Association Between Cancer Cachexia and Prognosis in Patients with Head and Neck Squamous Cell Carcinoma Who Received Chemoradiotherapy


 Objectives: This retrospective observational study is conducted to evaluate the association between cancer cachexia and prognosis in head and neck cancer patients treated with chemoradiotherapy using skeletal muscle mass index at the level of the third lumbar vertebra with computed tomography.Methods: Two hundred forty-two patients were enrolled and categorized into the following four groups based on cancer cachexia criteria and treatment setting: definitive chemoradiotherapy with cachexia, definitive chemoradiotherapy without cachexia, adjuvant chemoradiotherapy with cachexia, and adjuvant chemoradiotherapy without cachexia. Progression-free survival (PFS) and overall survival (OS) between cachexia and non-cachexia groups were compared by treatment setting using the long-rank test. Prognostic factors were evaluated using the Cox proportional hazards model.Results: Fifty patients were diagnosed with cancer cachexia (20.7%). In the definitive setting, both PFS and OS were significantly shorter in the cachexia group (median PFS, 15.5 months vs. not reached, p < 0.01; median OS, 48.4 months vs. not reached. p < 0.01). Conversely, there was no significant difference between the two groups in the adjuvant setting. UICC Stage IV, base of albumin of <4, and cachexia were significant poor prognostic factors in the definitive setting. However, no prognostic factors were detected in the adjuvant setting.Conclusion: Cancer cachexia was negatively related with prognosis in patients with head and neck squamous cell carcinoma who received definitive chemoradiotherapy. Nutritional intervention during chemoradiotherapy may improve survival in these patients. Further research is warranted.


Introduction
Head and neck cancer (HNC) was the seventh most common cancer worldwide in 2018, accounting for 3% of all cancer types [1].
Although risk factors for HNC are not completely understood, several different factors such as smoking, alcohol, diet, and chronic viral infection, including human papillomavirus-associated oropharyngeal carcinoma, have been reported to increase its risk [2][3] [4]. Conversely, several factors, such as improvement in lifestyle, reduce the risk of cancer.
Sarcopenia has been recognized to be an important prognostic factor in various types of cancer [5]. It is characterized as an age-related decline in muscle mass and strength, as opposed to increased muscle fat in ltration associated with frailty or poor physical function[6] [7] [5]. Sarcopenia is associated with negative outcomes such as higher risk for falls, loss of independence, hospitalization, and death [5]. It has also been associated with poor prognosis or severe toxicity in cancer patients with chemotherapy [8], and has no universal treatment [9]. However, both resistance treatment and aerobic exercise can increase muscle strength and reduce negative outcomes in general [10].
Patients with cancer also have a risk of decline of skeletal muscle mass via cachexia-a multifactorial disease in which skeletal muscle mass declines owing to systemic in ammation [11]; cachexia has also been recognized to be associated with hippocratic facies [12] [13]. It is caused by the activation of cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interferon-γ (IF-γ) [14], leading to a decline in protein synthesis and increase in proteolysis and lipolysis, frequently occurring in solid tumors, particularly gastric, pancreatic, lung, and Page 4/15 HNC cancers [15]. Cachexia is often present in patients with head and neck squamous cell carcinoma (HNSCC) and progresses during chemoradiotherapy, which is administered for a few months. Diagnosis is based on one of the following criteria: 1) weight loss of > 5% in 6 months (in the absence of simple starvation); 2) body mass index (BMI) of < 20 and weight loss of > 2%; 3) sarcopenia and weight loss of > 2% [11]. Thus, cachexia can be considered sarcopenia plus malnutrition.
Although cachexia can re ect conditions other than sarcopenia in patients with cancer, few reports associated with cachexia and prognosis. In this study, we evaluated the association between cachexia and prognosis in patients with HNSCC who received chemoradiotherapy.

Patients
We retrospectively analyzed prospectively collected data from consecutive patients with HNSCC who were initiated with concurrent chemoradiotherapy (CCRT) with cisplatin at the Cancer Institute Hospital of Japanese Cachexia was diagnosed as previously described [16]. We analyzed CT images, including the CT component of whole-body PET-CT scans, at the level of the third lumbar vertebra (L3). Skeletal muscle mass area was calculated using the Volume Analyzer SYNAPSE VINCENT image analysis system (Fuji lm Medical, Tokyo, Japan) [17].
The skeletal muscle mass index (SMI) which normalizes skeletal muscle area adjusted by height was used as an indicator of sarcopenia [8]. The cross-sectional area of skeletal muscle at L3 was measured using the SYNAPSE VINCENT with Houns eld unit thresholds of − 30 to + 150. After segmentation, minor manual measurements were performed as required. Sarcopenia was diagnosed with reference to Martin's cut-off value: SMI of < 43 cm 2 /m 2 for men with BMI < 25 kg/m 2 or < 53 cm 2 /m 2 for men with BMI ≥ 25 kg/m 2 and < 41 cm 2 /m 2 for women [18].
Cisplatin was administered at a dose of 80 mg/m 2 (from 2012 to August 2015) or 100 mg/m 2 (from August 2015 to 2018) every 3 weeks for a total of three cycles. Elderly patients and those with reduced organ function received a reduced cisplatin dose according to the discretion of their physician. If one or more severe adverse events were observed during the CCRT, a skip, delay, or dose reduction of the second or third cisplatin cycle was permitted.
Radiotherapy was performed as 3-dimensional conformal radiotherapy (3D-CRT) or intensity-modi ed radiotherapy (IMRT) with the conventional fraction, 2-2.12 Gy per fraction, once per day, ve times per week.
Prophylactic percutaneous endoscopic gastrostomy was performed unless particular reasons forbid it (such as refusal by the patient or past history of gastrectomy). Follow-up examinations using enhanced CT and measurements of blood biochemistry and serum tumor markers were performed approximately every 3 months after CCRT.

Statistical analysis
Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and logrank test. Data were censored on January 31, 2021. Patients who were lost to follow-up were censored at the date of last contact or follow-up. PFS was calculated from the date of radiation initiation to the date of disease relapse, disease progression or death from any cause. OS was calculated from the date of radiation initiation to the date of death from any cause. Patients who were alive on January 31, 2021 were censored for OS analysis. We estimated survival curves by de nitive or adjuvant CCRT using the Kaplan-Meier method and log-rank test. We performed univariate and multivariate analyses to estimate factors potentially prognostic for PFS and OS by calculating hazard ratios (HRs) using the Cox proportional hazards model. The level of signi cance was set at p value of < 0.1 for univariate analysis and of < 0.05 for multivariate analysis, which was two-sided. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a modi ed interface for R software (www.r-project.org) [19].  Table 1. The median interval between CT imaging and initial chemotherapy was 34 days (range: 1-235). In the de nitive CCRT setting, the groups with cachexia and without cachexia signi cantly differed in PS and base of albumin. In the adjuvant CCRT setting, the two groups showed no difference. Risk factor of prognosis In the de nitive CCRT setting, multivariate Cox proportional hazard analysis indicated that the stage (HR, 2.33; 95%CI, 1.25-4.36; p < 0.01*), base of albumin (HR, 3.11; 95%CI, 1.77-5.49; p < 0.01*), and cachexia (HR, 2.52; 95%CI, 1.35-4.72; p < 0.01*) were independent risk factors for PFS. Independent risk factors for poor OS were stage (HR, 2.58; 95%CI, 1.14-5.80; p = 0.02*), base of albumin (HR, 4.18; 95%CI, 2.05-8.53; p < 0.01*), and cachexia (HR, 3.30; 95%CI, 1.54-7.05; p < 0.01*). Analysis by adjuvant CCRT setting revealed no independent predictive factors ( Table 2, Table 3).

Adverse events
The frequency of grade 3-4 adverse events is presented in Table 3. In de nitive CCRT, all adverse events were strongly associated with cachexia. Among the grade 3-4 adverse events, the frequency of anemia and leukopenia had signi cant difference between the two groups (20% and 1.4%, p < 0.01, 60% and 34.7%, p < 0.01, respectively).
In the adjuvant CCRT setting, there were no signi cant differences in the frequency of severe adverse events.

Discussion
We investigated the association between cancer cachexia and prognosis in patients with HNSCC who received chemoradiotherapy. The results demonstrated that cachexia was an independent predictor of poor prognosis, particularly in the de nitive setting. Grade 3-4 adverse events occurred more frequently in patients with cachexia.
As mentioned above, skeletal muscle mass may decrease in patients with cancer via two mechanisms: sarcopenia and cachexia. Sarcopenia has also been previously reported as an indicator of poor prognosis of HNC [20] [21]. Sarcopenia is related to age, and reports show that aerobic exercise may be a feasible and effective therapy [22] [10]. Conversely, cachexia results from in ammation and malnutrition due to cancer. In patients with HNSCC receiving de nitive CCRT, decreased oral nutrition may result from complex factors, including tumor site and toxicity owing to chemoradiotherapy, which may lead to cachexia. The prevalence of cachexia is high in HNC, and its prevention is important for patients with HNC who received chemoradiotherapy.
To our knowledge, this is the rst study with a large sample size to evaluate the in uence of cachexia in patients with HNSCC who received chemoradiotherapy. Our ndings showed that cachexia is an important prognostic factor regardless of stage and that ongoing nutritional intervention before CCRT may improve prognosis.
Recently, in Japan, anamorelin-a high-a nity, selective agonist of the ghrelin receptor-was approved for the treatment of cachexia in patients with non-small-cell lung carcinoma, gastric cancer, pancreatic cancer, and colorectal cancer but not in those with HNC [23]. Thus, nutritional intervention may be one of the most effective approaches for the early stage of cachexia in HNSCC. However, several reports that evaluated the effects of nutritional intervention have failed to show any improvement for survival in HNSCC as setting of both de nitive and adjuvant chemotherapy [24]. Although nutritional status appears to improve with dietary counseling, megestrol acetate, and prophylactic enteral tube feeding, there is no evidence that nutritional intervention can improve prognosis of patients with HNC[25][26] [27]. However, these studies include few patients treated with chemotherapy; the results are limited; thus, further study in this area is warranted. Our data, at least, support the potential of a nutrition-based approach.
In this study, unlike several previous reports, we separately analyzed de nitive and adjuvant CCRT settings. As the standard treatment for HNSCC is surgery plus adjuvant CCRT (in cases at high risk for recurrence) or de nitive CCRT, several studies included both groups in their analysis.
Our study showed that cachexia was an independent prognostic factor in patients who received de nitive CCRT.
This may be because de nitive CCRT has a wide range of radiation, including cervical lymph nodes, causing patients to experience loss of oral intake.
Evaluation of cachexia in the adjuvant CCRT setting was di cult because its presence or absence was determined using preoperative abdominal CT imaging ndings. Postoperative imaging would have been more accurate; however, it provides no clinical bene t.
In sarcopenia, owing to reduced age-related changes in body composition, polar drugs that are mainly watersoluble tend to have smaller volumes of distribution, resulting in higher serum levels in sarcopenia.
Poor prognosis in elderly patients with cachexia may result from dose reduction owing to anticancer drug therapy [28]. In the same study, the frequency of grade 3-4 adverse events was high in cachexia. In our data, frequency of grade 3-4 some hematotoxicity were observed highly in cachexia, especially in de nitive CCRT. The frequency of other adverse events was low to begin with, so it was considered that there was no difference. It has been reported that cisplatin may improve prognosis at a total dose of ≥200 mg Our study has several limitations in being retrospective, based on data from a single-institution with potential selection bias and short follow-up duration. Manual skeletal mass measurement was sometimes necessary. However, in contrast to that in abdominal cavity cancer such as gastric cancer or pancreatic cancer, abdominal CT imaging is not routinely performed. Finally, because our electric medical records changed in 2018, we could not collect adverse events associated with nutrition, such as appetite loss or nausea. However, we consider our results meaningful.
We have retrospectively evaluated the association between cancer cachexia and prognosis in patients with HNSCC who received CCRT. Cachexia was an independent poor prognostic factor in patients with HNSCC who received de nitive CCRT. Ongoing nutritional intervention before CCRT can help improve survival. Further study is warranted.

Declarations
Ethics approval and consent to participate The requirement for informed consent was waived because data were reported anonymously. The study was approved by the Institutional Review Board of The Cancer Institute Hospital of JFCR (2021-1037). All procedures were performed in accordance with the ethical standards of the responsible committees on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and subsequent versions.
Funding: This research received no speci c grant from any funding agency in the public, commercial, or not-forpro t sectors.
Con icts of interest: All of the authors, except 5, report they have no con ict of interest to disclose. NH reports personal fees from TAIHO Pharmaceutical Co., Ltd. YS reports personal fees from ONO Pharmaceutical Co., Ltd., Bristol-Myers Squibb Company, MSD K.K., and TAIHO Pharmaceutical Co., Ltd. NF reports personal fees from Eisai. JT reports personal fees from Eisai. ST reports grants and personal fees from ONO Pharmaceutical Co., Ltd., Bristol-Myers Squibb, MSD, AstraZeneca, Chugai, and BAYER.
Data availability: The datasets generated and analyzed in this study are available from the corresponding author upon reasonable request   CONSORT diagram of this study