Journal of Cancer Research and Therapeutics

ORIGINAL ARTICLE
Year
: 2022  |  Volume : 18  |  Issue : 6  |  Page : 1461--1468

Long term outcome and late toxicity Of SIB-IMRT in definitive management of head and neck cancers in patients not suitable for chemo-radiotherapy


Narayan Pratap Singh1, Rohini Khurana1, Shantanu Sapru1, Madhup Rastogi1, Ajeet Kumar Gandhi1, Satyajeet Rath2, Rahat Hadi1, Surendra Prasad Mishra1, Anoop Kumar Srivastava1, Avinav Bharti1, Kamal Sahni1, Mohammad Ali3, Ramakant Tiwari4,  
1 Department of Radiation Oncology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Radiation Oncology, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
3 Department of Radiation Oncology, King Georges Medical University, Lucknow, Uttar Pradesh, India
4 Department of Radiation Oncology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India

Correspondence Address:
Rohini Khurana
Department of Radiation Oncology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh
India

Abstract

Objective: To evaluate efficacy and late toxicity of intensity-modulated radiotherapy with simultaneous integrated boost (IMRT-SIB) in definitive management of head-and-neck cancers. Methods: In this prospective interventional study, histological proven squamous cell carcinoma of oropharynx, hypopharynx, or larynx with stage T1-3 N0-3 M0 who were not candidates for concurrent chemotherapy were treated with IMRT-SIB with radical intent. Doses prescribed for IMRT-SIB to meet the clinical needs of nodal volumes were either SIB-66 schedule 66 Gray (Gy) prescribed to high risk (HR) planned target volume (PTV), 60 (Gy) to intermediate risk (IR) PTV and 54 Gy to low risk (LR) PTV in 30 fractions or SIB-70 schedule 70 Gy to PTV-HR, 59.4 Gy to PTV-IR and 56 Gy to PTV-LR in 33 fractions. Result: Forty-five patients were included. Forty-two patients were treated with SIB-66 schedule and three patients with SIB-70 schedule. The median follow-up period was 21 (6–68) months. There was residual disease in three patients. Recurrence was observed in 24 patients. Most recurrences were in HR volume (n = 19) and three patients had distant failure. Estimated 2-year locoregional control, disease-free survival, and overall survival were 55.55%, 49.7%, and 51.1%, respectively. Grade 3 late skin toxicity, subcutaneous fibrosis, and xerostomia were observed in three patients. Conclusions: Efficacy and late toxicity of IMRT-SIB observed in our study suggest it as a suitable treatment option for patients who are not fit for chemoradiation.



How to cite this article:
Singh NP, Khurana R, Sapru S, Rastogi M, Gandhi AK, Rath S, Hadi R, Mishra SP, Srivastava AK, Bharti A, Sahni K, Ali M, Tiwari R. Long term outcome and late toxicity Of SIB-IMRT in definitive management of head and neck cancers in patients not suitable for chemo-radiotherapy.J Can Res Ther 2022;18:1461-1468


How to cite this URL:
Singh NP, Khurana R, Sapru S, Rastogi M, Gandhi AK, Rath S, Hadi R, Mishra SP, Srivastava AK, Bharti A, Sahni K, Ali M, Tiwari R. Long term outcome and late toxicity Of SIB-IMRT in definitive management of head and neck cancers in patients not suitable for chemo-radiotherapy. J Can Res Ther [serial online] 2022 [cited 2022 Dec 2 ];18:1461-1468
Available from: https://www.cancerjournal.net/text.asp?2022/18/6/0/358613


Full Text



 Introduction



According to GLOBOCAN 2018, head-and-neck cancer is the 2nd most common cancer in India and other developing countries.[1] Definitive radiotherapy (RT) administered concomitantly with chemotherapy (CRT) is the current standard of care for locally advanced head-neck squamous cell carcinoma (HNSCC).[2] In patients unsuitable for CRT, concurrent bio-RT or altered fractionated RT are reasonable treatment options. Altered fractionated RT was associated with a significant benefit on overall survival (OS) with an absolute difference at 5 and 10 years of 31% and 12%, respectively. The OS benefit was restricted to the hyperfractionation group with absolute differences at 5 and 10 years of 81% and 39%, respectively. OS was significantly worse with altered fractionation RT compared with concomitant CRT, with absolute differences at 5 and 10 years of 58% and 51%, respectively.[3] Although intensification of treatment does improve locoregional control (LRC) and survival in locoregionally advanced HNSCC, it increased risk of acute and delayed toxicities with a potentially negative effect on health-related quality of life.[4] Early toxicity leading to consequential long-term pharyngeal toxicity is a major detrimental effect of some organ preservation approaches using CRT or aggressive accelerated RT. Late toxicities such as subcutaneous fibrosis and laryngeal edema are associated with aspiration and an increased risk of pneumonia. These, late toxicities limit the intensity of concurrent chemo-RT or accelerated RT regimens using 3DCRT and reduce their therapeutic ratio.[5] The Radiation Therapy Oncology Group (RTOG) 0129 trial compared SFRT plus concurrent cisplatin versus AFRT with cisplatin and found that there was no difference in outcome and late toxicity in these two schedules.[6] Most of these studies were conducted before the use of modern methods such as intensity modulated RT (IMRT). The advancement in radiation delivery in the past few years, such as IMRT, volumetric modulated arc therapy, IMRT using simultaneous integrated boost (IMRT-SIB) has significantly changed the approach.[7] IMRT offers a possibility of planned dose in homogeneity with in the planning target volume (PTV). At the PTV boundary the dose had a sharper fall-off. These factors may allow escalation of tumor dose, reduction of normal tissue dose, or both, leading to an improved outcome.[8] In addition, IMRT has the potential to be more efficient with regard to treatment delivery than standard 3DCRT as there are no secondary field-shaping devices other than the computer-controlled multi leaf collimator (MLC). In contrast, IMRT with simultaneous integrated boost technique allows the simultaneous delivery of individualized dose levels of selective target volumes (TV) by generating one single treatment plan. By increasing the dose per fraction focally to the tumor itself while maintaining lower dose to the elective areas, a more accurate dose distribution can be achieved, in order to improve locoregional tumor control without putting the neighboring organs at risk. In many cases posterior electron boost for large nodes can be dispensed with, permitting the use of the simultaneous integrated boost plan for the entire course of treatment.[9] We need to define the rationale and need of SIB-IMRT in a defined group of patient cohort. This would serve as the reason for conduct of this study. IMRT-SIB has emerged as a therapeutic option for such patients offering not only dose escalation but also reducing the overall treatment time. Acute effects were reported earlier,[10] and now, we report efficacy in terms of LRC, survival outcome, and long-term toxicities of IMRT-SIB in this subset of HNC patients in our population.

 Methods



The study included histopathologically confirmed 45 patients of squamous cell carcinoma of the oropharynx, hypopharynx, and larynx region with age ≥18 years, clinical stages T1-3 N0-2 M0, Karnofsky Performance Status of ≥70, and absence of serious uncontrolled comorbidities [Table 1]. All patients had to be deemed unsuitable for concurrent chemoradiation due to their being very frail, or elderly, poor nutritional status or having inadequate renal function. Frail was defined as people ≥60 years of age with inability to perform routine daily activities without assistance. Prior to commencement of the study, informed consent was obtained from each patient, and ethical clearance was obtained from the Institutional Ethics Committee (IEC Number 43/15). Staging was done as per American Joint Committee on Cancer (AJCC, 7th Edition, 2010).[11] Chest X-ray, complete hemogram, assessment of renal and liver function tests, and dental prophylaxis were done before commencing the treatment. Direct laryngoscopy, contrast enhanced computed tomography (CECT) of the face and neck were performed.{Table 1}

SIEMENS somatom sensation CECT simulation with appropriate thermoplastic cast immobilization was done in all patients, and computed tomography (CT) images were acquired with slice thickness of 3 mm. CT simulation data were transferred to Treatment Planning System (Monaco version 5.0) using DICOM protocol. TV and organ at risk (OAR) delineation was done. TV delineation was done on the contrast CT scan images and for each patient, three TVs with their respective PTVs were defined as per ICRU 50.62 and 83 guidelines.[12],[13],[14] Gross tumor volume included all clinically and radiologically demonstrable primary disease. Positive lymph nodes were defined as any lymph nodes ≥1 cm or nodes with a necrotic center. The clinical TVs (CTVs) of CTV- primary (CTV-P) and CTV-nodal (CTV-N) were created by an isotropic expansion of 5–15 mm appropriately to meet the topological and anatomical requirements. Further three CTVs were defined; CTV-high risk (CTV-HR) which includes CTV-P and CTV-N includes involved nodes. CTV-intermediate risk (CTV-IR) which encompassed the areas considered to be at intermediate risk of subclinical disease extension. CTV-low risk (CTV-LR) included the nodal drainage areas considered to be at LR involvement. Contours of the CTV-HR, CTV-IR, and CTV LR were expanded isotropically by 7 mm to generate their respective PTV (PTV-HR, PTV-IR, and PTV-LR respectively). The PTVs were cropped so that they were restricted to 3 mm inside the contoured body surface except in areas where the skin was considered to be a part of the CTV[15] [Figure 1]a and [Figure 1]b. In our study, the OARs were spinal cord, brainstem, and right and left parotid glands for each patient. Planning OAR volume (PRVs) for the spinal cord was created by isotropic expansion of 3 mm (as a “safety feature” during IMRT planning), and no PRV was generated for other OARs.{Figure 1}

Dose prescription to PTV has been summarized in [Table 2]. Plans generated were reviewed using cumulative dose volume histograms [Figure 1]d and a slice-by-slice review of dose color wash displays. Dose constraints prescribed to the OARs have been mentioned in [Table 3].{Table 2}{Table 3}

All treatment plans were evaluated and implemented only after the stringent quality assurance parameters were met. IMRT-SIB fields were delivered on ELEKTA Infinity linear accelerator with dynamic multi leaf collimation (40-pair MLC), leaf width of 1 cm at the isocentre. Setup and target reproducibility verification was mandatorily performed using cone beam CT (CBCT) using ELEKTA XVI [Figure 1]c prior to treatment delivery for first three fractions. Subsequent CBCTs were acquired twice in a week and online corrections were done when setup error ≥2 mm was noted in any direction.[10]

Ryle's tube was placed in those patients who experienced Grade 3 or higher odynophagia and dysphagia. The first posttreatment follow-up was scheduled after 2 weeks of completion of RT. Subsequent visits were scheduled as monthly for the first 6 months, then 2 monthly for the next 6 months and 3 monthly thereafter. At each follow-up visit, a complete physical examination was combined with an assessment late toxicity as per Late Radiation Morbidity Scoring Schema[16] and was recorded. Late toxicities were noted after 6 months. For statistical analysis IBM Corp. Released 2016. IBM SPSS Statistics for Windows, Version 24.0. Armonk, NY: IBM Corp was used. The P ≤ 0.05 was considered to be statistically significant for all analysis.

Response evaluation was done according to WHO response assessment criteria.[17] Clinical examination of the primary and nodal site was done after 3 months of treatment completion. Direct laryngoscopy and CT neck was done after 3 months of treatment completion. Biopsy/cytology was done if suspicious lesions were detected on clinical/radiological examination.

 Results



Forty-five patients were included in this study from December 2014 to December 2016 and followed up till September 2019 in the department of radiation oncology. The median age was 60 years (range 35–86) with 42.2% patients in >60 years age group. Old, frail, KFT deranged, and old with frail were 14, 17, 12, and 2 patients, respectively. Base of the tongue and supraglottic larynx were the most common sites. Patient characteristics are summarized in [Table 1]. Two sets of dosage were chosen for IMRT-SIB prescription to meet the clinical needs of nodal volumes: SIB-66 schedule (n = 42 patients), i.e., 66 Gy dose was prescribed to PTV-HR, 60 Gy to PTV-IR and 54 Gy to PTV-LR in 30 fractions; whereas SIB-70 schedule (n = 3 patients) included 70 Gy dose to PTV-HR, 59.4 Gy to PTV-IR, and 56 Gy to PTV-LR in 33 fractions. Comparative dose volume parameters for PTV are summarized in [Table 2]. In our patients, 95% PTV-HR volume received median dose 97%, PTV-IR received 99% and PTV-LR received 99%. Maximum dose delivered to OARs was in limits of prescribed dose constraints, although mean dose of both parotids glands was slightly higher than prescribe [Table 3].

All the patients have completed the treatment with good compliance with no treatment interruption. The median overall treatment time was calculated from the date of start of RT to the date of end of treatment was 43 days (range 38–48). Median follow-up period was 21 months (range 6–68) and lost to follow-up rate 11.11% was estimated.

Complete response was seen in 42 (93.33%), partial response in 2 (4.44%) and progressive disease in 1 (2.22%) patient.

Out of 45 patients, recurrences were observed in 24 patients. In which recurrences at primary were seen in 17 (70.83%), both primary and nodal in 3 (12.50%), distant and nodal in 1 (4.16%) and only distant metastasis in 3 (12.50%) patients.

On analyzing the pattern of recurrence, all residual 3 (6.66%) diseases were seen in HR CTV region. Most of recurrences in 19 (79.16%) patients of disease were seen in HR CTV region and 1 (4.16%) patient had recurrence both in HR and intermediate CTV region and 1 (4.16%) patient had recurrence combined in HRCTV, IRCTV, and distant region and rest recurrences 3 (12.5%) patients were seen in the distant region only.

The median disease-free survival (DFS) is 18 months (range 0–68 months) and median OS is 48 months (range 6–68 months). The OS and DFS of the cohort were evaluated using the Kaplan-Meier method [Figure 2].{Figure 2}

Four patients had distant metastasis, two in bony sites, i.e., sternum and pelvis and two cases had multi-organ metastasis.

Out of 25 deaths, 3 (12%) patients died due to nononcological causes like one patient died due to cardiac arrest and another due to respiratory cause and one death was due to aspiration. All these patients were disease free at the time of last follow-up.

Crude LRC rate was 55.55%, isolated local failure rate was 37.77%, isolated regional failure rate was 8.88%, crude distant metastasis control rate was 91.11%, crude death rate was 55.55%, and estimated 2-year DFS and OS was 49.7% and 51.1%, respectively. Various grade wise late toxicities were mentioned [Table 4] and [Figure 3], and overall grade ≥2 and ≥3 toxicities were mentioned [Table 5]. There were fewer Grade 3 late toxicities as compared to Grade 2. Grade 4 and 5 toxicities were not observed in any patient.{Figure 3}{Table 4}{Table 5}

 Discussion



SIB-IMRT provided the advantage of better target dose conformity with less dose spillage in critical organs.[18] At the same time, it permitted delivery of a higher dose of radiation to smaller sub volumes in the target in a shorter period of time.

SIB-IMRT has been evaluated in several clinics in many western institutions but experiences in radiotherapeutic clinical practices of this treatment modality has been less pronounced in developing countries like India.[19] In the published IMRT-SIB studies, the doses schedules which were used have significant heterogeneity in terms of total dose, dose per fraction, and TV selections. All above studies concluded that in IMRT-SIB both acute and late toxicity rates are less as compare to conventional or 3D-CRT technique. Chemotherapy is often avoided in older patients with advanced oropharyngeal cancer as well as in those with a poor performance status, since the use of concurrent chemotherapy may delay or prevent the completion of course of definitive RT. In fact, MACH-NC study suggests that benefit of concurrent chemotherapy added to RT is lost in those over 70-year-old and is indeed harmful in those over 80 years.[2] The results of the present study suggest that because of acceptable base line efficacy and late toxicity rates (most commonly Grade 2 and less commonly Grade 3 or 4), patient of HNSCC who are not eligible for concurrent chemotherapy due to malnutrition, poor kidney function, poor performance status or any other reasons can be treated with IMRT-SIB and analyze the data of the patients treated with IMRT-SIB technique in our institution. Most of the times, in such patients' hypofractionated palliative regimens, or with less than radical doses using standard fractionation, or with low-dose metronomic chemotherapy were used. However, this compromises their cure potential. This is also a good way to deliver potentially curable doses, even to such debilitated patients. 42 males and 3 females were recruited in our study which is not a true representative of incidence in India as it is a small study with only 45 patients' population. In the Asian origin, majority patients present with locally advanced HNC. Despite the best locoregional treatment, these are generally associated with a poor outcome, with 3-year OS rates of 40%–50%.[20],[21],[22] Patients treated and evaluated in this study by SIB-IMRT technique, the fractionation regimen followed in 42 patients was 66/60/54 Gy and in 3 patients 70/59.4/56 Gy to PTV-HR, PTV-IR, and PTV-LR, respectively, (biological equivalency to conventional doses of 70/60/50 Gy, respectively). Same fractionation was used in RTOG 00-22[23] and Vošmik et al.[24] The most common practice is the use of a higher dose has been 66 Gy in 30 fractions. On the other hand, there are data which firmly concluded that dose escalation has limits as it enhances the acute reactions. Outcome and delayed toxicity in contemporary IMRT series using SIB-IMRT have been uniformly good. Selected results are shown in [Table 6].{Table 6}

In our study, majority of patients were in locally advanced stage. Crude LRC 55.55%, 2 year DFS 49.7% and OS 55.1% was observed. We also observed that median time of persistence of highest-grade late toxicity is less as compare to conventional RT, suggesting early recovery as a result of lower dose to surrounding normal tissue. IMRT, with or without SIB, has demonstrated to decrease late toxicity (xerostomia) in parotid glands without impairing clinical results with respect to conformal techniques.[27] Xerostomia decreased with increasing time interval from the end of RT similar to that observed by Chao et al.[28] They have studied the functional improvement in salivary flow over time in a systematic manner. However, salivary output did not fully recover over time. In our study, xerostomia grade ≥ 2 was 48.88% which was comparable to study RTOG 00-22[23] in which xerostomia grade ≥2 was observed in 55% of patients at 6 months. Significant grade ≥2 late mucosal toxicity, skin toxicity, subcutaneous and laryngeal toxicity 9%, 5%, 3%, and 3% was reported in RTOG 00-22,[23]while in our study, these were 8.88%, 6.66%, 2.22%, and 6.66%, respectively. Grade 3 late toxicity occurred in very few patients as compared to Grade 2. Grade 4 toxicity was not observed in any patient. Significant Grade 3 pharyngeal toxicity was reported by de Arruda et al.[19] as 16% while in our study it was not seen after completion of 2 months following treatment. We also observed lack of long-term dependence on placed nasogastric tube (NG) with no patient requiring NG tube placement after 2 months of post-RT. None of the patients experienced pharyngo-esophageal strictures. Thus, the analysis of long-term toxicity has been found to be acceptable for the IMRT-SIB protocols selected for the study.

Our study has limitations in being a single arm with a smaller number of patients. We had clipped the PTV margin to 3 mm inside skin and did not give any additional constraints to the skin so higher skin toxicity is noted. The lack of quantification of salivary gland function and radiological assessment of dysphagia was not done which remains a drawback in the present study. The late toxicity reported is based on clinical observation alone as per RTOG criteria.

 Conclusions



A randomized control study with an appropriate sample size and a longer follow-up would be required to prove the equivalence of efficacy of IMRT-SIB to chemoradiation in locally advanced HNSCC patients who are not fit for concurrent chemotherapy. We report here the results of a single arm prospective study which are similar in terms of LRC, DFS and OS to those reported in various literature series. Late toxicities were analyzed in the form of mucosal, skin, salivary gland, laryngeal toxicity, and subcutaneous tissue. All toxicities were manageable, and the sparing of critical organs and conformal inclusion of TV could be achieved. Thus, SIB IMRT is a viable option for the intensification of treatment in a subgroup of locally advanced HNSCC patients who are unfit for chemotherapy.

Acknowledgments

All authors have contributed significantly to the article. All authors are in agreement with the concept of the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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