglobin level of <10% gm and platelet count of <100,000 during the entire course of treatment. Grade III leukopenia and neutropenia were noted in four patients during week 4 and 11 (26.8%) patients during week 5, with the maximum number of patients showing at week 5.

When toxicities were correlated with SMI loss, Grade III and above enteritis was associated with SMI loss with a P = 0.047 value, whereas the dyselectrolytemia and hematological toxicities had no significant correlation with P = 0.581 and 0.509, respectively, as shown in [Table 2].
Table 2: Correlation of sarcopenia with Grade III acute toxicities of concurrent cardiotoxicity of radiation therapy

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 > Discussion Top


This is a prospective study correlating the change in SMI with tolerance to chemoradiation for patients with cervical cancer. Similar studies have been done in head-and-neck cancer by Grossberg et al.,[7] pancreatic cancer by Choi et al.,[8] hepatocellular carcinoma by Sochi Iritani et al.,[12] Ovarian cancer by Aust et al.,[6] rectal cancer by Choi et al.,[9] and in cervical cancer by Kiyotoki et al.[10]

We correlated the change in SMI with acute toxicities (enteritis, dyselectrolytemia, and hematological) encountered during the course of treatment, whereas most others have analyzed the impact of sarcopenia on long-term outcomes in addition to acute toxicities, Kiyotoki et al. have looked into the long-term overall survival (OS) and DFS.[10]

Different methods of studying sarcopenia are used in various studies such as CT/magnetic resonance images, dual-energy absorptiometry, and bioelectrical impedance.[13] Since CT imaging is a part of radiation treatment, using CT-based measurement becomes a cost-effective tool in developing countries.

In our study, patients were treated with 3D-CRT technique to a dose of 45 Gy/25 Fr with weekly cisplatin while Kiyotoki et al. used four-field box technique to a dose of 50 Gy/25 Fr along with a variable chemotherapy regimen. Enteritis was seen in 31.7% of our patients, whereas they observed it in 16.7% of their cases. Hyponatremia, neutropenia, and leukopenia were seen by them in 8.3%, 23.3%, and 20% of patients, while the same was 26.8%, 26.8%, and 26.8%, respectively, in our study.[10] Higher incidence of toxicities (enteritis and hyponatremia) in our study can be attributed to the weekly review, whereas theirs was a retrospective analysis and probably represents maximum grade during the entire course. The other possible reason could be related to the nutritional aspect which we have not looked into. We also observed that bladder protocol compliance was difficult for patients once enteritis sets in and this could have included more of bowel in the irradiated volume. In our earlier study, we had measured urine output and correlated with enteritis and there was a 21% reduction in the bladder volume during the last week of radiation which significantly correlated with the Grade III enteritis (P < 0.001).[14]

The mean pretreatment SM area was 90.29 cm2 and the posttreatment SM area 84.20 cm2 in their study, whereas in our study, the SM area was normalized to height and documented as SMI; the mean pretreatment SMI was 57.41 cm2/m2 and the posttreatment SMI was 54.5 cm2/m2. The mean difference in SM loss before and after the treatment was similar in both studies (6.7% vs. 7.4%).

None of our patients were sarcopenic at presentation and more than half (53.65%) of our patients had <5% loss in SMI with CCRT. None of our patients had a loss of more than 15% in SMI, whereas their patients had an SMI loss of >15% in 15% of their patients probably due to the variable chemotherapy regimen. The radiation technique was 3D-CRT in our patients compared to four-field box technique which irradiates a larger field as well as a higher dose of 50 Gy in 25 Fr for EBRT.

Kiyotoki et al. observed that significant (P = 0.001) loss of more than 15% of SM area was associated with higher toxicity as well as lower long-term OS (P = 0.002) and DFS (P = 0.002). It was similar in our observation, and we correlated the loss of SMI with acute toxicity only.[10] In our study, none of the patients had loss of more than 15%.

Aust et al. observed that those who were sarcopenic at presentation did not achieve optimal cytoreduction compared to their nonsarcopenic counterparts, 57.1% versus 64% in (P = 0.046).[6] Similarly, Choi et al. studied the association of sarcopenia at presentation with OS and DFS in rectal cancer patients and observed that sarcopenia was negatively associated with OS (P = 0.013) with no effect on DFS, whereas the toxicities were seen in nonsarcopenic and sarcopenic patients at presentation were similar.[9]

Grossberg et al. studied the effects of SM depletion with long-term outcomes in head-and-neck cancers treated with radiation and observed that OS was negatively associated with SMA depletion (P = 0.007).[7]

In a study similar to ours, Hirofumi et al. studied tumor characteristics and long-term outcome in 236 patients of cervical cancer undergoing CCRT comparing to pretreatment SMI. They observed that pretreatment SMI correlated to parametrical involvement (P = 0.002); however, long-term outcome did not have any correlation.[15] We studied the change in the SMI with treatment whereas the compared with pretreatment SMI only.

All our patients had normal serum albumin at pre-EBRT and pre-BT assessment while Kiyotoki et al. found grade one hypoalbuminemia was much frequently seen in patients who exhibited more than 15% loss. However, we did not have any patients with more than 15% loss in SMI.[10]

We had an interesting observation while looking at BMI, SMI loss, and enteritis which was the only factor to have a significant correlation. While SMI loss correlated with Grade III enteritis, there was no BMI loss in three patients who had Grade III enteritis but had around 8% loss in SMI. Hence, we predict that SMI loss is a better indicator for toxicity than BMI loss; however, the patient number is very less and hence to be taken cautiously.

The strength of our study is that it is a prospective study and our study is the first of its kind being done on the Indian population and in one of the most common malignancies in our country. The limitations are that it has a small sample size and there are various other methods of assessing sarcopenia which have not been studied in the present study. Furthermore, long-term follow-up is required to study further correlation with the outcomes. Further work should probably focus on when to assess the SM changes, where does it stand with reference to other available biomarkers, and its relevance to patient management.


 > Conclusion Top


Evaluation of SM depletion is cost effective as CT scans are part of the treatment planning process. Loss in SMI is an additional factor contributing to Grade III enteritis in cervical cancer patients undergoing CTRT. Close monitoring, prevention, and timely treatment of enteritis may reduce sarcopenia which probably translates to a better long-term outcome.

Acknowledgment

We would like to acknowledge the help received by our statistician Mr. Shivaraj Assistant Professor, department of community medicine.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Green J, Kirwan J, Tierney J, Vale C. Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix. Cochrane Database Syst Rev 2005;20:CD002225.  Back to cited text no. 1
    
2.
Kirwan JM, Symonds P, Green JA, Tierney J, Collingwood M, Williams CJ. A systematic review of acute and late toxicity of concomitant chemoradiation for cervical cancer. Radiother Oncol 2003;68:217-26.  Back to cited text no. 2
    
3.
Fearon KC, Glass DJ, Guttridge DC. Cancer cachexia: Mediators, signaling, and metabolic pathways. Cell Metab 2012;16:153-66.  Back to cited text no. 3
    
4.
Pin F, Couch ME, Bonetto A. Preservation of muscle mass as a strategy to reduce the toxic effects of cancer chemotherapy on body composition. Curr Opin Support Palliat Care 2018;12:420-6.  Back to cited text no. 4
    
5.
Aubrey J, Esfandiari N, Baracos VE, Buteau FA, Frenette J, Putman CT, et al. Measurement of skeletal muscle radiation attenuation and basis of its biological variation. Acta Physiol (Oxf) 2014;210:489-97.  Back to cited text no. 5
    
6.
Aust S, Knogler T, Pils D, Obermayr E, Reinthaller A, Zahn L, et al. Skeletal muscle depletion and markers for cancer cachexia are strong prognostic factors in epithelial ovarian cancer. PLoS One 2015;10:e0140403.  Back to cited text no. 6
    
7.
Grossberg AJ, Chamchod S, Fuller CD, Mohamed AS, Heukelom J, Eichelberger H, et al. Association of body composition with survival and locoregional control of radiotherapy-treated head and neck squamous cell carcinoma. JAMA Oncol 2016;2:782-9.  Back to cited text no. 7
    
8.
Choi Y, Oh DY, Kim TY, Lee KH, Han SW, Im SA, et al. Skeletal muscle depletion predicts the prognosis of patients with advanced pancreatic cancer undergoing palliative chemotherapy, independent of body mass index. PLoS One 2015;10:e0139749.  Back to cited text no. 8
    
9.
Choi MH, Oh SN, Lee IK, Oh ST, Won DD. Sarcopenia is negatively associated with long-term outcomes in locally advanced rectal cancer. J Cachexia Sarcopenia Muscle 2018;9:53-9.  Back to cited text no. 9
    
10.
Kiyotoki T, Nakamura K, Haraga J, Omichi C, Ida N, Saijo M, et al. Sarcopenia is an important prognostic factor in patients with cervical cancer undergoing concurrent chemoradiotherapy. Int J Gynecol Cancer 2018;28:168-75.  Back to cited text no. 10
    
11.
Martin L, Birdsell L, Macdonald N, Reiman T, Clandinin MT, McCargar LJ, 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;31:1539-47.  Back to cited text no. 11
    
12.
Iritani S, Imai K, Takai K, Hanai T, Ideta T, Miyazaki T, et al. Skeletal muscle depletion is an independent prognostic factor for hepatocellular carcinoma. J Gastroenterol 2015;50:323-32.  Back to cited text no. 12
    
13.
Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, et al. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing 2010;39:412-23.  Back to cited text no. 13
    
14.
Bandanatham S, Gururajachar JM, Somashekar MK. Compliance with bladder protocol during concurrent chemoradiation for cancer of the cervix and its impact on enteritis: A prospective observational study. Rep Pract Oncol Radiother 2018;23:69-74.  Back to cited text no. 14
    
15.
Hirofumi M, Keiichiro N, Yuko M, Naoyuki I, Takeshi N, Chikako O, et al. Sarcopenia is not a prognostic factor of outcome in patients with cervical cancer undergoing concurrent chemoradiotherapy or radiotherapy. Anticancer Res 2019;39:933-9.  Back to cited text no. 15
    


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