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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 3  |  Page : 600-604

Clinical and dosimetric impact of adaptive intensity-modulated radiotherapy in locally advanced head-and-neck cancer


1 Department of Radiation Oncology, Sardar Patel Medical College, Bikaner, Rajasthan, India
2 Department of Internal Medicine, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India

Date of Submission30-Oct-2019
Date of Decision12-Jan-2020
Date of Acceptance27-Jan-2020
Date of Web Publication18-Jul-2020

Correspondence Address:
Shankar Lal Jakhar
Department of Radiation Oncology, Sardar Patel Medical College, Bikaner - 334 001, Rajasthan
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_928_19

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 > Abstract 


Background: Radiotherapy in head-and-neck cancer (HNC) is a challenging task, and the anatomical alterations occurring during the course of intensity-modulated radiotherapy (IMRT) can be compensated by adaptive radiotherapy (ART) which utilizes repeat computed tomography (CT) scans during the treatment course for replanning. In this study, the clinical and dosimetric benefits of ART were compared with the conventional IMRT.
Materials and Methods: Sixty patients with locally advanced HNC were randomized into two arms to receive IMRT up to a curative dose of 70 Gy with concurrent weekly chemotherapy and were prospectively analyzed between March 2018 and March 2019. Repeat CT scan was acquired after the 3rd week of radiation. Patients in the study arm underwent replanning, whereas those in the control arm continued with the first IMRT plan. Assessment was done weekly till the end of treatment and at 1, 3, and 6 months post IMRT for disease response and toxicities. Tumor volume reduction rate (TVRR) and dose reduction to organs at risk were also recorded.
Results: Complete response was observed in 90% and 96.7% patients in the control and study arms, respectively, at the end of 6 months. Insignificant differences were found between the two arms in terms of toxicities. Xerostomia was statistically significantly higher in the control arm at 6 months (P = 0.01). TVRR was found to be 31.85%. Dose to spinal cord, ipsilateral, and contralateral parotid reduced by 4.3%, 6%, and 2.2%, respectively, with ART.
Conclusion: Mid-treatment adaptive replanning can help in better target coverage and minimize toxicities in HNC patients.

Keywords: Adaptive radiotherapy, head-and-neck cancer, intensity-modulated radiotherapy, replanning, xerostomia


How to cite this article:
Maheshwari G, Dhanawat A, Kumar HS, Sharma N, Jakhar SL. Clinical and dosimetric impact of adaptive intensity-modulated radiotherapy in locally advanced head-and-neck cancer. J Can Res Ther 2020;16:600-4

How to cite this URL:
Maheshwari G, Dhanawat A, Kumar HS, Sharma N, Jakhar SL. Clinical and dosimetric impact of adaptive intensity-modulated radiotherapy in locally advanced head-and-neck cancer. J Can Res Ther [serial online] 2020 [cited 2020 Aug 7];16:600-4. Available from: http://www.cancerjournal.net/text.asp?2020/16/3/600/289978




 > Introduction Top


Head-and-neck cancer (HNC) is the sixth most common malignancy worldwide,[1] with an annual incidence of more than 835,000 cases and 431,000 deaths each year.[2] It is the third most common malignancy in India registering over 200,000 new cases every year.[3],[4] The male-to-female ratio ranges from 2:1 to 4:1. About 90% of all HNCs are squamous cell carcinomas, probably due to the higher indulgence in risk factors such as alcohol, tobacco, and betel nut chewing.[5] The median age at diagnosis is in the sixth decade, and almost 60%–80% are recognized in advanced stages compared to 40% in developed countries.[4]

Treatment of HNC is a great challenge due to the anatomical complexity of this region where the target volumes are situated in the vicinity of healthy organs such as salivary glands and spinal cord. The spinal cord lies within a concavity surrounded by the horseshoe-shaped planning target volume (PTV).[6] Homogeneous irradiation of these PTVs with the conventional radiation therapy (RT) is difficult. Intensity-modulated radiotherapy (IMRT) allows simultaneous pixel-by-pixel intensity modulation of radiation beams and delivery of nonuniform fluence from any given position of the treatment beam to optimize the composite dose distribution, thus allowing a much higher possibility to sculpt dose and improve the therapeutic ratio.[7],[8]

Use of these highly conformal techniques has, however, led to the formation of sharp dose gradients, implying that there should be no or minimal changes in the patient, tumor, and organs at risk (OARs) position.[9] Such changes occur owing to the shrinkage of primary tumor and nodal disease from the treatment, alterations in the normal tissue bulk, and position and weight loss.[10],[11],[12],[13],[14],[15] Applying the original plan to the altered patient anatomy can lead to higher-than-intended dose to the surrounding normal structures. These alterations can be compensated by adaptive radiotherapy (ART) which utilizes repeat computed tomography (CT) scans during the treatment course for replanning according to the altered regional anatomy.[16] In this study, the clinical and dosimetric benefits of ART were compared with the conventional IMRT.


 > Materials and Methods Top


A total of sixty biopsy-proven patients of previously untreated locally advanced HNCs were randomized into two arms. All patients were treated with IMRT and concurrent weekly cisplatin (40 mg/m2) between March 2018 and March 2019 at a regional cancer center in North-West India and were prospectively analyzed as per the institutional review board-approved protocol.

Patients included in the study were aged 18–70 years and had Stage III/IV squamous cell HNC located anywhere between the base of the skull up to the thoracic inlet (excluding salivary gland and thyroid tumors). The European Co-operative Oncology Group performance status was 0–2, and all patients had adequate baseline organ function (complete blood count, renal function test, liver function test, and others). Patients with distant metastasis, recurrent lesions, evidence of second malignancies, and associated severe comorbid diseases were excluded from the study.

All patients were immobilized and had pretreatment CT simulation with 3-mm slices. The data were transferred to Eclipse Treatment Planning System v. 13.8 (make: Varian Medical Systems, Palo Alto, USA) Target volume and normal structures were delineated as per the departmental protocol. Dynamic IMRT was delivered using 6 MV linear accelerator. All patients were treated up to a curative dose of 7000 cGy in 33–35 fractions with simultaneous integrated boost IMRT and prescribed weekly concurrent chemotherapy. PTV 70 received a total dose of 69.96 Gy in daily fractions of 2.12 Gy, PTV 60 received 59.4 Gy in 1.8 Gy/#, and PTV 54 received 54 Gy in 1.63 Gy/#. Repeat CT scan was acquired for each patient after the 3rd week (between 16 and 20#s) of radiation, and recontouring was done. Two plans were generated on repeat scan for each patient; an actual plan (study arm), which was generated by planning on repeat CT scan, and another hybrid plan (control arm), in which the first IMRT plan was applied on repeat scan with carefully matched isocenter and bony landmarks. Patients were assessed weekly till the end of treatment and at 1, 3, and 6 months thereafter for local disease response and development of any acute skin or mucosal reactions. Treatment response was assessed as per the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (v. 1.1). Acute toxicities were assessed as per the RTOG/EORTC acute radiation morbidity scoring system. Xerostomia was also assessed on the basis of the Common Terminology Criteria for Adverse Events (CTCAE) (v. 4.0). Total gross tumor volume (GTVt) changes between the original and rescan CT were analyzed and were used to calculate the tumor volume reduction rate (TVRR). Dose to OAR (spinal cord, ipsilateral, and contralateral parotid) was recorded in original and re-CT plans, and the percentage reduction in dose was calculated. Statistical analyses were performed by using unpaired Student's t-test to compare between the study arm and the control arm.


 > Results Top


Patient characteristics are described in [Table 1]. All patients completed the planned treatment with concurrent weekly cisplatin, however seven (23.3%) patients in the conventional arm and three (10%) patients in the adaptive arm missed 2–3 doses of weekly cisplatin after the 2nd week due to acute toxicities. Thus, a total of 23 (76.7%) patients in the conventional arm and 27 (90%) patients in the adaptive arm could complete 6–7 doses, resulting in a total cumulative dose of >200 mg/m2. Response evaluation was done according to the RECIST criteria. At the end of treatment, complete response (CR) was observed in 23 (76.7%) and 20 (66.7%) patients, respectively, in the control and study arms. In the control arm, seven (23.3%) patients showed partial response (PR) with residual disease at node in five patients and at primary site in two patients, whereas nine (30%) patients showed PR and one (3.3%) had stable disease in the study arm. At 6 months after treatment completion, 27 (90%) patients in the control arm whereas 29 (96.7%) patients in the study arm achieved CR.
Table 1: Patient characteristics

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Insignificant differences were observed in acute Grade 2 skin reactions, which were 70% and 66.7% in patients in the conventional and adaptive IMRT arms, respectively. Similarly, 60% and 63.4% of the patients in the conventional and adaptive arms, respectively, developed Grade 2 stomatitis. Acute Grade I, II, and III dysphagia occurred in 23.3%, 60%, and 36.6% of the patients, respectively, in the adaptive arm. All the reactions resolved within 2 weeks of treatment completion [Table 2]. Upon treatment completion, all patients suffered from RTOG Grade I or II xerostomia in both the arms. As per the CTCAE criteria, there were similar rates of Grade ≥2 Xerostomia in the control (96.7%) and adaptive arms (93.7%) at 6 months post treatment. However, a statistically significantly higher number of patients suffered from Grade 3 Xerostomia at 6 months in the control (50%) compared to the adaptive (30%) arm (P = 0.0149) [Table 3]. Our study also assessed the TVRR of the pre-RT and re-scan GTV, which was found to be 31.85%. The reduction in Dmean was also found to be 4 Gy (6%) and 1.9 Gy (2.2%) for ipsilateral and contralateral parotid glands, respectively, whereas the Dmax of spinal cord decreased by 3 Gy (4.3%) [Figure 1] and [Figure 2].
Table 2: Acute toxicity assessment

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Table 3: Xerostomia at 6 months (CTCAE)

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Figure 1: Tumor volume reduction rate in adaptive intensity-modulated radiotherapy arm

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Figure 2: Reduction in organs at risk dose in adaptive intensity-modulated radiotherapy arm

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 > Discussion Top


The IMRT technique gives the ability to create treatment fields with varying beam intensity by using inverse planning and iterative optimization algorithms.[17] In the current practice for HNC RT, many centers carry out the original treatment plan to completion without accounting for anatomical changes that can occur due to weight loss, tumor shrinkage, edema, inflammation, and normal tissue volume alterations.[10],[18] These volumetric changes could potentially lead to overdosing of normal tissues and underdosing or marginal geographical misses of target volumes during a course of treatment based on a single-planning data set. A possible solution to account for these changes is ART, which involves repeat imaging and replanning during a course of radiation treatment.

The purpose of this study was to verify the potential impact of ART on final clinical, toxicity, and dosimetric outcomes for HNC IMRT. The study also examined the use of ART to calculate TVRR and percentage reduction in OAR dose. Our study showed a 96.7% locoregional disease control rate with adaptive IMRT at 6 months, which was similar to a two-step IMRT study done for 31 nasopharyngeal carcinoma (NPC) patients at the Kinki University by Nishimura et al.[19] The results demonstrated the 3- and 5-year locoregional control rates to be 93% and 87%, respectively.

In this study, we also analyzed acute toxicities such as skin reactions, stomatitis, dysphagia, and xerostomia during treatment and at the end of treatment in both conventional and adaptive IMRT arms. Our results showed coherence with the prospective study on 22 patients undergoing adaptive IMRT for HNC conducted by Schwartz et al.,[16] which demonstrated equivalent acute toxicity profiles between conventional and adaptive IMRT at 1 year.

Xerostomia rates according to the RTOG criteria were similar in both the arms at the end of treatment and 6 months post radiotherapy. However, rates of xerostomia were statistically significantly lower in the adaptive arm at the end of 6 months, according to the CTCAE guidelines (P = 0.0149). Nishi et al.[20] in their study of volume and dosimetric changes and initial clinical experience of a two-step adaptive IMRT scheme for twenty patients of HNC, evaluated xerostomia scores 1–2 years after treatment and found that none of the patients complained of Grade 2 or more xerostomia.

In addition to the above benefits, the use of ART could improve local control for patients with HNC, while providing critical insight into TVRR, which could ultimately help to “tailor” therapy and management during an RT course.[18]

Our study also assessed the TVRR of the pre-RT and re-scan GTV, which was found to be 31.85%, which is similar to several studies that have demonstrated an obvious volume reduction of the GTV during RT. The result of a study by Tan et al.[21] which prospectively analyzed twenty patients with treatment-naïve, locally advanced NPC showed TVRR of 55.3% in the GTV. In the studies by Geets et al.[22] and Castadot et al.,[11] the GTV_T of ten patients with pharyngo-laryngeal cancer experienced significant volume reductions after receiving a mean dose of 45 Gy. The GTV_T decreased on an average of 65.5%. In our study, the reduction in Dmean was also calculated to be 4 Gy (6%) and 1.9 Gy (2.2%) for ipsilateral and contralateral parotid glands, respectively, whereas the Dmax of spinal cord decreased by 3 Gy (4.3%). These results were in agreement with a study by Bhandari et al.,[23] which prospectively analyzed the impact of repeat CT scans and replanning in IMRT for 15 HNC patients after the 3rd week of RT. There was a statistically significant increase in Dmean of right and left parotids in the control arm of 5.56 ± 4.99 Gy (P < 0.04) for the right parotid and 3.28 ± 3.32 Gy (P = 0.03) for the left parotid. Dmax of spinal cord also increased statistically significantly in the control arm, 1.25 ± 2.14 Gy (P = 0.04), compared to adaptive arm. Another study by Surucu et al.[24] analyzing the outcomes of adaptive IMRT in 51 HNC patients showed that the median dose reduction to spinal cord, brain stem, ipsilateral, and contralateral parotid was −4.5%, −3.0%, −6.2%, and −2.5%, respectively.

The limitation of our study was a small sample size and a short follow-up period. Further studies with larger sample size and longer follow-up are required to validate these results. Furthermore, implementing ART for routine use is a time- and resource-intensive process.[25] Hence, a more judicious use of ART would be to identify patients pre treatment who are more likely to experience significant tumor regression during RT course.


 > Conclusion Top


This study was undertaken to verify the potential impact of adaptive RT on final dosimetric, clinical, and toxicity outcomes for HNC when compared with the conventional IMRT during and after treatment up to 6 months. Both arms showed comparable results in terms of clinical response and toxicity profiles. However, there were reductions in tumor volumes and dose to OAR with adaptive IMRT, which resulted in significantly lower rates of xerostomia at 6 months. Hence, mid-treatment adaptive replanning can help in better target coverage and minimize toxicities in HNC patients.

Acknowledgments

The authors would like to thank the doctors and support staff of the Department of Radiation Oncology, Acharya Tulsi Regional Cancer Treatment and Research Institute, Bikaner, Rajasthan, India.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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