Diaphragm thickness, mobility and respiratory muscle strength in patients with head and neck cancer receiving chemoradiation therapy: A longitudinal pilot study

Introduction

Head and neck carcinoma (HNC) is a heterogeneous disease, encompassing a variety of tumors that originate in the hypopharynx, oropharynx, lip, oral cavity, nasopharynx, or larynx. Worldwide it represents the sixth most common neoplasia and accounts for 6% of all cases¹. Reported cases are more than 650,000 and 330,000 deaths annually. Men are affected more than women, with a ratio ranging from 2:1 to 4:1². In India HNC accounted for 30% of all the cancers out of which 60 to 80% of patients present with advanced disease in comparison to the 40% in developed countries³.

The etiology of HNC is primarily related to the major classical risk factors; cigarette smoking, tobacco consumption and alcohol abuse⁴. Signs and symptoms of the disease include hoarseness of voice, sore throat, tongue pain, mouth ulcer, dysphagia, mouth bleeding, cough, stridor and dyspnea⁵. Smoking, a common risk factor, causes an increase in oxidative stress and inflammatory fibrotic changes which leads to alterations in the respiratory function and diaphragm dysfunction as seen in patients with chronic obstructive pulmonary diseases (COPD)⁶. Similar features are also presented in HNC patients due to the common underlying factor. The incidence of pulmonary complications in this population is higher and they prolong the recovery of patients and further delay the span of rehabilitation⁷.

Clinically significant post-surgical pulmonary complications include atelectasis, bronchitis, pneumonia, respiratory failure, exacerbated lung disease and bronchospasm⁶. Pulmonary airway obstruction and impaired respiratory function with restrictive and obstructive pulmonary function test findings are also seen immediately after neck dissection surgeries⁸.

Chemoradiation has emerged as a radical treatment of choice in many medical centers which is accompanied by significant incidences of radiation induced toxicity which is a major cause of long-term disability during & after the treatment duration^9,10. Acute effects of chemo-radiation are completely reversible but late effects show damage to the renal, cardiac, hepatic, neuromuscular, musculoskeletal, and pulmonary systems¹¹.

Generalized peripheral muscle weakness that includes muscle wasting, cachexia and disuse muscle atrophy has proven to be an adverse effect of chemoradiation treatment (CRT), but this has not been studied in the respiratory muscle, specifically the diaphragm¹². A study published by Chauhan et al. in 2020, showed decrease in muscle mass, strength and physical activity among HNC patients during seven weeks of CRT. This decrease can cause changes in their metabolic process thereby leading to sarcopenia, which has now been linked to mortality in cancer¹³.

Pulmonary complications that are caused due to the long-standing chemoradiation treatment, led to inflammation and fibrotic changes followed by late fibro atrophic phase. These complications are characterized by damage to the parenchymal cells and gradual loss of type 2 pneumocytes, resulting in lung fibrosis and reduced respiratory functions¹⁴. CRT related toxicity also leads to higher rates of oral mucositis and administration of Ryle’s tube in HNC patients and thus an altered food intake among patients with HNC leads to lack of essential nutrition. Such reduction in essential nutrition amongst these patients causes changes in the muscle fiber diameter leading to peripheral muscle mass loss. This loss in muscle mass could also be seen in respiratory muscles as these patients do present with respiratory complications which thereby reduces their overall survival rate during CRT^14,15.

Although there is an upcoming body of research on sarcopenia in peripheral muscles there is limited information on respiratory muscle in terms of alterations in mobility, thickness and strength. Hence, we set out to discover if patients with HNC receiving CRT have any dysfunction in diaphragmatic mobility and thickness, in addition to other parameters like respiratory pressures and functional capacity that indicate the status of cardiopulmonary function in patients with head and neck cancer.

Methods

This was a pilot longitudinal study conducted from January 2019 to March 2020 among 12 patients with newly diagnosed head and neck cancer seeking chemoradiation and admitted to a tertiary care hospital in India. The sample size was time bound wherein all the patients referred to the oncologist in the mentioned time frame and who met the inclusion criteria were recruited. The study was approved by the Institutional Scientific Review Committee and Institutional Ethics Committee (IEC) of Kasturba Medical College, Mangalore with approval number IEC KMC MLR 11-18/411, in accordance with all their relevant guidelines and regulations. A written informed consent was obtained from all participants and their legal guardians to participate in the study. Eligibility for inclusion of patients was determined as being above 18 years of age, of both genders (male and female) and HNC stage III, IV, IVa, IVb receiving chemoradiation therapy. We excluded patients with HNC who have previously undergone a surgical treatment, metastatic HNC, patients with any artificial airways, any previous history of pulmonary complications, patients unable to perform the study procedure, any previous diaphragmatic dysfunction or neuromuscular diseases which could have an impact on the evaluation. Before the start of CRT, we recorded the demographic data and history of all the participants. We measured the diaphragm thickness, mobility, respiratory pressures and functional capacity at three different time points i.e., before the start of chemoradiation (baseline), at three weeks and at seven weeks (post chemoradiation).

Diaphragm mobility and thickness: The patients were asked to lie in a semi-recumbent position (bed inclination of 45°). Diaphragm mobility was evaluated by placing a convex transducer (3.5 MHz) pointing medially in the anterior subcostal region between the midclavicular and anterior axillary lines to visualize the posterior third of the hemi diaphragm with B-mode of the ultrasound. Then using the ultrasound M-mode the amplitude of diaphragmatic excursion was measured during quiet breathing and deep breathing. The average value of three consecutive measurements was recorded.

Diaphragm thickness was evaluated with ultrasound B-mode by placing the linear transducer from the middle of the pleural line to the middle of the peritoneal line over the diaphragm zone of apposition, close to the costophrenic angle between the right anterior and medial axillary lines. The thickness was measured at Functional Residual Capacity (FRC) and then at Total Lung Capacity (TLC) and the average value of three consecutive measurements was recorded^16,17.

Maximal respiratory pressures: This procedure was performed according to the guidelines of American Thoracic Society and the European Respiratory Society. The patients were asked to be in upright comfortable sitting position. Maximal inspiratory pressure (PImax) was measured by instructing the patient to perform maximal inspiration up to Total Lung Capacity (TLC), starting from residual volume (RV). Maximal expiratory pressure (PEmax) was measured by instructing the patient to perform maximal expiration starting from TLC. The averages of the pressures were measured and three measurements were taken over one minute interval. The highest value among the three was recorded¹⁸.

Functional capacity: Functional capacity was assessed using the six-minute walk test. The six-minute walk test protocol was performed according to the guidelines of American Thoracic Society¹⁹.

Data analysis

The collected data was entered into Statistical Package for Social Science (SPSS) for Windows, version 26. Data pertaining to all the outcome variables was found to be normally distributed. Therefore, mean and standard deviation were used as descriptive statistics. Repeated Measures Analysis of Variance was performed to determine whether changes in the outcome variables over the three points (baseline, three weeks, and seven weeks) are statistically significant. Further a significant Repeated Measures Analyses of Variance was followed by a post-hoc test with Bonferroni correction. The post-hoc test included following three comparisons: baseline versus three weeks, baseline versus seven weeks and three weeks versus seven weeks. A “p” value of <0.05 was considered as statistically significant in all the analyses.

Results

In this study 12 patients were recruited who underwent CRT for seven weeks. The baseline demographic data of the subjects are represented in Table 1. All the 12 patients who participated in the study were men although the inclusion criteria included both male and female patients. The Diaphragm thickness (mm) and diaphragm mobility (cm) which were evaluated using the ultrasound during quiet breathing at three different time points, showed no significant changes from baseline to seven weeks i.e., p=0.27 and p=0.051 respectively (Table 2).

Diaphragm mobility evaluated during deep inspiration (cm), showed statistically significant change from baseline to seven weeks among all the participants (p<0.05) (Table 2). Also, significant changes were depicted among other variables. The maximal expiratory and inspiratory pressures (cmH2O) showed changes from baseline to 7 weeks (p<0.05). Further comparisons between baseline vs three weeks and baseline vs seven weeks also showed significant changes in diaphragm mobility during deep inspiration, both MIP and MEP, which are non-invasive indicators of respiratory muscle strength (Table 3–Table 5).

Although statistically significant changes were seen in functional capacity among these patients, there was a more profound change seen from baseline to three weeks (Table 6).

Discussion

The purpose of this study was to evaluate the effect of treatment related side effects on the various components of respiratory muscles i.e., diaphragmatic thickness and mobility, respiratory muscle strength and the functional capacity in HNC patients receiving CRT. A study conducted by Santana et al. in 2014 concluded that there was a decrease in inspiratory muscle strength and diaphragm atrophy in HNC patients post neck dissection¹⁶. The findings of our study are in accordance with a case report that reported decline in diaphragmatic thickness, mobility, respiratory strength and the functional capacity²⁰.

Although the 12 HNC patients who underwent CRT did not show any statistically significant decline in diaphragm thickness and mobility on quiet breathing, a gradual decline was seen from baseline to the seventh week which was clinically significant. HNC patients prior to CRT present with sarcopenia and decrease in body composition¹³. Lack of adequate protein diet could have led to alterations in the diaphragm muscle thereby affecting its function¹⁵. In comparison to the diaphragm thickness and mobility measured during quiet breathing, statistically significant changes were seen in the diaphragm mobility which was measured during deep inspiration. This could be due to decrease in function of the diaphragmatic muscle itself as well as decrease in function of the external intercostals which help in complete expansion of the thorax during deep inspiration²¹.

The maximal inspiratory and expiratory pressure measurements are non-invasive measurements that provide an overall view of the inspiratory and expiratory muscle strength. In this study patients who underwent CRT demonstrated a gradual and considerable decrease in the respiratory pressures when evaluated from baseline to seven weeks after CRT, which indicates a significant decrease in respiratory muscle strength of these participants. Why did the respiratory strength decrease in these patients during chemoradiation? In this study during the treatment phase, subjects with HNC who underwent chemoradiation presented with many treatment related side effects. One of the side effects being radiation induced toxicity which due to long duration exposure causes damage to the respiratory system. This is characterized by an initial stage of inflammation, leading to fibro atrophic changes and gradual loss of type 2 pneumocytes which results in fibrosis and impaired function¹⁴.

Due to this, damage alterations in the elastic recoil of the lung and chest wall lead to a decrease in the respiratory pressures, which further increases the respiratory muscle effort against the damage caused due to long standing chemoradiation¹⁰. Another reason for the decrease in respiratory muscle strength in these patients could be because of sarcopenia which has been shown to be one of the major side effects of chemoradiation in head and neck cancer. A study conducted by Chauhan et al. in 2019 proved that sarcopenia and its poor effects are majorly seen in peripheral muscles in HNC patients especially in stage III, IVa and IVb¹³. The sarcopenia found in this study is similar to the loss in muscle function that we observed in the diaphragm muscle. This study could indicate that sarcopenia is not limited to peripheral muscles but is also seen in the muscle of inspiration. This needs to be authenticated further using studies of a larger sample size. Another reason for decrease in respiratory muscle strength, are changes in the musculoskeletal system which alters the joints and posture due to radiation. The areas of radiation for HNC patients are highly indicative of causing trismus, changes in the shoulder girdle and chest wall abnormalities. Due to this musculoskeletal dysfunction, muscle wasting and fatigue of the accessory muscles of respiration result in decreased inspiratory muscle strength¹⁶. Also based on the generalized loss of muscle mass we hypothesized that; abdominal muscle weakness could have led to the decrease in the expiratory muscle strength which may have contributed to the decrease in the MEP values.

The present study showed significant decline in the functional capacity of these patients by the end of the seventh week which is similar to other studies done by Samuel et al.^22,23. With the six-minute walk test as the tool to assess functional capacity, we established a statistically significant pattern of decline in the six-minute walk distance when compared from baseline to three weeks and baseline to seven weeks. Long duration radiation leads to development of oral mucositis and decrease in food intake which alters the general health and increases the difficulty in performing basic activities of daily living due to fatigue and weakness²⁴. Furthermore, physical inactivity caused by fatigue and depression is also one of the major reasons for reduced functional capacity and quality of life in HNC population²⁵.

To our knowledge, this is the first study to evaluate the respiratory components of HNC patients namely, diaphragmatic thickness and mobility and respiratory muscle strength during CRT. Since significant results were drawn from this study, it indicates that the evaluated data could be used to set an objective for early respiratory care and to prevent long term pulmonary complications in HNC patients by initiating pulmonary rehabilitation as an integral part of cancer care.

Limitations

Even though results showed statistically significant changes ours is a pilot study and a study with larger sample size could ensure better results.

Conclusion

Thus, this study concludes that HNC patients who underwent chemoradiation therapy for a duration of seven weeks showed statistically significant decrease in diaphragm mobility during deep inspiration, respiratory muscle strength and functional capacity.

Data availability statement