Unscheduled treatment breaks during radical radiotherapy for head and neck cancers: An audit from a tertiary care center

Treshita Dey; Ankita Gupta; Nagarjun Roa Ballari; Sushmita Ghoshal; Avradeep Datta

doi:10.4103/bjoc.bjoc_5_21

ORIGINAL ARTICLES

Year : 2021 | Volume : 1 | Issue : 2 | Page : 66-71

Unscheduled treatment breaks during radical radiotherapy for head and neck cancers: An audit from a tertiary care center

Treshita Dey, Ankita Gupta, Nagarjun Roa Ballari, Sushmita Ghoshal, Avradeep Datta
Department of Radiotherapy and Oncology, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission	15-Aug-2021
Date of Acceptance	17-Dec-2021
Date of Web Publication	24-Aug-2022

Correspondence Address:
Avradeep Datta
Department of Radiotherapy and Oncology, Post Graduate Institute of Medical Education and Research, Chandigarh
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bjoc.bjoc_5_21

Abstract

Aims: The aim of this article was to audit radical radiotherapy practice in head and neck cancer to assess unscheduled treatment breaks and their reasons thereof. Materials and Methods: Records of all patients of head and neck squamous cell carcinomas registered in the year preceding the pandemic were analyzed. A total of 287 patients treated with radical intent with doses equivalent to 66 Gy in 33 fractions were eligible for final analysis. Results: More than half (148/287) of our patients suffered from treatment breaks during their radiotherapy treatment with primary cause being treatment-related toxicities. Radiotherapy dose of 66 Gy and above (P < 0.001), primary in the oral cavity (P = 0.009), and preceding surgery and concurrent chemotherapy (P = 0.032) were found to be significantly associated with treatment breaks as well as breaks lasting for 15 days or more. Patients having a break in their treatment were also found to have a significantly low progression-free survival (25.8 vs. 12.7 months; P = 0.012). Conclusion: It is in the interest of the patients that stringent patients’ selection criteria identify the ideal candidates for treatment intensification.

Keywords: Head and neck cancer, radiotherapy, treatment breaks

How to cite this article:
Dey T, Gupta A, Ballari NR, Ghoshal S, Datta A. Unscheduled treatment breaks during radical radiotherapy for head and neck cancers: An audit from a tertiary care center. Bengal J Cancer 2021;1:66-71

How to cite this URL:
Dey T, Gupta A, Ballari NR, Ghoshal S, Datta A. Unscheduled treatment breaks during radical radiotherapy for head and neck cancers: An audit from a tertiary care center. Bengal J Cancer [serial online] 2021 [cited 2023 Feb 8];1:66-71. Available from: http://www.bengaljcancer.org/text.asp?2021/1/2/66/354412

Introduction

Locally advanced head and neck cancers are one of the more common cancers in our country.^[1] It is the commonest cancer in males as per our Hospital Based Cancer Registry (HBCR). While established guidelines recommend a multimodality treatment approach for cure, not all patients receive the ideal treatment for various reasons.^[2] Outside the setting of a trial, poor tolerance to treatment leads to treatment breaks in many of our patients.^[3],[4] The present audit was conducted to evaluate the compliance of our patients and to identify the probable reasons for the treatment breaks.

Materials and Methods

For this retrospective analysis, records of all patients of head and neck squamous cell carcinomas registered in the year preceding the pandemic were analyzed. Patients with histopathologically proven squamous cell carcinoma, treated with a radical intent, were eligible for further analysis. Patients with primaries in the nasopharynx and non-squamous histologies were excluded.

A total of 331 patients were assessed for eligibility, out of which 287 were eligible following the inclusion/exclusion criteria [Figure 1].

Figure 1: CONSORT diagram showing patient enrollment and allocation

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Patients were treated either by a Cobalt Teletherapy Unit or by a Linear Accelerator using 6 MV photon beam. All patients were immobilized by a suitable thermoplastic cast covering the head and neck. Only six patients were treated by the IMRT technique, whereas all others were treated by conventional 2D planning. Radical dose of radiation prescribed was equivalent to 66 Gy in 33 fractions either by concomitant or sequential boost.

Concurrent chemoradiotherapy was given to selected patients according to the departmental protocol. Weekly chemotherapy (40 mg/m²) and 3-weekly chemotherapy (100 mg/m²) were planned for 52 and 60 patients, respectively.

Radiotherapy treatment was delivered 5 days a week. Patients on radiotherapy are reviewed at least once weekly for their toxicities (severity of toxicity graded as per CTCAE version 4) and appropriate symptomatic management dispensed. Mucositis leading to progressive dysphagia was treated by anti-inflammatory agents and local anesthetics. Diet was modified and a nasogastric tube advised for grade 3 dysphagia. Pain was managed on the principles of the WHO analgesic ladder.^[5] Intravenous fluids were administered as and when required. Any interruption in continuous treatment by more than 1 day was considered as an unplanned treatment break for the purpose of this study. Treatment was interrupted for any patient developing grade 3 toxicity and restarted only when they resolved to grade 2 or below.

Treatment records were analyzed for demographic pattern, details of treatment received, grades of acute toxicities, treatment breaks with duration, and date of last follow-up. The univariate logistic regression analysis was conducted to evaluate the factors affecting the occurrence and duration of treatment breaks. The factors having significance were then evaluated by the multivariate analysis. Progression-free survival (PFS) and overall survival (OS) were analyzed by the Kaplan–Meier method and compared between patients with and without treatment breaks by using the log-rank test. PFS was calculated from the date of diagnosis to the date of recurrence, disease progression, or death, whereas OS was calculated from the date of diagnosis to the date of death due to any cause. A P-value of less than 0.05 was considered statistically significant. All statistical analyses were carried out with Statistical Package for Social Sciences (SPSS), version 23.

Results

Of the 331 patients treated radically during this period, 287 (86.7%) patients completed RT as planned and hence were considered for the final analysis. Most patients in the study cohort were males (89%) with primaries in the oropharynx (42%). A large number (59%) of patients had moderately differentiated squamous cell carcinomas in their histology. Only 18% of the patients presented with early stage disease, whereas the rest presented with locally advanced disease. Stage IVA was the most common stage at presentation (50%). Although 215 patients received radiotherapy as their primary modality of treatment, 72 patients received post-operative radiotherapy.

A total of 112 patients received concurrent chemotherapy, of which only 37 patients completed the planned number of chemotherapy cycles (55% in 3-weekly schedule and only 7.7% in the weekly schedule). Of the 52 patients planned for weekly concurrent cisplatin, 3 patients received only 1 cycle, 9 received 2 cycles, 3 and 4 cycles were received by 18 patients each, whereas only 4 patients received 200 mg/m² cisplatin.

The general characteristics of the study cohort have been enumerated in [Table 1].

Table 1: General characteristics of patients included in the final analysis

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All patients received symptomatic treatment such as analgesics and local anesthetics from the first day of radiotherapy. Sixty-five (22.6%) patients required Ryles’ tube insertion in view of progressive dysphagia, whereas 37 cases (12.9%) received i.v. fluids on a day-care basis. Only seven patients needed in-patient care owing to severe dehydration and very poor oral intake.

About 148 (51.6%) patients had documented unscheduled treatment breaks. The median duration of treatment breaks was 18 days (range 2–51). The overall median treatment time in the cohort was 49 days (31–93). Patients not suffering treatment breaks completed their treatment in a median duration of 44 days compared with 60 days for patients suffering breaks.

The most common reasons recorded for treatment breaks were treatment-related grade 3 toxicities, i.e., dysphagia (20 patients, 14%), mucositis (42 patients, 29%), and dermatitis (18 patients, 12.5%). Other documented reasons included severe dehydration requiring in-patient care (7 patients, 5%), significant deterioration in performance status (8 patients, 5.5%), other unrelated comorbidities (3 patients, 2%), and logistic reasons (18 patients, 12.5%). Some patients discontinued treatment in-between (undocumented reasons) only to return and complete treatment after a few days (28 patients, 19.5%). Out of the six patients treated with IMRT, three required unplanned treatment breaks.

It was also interesting to note that six patients in the concurrent chemotherapy arm suffered unscheduled breaks and needed in-patient care compared to just one such case in the entire cohort of patients not receiving concurrent chemotherapy. A total of 69 out of 112 patients (62%) had their chemotherapy discontinued due to treatment breaks, a majority of them (42 patients) receiving the 3-weekly regimen.

On the multivariate analysis, factors such as primary oral cavity, total radiation dose of ≥66 Gy, and preceding surgery were found to be significantly associated with causing treatment breaks. All these factors were also found to be significantly associated with treatment breaks of more than 15 days duration [Table 2].

Table 2: Univariate and multivariate analyses for factors affecting the occurrence and duration of treatment breaks

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The median follow-up duration was 9 months (range 1–35). The median PFS of the entire cohort was 20.5 months (2–34 months). Patients who suffered unscheduled breaks during treatment had a significantly lower median PFS of 12.7 months compared with a median PFS of 25.8 months in patients who had no treatment breaks (P = 0.012). The median OS was 20.9 months [Figure 2](a) and (b)].

Figure 2: Kaplan–Meier curve showing (a) median PFS and (b) median PFS between patients with or without treatment breaks

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Discussion

Radical treatment of cancer is guided by national and international guidelines. While stringent inclusion and exclusion criteria are followed for trial protocols, the same is not always true for patients outside a trial. Proper selection of patients is of utmost importance when assessing outcomes of treatment. The present audit was conducted to evaluate the tolerance of radical radiotherapy in head and neck cancer patients treated outside any trial protocol. The specific objective was to find treatment breaks and the possible causes.

Our audit of radically treated head and neck cancer patients revealed that more than half of our patients suffer treatment breaks during their radiotherapy treatment, with the primary cause being treatment-related toxicities. Radiotherapy dose of 66 Gy and above, primary in the oral cavity, prior surgery, and concurrent chemotherapy were found to be significantly associated with treatment breaks as well as breaks lasting for 15 days or more. Patients having a break in their treatment were also found to have a significantly low PFS.

Patients in our set up generally present with locally advanced disease, which are rarely amenable for radical treatment.^[2] The problems are compounded by poor oro-dental hygiene, poor nutritional status, and heavy use of tobacco and alcohol. Hence, many patients treated with a radical intent tolerate the prolonged treatment poorly. In the present study, half of the patients suffered treatment breaks with a median duration of 18 days, mostly due to treatment-associated toxicities. Only 12.5% of the patients suffered treatment breaks due to machine breakdown or other logistic reasons.^[6]

In 2002 and 2008, audit of all head and neck cancer patients treated in centers of the National Health Service, UK showed that 55% and 63% of all patients, respectively, suffered unplanned breaks during radical radiotherapy. These findings are in line with our observed incidence of 51.6%.^[7],[8],[9] Another audit from the Indian state of Jammu and Kashmir also reported unplanned breaks in 46.6% of their head and neck radiotherapy patients.^[10] However, while machine breakdown and repair were the primary causes of treatment breaks in the UK (37% in 2002 and 35% in 2008), only 8% patients suffered treatment breaks due to treatment-related toxicities. On the contrary, 65.5% of all treatment breaks in our study were treatment-related and only 12.5% were a result of logistic reasons. Similarly, the Indian audit reported 71.4% treatment breaks due to toxicities. The low maintenance and downtime of Telecobalt machines may have contributed to low numbers of treatment breaks due to logistical reasons in our setup.

While it is largely known that treatment intensification for head and neck cancers leads to more treatment interruptions as a result of increased acute toxicities, the factors contributing to these interruptions have been less clearly defined. In a SEER analysis of data between 1997 and 2003 for patients with head and neck cancer who were older than 66 years, it was found that concurrent chemotherapy, locoregional disease, and non-surgical candidates were most susceptible to suffer treatment breaks during radiotherapy.^[11] Our data also suggest that concurrent chemotherapy adds to treatment breaks. Also, radiotherapy dose of >66 Gy, previous surgery, and oral cavity primaries were the other factors that significantly correlated with the treatment breaks in our study population. While increasing the radiation dose is directly proportional to the severity of toxicities leading to more treatment breaks,^[12] an oral cavity primary will necessitate the radiation portals to cover the entire oral cavity and neck and hence cause earlier and more severe oral mucositis.^[13] Since conformal radiation cannot be offered to all due to logistic reasons and most patients present with locally advanced disease, a large volume of normal tissue is irradiated. Also, patients in the SEER analysis who underwent surgery had smaller tumors and no comorbidities and hence had better outcomes. In contrast, most of our patients undergoing surgery had large tumors and adverse histopathological features, necessitating larger radiation fields and the use of concurrent chemotherapy. Large tumors may have also made normal tissue sparing by redundant multi-leaf collimators. This could have led to increased morbidity and resultant treatment breaks in these patients.

Aggressive treatment protocols aimed at improving tumor control is also associated with increased toxicities. A study combining concomitant-boost with concurrent chemotherapy had reported very high rates of toxicity and even led to treatment-related deaths.^[14] Higher rates of acute toxicity have also been reported in trials published from our center [Table 3]. At the same time, toxicities have been found to be more “tolerable” in trials due to stringent patient selection and care extended to these patients with regard to their treatment. This amounts to lower rates of attrition and better outcomes in these patients even with higher rates of toxicities. The same is not always true for patients receiving similar treatment in the community level.

Table 3: Incidence of severe acute radiation toxicities in studies from our center

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Treatment interruptions lead to loss of tumor control by as much as 12–14% per week across all head and neck subsites both for primary as well as post-operative treatment due to accelerated repopulation.^[17] Patients who suffered treatment breaks in our study had significantly low PFS compared with those who did not suffer treatment breaks. In a secondary analysis of the TROG 02.02 (HeadSTART) trial, which included patients with locoregionally advanced head and neck cancers from 16 countries, it was noted that the OS was 20% higher in the group with compliant radiotherapy protocols, which far exceeds the survival benefit of standard concurrent therapies.^[18]

Lack of awareness about cancer hindering early diagnosis, diet, lack of dedicated nurses and dieticians in our set up also contribute to treatment delays. Patients are encouraged to create individualized diet plans, with food already available in their kitchens, that are both nutritious and easy to swallow and digest.

Thus, it is in the interest of the patients that stringent patient selection criteria identify the ideal candidates for treatment intensification. Surgery, concurrent chemotherapy, and increasing radiotherapy dose are all treatment intensification strategies that may lead to significant improvements in cure rates, but also may lead to interruptions and thus poor local control in unsuitable patients. Oral cavity cancers are best tackled by surgery, and post-operative radiotherapy can be added when indicated. Patients who are not suitable for surgery due to comorbidities or advanced disease should be considered for palliative treatment. Attempts can be made through radiogenomic studies to identify patients who are at high risk for radiotherapy-induced toxicities, who could be candidates for more conformal radiation techniques and active interventions for toxicity management.

Also, more emphasis needs to be paid to supportive management of patients on radiotherapy. A stringent review policy for early identification and management of toxicities, services of a dedicated dietician or nutritionist for patients, and a social support volunteer are all warranted for better treatment compliance. When resources are limited, the treating physicians have the added responsibility to address these issues. It is important to understand the concept of planned treatment gap in the background of radical treatment. Introducing a planned gap will help to complete the planned treatment without unnecessarily prolonged unplanned interruptions. It is of utmost importance to identify patients who are suitable for radical treatment and counsel them properly regarding the disease status, management options, and their expected toxicities which may improve compliance to treatment.

Triaging of patients and early integration of palliative care for advanced cancer may improve therapeutic outcomes and quality of life.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Mathur P, Sathishkumar K, Chaturvedi M, Das P, Sudarshan KL, Santhappan S, et al; ICMR-NCDIR-NCRP Investigator Group. Cancer Statistics, 2020: Report from National Cancer Registry Programme, India. JCO Glob Oncol 2020;6:1063-75.
2.	Thakur. Split-Course Radiotherapy: A Nonideal Treatment in a Nonideal Patient. Available from: https://www.jhnps.org/article.asp?issn=2347–8128;year=2018;volume=6;issue=1;spage=43;epage=47;aulast=Thakur [last accessed on December 1, 2020].
3.	Rishi A, Ghoshal S, Verma R, Oinam AS, Patil VM, Mohinder R, et al. Comparison of concomitant boost radiotherapy against concurrent chemoradiation in locally advanced oropharyngeal cancers: A phase III randomised trial. Radiother Oncol 2013;107:317-24.
4.	Gupta A, Mathew D, Ghoshal S, Pal A XRCC1 (rs25487) polymorphism is associated with severe oral mucositis and poor treatment response after radiotherapy for oropharyngeal carcinoma. Oral Cancer 2019;3:37-47.
5.	Anekar AA, Cascella M WHO analgesic ladder. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2022.
6.	Diegues SS, Ciconelli RM, Segreto RA Causas de interrupção não-programadas da radioterapia. Radiologia Brasileira 2008;41:103-8.
7.	James ND, Robertson G, Squire CJ, Forbes H, Jones K, Cottier B; RCR Clinical Oncology Audit Sub-committee. A national audit of radiotherapy in head and neck cancer. Clin Oncol (R Coll Radiol) 2003;15:41-6.
8.	James ND, Williams MV, Summers ET, Jones K, Cottier B; Royal College of Radiologists Clinical Audit Subcommittee. The management of interruptions to radiotherapy in head and neck cancer: An audit of the effectiveness of national guidelines. Clin Oncol (R Coll Radiol) 2008;20:599-605.
9.	PRIME PubMed \| Adverse Events Associated with Concurrent Chemoradiation Therapy in Patients with Head and Neck Cancer. Available from: https://neuro.unboundmedicine.com/medline/citation/20026818/Adverse_events_associated_with_concurrent_chemoradiation_therapy_in_patients_with_head_and_neck_cancer_ [Last accessed on August 1, 2021].
10.	Manzoor NA. Department of Radiation Oncology, Sheri-Kashmir Institute of Medical Sciences, Srinagar J&K India. Unplanned interruption of radiotherapy in head and neck cancers: Report from a Regional Cancer Centre. JMSCR 2017;05:20294-300.
11.	Fesinmeyer MD, Mehta V, Tock L, Blough D, McDermott C, Ramsey SD Completion of radiotherapy for local and regional head and neck cancer in Medicare. Arch Otolaryngol Head Neck Surg 2009;135:860-7.
12.	Marcu LG Improving therapeutic ratio in head and neck cancer with adjuvant and cisplatin-based treatments. Biomed Res Int 2013;2013:817279.
13.	Chen SC, Lai YH, Huang BS, Lin CY, Fan KH, Chang JT Changes and predictors of radiation-induced oral mucositis in patients with oral cavity cancer during active treatment. Eur J Oncol Nurs 2015;19:214-9.
14.	Kumar S, Pandey M, Lal P, Rastogi N, Maria Das KJ, Dimri K Concomitant boost radiotherapy with concurrent weekly cisplatin in advanced head and neck cancers: A phase II trial. Radiother Oncol 2005;75:186-92.
15.	Ghoshal S, Goda JS, Mallick I, Kehwar TS, Sharma SC Concomitant boost radiotherapy compared with conventional radiotherapy in squamous cell carcinoma of the head and neck—A phase III trial from a single institution in India. Clin Oncol 2008;20:212-20.
16.	Hakim A, Ghoshal S, Verma R, Sharma SC Comparison of functional organ preservation by concomitant boost radiotherapy versus concurrent chemoradiation in locally advanced carcinoma of larynx or hypopharynx: A prospective randomized study. Indian J Otolaryngol Head Neck Surg 2019;71:360-6.
17.	González Ferreira JA, Jaén Olasolo J, Azinovic I, Jeremic B Effect of radiotherapy delay in overall treatment time on local control and survival in head and neck cancer: Review of the literature. Rep Pract Oncol Radiother 2015;20:328-39.
18.	Rischin D, Peters LJ, O’Sullivan B, Giralt J, Fisher R, Yuen K, et al. Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): A phase III trial of the Trans-Tasman Radiation Oncology Group. J Clin Oncol 2010;28:2989-95.