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ORIGINAL ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 1  |  Page : 120-126
 

Continuous hyperfractionated accelerated radiotherapy using modern radiotherapy techniques for nonsmall cell lung cancer patients unsuitable for chemoradiation


Department of Radiation Oncology, Tata Medical Center, Kolkata, West Bengal, India

Date of Web Publication1-Dec-2017

Correspondence Address:
Dr. R K Shrimali
Department of Radiation Oncology, Tata Medical Center, Kolkata, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_158_17

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 » Abstract 

INTRODUCTION: The continuous hyperfractionated and accelerated radiotherapy (CHART) regimen of radiotherapy (RT) for nonsmall cell lung cancer is underused outside the UK. We present the first Indian experience of using CHART for patients, who were not suitable for chemotherapy or concurrent chemo-RT. METHODS: We retrospectively reviewed the data of patients treated using CHART at our institution between January 2014 and December 2015. RESULTS: Thirty-seven patients were treated using CHART. Planning methods and dosimetry parameters are described. Three-dimensional conformal RT was used for treatment planning and delivery in 23 patients and volumetric modulated arc RT was necessary for 14 patients. Patients in our series had a median age of 70 years (interquartile range 65.50–74.00) and 86.5% had Stage III disease. Median follow-up was short at 13.0 months. Actuarial rates of 1-year progression-free survival, 1-year overall survival (OS), and 2-year OS were 31.9%, 59.5%, and 28.5%, respectively. This treatment was well tolerated with manageable and some reversible acute esophageal toxicity (91.9% CONCLUSION: Our results indicate that CHART is feasible, safe, and well tolerated in Indian patients who are clinically found to be not suitable for either sequential or concurrent chemo- RT.


Keywords: Accelerated hyperfractionation, continuous hyperfractionated and accelerated radiotherapy, lung cancer, three-dimensional conformal radiotherapy, volumetric modulated arc radiotherapy


How to cite this article:
Shrimali R K, Arunsingh M, Das A, Mallick I, Mahata A, Prasath S, Achari R, Chatterjee S. Continuous hyperfractionated accelerated radiotherapy using modern radiotherapy techniques for nonsmall cell lung cancer patients unsuitable for chemoradiation. Indian J Cancer 2017;54:120-6

How to cite this URL:
Shrimali R K, Arunsingh M, Das A, Mallick I, Mahata A, Prasath S, Achari R, Chatterjee S. Continuous hyperfractionated accelerated radiotherapy using modern radiotherapy techniques for nonsmall cell lung cancer patients unsuitable for chemoradiation. Indian J Cancer [serial online] 2017 [cited 2020 Apr 5];54:120-6. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/120/219545



 » Introduction Top


Nonsmall cell lung cancer (NSCLC) is the most common cause of cancer death in the world.[1],[2] Radical radiotherapy (RT) with curative intent is commonly used for inoperable patients (Stage: I–III) with NSCLC. The reported long-term survival rate is 15% in 5 years.[2] The typical radical RT schedule delivers 60 Gy in 30 fractions, over 6 weeks, using 2-Gy fractions daily.[3] Concurrent chemo-RT is widely used for inoperable Stage II and III NSCLC.[4]

Lung cancer cells undergo rapid proliferation with short doubling and repopulation during prolonged RT is well recognized. Hence, it is more efficacious to complete radiation within the shortest possible overall treatment time than conventional or prolonged fractionation.[5],[6],[7],[8],[9],[10] A recent meta-analysis of lung RT schedules included data from 2685 patients from 10 randomized studies from 1970 to 2005. Of 2000 patients with NSCLC, at a median follow-up of 6.9 years, 1849 had died. The hazard ratio from altered fractionation schedules was 0.88 (95% confidence interval [CI]: 0.80–0.97), with reduction in the risk of death by 12%.[11]

The continuous hyperfractionated and accelerated RT (CHART) regimen of RT, delivering 54 Gy in 36 fractions of 1.5 Gy/fraction delivered thrice daily (at least 6 h apart) over 12 consecutive days, has provided strong evidence from a randomized trial that reducing tumor repopulation by shortening the overall treatment time results in improved local control rates and survival in NSCLC.[7],[8] The CHART trial reported a 9% improvement in 2-year survival (29% vs. 20%, P = 0.004).[7] The reduction in the relative risk of local progression was 21% (P = 0.033). Acute esophageal morbidity was higher, but no significant difference was reported in long-term toxicity.[7] More mature data confirmed the benefits and established that CHART was superior to conventional radical RT in inoperable NSCLC.[8] The CHART trial has not resulted in widespread change in practice because of logistical issues such as hospitalization and weekend treatment.[9],[12],[13] In addition, national holidays and planned machine maintenance can limit the number of weekends available for treatment. Compounding this was clinical concerns about acute mucosal side effects, micrometastases, and distant failure.[7],[12],[14] Besides, radical RT was already evolving into combined modality treatment with platinum-based chemotherapy and conventional radical RT and CHART had not been compared with chemo-RT in the original study.[9],[13] Therefore, in the UK, CHART is currently the recommended standard only when patients are prescribed radical RT alone (guidance.nice.org.uk/cg121).[15]

The recent Radiation Therapy Oncology Group (RTOG) 0617 study showed no benefit in improving outcomes from dose escalation using a longer treatment schedule.[16] With the evidence in favor of accelerated RT, there have been efforts to improve local control and survival in this setting of accelerated RT by intensification of treatment like addition of chemotherapy or dose escalation.[9],[11],[12] Recent CHART trials including MRC-INCH (using induction chemotherapy before CHART) and CHART-escalated dose (CHART-ED) have also used three-dimensional conformal radiation therapy (3D-CRT) but not volumetric modulated arc therapy (VMAT) for delivering RT. CHART-ED, a Phase I trial of intensifying CHART using dose escalation has been published recently.[17] CHART-ED was proposed as one of the dose escalation arms in ADSCaN trial.[13],[17] CHART has also been combined with chemotherapy with better response rates, but reports of toxicity-related deaths have hindered progress.[18],[19] Phase III randomized trials using induction chemotherapy combined with accelerated hyperfractionated RT failed to recruit the required number of patients.[20],[21] Modern RT techniques (such as 3D-CRT, intensity-modulated RT [IMRT], or VMAT) are necessary toward the greater objective of dose escalation without increasing toxicities.

In our institution, concurrent chemo-RT is the treatment of choice for patients with inoperable, Stage II and III, NSCLC. However, toxicity from chemo-RT can be significant.[4] Patients who decline chemotherapy, or are not fit for chemotherapy (either because of comorbidity or poor general condition), are treated with radical RT alone.[15] It is this group of patients that CHART is used as an effective alternative to conventional RT alone.

The standard approach is 3D-CRT, keeping doses to spinal cord, normal lung, and esophagus as low as possible. With CHART, careful study of the dose-volume histograms (DVHs) for spinal cord, esophagus, and normal lung are essential. When the target volume coverage or dose constraints to the organs-at-risk (OAR) were difficult or impossible to satisfy using 3D-CRT VMAT was used instead.[22] By applying advanced RT techniques such as VMAT, where necessary, CHART has been extended to patients who would previously not have been candidates for radical RT.

In this article, we present our experience of treating non-Caucasian NSCLC patients using CHART, including a subgroup of patients where VMAT was necessary. No previous literature has been found reporting on this group of patients. Apart from detailing our tumor and dosimetry parameters and early outcome data, we were primarily looking at the feasibility and safety of using CHART in our patient population and of combining CHART with VMAT.


 » Methods Top


Thirty-seven patients with confirmed NSCLC, by histology or cytology, received CHART at our hospital, from January 2014 to December 2015. They were deemed unsuitable for concurrent chemoradiation as they had either declined chemotherapy or were not fit for chemotherapy. Of the patients who were older than 70 years and had Eastern Cooperative Oncology Group performance status of 2, 7 patients (19%) declined concurrent chemotherapy. The rest of these patients (81%) were deemed unfit or unsuitable for concurrent chemoradiation, by the lung cancer multidisciplinary tumor board because of comorbidity (often two or more) such as history of poorly controlled angina, myocardial infarction, coronary bypass surgery or angioplasty, previous cerebral stroke, transient ischemic attacks, renal impairment, recent sepsis, debilitating arthritis, and poorly controlled diabetes. The epidemiological data, the response assessments, and the follow-up data were extracted retrospectively from the case records available on the electronic hospital management system. The planning dosimetric details were collected from the archived plan files in the treatment planning system (Eclipse version 10.0.42, Varian Medical Systems, Palo Alto, CA, USA). Considering the retrospective nature of the study, full exemption to consent from the patients was granted by the Institutional Review Board of Tata Medical Centre (irb@tmckolkata.com).

Patients were staged with a whole-body positron emission tomography using fluorodeoxy glucose-computed tomography (FDG-PET-CT) and a magnetic resonance imaging of the brain. Lung function tests included spirometry and diffusing capacity of the lungs for carbon monoxide.

Treatment planning

Standard (helical) and slow CT scans (axial) were acquired in supine position, in quick succession, in the same sitting. The “slow scan” was an axial CT scan whereby the couch moved for the preset slice thickness and images were acquired and so on, for the entire volume of interest. The standard settings used at our center aim to acquire axial slices of 2.5 mm thickness at a rate of four images per gantry rotation. Images of the tumor acquired during a slow CT scan approximate an internal target volume (summation of gross tumor volume [GTV] in all the phases of a respiratory cycle). Slow CT scanning is often used as a surrogate for 4D CT scan.[23] The GTV comprised the primary tumor and involved lymph nodes delineated on the helical scan. Information from staging FDG-PET was used in GTV delineation and the slow scan was used to obtain the volume including the entire motion envelope. The clinical target volume (CTV) was obtained using a margin of 5 mm around GTV. The planning target volume (PTV) was defined using a margin of 1 cm around the CTV and 1.3 cm in the craniocaudal direction. The craniocaudal margin was larger to account for the greater uncertainty due to respiratory motion in this direction. The spinal cord as visualized by the bony canal limits in all slices of the scan, and bilateral lungs were outlined as OAR. The esophagus (outer margin as visualized from the cricopharynx to the gastroesophageal junction) and heart (defined by the pericardial sac from the superior aspect of pulmonary artery to the inferior most clearly visible section) were contoured for dose evaluation.

A 3D-CRT plan was generated for all patients and the use of VMAT was decided on a case-by-case basis by the clinical oncologist and medical physicist, where they felt the 3D-CRT plan was not satisfying the dose-volume criteria for either the PTV or OARs.[22],[23],[24] This was usually because of large disease volume such as mediastinal node-positive peripheral tumor or involvement of contralateral lymph nodes (N3 disease) or challenging tumor positions such as tumors close to the spinal cord.[25] Of the 14 patients treated using VMAT in the current series, 8 had Stage IIIb (either N3 or T4 N2) lung cancer and 5 patients were staged as IIIa (often multi-station N2 nodes). They had bulky tumors resulting in significantly larger target volumes, with a mean PTV of 892.83 cc compared with 611.05 cc for patients treated using 3D-CRT (P = 0.046). Specific reasons for choosing VMAT for individual patients were not prospectively recorded at the time of planning.

The plans aimed to achieve PTV coverage of 95%–107% of the prescribed dose. Our dose criteria for OARs are summarized in [Table 1]. The Eclipse treatment planning system (version 10.0.42, Varian Medical Systems, Palo Alto, CA, USA) was used to generate both the 3D-CRT and VMAT plans. VMAT plans were generated using RapidArc (Varian Medical Systems, Palo Alto, CA, USA) which manipulates dynamic multileaf collimators, dose rate, and gantry positions to produce precise dose distributions. Our planning techniques for lung cancer using 3D-CRT and VMAT have been described in our earlier publication.[22] Every patient had a backup plan generated for tomotherapy, to ensure continuity of treatment in case of unplanned machine downtime. All patients receiving CHART underwent daily verification imaging with cone beam CT (CBCT) for at least 1 fraction and kV (electronic portal imaging devices) for the remaining 2 fractions. CBCT was restricted to 1 fraction/day to minimize radiation exposure and workload. Subgroup analyses have been carried out comparing the VMAT group and 3D-CRT group, comparing tumor parameters, dose-volume parameters, and acute toxicity.
Table 1: Dose constraints for continuous hyperfractionated and accelerated radiotherapy planning

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All patients were admitted through the course of the treatment. All patients were then reviewed a week after completion of treatment and then on a fortnightly basis until 6 weeks after completion of RT. A CT was carried out about 2.5–3 months after treatment to assess response.

Statistical analysis

Statistical analysis was carried out using the statistical package SPSS version 23 (IBM, Armonk, New York, USA). The disease and treatment data were summarized. Subgroups, based on histology and treatment techniques, within the treated patients were compared using Mann–Whitney U-test, and Fisher's exact tests as appropriate. The survival analyses were performed using the Kaplan–Meier test and the subgroups within were compared using the log-rank test.


 » Results Top


The demographic details of the patients, tumor histology, and the clinical stage are detailed in [Table 2]. The tumor volumes and planning parameters are detailed in [Table 3]. VMAT was used for 14 out of 37 patients with Stage III NSCLC. Although PTV size was not the only criterion for deciding in favor of VMAT, the median PTV was found to be significantly larger for patients requiring VMAT compared with patients treated using 3D-CRT (P = 0.046). The parameters for target coverage are detailed in [Table 4]. The proportion of PTV covered by the 95% dose distribution (PTV-95%) was found to be acceptable overall. There was a trend toward better coverage for the 3D-CRT group (P = 0.066), probably because of smaller PTVs. The indices of quality of coverage, namely, conformity indexRTOG(CIRTOG= prescription isodose volume/PTV) and conformity number (CN = PTVPI2/PTV × VPI, where PTVPI= PTV covered by prescription isodose in cc) were significantly better with VMAT (P< 0.001).[26],[27] There was no difference in homogeneity indexRTOG(HIRTOG= maximum dose within PTV/prescription dose) between the VMAT and 3D-CRT groups (P = 0.344), probably because we had used a field-in-field technique for reducing the heterogeneity in dose distributions.[26]
Table 2: Demographics

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Table 3: Tumor volumes and parameters

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Table 4: Target coverage parameters, indices of conformality, and homogeneity

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The doses to the OARs were found to be acceptable and are detailed in [Table 5]. The median V5 (proportion of lung receiving at least 5 Gy, expressed as percentage) significantly increased from 50.8% to about 59% with the use of VMAT, when compared with the 3D-CRT group (P = 0.039). The maximum esophagus dose (57.3 vs. 55 Gy; P = 0.002) and the V55 Gy (4.3% vs. 2.3%; P = 0.012) were significantly higher in the VMAT group when compared to the 3D-CRT group. No significant difference was found between the groups (VMAT and 3D-CRT) for other OAR parameters.
Table 5: Doses to the organs-at-risk

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Dysphagia was the major acute toxicity, where 14 patients had Grade 1 and 12 patients had Grade 2 (Common Terminology Criteria for Adverse Events version 4.03) toxicity.[28] The overall breakdown of dysphagia based on 3D-CRT and VMAT patients is detailed in [Table 6]. Grade 3 dysphagia was seen in three patients, all of who received 3D-CRT. One patient who was treated using 3D-CRT had Grade 2 pneumonitis. None of the VMAT patients had any pneumonitis. There have been no incidence of long-term dysphagia or radiation-induced myelopathy.
Table 6: Acute esophageal toxicity according to Common Terminology Criteria for Adverse Events version 4.03

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Median follow-up is 13 months (inter quartile range – 4.0–20.5 months). Actuarial rate of 1-year progression-free survival (PFS) was 31.9%. Actuarial rates of 1-year and 2-year overall survival (OS) were 59.5% and 28.5%, respectively, seen in the Kaplan–Meier curve displayed in [Figure 1]. Subgroups analyse looking at the PFS and OS based on histology, the treatment groups, and the stage groups (II or III) did not show any statistically significant difference between the groups, possibly due to smaller patient numbers and a short follow-up.
Figure 1: Kaplan–Meier curve for overall survival

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 » Discussion Top


CHART has been an accepted form of radical RT since the CHART trial publications.[7],[8] The CHART series presented in this paper is unique in many ways. This is the first paper to report on the clinical use of CHART for lung cancer outside the UK and Europe. In particular, this paper confirms that CHART is feasible and well tolerated in our non-Caucasian population.

The original CHART trial used conventional two-dimensional planning and limited the area of high-dose field (54 Gy) when viewed anteriorly to 140 cm 2.[27] DVH for lung and other OARs were not possible at the time.[18],[19] Since the initial CHART trial, there have been technological leaps in RT techniques. Experience is limited in combining these technologies with CHART. In the current series, modern RT techniques were used, with 37.8% (n = 14) receiving VMAT for reasons described earlier, and the rest receiving 3D-CRT. Elective nodal irradiation (ENI), which was standard during the initial CHART trial, is no longer used. With omission of the ENI and use of modern RT techniques (3D-CRT, IMRT or VMAT), it is possible to reduce excessive radiation doses to the spinal cord, esophagus, and normal lung. Computerized planning has made it possible to generate DVH data and to ensure that the doses to esophagus and normal lung are within tolerance. With CHART, the major toxicity concerns include damage to esophagus and lungs.[7],[8],[14] Both V-20 of lung and mean lung dose (MLD) have been shown to have correlation with the risk for radiation pneumonitis. A V-20 of 35% or less and a MLD value of <20 are acceptable constraints.[23],[24] The V20 in our series (mean – 23.49%) was comparable to that of other contemporary studies such as the CHART-ED (mean – 25.4%). Similarly, the maximum dose to the spinal cord (mean – 16.68 Gy) was well below the reported dose in CHART-ED study (mean – 34.7 Gy). In our small series with early data, CHART using VMAT was well tolerated with manageable and reversible esophageal toxicity. In the current series, 86.5% of the patients had mainly Stage III NSCLC (n = 32), compared to about 61% in the original CHART study.[7],[8] No patient with Stage I was present in our series. A significant proportion (36%) of patients in the original CHART trial had Stage I–II disease whereas the standard treatment for most of these patients in contemporary practice would be surgery or stereotactic ablative body RT. Our patients were older compared to only 26% above 70 years in the original study, less fit and deemed to be unsuitable for chemotherapy or chemoradiation compared to the patients in the original study who were all classified performance status 0–1. Therefore, the patients in our series were very unlikely to receive any salvage therapy on progression.

The 1-year OS estimates of 59.5% observed in our series, although calculated at short median follow-up, is comparable with the published original CHART study with a 1-year OS of 63%. The survival figures are even more encouraging because the patients in our series were considerably more advanced stage than patients in the original CHART study and the latter CHART series published by Din et al., reporting a retrospective series from five UK centers treated with 3D-CRT having a 2-year OS of 34%with a minimum of 2-years of follow-up.[7],[29] However, the slightly less OS estimate compared to that of the recent randomized trials of INCH and CHART-ED can be explained by the fact that these were largely poor performance status patients who were unfit for more intensive treatment.

The incidence of severe acute dysphagia, Grade 3 or more (8.11%), was also comparable with other studies which used 3D-CRT like the INCH (13%) and the CHART-ED (16.67%) while Din et al. reported 10%. Dysphagia was not graded in the original CHART study, but it reports severe dysphagia (restricted to fluids) have been 19%. There was very low incidence of Grade 2 or more pulmonary toxicity (<1%) compared to 16% reported incidence of pulmonary fibrosis at 2 years in the original CHART study and was comparable to the more recent CHART-ED which did not report any Grade 2 pulmonary toxicity. There were no cases of radiation myelopathy despite the more advanced nature of disease in our group of patients. This too is favorable compared to similar reports in the INCH and CHART-ED studies while Din et al. had 2% Grade 2 myelitis. Both pulmonary and neurological toxicity are known to be a late developing toxicity and hence will require more long-term follow-up to firmly comment upon. The use of VMAT and the use of DVH for analyzing the dose distributions to the OARs have definitely helped in limiting the severe toxicities.

RT services are grossly inadequate in large areas of the developing world, particularly middle-income, lower middle-income, and low-income countries.[30],[31] In our series, 16 patients (out of 37) had travelled long distances and 4 patients crossed international borders to undergo treatment for NSCLC. For these patients, accelerated treatments such as CHART have an added advantage of completing treatment within 12 days. These patients spend shorter time away from their homes, effectively reducing the logistic and financial burden of cancer.

The limitations of the present study were that this was a retrospective analysis of the patients who received CHART at our center and also the short follow-up of the patients precludes strong conclusions on survival data.


 » Conclusion Top


CHART using 3D-CRT or VMAT (as necessary) was feasible and well tolerated for routine use in the non-Caucasian patient population and is an effective single modality treatment for NSCLC patients who are not suitable for chemoradiation. The main side effect was manageable and reversible acute esophageal toxicity. Clinical impact of this experience needs to be evaluated further for toxicity, local control, and survival. The authors feel that the next logical step in our setting would be carefully intensifying treatment by either dose escalation or by adding chemotherapy to CHART, in a well-designed clinical trial for patients who are eligible to undergo concurrent chemoradiation.

Acknowledgements

Dr Matthew Hatton, Department of Clinical Oncology, Weston Park Hospital, Whitham Road, Sheffield, UK.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]

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