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Accelerated Radiation Therapy Using Weekend Boost with Concurrent Cisplatin in Head and Neck Squamous Cell Cancers: An Indian Institutional Experience
Journal of Medical Imaging and Radiation Sciences
Journal of Medical Imaging and Radiation Sciences xx (2017) 1-9
Journal de l’imagerie médicale et des sciences de la radiation
www.elsevier.com/locate/jmir
Accelerated Radiation Therapy Using Weekend Boost with Concurrent Cisplatin in Head and Neck Squamous Cell Cancers: An Indian Institutional Experience Pushpa Naga C.H., MD, DNBa*, Janaki M.G., MD, DNBb, Arul Ponni T.R., MDb, Rajeev A.G., MDc, Kirthi Koushik A.S., MDb and Mohan Kumar S., MDb a
b
Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India Department of Radiation Oncology, M.S. Ramaiah Medical College and Hospitals, Bengaluru, Karnataka, India c Department of Radiation Oncology, Radiant Cancer Hospital, Mysooru, Karnataka, India
ABSTRACT Purpose: The purpose of the study was to evaluate the feasibility and efficacy of an accelerated radiotherapy schedule using weekend boost in terms of tumor response, compliance, and acute toxicities for head and neck squamous cell carcinoma, and to report long-term clinical outcomes. Materials and methods: Twenty-six patients with stages III-IV head and neck squamous cell carcinoma receiving radical chemoradiotherapy were accrued prospectively into the study. External beam radiation therapy to a total dose of 66–70 Gy in 33–35 fractions, 1.8– 2.0 Gy per fraction along with concurrent weekly cisplatin was planned. Radiation regimen included delivery of six fractions per week, with boost field delivered as the sixth fraction on the weekend. The compliance, tumor response, and toxicities were recorded. Survival curves were estimated using the Kaplan–Meier method. Results: Twenty-one of 26 patients (81%) completed treatment as planned and five patients died during the course of treatment. Sixteen patients (62%) completed treatment in less than 44 days and, at the end of 3 months’ follow-up, 18 patients (69%) showed complete response and two patients (8%) showed partial response. The 2- and 5-year actuarial disease-free survival were 90% and 65%, respectively, and 2- and 5-year actuarial overall survival were 60% and 38%, respectively. Conclusion: Accelerated fractionation using weekend boost, along with concurrent weekly concurrent cisplatin, is an effective and
Financial disclosure: None. Conflict of interest: None. Prior presentation: None. Work attributed to Department of Radiation Oncology, M.S. Ramaiah Medical College and Hospitals, Bengaluru, India. * Corresponding author: Dr. Pushpa Naga C.H., MD, DNB, Department of Radiation Oncology, Tata Memorial Hospital, Dr. Ernest-Borges Road, Parel, Mumbai 400012, Maharashtra, India. E-mail address: [email protected] (P.N. C.H.).
promising approach with favorable impact on initial tumor response, comparable results, and acceptable toxicities. RESUM E Objet : Evaluer la faisabilite et l’efficacite d’un calendrier de radiotherapie accelere utilisant un complement de dose (boost) le weekend en termes de reponse de la tumeur, conformite et toxicites pour l’epithelioma malpighien spinocellulaire de la t^ete et du cou (EMSTC) et presenter les resultats cliniques a long terme. Materiel et methodologie : Vingt-six patients atteints d’un EMSTC de stade III-IV recevant des traitements de chimiotherapie ont ete ajoutes a l’etude de fac¸on prospective. La planification comprenait des traitements de radiotherapie externe, pour une dose totale de 66-70 Gy, en 33-35 fractions, 1,8-2,0 Gy par fraction combinee a des injections hebdomadaires de cisplatine. Le regime de rayonnement prevoyait l’administration de six fractions par semaine, le complement de dose representant la sixieme fraction, administree durant le week-end. La conformite, la reponse tumorale et les toxicites ont ete compilees. Les courbes de survie ont ete estimees par la methode Kaplan–Meier. Resultats : Vingt-et-un des 26 patients (81%) ont complete le traitement comme prevu et cinq patients sont morts avant la fin du traitement. Seize patients (62%) ont complete le traitement en moins de 44 jours, et a la fin de trois mois de suivi, 18 patients (69%) affichaient une reponse complete (CR) alors que deux patients (8%) affichaient une reponse partielle (RP). Le taux actuariel de survie sans maladie (SSM) apres deux et cinq ans etait respectivement de 90% et de 65%, alors que le taux actuariel de survie globale (SG) etait respectivement de 60% et 38%. Conclusion : Un fractionnement accelere utilisant un complement de dose administre durant la fin de semaine avec injection hebdomadaire concurrente de cisplatine est une approche efficace et prometteuse avec des repercussions favorable sur la reponse tumorale initiale, des resultats comparables et des toxicites acceptables.
1939-8654/$ - see front matter Ó 2017 Published by Elsevier Inc. on behalf of Canadian Association of Medical Radiation Technologists. http://dx.doi.org/10.1016/j.jmir.2017.05.001
Keywords: Head and neck cancer; accelerated fractionation; weekend boost; concurrent chemoradiation
Introduction Among the various accelerated fractionation schedules studied in head and neck squamous cell carcinoma (HNSCC), acceleration of radiation by 1 week without dose reduction (ie, delivering six fractions instead of the conventional five fractions per week) is found to have a beneficial effect on locoregional control (LRC) along with a modest reduction in overall treatment time (OTT), and without an increase in late effects [1, 2]. However, results with this approach alone are widely variable, and improvement in survival has not been consistent [3, 4]. Substantial clinical investigations have demonstrated consistent survival gain along with favorable impact on LRC rates with concurrent chemoradiation. However, benefits of combined modality treatment come at the expense of additional acute mucocutaneous toxicities [5]. Consequently, concurrent chemoradiotherapy is the preferred nonsurgical treatment modality for locally advanced diseases, whereas altered fractionation is generally selected for early and intermediate stage tumors or for patients who are medically unfit for chemotherapy [6, 7]. Furthermore, evidence is needed for combining an altered fractionation regimen with concurrent chemotherapy without resulting significant compromise in normal tissues. Theoretically, delivery of a smaller boost field on a weekend as sixth fraction of the week, instead of a larger field, will effectively reduce OTT by one week, and without much increase in toxicity. With an aim to evaluate the feasibility and efficacy of this approach, we undertook this study. In this study, we intend to reduce OTT by delivering six fractions per week, wherein the sixth fraction is a boost field encompassing only gross tumor volume on the weekend, along with concurrent weekly cisplatin chemotherapy.
chemoradiotherapy with radical intent at M.S. Ramaiah Hospitals, Bengaluru were considered. Patients aged between 18 and 80 years, with Karnofsky performance status 70 and adequate baseline bone marrow function (hemoglobin >10 gram%, absolute neutrophil count >1500 per microliter, platelets >100,000 per microliter), normal hepatic and renal function were accrued. Nasopharyngeal, early laryngeal (T1 and T2), postoperative cases, history of prior radiation or chemotherapy, any previous or synchronous malignancy and hypersensitivity to platinum agents were excluded. Sample Size Calculation The sample size was estimated in consultation with a biostatistician using ‘‘n-Master’’ Software based on previous trial by Skladowski et al [8] which compared 7-day continuous accelerated irradiation (CAIR) with conventional fractionation schedule in a randomized clinical trial. Considering 25% precision and 90% desired confidence limit, minimum sample size required accruing in one and half year period was 25. A total of 26 patients were accrued into study in the previously mentioned study period. Pretreatment Evaluation Initial work up consisted of clinical examination, laboratory tests including complete blood count, and renal and hepatic function tests were done for all patients to assess the general condition of the patient. Computed tomography and/or magnetic resonance imaging of head and neck region was done to document local extent of disease. Chest radiograph and abdominal sonography were done to rule out metastases. Each patient was clinically staged as per American Joint Committee on Cancer Tumor Node Metastasis, 2010 staging system after complete work up.
Methods and Materials
Treatment
Study Design
All patients were immobilized with four-clamp head and neck thermoplastic orfit and planning simulation done on a conventional x-ray or computed tomography simulator. During simulation, enlarged lymph nodes were externally delineated with a lead wire to ensure adequate encompass within portals. External beam radiation therapy either on telecobalt machine or linear accelerator (6 MV) using conventional or three-dimensional conformal radiation therapy techniques were permitted. A total dose of 66–70 Gy in 33–35 fractions with 1.8–2.0 Gy per fraction over a 6.5-week period was administered with parallel opposed lateral portals using shrinking field technique in three phases without any tissue compensators. Nodes were treated electively in all patients. A direct anterior lower neck field was used in selected patients. Initial dose of 45 Gy was delivered to Phase 1 radiation portals, which encompassed gross tumor and microscopic
The trial was designed as a prospective, single-center, onearmed study to assess the efficacy and safety of accelerated fractionation schedule using weekend boost (WEB) and concurrent chemotherapy for locally advanced head and neck cancers. The study protocol was approved by the institutional ethics committee. Written informed consent was obtained from each eligible patient before inclusion into the study after explaining in detail the nature, scope and possible consequences of participation in the trial. Data Collection and Inclusion–Exclusion Criteria Between December 2011 and July 2013, all histopathologically proven HNSCC patients receiving concurrent 2
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diseases of both primary and draining lymph nodes, 5 days a week (from Monday to Friday). Additional Phase 3 boost field fraction, which encompassed only gross disease with a margin, was delivered on Saturdays as the sixth fraction of the week to a dose of 16–20 Gy, starting from first week of treatment. Electron beams were used to boost the dose delivered to the posterior cervical lymph nodes. In case of holidays, protocol recommended delivery of boost treatment as a second fraction after the last fraction of week, with minimum of 6 hours gap between fractions. The remaining boost treatments were delivered during the last week of treatment after completion of planned Phase 2 (shrunken field to spare spinal cord to a dose of 5.4-6 Gy) fractions (Figures 1 and 2). The dose delivered to the spinal cord was kept below 45 Gy in all instances. On-treatment verification of portals was confirmed using conventional portal films or electronic portal imaging device as per institution protocol. Images of orthogonal setup fields were acquired daily for the initial 3 days, and weekly thereafter, until the completion of treatment. These images were verified by comparing with corresponding simulator images or digitally reconstructed radiographs obtained on treatment planning system. Any deviations beyond the prescribed margins were noted and corrected before the treatment delivery. Concurrent weekly cisplatin chemotherapy (40 mg/m2) was administered as intravenous infusion once weekly for 5– 6 weeks. A complete blood count and renal function tests were repeated before every cycle of chemotherapy. Chemotherapy was withheld in cases of any grade II or higher hematologic or renal toxicity, until recovery. In an effort to maximize delivery of core therapy, reducing or omitting chemotherapy before interrupting radiotherapy was allowed. The majority of patients received this treatment on outpatient basis. Assessments All 26 patients recruited in the study were continuously assessed, and recordings of weight, skin, and mucosal toxicity were noted weekly during treatment, at 15 days, and at 3 month follow-ups using common terminology criteria for adverse events (NCI-CTCAE) 2.0 [9]. Weekly grading of the toxicity was assigned based on highest grade observed in that week. Any interruptions or gap during treatment were also recorded with reasoning for the same.
Tumor control was assessed by means of clinical examination at the end of treatment, at 6 weeks, and 3 months later using response evaluation criteria in solid tumors guidelines [10]. Thereafter, routine follow-up was done with clinical examination (and imaging if required) at 3 months in first 2 years followed by 6 months for next 3 years and thereafter annually. Statistical Analysis Primary analysis was conducted for all patients for efficacy, outcomes, and toxicity. Descriptive statistical analysis was carried out for study parameters. Baseline weight was compared with subsequent weekly weight recording using Student’s paired t-test. Wilcoxon matched-pairs test has been used to find the significance of skin and mucosal toxicities in comparison of baseline to subsequent grading. For actuarial survival analysis, Kaplan–Meier’s method was used to compute overall survival (OS) and disease-free survival (DFS). OS was calculated from the date of diagnosis to the date of death (all causes) or to the last follow-up. DFS was defined from the date of diagnosis (biopsy confirmation) to date of first documented relapse or death because of any cause. Only patients with complete clinical response were considered for the DFS analysis, and those who were alive at last followup and disease free were censored. For all statistical tests, P < .05 was considered significant. Statistical Programme for Social Sciences software for Windows (SPSS Inc, Version 22, Chicago, USA) was used for analyses and Microsoft Excel has been used to generate graphs and tables. Results Patient and Tumor Characteristics The study population included 26 patients of HNSCC of various subsites and stages who received radical chemoradiation. The median age was 60 years (range, 49–76 years), 16 patients (61.5%) were aged >60 years. Baseline patient and tumor characteristics are shown in Table 1. Treatment Characteristics Of the 26 patients in the study, 21 patients (80.8%) completed the radiation treatment as scheduled, wherein 17 patients (65.4%) received minimum five cycles of weekly concurrent cisplatin and
Figure 1. Schematic representation of weekend boost study protocol.
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3
Figure 2. Representative sagittal images of planning computed tomography scan showing volumes and isodose coverage of three different phases: (A) Phase 1, (B) Phase 2; (C) Phase 3.
16 patients (76%) could finish treatment <44 days as planned (median 43 days). In others, OTT was ranging from 46 to 50 days because of various reasons, majority in view of poor intake associated with mucositis. Reasons for noncompliance of chemotherapy were mostly toxicity related. Among the five patients who could not complete treatment, two patients documented disease related events (aspiration pneumonia), three patients had treatment related events (septic shock and severe electrolyte imbalance), and one had diseaseunrelated death (myocardial infarction). An additional patient died after 2 months of treatment completion due to a cardiac event. Clinical Outcomes Response to Treatment Of the 20 patients who were alive at the end of 3-months’ post-treatment, 18 patients (69.2%) documented complete Table 1 Patient and Tumor Characteristics Parameter Sex Men Women Age Median (range) Tumor sites Oral cavity Oropharynx Hypopharynx Larynx Grade Well differentiated Moderately differentiated Poorly differentiated Undifferentiated Stage grouping Stage III Stage IV Nodal status Negative Positive
4
Frequency (%) 15 (57.69) 11 (42.31) 60 (49–76) y 7 11 3 5
(26.92) (42.30) (11.54) (19.24)
6 13 5 2
(23.00) (50.00) (19.2) (.80)
14 (53.50) 12 (46.20) 4 (15.40) 22 (84.60)
response (CR) and two patients (0.7%) had partial response (PR). None had stable or progressive disease according to response evaluation criteria in solid tumors guidelines. Univariate subgroup analysis of CR seen in different subsites with tumor and nodal staging was attempted but it did not reveal any statistical significance. However, a significant P value was observed on comparing node negative (n ¼ 4) vs. node positive (n ¼ 22) and also with tumor differentiation showing benefit for well and moderately differentiated tumors (n ¼ 19) compared with poorly or undifferentiated tumors (n ¼ 7). Toxicity During 4, 5, and 6 weeks of treatment, 50% (n ¼ 13) and 20% (n ¼ 7) had grade II or worse skin and mucosal toxicities respectively, which resolved by 6 weeks of treatment completion (Figure 3 and Tables 2 and 3). At the end of the first week, incidence of acute dysphagia was 12% (n ¼ 3) and reached 59% (n ¼ 15) at completion of treatment. Most of the patients were managed with symptomatic treatment with antiseptic liquids, analgesics, anti-inflammatory drugs, and local corticosteroids. Systemic corticosteroids and/or antibiotics were administered whenever severity of mucositis/ dysphagia exceeded grade II. Comparison of weekly mean values of skin and mucosal toxicity grading depicted together is shown in Figure 4. Recorded baseline mean weight of entire cohort was 51.8 kg and reached 47.3 kg by the end of treatment with median weight loss of 4 kg over the course of treatment. Comparison of weekly weight loss/gain with subsequent weeks up to last follow-up using paired t-test showed statistically significant differences (P < .0001; Table 4). Regular nutritional assessments and intervention were done whenever necessary. Seven patients (27%) had prophylactic percutaneous endoscopic gastrostomy insertion and commenced feeding when oral intake was <50% and/or >5 kg weight loss from commencement of treatment. Another 10 patients (38%) required nasogastric tube insertion during the course of treatment. Overall, 73% (n ¼ 19) patients received systemic supportive care by week 4 or 5 of the treatment that was discontinued on settling of severe toxicities.
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Figure 3. Bar-graph showing mucosal (A) and skin (B) toxicity incidences in percentage.
Follow-up and Survivals Patients who achieved CR were considered for DFS analysis. At the last follow-up at 18 months, 33.3% patients (n ¼ 6) were disease free. Two patients had a local recurrence after 12 and 15 months, respectively. One patient had a second malignancy in the postcricoid region after 16 months of primary treatment to the tonsillar lesion and was locally free of disease at the primary site. None had distant metastasis. Death occurred in five patients after median follow-up time of 20 months (range, 4.5–35 months). Three patients had disease-related death and two died of cardiac events. Status of five patients was unknown, since they defaulted. At the time of analysis, median follow-up was 9 months (range, 2–55 months) for the entire group, and one of the
six disease-free patients relapsed locally and succumbed to disease. Overall compliance with follow-up was poor. The actuarial 2 and 5-year DFS of patients with complete CR were 90% and 65%, respectively, and 2 and 5-year actuarial OS were 60% and 38%, respectively (Figure 5).
Discussion An accelerated fractionation regimen shortening OTT minimizes tumour repopulation during treatment, which is a major cause of relapse and, therefore, increases the probability of tumour control for a similar total dose. The present study has documented efficacy, toxicity, and outcomes with accelerated radiation therapy with reduction of OTT by
Table 2 Comparison of Weekly Grading of Skin Reactions by Wilcoxon Matched-Pairs Test Time Point
Mean
Median
SD
Baseline/week 1 Week 2
0.00 0.00
0.0 0.0
0.00 0.00
0.00
Week 2 Week 3
0.00 0.12
0.0 0.0
0.00 0.33
0.12
Week 3 Week 4
0.12 0.84
0.0 1.0
0.33 0.55
Week 4 Week 5
0.84 1.30
1.5 2.0
Week 5 Week 6
1.30 0.95
Week 6 1st FU 1st FU 2nd FU *
Mean Difference
SD Difference
Percentage of Change
–
Z Value
P Value
0.00
–
–
0.33
15.87
1.6036
.1088
0.69
0.65
500.00
3.4078
.0004*
0.57 0.51
0.26
0.73
400.00
2.8904
.0057*
2.0 2.0
0.53 0.52
0.04
0.80
200.00
1.9780
.0281*
0.95 0.61
2.0 1.0
0.54 0.56
0.34
0.54
433.33
3.0594
.0022*
0.61 0.00
1.0 0.0
0.55 0.00
0.61
0.55
600.00
3.6214
.0003*
1st FU, 15 days posttreatment; 2nd FU, 3 months posttreatment; SD, standard deviation. P < .05.
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Table 3 Comparison of Weekly Grading of Mucositis by Wilcoxon Matched-Pairs Test Time Point
Mean
Median
SD
Mean Difference
SD Difference
Z Value
P Value
Baseline/week 1 Week 2
0.00 0.19
0.0 0.0
0.00 0.35
0.19
0.35
100.00
1.6466
.1091
Week 2 Week 3
0.19 0.85
0.0 1.0
0.35 0.37
0.66
0.63
500.00
3.4254
.0004*
Week 3 Week 4
0.85 1.46
1.0 1.5
0.37 0.58
0.61
0.50
72.73
3.5162
.0004*
Week 4 Week 5
1.46 1.52
1.5 1.5
0.58 0.60
0.13
0.21
3.13
4.4045
.0058*
Week 5 Week 6
1.52 1.55
1.5 1.5
0.60 0.62
0.03
0.43
6.90
0.9129
.3613
Week 6 1st FU
1.55 0.48
1.5 1.0
0.62 0.18
1.07
0.64
63.16
3.0594
.0022*
1st FU 2nd FU
0.48 0.00
1.0 0.0
0.18 0.00
0.48
0.76
72.22
2.9341
.0033*
*
1st FU, 15 days posttreatment; 2nd FU, 3 months posttreatment; SD, standard deviation. P < .05.
7 days using WEB and concurrent weekly cisplatin chemotherapy. Our study population consisted of a majority of oropharyngeal cases (oral cavity 30% vs. oropharynx 42.3% vs. hypopharynx 11.5% vs. larynx 19.2%) as opposed to the study by Overgaard et al [11], which had included more laryngeal tumors (larynx 46% vs. oropharynx and hypopharynx 37% vs. oral cavity 25%; P < .0001). Of 26 patients accrued, overall response (CR þ PR) was observed in all 21 patients who completed treatment as scheduled, suggesting improved initial tumor response. Twenty patients were available for analyses of tumor response at the end of 3-month follow-up, wherein CR was documented in 18 patients (69.2%). A similar study by Skladowski et al [8], which had shortening of OTT by 14 days with CAIR, demonstrated early response at the end of treatment. It also showed complete regression of tumor in 88% of patients in the CAIR arm vs. 69% in the control arm (P < .05) and complete nodal clearance was 100% vs. 78% (P > .05) in CAIR and control arm, respectively, at the end of 3 months of treatment.
Figure 4. Graph showing trend in changes in mean values of mucosal and skin reactions.
6
Percentage of Change
It is well documented that OTT is an important prognostic factor that determines the outcome in HNSCC. Accelerated repopulation of tumour clonogens is a principle factor responsible for a disadvantageous effect of prolonged OTT [12]. With conventional fractionation, a break of about 1 week is associated with an absolute reduction in local control rates of 10%–12% [13]. Hence, a break of even 1 day is associated with reduction in LRC rate by about 1.4% (range, 0.4%– 2.5%). In our series, median OTT planned was 42 days (range, 41–44 days) and 76% (n ¼ 16) patients could finish treatment <44 days as planned. In others, OTT ranged from 46 to 50 days, mainly because of treatment interruptions due to higher grades of skin reactions and poorer intake due to grade III mucosal toxicities. In the Skladowski et al study [8], OTT was prolonged by 1 2 day in four patients (8%) in the CAIR and by 1 4 days for three patients (6%) in the control arm as opposed to 36–40 days in CAIR and 51–54 days in control arm. Two patients (2%) in CAIR arm did not complete the planned treatment. In a study by the Danish Head and Neck Cancer study group [14], OTT was kept as planned, with a median treatment time of 39 days in the six fractions per week schedule and 46 days in the five fractions per week schedule. No gap was given in spite of higher grades of acute toxicities. We observed grade II or worse skin and mucosal reactions in 50% and 20%, respectively, during last 2–3 weeks of treatment requiring symptomatic management and also enteral feeding procedures for nutritional support. In total, 19 of 26 patients (73%) were put on a feeding tube, either with percutaneous endoscopic gastrostomy tube or Ryle’s tube, by the fifth week of treatment compared with Skladowski et al [8], which demonstrated significant early onset of confluent mucositis with CAIR regimen, but none of the patients in both groups needed tube feeding although more frequent supportive treatment was given in CAIR (n ¼ 45; 92%). Overgaard et al showed 5% increase in frequency of confluent mucositis, 7% increased frequency of use of tube
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Table 4 Comparison of Weekly Weights (in kilogram) by Paired T-test Mean
SD
Baseline/week 1 Week 2
51.81 51.10
9.00 8.78
0.71
0.68
1.37
5.3294
.00001*
Week 2 Week 3
51.10 49.98
8.78 8.90
1.12
0.62
2.17
9.1523
.00001*
Week 3 Week 4
49.98 48.81
8.90 8.46
1.17
0.94
2.25
6.3805
.00001*
Week 4 Week 5
48.83 47.67
8.73 8.91
1.14
0.63
2.22
8.7781
.00001*
Week 5 Week 6
48.16 47.28
8.79 8.49
0.89
0.71
1.72
5.8893
.00001*
Week 6 1st FU
47.33 46.48
8.69 8.21
0.86
1.16
1.66
3.3761
.006*
1st FU 2nd FU
46.48 47.29
8.21 8.23
0.81
1.21
1.56
3.0682
.00001*
Week 1 Week 3
51.81 49.98
9.00 8.90
1.83
0.88
3.53
10.556
.00001*
Week 1 Week 4
51.81 48.81
9.00 8.46
3.00
1.22
5.80
12.490
.00001*
Week 1 Week 5
51.80 47.67
9.27 8.91
4.13
1.33
7.98
14.857
.00001*
Week 1 Week 6
52.34 47.27
9.12 8.49
5.06
1.58
9.76
15.014
.00001*
Week 1 1st FU
52.40 46.48
9.34 8.21
5.93
1.76
11.45
15.413
.00001*
Week 1 2nd FU
52.40 47.29
9.34 8.23
5.12
2.28
9.88
10.290
.00001*
*
Mean Difference
Paired SD Difference
Percentage of Change
Paired T-score
P Value (Two-tailed)
Time Point
1st FU, 15 days posttreatment; 2nd FU, 3 months posttreatment; SD, standard deviation. P < .05.
feeding, and 9% increase in frequency of skin reactions in the accelerated arm. Regarding healing of acute reactions, similar findings were found with the present study that all acute toxicities resolved within 3 months of starting radiation with
symptomatic management [11]. Also, the Danish Head and Neck Cancer study group 6 and 7 demonstrated 20% increase in frequency of confluent mucositis with accelerated fractionation that persisted longer but all healed within 3 months of
Figure 5. Disease free and overall survival curves.
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7
treatment [14]. Early occurrence of higher grades of toxicities requiring more frequent treatment interruptions observed in our study is probably because of the addition of concurrent chemotherapy, unlike in most accelerated regimen studies, which practiced radiation alone. Among the total 11 mortalities observed in our study, death due to aspiration pneumonia and severe electrolyte imbalance can be correlated to treatment or disease-related cause of death (n ¼ 7). Another four deaths were due to other illness. Meta-analysis of radiotherapy in carcinomas of head and neck (MARCH) [15] collaborative group revealed death due to other causes than cancer was higher in both altered fractionation (n ¼ 3650) and conventional arm (n ¼ 3423; 13.3% and 11.1%) compared with cancer-related mortality (1.7% and 1.9%, respectively). The death of nine patients that occurred in the present study were from the age group of 61–70 years, suggesting an increased hazard ratio of death and poorer prognosis to altered fractionation in an elderly age group, as analyzed in the MARCH meta-analysis, which showed benefits of altered fractionated radiotherapy differed significantly according to the patient’s age. In patients who were aged 50 years, altered fractionated radiotherapy was associated with a 45.6% reduction in the hazard ratio of death, whereas its effects were marginal in patients aged 51– 70 years; patients aged 71 years tended to have a poor prognosis compared with those given conventional fractionation. Indeed, a test for trend revealed a significant interaction between age and treatment effect for OS (P ¼ .007), and death related to cancer (P ¼ .008), local control (P ¼ .002), and LRC (P ¼ .002) [16]. These findings suggest that accelerated radiotherapy causes substantial toxic effects in elderly patients, leading to interruptions in treatment. Hence, it is prudent not to attempt in patients aged >70 years. It should be used in those <50 years and for those between 51 and 70 years it should be incorporated with close monitoring. Actuarial 2- and 5-year OS in the present study were 60% and 38%, respectively, and actuarial 2- and 5-year DFS of patients with complete CR were 90% and 65%, respectively, which is comparable with results observed by Garden et al [7], that evaluated concomitant boost accelerated radiation regimen along with cisplatin and showed 2- and 4-year local-regional failure rates of 33% and 36%, respectively, and OS rates of 70% and 54%, respectively. Similarly, in comparison of results with patients treated with IMRT technique [17, 18], no significant differences in disease outcomes were seen, although IMRT has a documented advantageous effect on long-term toxicities. With the previously mentioned observations, we propose usage of boost field as a sixth fraction starting from first week of treatment itself, and in last 2 weeks of treatment as concomitant boost regimen [19, 20]. It is found to be feasible to combine it with concurrent weekly cisplatin chemotherapy. Also, it is logical to use radiation alone with WEB regimen rather than conventional fractionation in patients who are medically unfit for chemotherapy, and in elderly patients with comorbidities. Although IMRT is considered as the state 8
of art for head and neck cancer in present era, conventional three-dimensional conformal radiation therapy technique is still being used widely in developing countries like India. Present data from a low-middle income country where the conditions are challenged by availability of resources reveal the WEB regimen is a feasible and an attractive alternative approach to achieve the benefits of acceleration radiation. Single arm with small sample size was a one of the major limitations of present study, which necessitates larger casecontrolled study to evaluate the efficacy in detail. Conclusion Our study showed the modest acceleration of radiotherapy schedule using weekend boost along with weekly concurrent cisplatin in locally advanced head and neck cancer is feasible with better initial tumor response. However, its association with higher acute toxicities observed during fourth and fifth week of treatment in our study, necessitates proper patient selection, rigorous monitoring, and supportive care. References [1] Olmi, P., Cellai, E., & Chiavacci, A., et al. (1990). Accelerated fractionation in advanced head and neck cancer: results and analysis of late sequelae. Radiother Oncol 17, 199–207. [2] Lamb, D. S., Spry, N. A., & Gray, A. J., et al. (1990). Accelerated fractionation radiotherapy for advanced head and neck cancer. Radiother Oncol 18, 107–116. [3] Ang, K. K. (1998). Altered fractionation trials in head and neck cancer. Semin Rad Oncol 8, 230–236. [4] Fu, K. K., Pajak, T. F., & Trotti, A., et al. (2000). A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys 48, 7–16. [5] Pignon, J. P., Bourhis, J., & Domenge, C., et al. (2000). Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data MACH-NC Collaborative Group: meta-analysis of chemotherapy on head and neck cancer. Lancet 355, 949–955. [6] Pignon, J. P., le Maitre, A., & Maillard, E., et al. (2009). Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomized trials and 17,346 patients. Radiother Oncol 92, 4–14. [7] Garden, A. S., Harris, J., & Trotti, A., et al. (2008). Long-term results of concomitant boost radiation plus concurrent cisplatin for advanced head and neck carcinomas: a Phase II trial of the Radiation Therapy Oncology Group (RTOG 99-14). Int J Radiat Oncol Biol Phys 71(5), 1351–1355. [8] Skladowski, K., Maciejewski, B., & Golen, M., et al. (2000). Randomized clinical trial on 7- days-continuous accelerated irradiation (CAIR) of head and neck cancer - report on 3-year tumor control and normal tissue toxicity. Radiother Oncol 55, 101–110. [9] National cancer institute (1999). Cancer Therapy Evaluation Program. Common Toxicity Criteria manual-CTC V:2.0 (pp. 1–25). [10] Eisenhauer, E. A., Therasse, P., & Bogaerts, J., et al. (2009). New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 45, 228–247. [11] Overgaard, J., Mohanti, B. K., & Begum, N., et al. (2010). Five versus six fractions of radiotherapy per week for squamous cell carcinoma of
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[12]
[13] [14]
[15]
[16]
the head and neck (IAEA-ACC study NCT00120211): a randomized, multicentric trial. Lancet 11(6), 553–560. Withers, H. R., Taylor, J. M. G., & Maciejewski, B. (1988). The hazard of accelerated tumour clonogen repopulation during radiotherapy. Acta Oncol 27, 131–146. Fowler, J. F., & Lindstrom, M. J. (1992). Loss of local control with prolongation in radiotherapy. Int J Radiat Oncol Biol Phys 23, 457–467. Overgaard, J., Hansen, H. S., & Specht, L., et al. (2003). Five compared with six fractions per week of conventional radiotherapy of squamouscell carcinoma of head and neck: DAHANCA 6&7 randomised controlled trial. Lancet 362, 933–940. Bourhis, J., Overgaard, J., & Audry, H., et al.on behalf of MARCH Collaborative Group (2006). Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet 368, 843–854. Baujat, B., Bourhis, J., & Blanchard, P., et al. (2010). Hyperfractionated or accelerated radiotherapy for head and neck cancer. The Cochrane Collaboration. Published The Cochrane Libr 12, 1–60.
[17] Spiotto, M. T., & Weichselbaum, R. R. (2014). Comparison of 3D conformal radiotherapy and intensity modulated radiotherapy with or without simultaneous integrated boost during concurrent chemoradiation for locally advanced head and neck cancers. PLoS ONE 9(4), e94456. [18] Gupta, T., Agarwal, J. P., & Jain, S., et al. (2012). Three-dimensional conformal radiotherapy (3D-CRT) versus intensity modulated radiation therapy (IMRT) in squamous cell carcinoma of the head and neck: a randomized controlled trial. Radiother Oncol 104(3), 343–348. [19] Trotti, A., Fu, K. K., & Pajak, T. F., et al. (2005). Long term outcomes of RTOG 90–03: a comparison of hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 63(1), 70–71. [20] Ang, K. K., Peters, L. J., & Weber, R. S., et al. (1990). Concomitant boost radiotherapy schedules in the treatment of carcinoma of the oropharynx and nasopharynx. Int J Radiat Oncol Biol Phys 19, 1339–1345.
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Journal of Medical Imaging and Radiation Sciences xx (2017) 1-9
Journal de l’imagerie médicale et des sciences de la radiation
www.elsevier.com/locate/jmir
Accelerated Radiation Therapy Using Weekend Boost with Concurrent Cisplatin in Head and Neck Squamous Cell Cancers: An Indian Institutional Experience Pushpa Naga C.H., MD, DNBa*, Janaki M.G., MD, DNBb, Arul Ponni T.R., MDb, Rajeev A.G., MDc, Kirthi Koushik A.S., MDb and Mohan Kumar S., MDb a
b
Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India Department of Radiation Oncology, M.S. Ramaiah Medical College and Hospitals, Bengaluru, Karnataka, India c Department of Radiation Oncology, Radiant Cancer Hospital, Mysooru, Karnataka, India
ABSTRACT Purpose: The purpose of the study was to evaluate the feasibility and efficacy of an accelerated radiotherapy schedule using weekend boost in terms of tumor response, compliance, and acute toxicities for head and neck squamous cell carcinoma, and to report long-term clinical outcomes. Materials and methods: Twenty-six patients with stages III-IV head and neck squamous cell carcinoma receiving radical chemoradiotherapy were accrued prospectively into the study. External beam radiation therapy to a total dose of 66–70 Gy in 33–35 fractions, 1.8– 2.0 Gy per fraction along with concurrent weekly cisplatin was planned. Radiation regimen included delivery of six fractions per week, with boost field delivered as the sixth fraction on the weekend. The compliance, tumor response, and toxicities were recorded. Survival curves were estimated using the Kaplan–Meier method. Results: Twenty-one of 26 patients (81%) completed treatment as planned and five patients died during the course of treatment. Sixteen patients (62%) completed treatment in less than 44 days and, at the end of 3 months’ follow-up, 18 patients (69%) showed complete response and two patients (8%) showed partial response. The 2- and 5-year actuarial disease-free survival were 90% and 65%, respectively, and 2- and 5-year actuarial overall survival were 60% and 38%, respectively. Conclusion: Accelerated fractionation using weekend boost, along with concurrent weekly concurrent cisplatin, is an effective and
Financial disclosure: None. Conflict of interest: None. Prior presentation: None. Work attributed to Department of Radiation Oncology, M.S. Ramaiah Medical College and Hospitals, Bengaluru, India. * Corresponding author: Dr. Pushpa Naga C.H., MD, DNB, Department of Radiation Oncology, Tata Memorial Hospital, Dr. Ernest-Borges Road, Parel, Mumbai 400012, Maharashtra, India. E-mail address: [email protected] (P.N. C.H.).
promising approach with favorable impact on initial tumor response, comparable results, and acceptable toxicities. RESUM E Objet : Evaluer la faisabilite et l’efficacite d’un calendrier de radiotherapie accelere utilisant un complement de dose (boost) le weekend en termes de reponse de la tumeur, conformite et toxicites pour l’epithelioma malpighien spinocellulaire de la t^ete et du cou (EMSTC) et presenter les resultats cliniques a long terme. Materiel et methodologie : Vingt-six patients atteints d’un EMSTC de stade III-IV recevant des traitements de chimiotherapie ont ete ajoutes a l’etude de fac¸on prospective. La planification comprenait des traitements de radiotherapie externe, pour une dose totale de 66-70 Gy, en 33-35 fractions, 1,8-2,0 Gy par fraction combinee a des injections hebdomadaires de cisplatine. Le regime de rayonnement prevoyait l’administration de six fractions par semaine, le complement de dose representant la sixieme fraction, administree durant le week-end. La conformite, la reponse tumorale et les toxicites ont ete compilees. Les courbes de survie ont ete estimees par la methode Kaplan–Meier. Resultats : Vingt-et-un des 26 patients (81%) ont complete le traitement comme prevu et cinq patients sont morts avant la fin du traitement. Seize patients (62%) ont complete le traitement en moins de 44 jours, et a la fin de trois mois de suivi, 18 patients (69%) affichaient une reponse complete (CR) alors que deux patients (8%) affichaient une reponse partielle (RP). Le taux actuariel de survie sans maladie (SSM) apres deux et cinq ans etait respectivement de 90% et de 65%, alors que le taux actuariel de survie globale (SG) etait respectivement de 60% et 38%. Conclusion : Un fractionnement accelere utilisant un complement de dose administre durant la fin de semaine avec injection hebdomadaire concurrente de cisplatine est une approche efficace et prometteuse avec des repercussions favorable sur la reponse tumorale initiale, des resultats comparables et des toxicites acceptables.
1939-8654/$ - see front matter Ó 2017 Published by Elsevier Inc. on behalf of Canadian Association of Medical Radiation Technologists. http://dx.doi.org/10.1016/j.jmir.2017.05.001
Keywords: Head and neck cancer; accelerated fractionation; weekend boost; concurrent chemoradiation
Introduction Among the various accelerated fractionation schedules studied in head and neck squamous cell carcinoma (HNSCC), acceleration of radiation by 1 week without dose reduction (ie, delivering six fractions instead of the conventional five fractions per week) is found to have a beneficial effect on locoregional control (LRC) along with a modest reduction in overall treatment time (OTT), and without an increase in late effects [1, 2]. However, results with this approach alone are widely variable, and improvement in survival has not been consistent [3, 4]. Substantial clinical investigations have demonstrated consistent survival gain along with favorable impact on LRC rates with concurrent chemoradiation. However, benefits of combined modality treatment come at the expense of additional acute mucocutaneous toxicities [5]. Consequently, concurrent chemoradiotherapy is the preferred nonsurgical treatment modality for locally advanced diseases, whereas altered fractionation is generally selected for early and intermediate stage tumors or for patients who are medically unfit for chemotherapy [6, 7]. Furthermore, evidence is needed for combining an altered fractionation regimen with concurrent chemotherapy without resulting significant compromise in normal tissues. Theoretically, delivery of a smaller boost field on a weekend as sixth fraction of the week, instead of a larger field, will effectively reduce OTT by one week, and without much increase in toxicity. With an aim to evaluate the feasibility and efficacy of this approach, we undertook this study. In this study, we intend to reduce OTT by delivering six fractions per week, wherein the sixth fraction is a boost field encompassing only gross tumor volume on the weekend, along with concurrent weekly cisplatin chemotherapy.
chemoradiotherapy with radical intent at M.S. Ramaiah Hospitals, Bengaluru were considered. Patients aged between 18 and 80 years, with Karnofsky performance status 70 and adequate baseline bone marrow function (hemoglobin >10 gram%, absolute neutrophil count >1500 per microliter, platelets >100,000 per microliter), normal hepatic and renal function were accrued. Nasopharyngeal, early laryngeal (T1 and T2), postoperative cases, history of prior radiation or chemotherapy, any previous or synchronous malignancy and hypersensitivity to platinum agents were excluded. Sample Size Calculation The sample size was estimated in consultation with a biostatistician using ‘‘n-Master’’ Software based on previous trial by Skladowski et al [8] which compared 7-day continuous accelerated irradiation (CAIR) with conventional fractionation schedule in a randomized clinical trial. Considering 25% precision and 90% desired confidence limit, minimum sample size required accruing in one and half year period was 25. A total of 26 patients were accrued into study in the previously mentioned study period. Pretreatment Evaluation Initial work up consisted of clinical examination, laboratory tests including complete blood count, and renal and hepatic function tests were done for all patients to assess the general condition of the patient. Computed tomography and/or magnetic resonance imaging of head and neck region was done to document local extent of disease. Chest radiograph and abdominal sonography were done to rule out metastases. Each patient was clinically staged as per American Joint Committee on Cancer Tumor Node Metastasis, 2010 staging system after complete work up.
Methods and Materials
Treatment
Study Design
All patients were immobilized with four-clamp head and neck thermoplastic orfit and planning simulation done on a conventional x-ray or computed tomography simulator. During simulation, enlarged lymph nodes were externally delineated with a lead wire to ensure adequate encompass within portals. External beam radiation therapy either on telecobalt machine or linear accelerator (6 MV) using conventional or three-dimensional conformal radiation therapy techniques were permitted. A total dose of 66–70 Gy in 33–35 fractions with 1.8–2.0 Gy per fraction over a 6.5-week period was administered with parallel opposed lateral portals using shrinking field technique in three phases without any tissue compensators. Nodes were treated electively in all patients. A direct anterior lower neck field was used in selected patients. Initial dose of 45 Gy was delivered to Phase 1 radiation portals, which encompassed gross tumor and microscopic
The trial was designed as a prospective, single-center, onearmed study to assess the efficacy and safety of accelerated fractionation schedule using weekend boost (WEB) and concurrent chemotherapy for locally advanced head and neck cancers. The study protocol was approved by the institutional ethics committee. Written informed consent was obtained from each eligible patient before inclusion into the study after explaining in detail the nature, scope and possible consequences of participation in the trial. Data Collection and Inclusion–Exclusion Criteria Between December 2011 and July 2013, all histopathologically proven HNSCC patients receiving concurrent 2
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diseases of both primary and draining lymph nodes, 5 days a week (from Monday to Friday). Additional Phase 3 boost field fraction, which encompassed only gross disease with a margin, was delivered on Saturdays as the sixth fraction of the week to a dose of 16–20 Gy, starting from first week of treatment. Electron beams were used to boost the dose delivered to the posterior cervical lymph nodes. In case of holidays, protocol recommended delivery of boost treatment as a second fraction after the last fraction of week, with minimum of 6 hours gap between fractions. The remaining boost treatments were delivered during the last week of treatment after completion of planned Phase 2 (shrunken field to spare spinal cord to a dose of 5.4-6 Gy) fractions (Figures 1 and 2). The dose delivered to the spinal cord was kept below 45 Gy in all instances. On-treatment verification of portals was confirmed using conventional portal films or electronic portal imaging device as per institution protocol. Images of orthogonal setup fields were acquired daily for the initial 3 days, and weekly thereafter, until the completion of treatment. These images were verified by comparing with corresponding simulator images or digitally reconstructed radiographs obtained on treatment planning system. Any deviations beyond the prescribed margins were noted and corrected before the treatment delivery. Concurrent weekly cisplatin chemotherapy (40 mg/m2) was administered as intravenous infusion once weekly for 5– 6 weeks. A complete blood count and renal function tests were repeated before every cycle of chemotherapy. Chemotherapy was withheld in cases of any grade II or higher hematologic or renal toxicity, until recovery. In an effort to maximize delivery of core therapy, reducing or omitting chemotherapy before interrupting radiotherapy was allowed. The majority of patients received this treatment on outpatient basis. Assessments All 26 patients recruited in the study were continuously assessed, and recordings of weight, skin, and mucosal toxicity were noted weekly during treatment, at 15 days, and at 3 month follow-ups using common terminology criteria for adverse events (NCI-CTCAE) 2.0 [9]. Weekly grading of the toxicity was assigned based on highest grade observed in that week. Any interruptions or gap during treatment were also recorded with reasoning for the same.
Tumor control was assessed by means of clinical examination at the end of treatment, at 6 weeks, and 3 months later using response evaluation criteria in solid tumors guidelines [10]. Thereafter, routine follow-up was done with clinical examination (and imaging if required) at 3 months in first 2 years followed by 6 months for next 3 years and thereafter annually. Statistical Analysis Primary analysis was conducted for all patients for efficacy, outcomes, and toxicity. Descriptive statistical analysis was carried out for study parameters. Baseline weight was compared with subsequent weekly weight recording using Student’s paired t-test. Wilcoxon matched-pairs test has been used to find the significance of skin and mucosal toxicities in comparison of baseline to subsequent grading. For actuarial survival analysis, Kaplan–Meier’s method was used to compute overall survival (OS) and disease-free survival (DFS). OS was calculated from the date of diagnosis to the date of death (all causes) or to the last follow-up. DFS was defined from the date of diagnosis (biopsy confirmation) to date of first documented relapse or death because of any cause. Only patients with complete clinical response were considered for the DFS analysis, and those who were alive at last followup and disease free were censored. For all statistical tests, P < .05 was considered significant. Statistical Programme for Social Sciences software for Windows (SPSS Inc, Version 22, Chicago, USA) was used for analyses and Microsoft Excel has been used to generate graphs and tables. Results Patient and Tumor Characteristics The study population included 26 patients of HNSCC of various subsites and stages who received radical chemoradiation. The median age was 60 years (range, 49–76 years), 16 patients (61.5%) were aged >60 years. Baseline patient and tumor characteristics are shown in Table 1. Treatment Characteristics Of the 26 patients in the study, 21 patients (80.8%) completed the radiation treatment as scheduled, wherein 17 patients (65.4%) received minimum five cycles of weekly concurrent cisplatin and
Figure 1. Schematic representation of weekend boost study protocol.
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3
Figure 2. Representative sagittal images of planning computed tomography scan showing volumes and isodose coverage of three different phases: (A) Phase 1, (B) Phase 2; (C) Phase 3.
16 patients (76%) could finish treatment <44 days as planned (median 43 days). In others, OTT was ranging from 46 to 50 days because of various reasons, majority in view of poor intake associated with mucositis. Reasons for noncompliance of chemotherapy were mostly toxicity related. Among the five patients who could not complete treatment, two patients documented disease related events (aspiration pneumonia), three patients had treatment related events (septic shock and severe electrolyte imbalance), and one had diseaseunrelated death (myocardial infarction). An additional patient died after 2 months of treatment completion due to a cardiac event. Clinical Outcomes Response to Treatment Of the 20 patients who were alive at the end of 3-months’ post-treatment, 18 patients (69.2%) documented complete Table 1 Patient and Tumor Characteristics Parameter Sex Men Women Age Median (range) Tumor sites Oral cavity Oropharynx Hypopharynx Larynx Grade Well differentiated Moderately differentiated Poorly differentiated Undifferentiated Stage grouping Stage III Stage IV Nodal status Negative Positive
4
Frequency (%) 15 (57.69) 11 (42.31) 60 (49–76) y 7 11 3 5
(26.92) (42.30) (11.54) (19.24)
6 13 5 2
(23.00) (50.00) (19.2) (.80)
14 (53.50) 12 (46.20) 4 (15.40) 22 (84.60)
response (CR) and two patients (0.7%) had partial response (PR). None had stable or progressive disease according to response evaluation criteria in solid tumors guidelines. Univariate subgroup analysis of CR seen in different subsites with tumor and nodal staging was attempted but it did not reveal any statistical significance. However, a significant P value was observed on comparing node negative (n ¼ 4) vs. node positive (n ¼ 22) and also with tumor differentiation showing benefit for well and moderately differentiated tumors (n ¼ 19) compared with poorly or undifferentiated tumors (n ¼ 7). Toxicity During 4, 5, and 6 weeks of treatment, 50% (n ¼ 13) and 20% (n ¼ 7) had grade II or worse skin and mucosal toxicities respectively, which resolved by 6 weeks of treatment completion (Figure 3 and Tables 2 and 3). At the end of the first week, incidence of acute dysphagia was 12% (n ¼ 3) and reached 59% (n ¼ 15) at completion of treatment. Most of the patients were managed with symptomatic treatment with antiseptic liquids, analgesics, anti-inflammatory drugs, and local corticosteroids. Systemic corticosteroids and/or antibiotics were administered whenever severity of mucositis/ dysphagia exceeded grade II. Comparison of weekly mean values of skin and mucosal toxicity grading depicted together is shown in Figure 4. Recorded baseline mean weight of entire cohort was 51.8 kg and reached 47.3 kg by the end of treatment with median weight loss of 4 kg over the course of treatment. Comparison of weekly weight loss/gain with subsequent weeks up to last follow-up using paired t-test showed statistically significant differences (P < .0001; Table 4). Regular nutritional assessments and intervention were done whenever necessary. Seven patients (27%) had prophylactic percutaneous endoscopic gastrostomy insertion and commenced feeding when oral intake was <50% and/or >5 kg weight loss from commencement of treatment. Another 10 patients (38%) required nasogastric tube insertion during the course of treatment. Overall, 73% (n ¼ 19) patients received systemic supportive care by week 4 or 5 of the treatment that was discontinued on settling of severe toxicities.
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Figure 3. Bar-graph showing mucosal (A) and skin (B) toxicity incidences in percentage.
Follow-up and Survivals Patients who achieved CR were considered for DFS analysis. At the last follow-up at 18 months, 33.3% patients (n ¼ 6) were disease free. Two patients had a local recurrence after 12 and 15 months, respectively. One patient had a second malignancy in the postcricoid region after 16 months of primary treatment to the tonsillar lesion and was locally free of disease at the primary site. None had distant metastasis. Death occurred in five patients after median follow-up time of 20 months (range, 4.5–35 months). Three patients had disease-related death and two died of cardiac events. Status of five patients was unknown, since they defaulted. At the time of analysis, median follow-up was 9 months (range, 2–55 months) for the entire group, and one of the
six disease-free patients relapsed locally and succumbed to disease. Overall compliance with follow-up was poor. The actuarial 2 and 5-year DFS of patients with complete CR were 90% and 65%, respectively, and 2 and 5-year actuarial OS were 60% and 38%, respectively (Figure 5).
Discussion An accelerated fractionation regimen shortening OTT minimizes tumour repopulation during treatment, which is a major cause of relapse and, therefore, increases the probability of tumour control for a similar total dose. The present study has documented efficacy, toxicity, and outcomes with accelerated radiation therapy with reduction of OTT by
Table 2 Comparison of Weekly Grading of Skin Reactions by Wilcoxon Matched-Pairs Test Time Point
Mean
Median
SD
Baseline/week 1 Week 2
0.00 0.00
0.0 0.0
0.00 0.00
0.00
Week 2 Week 3
0.00 0.12
0.0 0.0
0.00 0.33
0.12
Week 3 Week 4
0.12 0.84
0.0 1.0
0.33 0.55
Week 4 Week 5
0.84 1.30
1.5 2.0
Week 5 Week 6
1.30 0.95
Week 6 1st FU 1st FU 2nd FU *
Mean Difference
SD Difference
Percentage of Change
–
Z Value
P Value
0.00
–
–
0.33
15.87
1.6036
.1088
0.69
0.65
500.00
3.4078
.0004*
0.57 0.51
0.26
0.73
400.00
2.8904
.0057*
2.0 2.0
0.53 0.52
0.04
0.80
200.00
1.9780
.0281*
0.95 0.61
2.0 1.0
0.54 0.56
0.34
0.54
433.33
3.0594
.0022*
0.61 0.00
1.0 0.0
0.55 0.00
0.61
0.55
600.00
3.6214
.0003*
1st FU, 15 days posttreatment; 2nd FU, 3 months posttreatment; SD, standard deviation. P < .05.
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Table 3 Comparison of Weekly Grading of Mucositis by Wilcoxon Matched-Pairs Test Time Point
Mean
Median
SD
Mean Difference
SD Difference
Z Value
P Value
Baseline/week 1 Week 2
0.00 0.19
0.0 0.0
0.00 0.35
0.19
0.35
100.00
1.6466
.1091
Week 2 Week 3
0.19 0.85
0.0 1.0
0.35 0.37
0.66
0.63
500.00
3.4254
.0004*
Week 3 Week 4
0.85 1.46
1.0 1.5
0.37 0.58
0.61
0.50
72.73
3.5162
.0004*
Week 4 Week 5
1.46 1.52
1.5 1.5
0.58 0.60
0.13
0.21
3.13
4.4045
.0058*
Week 5 Week 6
1.52 1.55
1.5 1.5
0.60 0.62
0.03
0.43
6.90
0.9129
.3613
Week 6 1st FU
1.55 0.48
1.5 1.0
0.62 0.18
1.07
0.64
63.16
3.0594
.0022*
1st FU 2nd FU
0.48 0.00
1.0 0.0
0.18 0.00
0.48
0.76
72.22
2.9341
.0033*
*
1st FU, 15 days posttreatment; 2nd FU, 3 months posttreatment; SD, standard deviation. P < .05.
7 days using WEB and concurrent weekly cisplatin chemotherapy. Our study population consisted of a majority of oropharyngeal cases (oral cavity 30% vs. oropharynx 42.3% vs. hypopharynx 11.5% vs. larynx 19.2%) as opposed to the study by Overgaard et al [11], which had included more laryngeal tumors (larynx 46% vs. oropharynx and hypopharynx 37% vs. oral cavity 25%; P < .0001). Of 26 patients accrued, overall response (CR þ PR) was observed in all 21 patients who completed treatment as scheduled, suggesting improved initial tumor response. Twenty patients were available for analyses of tumor response at the end of 3-month follow-up, wherein CR was documented in 18 patients (69.2%). A similar study by Skladowski et al [8], which had shortening of OTT by 14 days with CAIR, demonstrated early response at the end of treatment. It also showed complete regression of tumor in 88% of patients in the CAIR arm vs. 69% in the control arm (P < .05) and complete nodal clearance was 100% vs. 78% (P > .05) in CAIR and control arm, respectively, at the end of 3 months of treatment.
Figure 4. Graph showing trend in changes in mean values of mucosal and skin reactions.
6
Percentage of Change
It is well documented that OTT is an important prognostic factor that determines the outcome in HNSCC. Accelerated repopulation of tumour clonogens is a principle factor responsible for a disadvantageous effect of prolonged OTT [12]. With conventional fractionation, a break of about 1 week is associated with an absolute reduction in local control rates of 10%–12% [13]. Hence, a break of even 1 day is associated with reduction in LRC rate by about 1.4% (range, 0.4%– 2.5%). In our series, median OTT planned was 42 days (range, 41–44 days) and 76% (n ¼ 16) patients could finish treatment <44 days as planned. In others, OTT ranged from 46 to 50 days, mainly because of treatment interruptions due to higher grades of skin reactions and poorer intake due to grade III mucosal toxicities. In the Skladowski et al study [8], OTT was prolonged by 1 2 day in four patients (8%) in the CAIR and by 1 4 days for three patients (6%) in the control arm as opposed to 36–40 days in CAIR and 51–54 days in control arm. Two patients (2%) in CAIR arm did not complete the planned treatment. In a study by the Danish Head and Neck Cancer study group [14], OTT was kept as planned, with a median treatment time of 39 days in the six fractions per week schedule and 46 days in the five fractions per week schedule. No gap was given in spite of higher grades of acute toxicities. We observed grade II or worse skin and mucosal reactions in 50% and 20%, respectively, during last 2–3 weeks of treatment requiring symptomatic management and also enteral feeding procedures for nutritional support. In total, 19 of 26 patients (73%) were put on a feeding tube, either with percutaneous endoscopic gastrostomy tube or Ryle’s tube, by the fifth week of treatment compared with Skladowski et al [8], which demonstrated significant early onset of confluent mucositis with CAIR regimen, but none of the patients in both groups needed tube feeding although more frequent supportive treatment was given in CAIR (n ¼ 45; 92%). Overgaard et al showed 5% increase in frequency of confluent mucositis, 7% increased frequency of use of tube
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Table 4 Comparison of Weekly Weights (in kilogram) by Paired T-test Mean
SD
Baseline/week 1 Week 2
51.81 51.10
9.00 8.78
0.71
0.68
1.37
5.3294
.00001*
Week 2 Week 3
51.10 49.98
8.78 8.90
1.12
0.62
2.17
9.1523
.00001*
Week 3 Week 4
49.98 48.81
8.90 8.46
1.17
0.94
2.25
6.3805
.00001*
Week 4 Week 5
48.83 47.67
8.73 8.91
1.14
0.63
2.22
8.7781
.00001*
Week 5 Week 6
48.16 47.28
8.79 8.49
0.89
0.71
1.72
5.8893
.00001*
Week 6 1st FU
47.33 46.48
8.69 8.21
0.86
1.16
1.66
3.3761
.006*
1st FU 2nd FU
46.48 47.29
8.21 8.23
0.81
1.21
1.56
3.0682
.00001*
Week 1 Week 3
51.81 49.98
9.00 8.90
1.83
0.88
3.53
10.556
.00001*
Week 1 Week 4
51.81 48.81
9.00 8.46
3.00
1.22
5.80
12.490
.00001*
Week 1 Week 5
51.80 47.67
9.27 8.91
4.13
1.33
7.98
14.857
.00001*
Week 1 Week 6
52.34 47.27
9.12 8.49
5.06
1.58
9.76
15.014
.00001*
Week 1 1st FU
52.40 46.48
9.34 8.21
5.93
1.76
11.45
15.413
.00001*
Week 1 2nd FU
52.40 47.29
9.34 8.23
5.12
2.28
9.88
10.290
.00001*
*
Mean Difference
Paired SD Difference
Percentage of Change
Paired T-score
P Value (Two-tailed)
Time Point
1st FU, 15 days posttreatment; 2nd FU, 3 months posttreatment; SD, standard deviation. P < .05.
feeding, and 9% increase in frequency of skin reactions in the accelerated arm. Regarding healing of acute reactions, similar findings were found with the present study that all acute toxicities resolved within 3 months of starting radiation with
symptomatic management [11]. Also, the Danish Head and Neck Cancer study group 6 and 7 demonstrated 20% increase in frequency of confluent mucositis with accelerated fractionation that persisted longer but all healed within 3 months of
Figure 5. Disease free and overall survival curves.
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treatment [14]. Early occurrence of higher grades of toxicities requiring more frequent treatment interruptions observed in our study is probably because of the addition of concurrent chemotherapy, unlike in most accelerated regimen studies, which practiced radiation alone. Among the total 11 mortalities observed in our study, death due to aspiration pneumonia and severe electrolyte imbalance can be correlated to treatment or disease-related cause of death (n ¼ 7). Another four deaths were due to other illness. Meta-analysis of radiotherapy in carcinomas of head and neck (MARCH) [15] collaborative group revealed death due to other causes than cancer was higher in both altered fractionation (n ¼ 3650) and conventional arm (n ¼ 3423; 13.3% and 11.1%) compared with cancer-related mortality (1.7% and 1.9%, respectively). The death of nine patients that occurred in the present study were from the age group of 61–70 years, suggesting an increased hazard ratio of death and poorer prognosis to altered fractionation in an elderly age group, as analyzed in the MARCH meta-analysis, which showed benefits of altered fractionated radiotherapy differed significantly according to the patient’s age. In patients who were aged 50 years, altered fractionated radiotherapy was associated with a 45.6% reduction in the hazard ratio of death, whereas its effects were marginal in patients aged 51– 70 years; patients aged 71 years tended to have a poor prognosis compared with those given conventional fractionation. Indeed, a test for trend revealed a significant interaction between age and treatment effect for OS (P ¼ .007), and death related to cancer (P ¼ .008), local control (P ¼ .002), and LRC (P ¼ .002) [16]. These findings suggest that accelerated radiotherapy causes substantial toxic effects in elderly patients, leading to interruptions in treatment. Hence, it is prudent not to attempt in patients aged >70 years. It should be used in those <50 years and for those between 51 and 70 years it should be incorporated with close monitoring. Actuarial 2- and 5-year OS in the present study were 60% and 38%, respectively, and actuarial 2- and 5-year DFS of patients with complete CR were 90% and 65%, respectively, which is comparable with results observed by Garden et al [7], that evaluated concomitant boost accelerated radiation regimen along with cisplatin and showed 2- and 4-year local-regional failure rates of 33% and 36%, respectively, and OS rates of 70% and 54%, respectively. Similarly, in comparison of results with patients treated with IMRT technique [17, 18], no significant differences in disease outcomes were seen, although IMRT has a documented advantageous effect on long-term toxicities. With the previously mentioned observations, we propose usage of boost field as a sixth fraction starting from first week of treatment itself, and in last 2 weeks of treatment as concomitant boost regimen [19, 20]. It is found to be feasible to combine it with concurrent weekly cisplatin chemotherapy. Also, it is logical to use radiation alone with WEB regimen rather than conventional fractionation in patients who are medically unfit for chemotherapy, and in elderly patients with comorbidities. Although IMRT is considered as the state 8
of art for head and neck cancer in present era, conventional three-dimensional conformal radiation therapy technique is still being used widely in developing countries like India. Present data from a low-middle income country where the conditions are challenged by availability of resources reveal the WEB regimen is a feasible and an attractive alternative approach to achieve the benefits of acceleration radiation. Single arm with small sample size was a one of the major limitations of present study, which necessitates larger casecontrolled study to evaluate the efficacy in detail. Conclusion Our study showed the modest acceleration of radiotherapy schedule using weekend boost along with weekly concurrent cisplatin in locally advanced head and neck cancer is feasible with better initial tumor response. However, its association with higher acute toxicities observed during fourth and fifth week of treatment in our study, necessitates proper patient selection, rigorous monitoring, and supportive care. References [1] Olmi, P., Cellai, E., & Chiavacci, A., et al. (1990). Accelerated fractionation in advanced head and neck cancer: results and analysis of late sequelae. Radiother Oncol 17, 199–207. [2] Lamb, D. S., Spry, N. A., & Gray, A. J., et al. (1990). Accelerated fractionation radiotherapy for advanced head and neck cancer. Radiother Oncol 18, 107–116. [3] Ang, K. K. (1998). Altered fractionation trials in head and neck cancer. Semin Rad Oncol 8, 230–236. [4] Fu, K. K., Pajak, T. F., & Trotti, A., et al. (2000). A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys 48, 7–16. [5] Pignon, J. P., Bourhis, J., & Domenge, C., et al. (2000). Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data MACH-NC Collaborative Group: meta-analysis of chemotherapy on head and neck cancer. Lancet 355, 949–955. [6] Pignon, J. P., le Maitre, A., & Maillard, E., et al. (2009). Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomized trials and 17,346 patients. Radiother Oncol 92, 4–14. [7] Garden, A. S., Harris, J., & Trotti, A., et al. (2008). Long-term results of concomitant boost radiation plus concurrent cisplatin for advanced head and neck carcinomas: a Phase II trial of the Radiation Therapy Oncology Group (RTOG 99-14). Int J Radiat Oncol Biol Phys 71(5), 1351–1355. [8] Skladowski, K., Maciejewski, B., & Golen, M., et al. (2000). Randomized clinical trial on 7- days-continuous accelerated irradiation (CAIR) of head and neck cancer - report on 3-year tumor control and normal tissue toxicity. Radiother Oncol 55, 101–110. [9] National cancer institute (1999). Cancer Therapy Evaluation Program. Common Toxicity Criteria manual-CTC V:2.0 (pp. 1–25). [10] Eisenhauer, E. A., Therasse, P., & Bogaerts, J., et al. (2009). New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 45, 228–247. [11] Overgaard, J., Mohanti, B. K., & Begum, N., et al. (2010). Five versus six fractions of radiotherapy per week for squamous cell carcinoma of
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(2017) 1-9
[12]
[13] [14]
[15]
[16]
the head and neck (IAEA-ACC study NCT00120211): a randomized, multicentric trial. Lancet 11(6), 553–560. Withers, H. R., Taylor, J. M. G., & Maciejewski, B. (1988). The hazard of accelerated tumour clonogen repopulation during radiotherapy. Acta Oncol 27, 131–146. Fowler, J. F., & Lindstrom, M. J. (1992). Loss of local control with prolongation in radiotherapy. Int J Radiat Oncol Biol Phys 23, 457–467. Overgaard, J., Hansen, H. S., & Specht, L., et al. (2003). Five compared with six fractions per week of conventional radiotherapy of squamouscell carcinoma of head and neck: DAHANCA 6&7 randomised controlled trial. Lancet 362, 933–940. Bourhis, J., Overgaard, J., & Audry, H., et al.on behalf of MARCH Collaborative Group (2006). Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet 368, 843–854. Baujat, B., Bourhis, J., & Blanchard, P., et al. (2010). Hyperfractionated or accelerated radiotherapy for head and neck cancer. The Cochrane Collaboration. Published The Cochrane Libr 12, 1–60.
[17] Spiotto, M. T., & Weichselbaum, R. R. (2014). Comparison of 3D conformal radiotherapy and intensity modulated radiotherapy with or without simultaneous integrated boost during concurrent chemoradiation for locally advanced head and neck cancers. PLoS ONE 9(4), e94456. [18] Gupta, T., Agarwal, J. P., & Jain, S., et al. (2012). Three-dimensional conformal radiotherapy (3D-CRT) versus intensity modulated radiation therapy (IMRT) in squamous cell carcinoma of the head and neck: a randomized controlled trial. Radiother Oncol 104(3), 343–348. [19] Trotti, A., Fu, K. K., & Pajak, T. F., et al. (2005). Long term outcomes of RTOG 90–03: a comparison of hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 63(1), 70–71. [20] Ang, K. K., Peters, L. J., & Weber, R. S., et al. (1990). Concomitant boost radiotherapy schedules in the treatment of carcinoma of the oropharynx and nasopharynx. Int J Radiat Oncol Biol Phys 19, 1339–1345.
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