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A phase 2 randomized study to compare short course palliative radiotherapy with short course concurrent palliative chemotherapy plus radiotherapy in advanced and unresectable head and neck cancer
Radiotherapy and Oncology 117 (2015) 145–151
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Phase II randomised trial
A phase 2 randomized study to compare short course palliative radiotherapy with short course concurrent palliative chemotherapy plus radiotherapy in advanced and unresectable head and neck cancer Arvind Kumar a, Atul Sharma a,⇑,1, Bidhu Kalyan Mohanti b, Alok Thakar c, Nootan Kumar Shukla d, Sanjay P. Thulkar e, Kapil Sikka c, Suman Bhasker b, Chirom Amit Singh c, Sreenivas Vishnubhatla f a Department of Medical Oncology; b Department of Radiotherapy; c Department of Otorhinolaryngology; d Department of Surgical Oncology, Dr BRA IRCH; e Department of Radiology, Dr BRA IRCH; and f Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India
a r t i c l e
i n f o
Article history: Received 9 May 2015 Received in revised form 3 July 2015 Accepted 7 July 2015 Available online 21 August 2015 Keywords: Advanced and incurable HNSCC Palliative RT CTRT C15-PAL HN-35 questionnaire
a b s t r a c t Background: Treatment of unresectable HNSCC is not well defined and has a poor outcome. This study has been designed to address the unmet needs of such groups of patients with primary end points of (a) proportion of patients eligible for radical treatment in each arm (b) loco-regional disease control at 6 months between two arms. Materials and methods: Locally advanced and unresectable HNSCC patients (except Nasopharynx and Larynx) unfit for radical treatment were randomized to arm A [short course RT alone (4 Gy/#/day for 5 days)] or arm B [RT as arm A + concurrent cisplatin at 6 mg/m2/day IV bolus for 5 days]. Those with at least PR were taken for further RT to complete biological equivalent dose of 70 Gy, in both the arms. In arm B, concurrent CDDP at a dose of 40 mg/m2/week was administered. Results: 114 patients (57 in each arm) were randomized but 111 were analyzable. 15 (27.27%) patients in arm A and 28 (50%) patients in arm B had PPR (p = 0.01) however patients taken for FRT were 14 (25.45%) and 26 (46.42%) in arms A and B respectively (p = 0.02). Locoregional control i.e. (CR + PR) at 6 months was 16.36% in arm A versus 32.14% in arm B (p = 0.15). Median PFS (arm A – 3.2 months, arm B – 6.2 months; p = 0.02) and OS (arm A – 5.9 months, arm B – 10.1 months; p = 0.03) was significantly more in arm B. There was relative improvement in quality of life for most parameters in arm B. Conclusion: Concurrent low dose CTRT can be an effective treatment modality in advanced and incurable HNSCC. However, a larger phase III trial is required. Ó 2015 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 117 (2015) 145–151
Head and neck squamous cell cancer (HNSCC) is a major oncological burden in developing countries. It constitutes 5% of all cancers in the world but 15% of all cancers in developing countries and is ranked as the 6th most common cancer in the world among men [1,2]. Head and neck cancer occurs in multiple subsites which varies greatly as per geographic location. In India lip, oral cavity, oropharynx and hypopharynx cancer constitute about 80% of all head and neck cancer [2]. The reason for this high prevalence is due to common practice of chewing tobacco in this region. Single modality treatment may be adequate for early stage disease whereas advanced cases are treated by combined modality. In ⇑ Corresponding author at: Room no. 229, 2nd Floor, Department of Medical Oncology, Dr BRA Institute Rotary Cancer Hospital (IRCH), All India Institute of Medical Sciences, New Delhi 110029, India. E-mail address: [email protected] (A. Sharma). 1 Current location – sabbatical. http://dx.doi.org/10.1016/j.radonc.2015.07.026 0167-8140/Ó 2015 Elsevier Ireland Ltd. All rights reserved.
India, unfortunately about 40% or more HNSCC patients presents in advanced and unresectable stage [3]. Available literature is almost silent on how these patients should be managed. These patients are neither suitable for surgery and post operative radiation nor fit for curative RT or chemo-RT approaches. Some of these patients are treated with radical radiation or concurrent chemo-radiation. Many of these patients are considered for palliative therapy or best supportive care similar to advanced cancers of Gall Bladder, Lung, Esophagus, etc. A number of studies have proven the superiority of concurrent chemo-radiation over radiation alone in achieving loco-regional control and overall survival in locally advanced head and neck squamous cell carcinoma [4]. We, believe that when palliation is the intent, it may be reasonable to consider a treatment which is not very toxic. Also in the absence of robust clinical studies, whether radical RT or concurrent chemo-radiation is the most appropriate in such a situation is still not known. In advanced
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short course RT Vs Chemo RT for unresectable head and neck cancer
and incurable HNSCC our policy is to deliver 20 Gy/5# with 4 Gy/day over 5 consecutive days and then reassess them after 4 weeks [5]. If there is partial response or more then we consider them for further radical radiotherapy. We have designed this study to show if any, the benefit of adding low dose CDDP with palliative RT over palliative RT alone. To best of our knowledge no study has compared short course palliative RT versus short course palliative chemo-radiation using IV bolus low dose daily CDDP in unresectable HNSCC. The hypothesis behind this study is that addition of chemotherapy to palliative radiation will lead to improvement in loco regional disease control, survival and symptomatic relief compared to palliative radiation alone. Early response to palliative RT or palliative chemo-radiation will help identify a sub group of patients who will be taken up for further treatment. This is likely to have a major impact on the delivery of health care to a large number of advanced unresectable HNSCC in a resource limited country. Methods This study was conducted at Dr B.R.A., Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi. It was a randomized phase II clinical trial. The protocol of this study was approved by the Institute ethics committee. Written informed consent was taken from all patients. Main inclusion criteria were any locally advanced squamous cell carcinoma of the oral cavity, oropharynx, and hypo pharynx that had been unanimously defined as inoperable and incurable by multidisciplinary team members with adequate organ functions (bone marrow, kidney, liver) with an ECOG Performance status (PS) of I–III were enrolled in this study. Exclusion criteria were ECOG PS IV, or non-squamous histology or recurrent or metastatic disease or who had received radiotherapy or chemotherapy in the past. Study design Patients had a full clinical examination with recording of site, size and extent of primary tumor and neck nodes. CBC and serum biochemistry (liver function test, kidney function test), chest X-ray PA view, biopsy from primary site, ENT examination, Contrast Enhanced Computed Tomography (CECT) of face and neck was done for all subjects at the base line. Patients who fulfilled inclusion criteria were randomly assigned to either palliative RT (arm A) or palliative RT + CT (arm B) arm by a computer-generated balanced randomization algorithm. Arm A: 20 Gy in 5 fractions (4 Gy daily for 5 consecutive days) by cobalt or linear accelerator. Arm B: radiation as in arm A with concurrent cisplatin at the dose of 6 mg/m2/day administered as IV bolus as radio sensitizer. 20 Gy in 5 fractions over 1 week is equivalent in biologically effective dose (BED) to 28 Gy at 2 Gy per fraction, 5 fractions per week. Patients in both the arms were assessed at nearly 4 weeks for response and toxicities. Patients in both the arms were taken for further radical treatment [FRT] only if they had at least a partial response after short course RT or chemo-RT. Patients eligible for FRT were administered RT as 2 Gy/fraction/day completing a total radiobiological equivalent dose of 70 Gy, in both the arms. In arm B, concurrent cisplatin at a dose of 40 mg/m2/week was administered along with RT. Radiation planning and optimization were done using 2D or 3D-CRT techniques. Treatment field encompassed primary disease, neck nodes and area of potential microscopic spread in the first phase. Cord sparing was accomplished after delivery of external beam radiotherapy (EBRT) up to 44 Gy. Gross primary and nodal disease were boosted by shrinking field technique after EBRT up
to 56 Gy. Gross posterior neck disease after cord sparing was boosted with electrons of suitable energy. All subjects received best supportive care as and when needed. Proper oral intake was maintained and Ryle’s tube was inserted if required. Primary endpoints were (1) to compare proportion of patients eligible for radical treatment in each arm and (2) to assess loco-regional disease control at 6 months between two arms. Secondary end points were to compare (1) progression free survival (PFS), (2) overall survival (OS), (3) to assess and compare the degree of symptom relief, palliation and quality of life (QOL) and (4) to compare toxicity between two arms. Response assessment Response assessment was done at 1 and 6 months. Subjective response was assessed by degree of symptomatic relief & palliation expressed by study subjects. Clinical evaluation including indirect laryngoscopy was carried out at each visit. CECT of face and neck was also done at 1 and 6 months for response assessment. Quality of life assessment was done at the base line, 1 and 6 months for all available patients by EORTC QLQ-C15-PAL and HN35 questionnaire. It was evaluated by the primary clinician himself. Toxicity was assessed at each visit by CTACE version 3. Statistical methods Rates of conversion to radical treatment, loco-regional disease control, symptom assessment, toxicity between the two arms were compared using the chi-square test. Survival curves were plotted using Kaplan Meier survival analysis. QOL within a group was compared using a paired t test and change in score for the different parameters of QOL assessment at 1 and 6 months from the baseline between the two groups were compared using wilcoxon rank-sum test. All statistical analysis was done using Stata 12.1. A p value of <0.05 was considered statistically significant. Results One hundred and fourteen patients (57 in each arm) were randomized between March 2012 and October 2013. There was no significant difference between 2 groups regarding baseline presentations, sites, stages, etc. (Table 1). Three patients were excluded from analysis. Two patients in arm A (abdominal metastasis was detected in one of the patient and the other had deranged renal functions at the baseline) and one patient in arm B (had stable disease post palliative CTRT but still taken for FRT in view of young age and good PS). Hence final analysis was done on 55 patients in arm A and 56 patients in arm B. At presentation, pain was the most common symptom in both the groups (98.18% and 94.55% in arms A and B respectively) followed by dysphagia and swelling. Trismus was more common in arm B (60% in arm B and 48.15% in arm A; p – 0.21) (See Fig. 1). Response assessment post 1 month of palliative treatment showed that 15 (27.27%) patients in arm A and 28 (50%) patients in arm B had either CR or PR (p = 0.01) (Table 2). One patient in each arm could not be taken for FRT due to poor PS and 1 patient in arm B developed fistula in cheek post one week of palliative CTRT. Hence 14 (25.45%) patients in arm A and 26 (46.42%) patients in arm B were taken for FRT (p = 0.02) (Table 2). Locoregional disease control i.e. (CR + PR) at 6 months was seen in 9 (16.36%) patients in arm A versus 18 (32.14%) patients in arm B (p = 0.15). Twenty four patients in arm A and 32 patients in arm B were alive at 6 months. Median PFS in arm A was
A. Kumar et al. / Radiotherapy and Oncology 117 (2015) 145–151 Table 1 Demographic details. RT (n = 55) n (%)
CTRT (n = 56) n (%)
p value
Age Mean ± SD
55.27 ± 12.40
53.41 (±11.16)
0.40
Sex Male Female
47 (85.45) 8 (14.55)
49 (87.50) 7 (12.50)
0.75
ECOG PS 0 1 2 3
5 (9.09) 20 (36.36) 27 (49.09) 3 (5.45)
4 (7.14) 23 (41.07) 21 (37.50) 8 (14.29)
SITE Oral cavity Oro pharynx Hypo pharynx
18 (32.73) 32 (58.18) 5 (9.09)
19 (33.93) 36 (64.29) 1 (64.29)
0.23
1 (1.82) 24 (43.64) 30 (54.55)
2 (3.57) 31 (55.36) 23 (41.07)
0.34
Histopathology (differentiation) Well 12 (21.82) Moderate 31 (56.36) Poor 1 (1.82) Not known 11 (20)
7 (17.27) 36 (60.91) 6 (10.91) 6 (10.91)
Serum albumin <3.5 >3.5
8 (14.54) 47 (85.45)
9 (16.07) 47 (83.92)
0.82
Addiction to tobacco Smoking Chewing Alcohol
31 (56.36) 18 (34) 21 (39)
38 (67.86) 14 (26) 24 (43)
0.21 0.33 0.61
Stage 3 Stage 4a Stage 4b
0.34
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3.2 months and arm B was 6.2 months (Hazard ratio {HR} – 0.6%, 95% Confidence Interval {CI} 0.38–0.92; p = 0.02, Fig. 2a). Median OS in arm A was 5.9 months compared to 10.1 months in arm B (HR – 0.62, CI – 0.40–0.96; p = 0.03, Fig. 2b, Table 2). Among those patients in the RT arm who underwent FRT versus those who didn’t PFS (HR – 0.19, CI – 0.8–0.42; p 6 0.001) and OS (HR – 0.25, CI – 0.11–0.56. p = 0.001) were highly significant. Similarly, in the CTRT arm among those patients who underwent FRT versus those who didn’t PFS (HR – 0.21, CI – 0.1–0.44; p 6 0.001) and OS (HR – 0.4, CI – 0.2–0.78; p = 0.007) were significant. Except difficulty in tongue protrusion (suggesting involvement of deep muscles of the tongue at 1 month), all other symptoms were better controlled in arm B, both at 1 and 6 months. Pain was better controlled in arm B as compared to arm A (45.83% in arm A versus 67.92% patients in arm B had >50% reduction from base line; p = 0.02). Forty seven percent patients in arm A and 85.19% patients in arm B had >50% reduction of trismus at 6 months compared to baseline; p = 0.007). We have not carried out any separate analysis as regards response or toxicity to 2-D versus 3-D based radiotherapy delivery.
0.08
Toxicity assessment Mostly Grade 1 or 2 toxicity was present at any time point. Post 1 week of palliative treatment, one patient died due to pneumonia and sepsis in the CTRT arm but there was no toxic death in the RT arm. Post radical treatment there was 1 toxic death in the RT arm due to radiation induced late grade 3 dryness and mucosal edema. In the CTRT arm 1 patient died secondary to grade 3/4 mucositis and renal failure and another patient died due to sudden
Assessed for eligibility (n= 136)
Excluded (n = 22) Not meeng inclusion criteria (n = 14) Refused to parcipate (n = 5). Other reasons (n=3)
Randomized (n = 114)
Randomized to arm A {RT} (N=57) ST
Received allocated 1 week of Rx (n= 56). One paent defaulted aer 2 days of RT.
Randomized to arm B {CTRT} (N=57) Received allocated 1ST week of Rx (n= 55). Two paents defaulted one day of concurrent CDDP in first phase.
Paents evaluable at 1 months (n=53).
Paents evaluable at 1 months (n=57).
Radical Rx received (n=14)
Radical Rx received (n=26)
Toxic death aer 1 week of Rx (n=0)
Toxic death aer 1st week of Rx (n=1)
Toxic death aer/during radical Rx (n=1)
Toxic death aer/during radical Rx (n=3)
Lost to follow up (n=2)
Lost to follow up (n=2)
Alive at 6 months (n=24)
Alive at 6 months (n=32)
st
Analyzed (n = 55)
Analyzed (n = 56)
Excluded from analysis (n = 2) (abdominal metastasis was detected in one of the patient and the another had deranged renal functions at baseline)
Excluded from analysis (n = 1)( Had stable disease post palliative CTRT but still taken for radical treatment.)
Fig. 1. Consort diagram of the study.
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short course RT Vs Chemo RT for unresectable head and neck cancer
Table 2 Response and survival results between the two treatment arms.
CR or PR at 1 month of palliative treatment Radical treatment received CR + PR at 6 months Median PFS Median OS
Discussion
RT arm
CTRT arm
p value
15 (27.27%)
28 (50%)
0.01
14 (25.45%) 9 (16.36%) 3.2 5.9
26 (46.42%) 18 (32.14%) 6.2 10.1
0.02 0.15 0.02 0.03
CR – complete response, PR – partial response, PFS – progression free survival, OS – overall survival.
aspiration. The third patient in the CTRT arm had a sudden rupture of carotid vessels post neck dissection for residual node after FRT. There was no incidence of grade 3 or 4 renal toxicity post 1 week of palliative CTRT. Grade 3 and 4 dysphagia was more in arm B during radical treatment (7.69% in arm A versus 68% in arm B, p 6 0.001). But at the 6 month grade 3 and 4 dysphagia between two arms were not significantly different. Quality of life assessment
0.00
0.00
0.25
0.25
0.50
0.50
0.75
0.75
1.00
1.00
At 1 month QLQ was missing in 9 patients (1 set of questions lost, 6 patients didn’t attend OPD and in 2 patients QLQ was not taken). Questions related to sexual issues were missing the most (nearly 2.5%). In the C15-PAL questionnaire, at one month statistically significant improvement in the CTRT arm was seen in emotional functioning (p = 0.009), global health status (p = 0.04), pain (p = 0.01) and insomnia (p = 0.01) (Table 3). At 6 months improvement was still seen in the CTRT arm in emotional functioning, global health status, and pain though it was not significant. At 6 months there was significantly more improvement in fatigue in the CTRT arm as compared to the RT arm (p = 0.03). At 6 months there was a non significant improvement in appetite in the RT as compared to CTRT arm (p = 0.20). There was deterioration of symptoms for fatigue, vomiting and constipation in both the arms at 1 month but more so in the RT arm (p value not significant). Similarly there was deterioration in physical functioning, dyspnea and constipation in both the arms at 6 months but more so in the RT arm (p value not significant) (Table 4). In the HN-35 questionnaire, at 1 month (Table 5) significant improvement was noted in the CTRT arm as compared to the RT arm for pain (p = 0.006), speech (p = 0.03), social contact (p = 0.03), dental complaints (p = 0.01) and mouth opening (0.03). Even at 6 months (Table 6), improvement was noted in the CTRT arm for pain (p = 0.02), swallowing (p = 0.05), social contact (p = 0.01), dysphagia (p = 0.04) and dental problems (p = 0.02).
0 Number at risk arm = RT arm = CTRT
NCCN guidelines recommend concurrent chemo-radiation for advanced head and neck cancer with performance status of PS 0/1 [6]. Induction chemotherapy followed by CTRT or definitive RT+/-concurrent CT is preferred if PS drops to 2. Combined modality treatment is not recommended with patients of PS 3 or more. In many countries including India HNSCC presents in an advanced and incurable state in a major proportion of cases which is different than Western countries [3,7,8]. Ironically we don’t have definitive treatment plan for such patients. A number of treatment options are described, which include radiotherapy, chemotherapy and targeted agents either singly or in combinations [9–12]. Inspite of having dismal prognosis even after aggressive treatment we are still tempted to address such patients with radical and aggressive treatment which may worsen their quality of life. In a study comparing treatment versus best supportive care Carvalho et al. showed a significant improvement in survival in the treated group versus not treated group (p < 0.00001). However, there was no difference in survival between different treatment groups (p = 0.706). It was reported that patients responding to treatment had a better survival outcome (p = 0.00002) [13]. Hitt et al. have reported that neoadjuvant chemotherapy prior to chemo-radiation doesn’t improve outcome in advanced/unresectable HNSCC [14]. In a study reported in 2003 it was shown that concurrent chemoradiation is better than radiation alone in unresectable HNSCC [15]. Our standard practice is to give palliative radiation in unresectable HNSCC. Mohanti et al. did a study in incurable HNSCC in which radiotherapy was given in two stages. In the first phase palliative RT of 20 Gy was given and in the second phase only responding patients were taken for radical RT [5]. Responding patients got the benefit of radical RT and toxicities of radical RT were omitted from non responding patients. The present study had been designed to address the benefit of adding cisplatin to RT on the background of previous study from this center reported by Mohanti et al. In a study reported by Ma et al. iv bolus, 3 h and 20 h infusion of CDDP had non-significant differences in the magnitude of the area under the concentration-time curve of unbound CDDP between the three dose-input functions and also the area under the CDDP-DNA adduct–time curves suggesting that either of the three modalities of administration had equal efficacy [16]. First phase of palliative CTRT showed a significant conversion to FRT as compared to palliative RT alone (46.42% versus 25.45%, p = 0.02) with a similar toxicity profile. Mohanti et al. had shown
53 56
3 28 37
6 9 analysis time 16 25 arm = RT
8 17
12 5 12
15 3 7
arm = CTRT
Fig. 2a. Progression free survival (PFS) of the patients between two treatment arms. X-axis: time in months. Y-axis: progression free survival (proportion). Median PFS in favor of CTRT arm; HR – 0.6 (95% CI, 0.38–0.92); p = 0.02. HR – Hazard ratio. CI – Confidence Interval.
Number at risk arm = RT arm = CTRT
0
3
6
9 analysis time
12
15
18
55 56
46 48
27 33
14 26
8 21
5 9
3 6
arm = RT
arm = CTRT
Fig. 2b. Overall survival (OS) of the patients between the two treatment arms. Xaxis: time in months. Y-axis: overall survival (proportion). Median OS in favor of CTRT arm; HR – 0.62 (95% CI, 0.40–0.96); p = 0.03. HR – Hazard ratio. CI – Confidence Interval.
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A. Kumar et al. / Radiotherapy and Oncology 117 (2015) 145–151 Table 3 QLQ-C15-PAL at base line and at 1 month between the two groups. Characteristic
Physical functioning+ Emotional functioning Global Fatigue+ Pain Dyspnea Insomnia Appetite Vomiting+ Constipation+
RT (N = 43)
RT + CT (N = 47)
Baseline (mean ± SD)
1 month (mean ± SD)
p
Baseline (mean ± SD)
1 month (mean ± SD)
p
90.58 ± 13.85 65.18 ± 28.82 28.03 ± 20.88 37.40 ± 26.86 42.22 ± 26.73 11.59 ± 25.54 25.75 ± 32.83 19.25 ± 27.04 6.66 ± 18.25 14.72 ± 22.18
81.64 ± 30.74 62.22 ± 35.24 51.13 ± 36.72 51.48 ± 32.53 36.29 ± 31.64 10.14 ± 23.16 24.24 ± 34.74 21.48.±31.90 10.36 ± 24.43 23.25 ± 32.14
0.21 0.39 0.005 0.01 0.22 0.48 0.8 0.44 0.25 0.05
91.88 ± 13.76 64.74 ± 32.44 27.77 ± 19.34 31.73 ± 26.04 48.07 ± 27.14 12.17 ± 18.70 30.76 ± 31.54 20.97 ± 28.21 4.48 ± 13.24 11.76 ± 21.93
89.74 ± 19.90 78.84 ± 27.03 65.03 ± 30.95 35.57 ± 25.35 25.32 ± 29.42 4.48 ± 11.48 13.46 ± 23.11 15.68 ± 24.35 5.12 ± 12.14 17.64 ± 26.11
0.64 0.002 <0.001 0.14 <0.0001 0.007 0.002 0.13 0.59 0.21
Difference in reduction (CTRT – RT) (mean ± SE)
p
6.8 ± 5.03 17.06 ± 7.2 14.14 ± 6.83 10.22 ± 6.35 16.83 ± 6.42 6.24 ± 4.30 15.79 ± 7.34 7.50 ± 7.00 3.06 ± 3.64 2.64 ± 5.36
0.53 0.009 0.04 0.16 0.01 0.12 0.01 0.12 0.72 0.52
SD – standard deviation, SE – standard error. + RT arm is having more deterioration in symptoms than in the CTRT arm.
Table 4 QLQ-C15-PAL at the base line and at 6 months between the groups. Characteristic
Physical functioning+ Emotional functioning Global Fatigue Pain Dyspnea+ Insomnia Appetite## Vomiting Constipation+
RT (n – 13)
RT + CT (n – 15)
Baseline
6 months
p
Baseline
6 months
p
91.45 ± 14.45 66.66 ± 32.68 30.76 ± 26.21 29.48 ± 32.74 38.88 ± 30.42 7.69 ± 19.96 15.38 ± 29.23 25.63 ± 30.89 0 10.25 ± 16.01
73.50 ± 40.70 65.47 ± 40.01 57.69 ± 37.64 57.69 ± 38.25 37.5 ± 37.68 17.94 ± 37.55 12.81 ± 25.59 5.12 ± 12.51 5.12 ± 12.51 20.51 ± 32.02
0.21 0.57 0.04 0.09 0.78 0.57 0.71 0.05 0.15 0.41
95.67 ± 8.63 70.45 ± 25.68 34.09 ± 20.87 29.85 ± 25.99 41.30 ± 29.67 7.24 ± 14.05 20.28 ± 26.08 17.39 ± 24.34 4.54 ± 15.58 12.12 ± 26.31
90.74 ± 19.89 79.54 ± 32.50 71.96 ± 32.68 19.44 ± 21.79 24.63 ± 28.81 11.59 ± 21.57 14.49 ± 28.11 11.59 ± 21.57 4.54 ± 11.70 13.63 ± 28.46
0.58 0.19 <0.003 0.14 0.04 0.44 0.26 0.33 0.70 0.92
Difference in reduction (CTRT – RT) (mean ± SE)
p
5.03 ± 11.66 12.50 ± 13.69 19.54 ± 12.35 38.62 ± 12.73 23.18 ± 14.51 10.57 ± 11.00 11.42 ± 13.40 14.71 ± 10.69 7.14 ± 6.01 7.73 ± 12.36
0.98 0.18 0.13 0.03 0.15 0.47 0.35 0.31 0.26 0.54
SD – standard deviation, SE – standard error. + RT arm is having more deterioration in symptoms than in the CTRT arm. ## Improvement in symptoms in RT arm as compared to the CTRT arm.
Table 5 HN–35 at the baseline and at 1 month between the two groups. Characteristic
Pain Swallowing Sense+ Speech Dysphagia Social contact Sex Teeth Mouth opening Dryness++ Salivary gland+ Cough Felt ill
RT (n – 45)
RT+CT (51)
Baseline (mean ± SD)
1 month (mean ± SD)
p
Baseline (mean ± SD)
1 month (mean ± SD)
p
32.58 ± 21.23 29.43 ± 24.14 8.5 ± 16.52 27.35 ± 28.89 35.14 ± 27.73 19.99 ± 23.09 62.49 ± 41.31 15.55 ± 27.15 35.55 ± 39.82 19.25 ± 27.04 31.10 ± 29.64 14.81 ± 28.02 47.40 ± 32.94
30.17 ± 25.76 33.03 ± 29.51 21.11 ± 26.44 28.97 ± 32.36 34.62 ± 34.22 27.62 ± 34.63 56.43 ± 44.34 17.77 ± 24.20 31.85 ± 37.57 31.10 ± 26.96 35.55 ± 32.09 19.99 ± 33.63 39.99 ± 41.19
0.5 0.54 0.001 0.7 0.76 0.09 0.4 0.65 0.44 0.01 0.45 0.29 0.17
40.47 ± 23.78 28.90 ± 26.00 9.79 ± 18.60 31.71 ± 29.42 33.29 ± 33.03 22.08 ± 25.03 67.54 ± 41.34 28.10 ± 37.34 34.18 ± 36.04 20.25 ± 29.11 31.56 ± 32.09 13.26 ± 22.11 42.19 ± 35.93
23.84 ± 17.72 23.84 ± 25.65 17.86 ± 19.69 21.1 ± 26.29 26.78 ± 31.11 15.68 ± 23.54 60.20 ± 43.54 13.72 ± 22.28 21.91 ± 27.45 36.59 ± 25.16 34.63 ± 23.99 10.45 ± 20.53 26.66 ± 30.11
<0.001 0.24 0.009 0.01 0.22 0.12 0.30 0.007 0.003 0.005 0.57 0.39 0.006
Difference in reduction (CTRT – RT) (mean ± SE)
p
14.21 ± 4.93 7.65 ± 6.09 4.52 ± 4.62 12.22 ± 6.01 5.99 ± 7.07 14.03 ± 6.04 1.28 ± 10.14 16.60 ± 7.21 9.56 ± 6.38 4.48 ± 7.4 1.37 ± 7.9 8 ± 5.75 8.12 ± 7.69
0.006 0.24 0.68 0.03 0.37 0.03 0.20 0.01 0.03 0.4 0.57 0.15 0.18
SD – standard deviation, SE – standard error. + RT arm is having more deterioration in symptoms than in the CTRT arm. ++ CTRT arm is having more deterioration in symptoms than in the RT arm.
in their retrospective analysis that OS in such a group of patients treated with palliative treatment was only 3.2 months [3]. In the present study OS in the RT arm was 5.9 months and in the CTRT arm was 10.13 months. Adelstein et al. had showed a median OS of 12.6 months in the RT arm versus 19.1 months in the CTRT arm in advanced and unresectable head and neck cancers. In that study they included only ECOG PS of 0 or 1 patients whereas in present study we have included ECOG I–III [15]. Patients who received further treatment (RT or CTRT) did better than those
who did not. This suggests an initial response helped in identifying responding patients who would benefit from subsequent further treatment and non responding patients were spared toxicity of radical treatment. However, a larger and adequately powered phase III study should be able to answer this in a definite manner. Grade 3/4 mucositis during radical treatment in RT arm was 30.77% that corresponds to available literature of 20–34% with conventional RT schedule [17,18]. Grade 3/4 mucositis during radical treatment in the CTRT arm was 52% that is higher than available
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short course RT Vs Chemo RT for unresectable head and neck cancer
Table 6 HN-35 at the baseline and at 6 months between the two groups. Characteristic
Pain Swallowing Sense++ Speech Dysphagia Social contact Sex Teeth Mouth opening Dryness+ Salivary gland## Cough+ Felt ill
RT (N = 13)
RT + CT (N = 17)
Baseline (mean ± SD)
6 months (mean ± SD)
p
Baseline (mean ± SD)
6 months (mean ± SD)
p
26.91 ± 20.17 29.47 ± 29.58 5.12 ± 10.50 25.58 ± 30.53 25.50 ± 18.91 11.28 ± 12.58 66.66 ± 43.22 12.82 ± 28.99 17.94 ± 32.24 23.07 ± 25.03 28.20 ± 26.68 20.51 ± 37.36 41.02 ± 36.39
32.04 ± 24.73 41.91 ± 27.61 16.66 ± 15.21 43.55 ± 36.38 38.19 ± 32.21 32.81 ± 35.42 80.55 ± 36.12 28.20 ± 32.90 17.94 ± 32.24 51.27 ± 32.24 25.63 ± 14.61 41.02 ± 36.39 46.15 ± 51.88
0.44 0.25 0.04 0.14 0.18 0.06 0.42 0.02 1 0.009 0.75 0.15 0.76
40.67 ± 28.85 23.52 ± 25.72 6.86 ± 14.50 26.08 ± 29.65 27.44 ± 34.45 23.13 ± 24.84 68.88 ± 40.76 29.41 ± 38.87 23.52 ± 30.65 19.60 ± 26.50 31.37 ± 39.91 11.76 ± 20.20 50.97 ± 37.48
20.08 ± 17.69 14.69 ± 18.28 25.49 ± 30.68 18.92 ± 22.10 18.12 ± 27.83 8.62 ± 16.45 52.22 ± 45.80 15.68 ± 23.91 6.46 ± 26.65 41.17 ± 25.08 29.40 ± 30.91 13.72 ± 16.90 29.41 ± 37.04
0.01 0.1 0.02 0.43 0.36 0.04 0.21 0.16 0.21 0.02 0.87 0.71 0.11
Difference in reduction (CTRT – RT) (mean ± SE)
p
25.72 ± 9.87 21.26 ± 12.30 7.09 ± 10.01 25.12 ± 14.36 22.01 ± 13.99 36.04 ± 12.02 30.55 ± 20.64 29.10 ± 12.13 7.84 ± 10.13 6.63 ± 12.62 0.60 ± 15.37 18.55 ± 13.13 26.69 ± 20.70
0.02 0.05 0.61 0.02 0.04 0.01 0.20 0.02 0.42 0.57 0.8 0.05 0.17
SD – standard deviation, SE – standard error. + RT arm is having more deterioration in symptoms than in the CTRT arm. ++ CTRT arm is having more deterioration in symptoms than in the RT arm. ## Improvement in symptoms in the RT arm as compared to the CTRT arm.
literature of 43% [19]. This in turn resulted in higher incidence of grade 3/4 dysphagia in the CTRT as compared to the RT arm (68% versus 7.69% p 6 0.001). This is due to more of treatment related mucositis, submucosal fibrosis and functional loss of pharyngeal constrictor muscle in CTRT than in RT only mode of treatment. In Mohanti et al. study, 37% of the patients had at least PR as compared to 27.27% of patients in RT arm in the present study. Maximum response was seen in laryngeal cancers (43%) in Mohanti et al. study but in the present study laryngeal cancers were excluded. If we exclude laryngeal cancer from Mohanti et al. study then 28.72% had at least PR which is comparable to 27.27% in the RT arm in the present study. In the quality of life assessment we noticed an improvement in most of the symptoms and functional score at 1 and 6 months in the CTRT arm as compared to the RT arm with significant improvement in some of the parameters. Apart from primary symptom control proper care should be taken for cough, constipation, and insomnia at each visit. Compliance to OPD visit is a major problem in any palliative study. Patients enrolled in this study came from as far as 1500 km from the study center and once they were kept in best supportive group then they rarely came for regular OPD visits. About 16% of the patients didn’t attend even a single OPD post the decision to keep them in best supportive care. Quality of life should have been taken by an independent investigator. In the first week and post 1 month of palliative treatment nearly 15% of value for few of the hematological parameters was either missing or not done. This should have been minimized as much as possible.
Conclusion This phase 2 randomized study has shown that a short course of palliative CTRT over palliative RT alone leads to more partial responses and helps in identifying patients who may be offered radical treatment. It also leads to improvement in PFS and OS. Quality of life assessment also showed improvement in the CTRT arm and in any incurable cancer quality of life assessment is as important as survival analysis. The entire study can be summarized as this type of study design and its results aim to add the benefit of radical treatment in responders and subtract the toxicity of radical treatment in non responders.
Disclaimers Nil. Funding None. Conflict of interest None. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.radonc.2015.07. 026. References [1] Wei WI. Commentary: head and neck carcinomas in the developing world. BMJ 2002 Oct 12;325:827. [2] GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from:. [3] Mohanti BK, Nachiappan P, Pandey RM, Sharma A, Bahadur S, Thakar A. Analysis of 2167 head and neck cancer patients’ management, treatment compliance and outcomes from a regional cancer centre, Delhi. India J Laryngol Otol 2007 Jan;121:49–56. [4] Pignon J-P, le, Maître A, Maillard E, Bourhis J, MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol J Eur Soc Ther Radiol Oncol 2009 Jul;92:4–14. [5] Mohanti BK, Umapathy H, Bahadur S, Thakar A, Pathy S. Short course palliative radiotherapy of 20 Gy in 5 fractions for advanced and incurable head and neck cancer: AIIMS study. Radiother Oncol J Eur Soc Ther Radiol Oncol. 2004 Jun;71:275–80. [6] NCCN-2014/HnNk +lung/head-and-neck.pdf [Internet]. p. MS–27. Available from:
A. Kumar et al. / Radiotherapy and Oncology 117 (2015) 145–151 [10] Gibson MK, Li Y, Murphy B, et al. Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol Off J Am Soc Clin Oncol. 2005 May 20;23:3562–7. [11] Tan IB, Dolivet G, Ceruse P, Vander Poorten V, Roest G, Rauschning W. Temoporfin-mediated photodynamic therapy in patients with advanced, incurable head and neck cancer: a multicenter study. Head Neck 2010 Dec;32:1597–604. [12] Mehra R, Cohen RB, Burtness BA. The role of cetuximab for the treatment of squamous cell carcinoma of the head and neck. Clin Adv Hematol Oncol HO 2008 Oct;6:742–50. [13] Carvalho AL, Salvajoli JV, Kowalski LP. A comparison of radiotherapy or radiochemotherapy with symptomatic treatment alone in patients with advanced head and neck carcinomas. Eur Arch Oto-Rhino-Laryngol Off J Eur Fed Oto-Rhino-Laryngol Soc EUFOS Affil Ger Soc Oto-Rhino-Laryngol - Head Neck Surg. 2000;257:164–7. [14] Hitt R, Grau JJ, López-Pousa A, et al. A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer. Ann Oncol Off J Eur Soc Med Oncol ESMO 2014 Jan;25:216–25.
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[15] Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2003 Jan 1;21:92–8. [16] Ma J, Verweij J, Kolker HJ, van Ingen HE, Stoter G, Schellenss JH. Pharmacokinetic-dynamic relationship of cisplatin in vitro: simulation of an i.v. bolus and 3 h and 20 h infusion. Br J Cancer 1994 May;69:858–62. [17] Sharma A, Mohanti BK, Thakar A, Bahadur S, Bhasker S. Concomitant chemoradiation versus radical radiotherapy in advanced squamous cell carcinoma of oropharynx and nasopharynx using weekly cisplatin: a phase II randomized trial. Ann Oncol Off J Eur Soc Med Oncol ESMO 2010 Nov;21:2272–7. [18] Trotti A, Bellm LA, Epstein JB, et al. Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review. Radiother Oncol J Eur Soc Ther Radiol Oncol 2003 Mar;66:253–62. [19] Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003 Nov 27;349:2091–8.
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Phase II randomised trial
A phase 2 randomized study to compare short course palliative radiotherapy with short course concurrent palliative chemotherapy plus radiotherapy in advanced and unresectable head and neck cancer Arvind Kumar a, Atul Sharma a,⇑,1, Bidhu Kalyan Mohanti b, Alok Thakar c, Nootan Kumar Shukla d, Sanjay P. Thulkar e, Kapil Sikka c, Suman Bhasker b, Chirom Amit Singh c, Sreenivas Vishnubhatla f a Department of Medical Oncology; b Department of Radiotherapy; c Department of Otorhinolaryngology; d Department of Surgical Oncology, Dr BRA IRCH; e Department of Radiology, Dr BRA IRCH; and f Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India
a r t i c l e
i n f o
Article history: Received 9 May 2015 Received in revised form 3 July 2015 Accepted 7 July 2015 Available online 21 August 2015 Keywords: Advanced and incurable HNSCC Palliative RT CTRT C15-PAL HN-35 questionnaire
a b s t r a c t Background: Treatment of unresectable HNSCC is not well defined and has a poor outcome. This study has been designed to address the unmet needs of such groups of patients with primary end points of (a) proportion of patients eligible for radical treatment in each arm (b) loco-regional disease control at 6 months between two arms. Materials and methods: Locally advanced and unresectable HNSCC patients (except Nasopharynx and Larynx) unfit for radical treatment were randomized to arm A [short course RT alone (4 Gy/#/day for 5 days)] or arm B [RT as arm A + concurrent cisplatin at 6 mg/m2/day IV bolus for 5 days]. Those with at least PR were taken for further RT to complete biological equivalent dose of 70 Gy, in both the arms. In arm B, concurrent CDDP at a dose of 40 mg/m2/week was administered. Results: 114 patients (57 in each arm) were randomized but 111 were analyzable. 15 (27.27%) patients in arm A and 28 (50%) patients in arm B had PPR (p = 0.01) however patients taken for FRT were 14 (25.45%) and 26 (46.42%) in arms A and B respectively (p = 0.02). Locoregional control i.e. (CR + PR) at 6 months was 16.36% in arm A versus 32.14% in arm B (p = 0.15). Median PFS (arm A – 3.2 months, arm B – 6.2 months; p = 0.02) and OS (arm A – 5.9 months, arm B – 10.1 months; p = 0.03) was significantly more in arm B. There was relative improvement in quality of life for most parameters in arm B. Conclusion: Concurrent low dose CTRT can be an effective treatment modality in advanced and incurable HNSCC. However, a larger phase III trial is required. Ó 2015 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 117 (2015) 145–151
Head and neck squamous cell cancer (HNSCC) is a major oncological burden in developing countries. It constitutes 5% of all cancers in the world but 15% of all cancers in developing countries and is ranked as the 6th most common cancer in the world among men [1,2]. Head and neck cancer occurs in multiple subsites which varies greatly as per geographic location. In India lip, oral cavity, oropharynx and hypopharynx cancer constitute about 80% of all head and neck cancer [2]. The reason for this high prevalence is due to common practice of chewing tobacco in this region. Single modality treatment may be adequate for early stage disease whereas advanced cases are treated by combined modality. In ⇑ Corresponding author at: Room no. 229, 2nd Floor, Department of Medical Oncology, Dr BRA Institute Rotary Cancer Hospital (IRCH), All India Institute of Medical Sciences, New Delhi 110029, India. E-mail address: [email protected] (A. Sharma). 1 Current location – sabbatical. http://dx.doi.org/10.1016/j.radonc.2015.07.026 0167-8140/Ó 2015 Elsevier Ireland Ltd. All rights reserved.
India, unfortunately about 40% or more HNSCC patients presents in advanced and unresectable stage [3]. Available literature is almost silent on how these patients should be managed. These patients are neither suitable for surgery and post operative radiation nor fit for curative RT or chemo-RT approaches. Some of these patients are treated with radical radiation or concurrent chemo-radiation. Many of these patients are considered for palliative therapy or best supportive care similar to advanced cancers of Gall Bladder, Lung, Esophagus, etc. A number of studies have proven the superiority of concurrent chemo-radiation over radiation alone in achieving loco-regional control and overall survival in locally advanced head and neck squamous cell carcinoma [4]. We, believe that when palliation is the intent, it may be reasonable to consider a treatment which is not very toxic. Also in the absence of robust clinical studies, whether radical RT or concurrent chemo-radiation is the most appropriate in such a situation is still not known. In advanced
146
short course RT Vs Chemo RT for unresectable head and neck cancer
and incurable HNSCC our policy is to deliver 20 Gy/5# with 4 Gy/day over 5 consecutive days and then reassess them after 4 weeks [5]. If there is partial response or more then we consider them for further radical radiotherapy. We have designed this study to show if any, the benefit of adding low dose CDDP with palliative RT over palliative RT alone. To best of our knowledge no study has compared short course palliative RT versus short course palliative chemo-radiation using IV bolus low dose daily CDDP in unresectable HNSCC. The hypothesis behind this study is that addition of chemotherapy to palliative radiation will lead to improvement in loco regional disease control, survival and symptomatic relief compared to palliative radiation alone. Early response to palliative RT or palliative chemo-radiation will help identify a sub group of patients who will be taken up for further treatment. This is likely to have a major impact on the delivery of health care to a large number of advanced unresectable HNSCC in a resource limited country. Methods This study was conducted at Dr B.R.A., Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi. It was a randomized phase II clinical trial. The protocol of this study was approved by the Institute ethics committee. Written informed consent was taken from all patients. Main inclusion criteria were any locally advanced squamous cell carcinoma of the oral cavity, oropharynx, and hypo pharynx that had been unanimously defined as inoperable and incurable by multidisciplinary team members with adequate organ functions (bone marrow, kidney, liver) with an ECOG Performance status (PS) of I–III were enrolled in this study. Exclusion criteria were ECOG PS IV, or non-squamous histology or recurrent or metastatic disease or who had received radiotherapy or chemotherapy in the past. Study design Patients had a full clinical examination with recording of site, size and extent of primary tumor and neck nodes. CBC and serum biochemistry (liver function test, kidney function test), chest X-ray PA view, biopsy from primary site, ENT examination, Contrast Enhanced Computed Tomography (CECT) of face and neck was done for all subjects at the base line. Patients who fulfilled inclusion criteria were randomly assigned to either palliative RT (arm A) or palliative RT + CT (arm B) arm by a computer-generated balanced randomization algorithm. Arm A: 20 Gy in 5 fractions (4 Gy daily for 5 consecutive days) by cobalt or linear accelerator. Arm B: radiation as in arm A with concurrent cisplatin at the dose of 6 mg/m2/day administered as IV bolus as radio sensitizer. 20 Gy in 5 fractions over 1 week is equivalent in biologically effective dose (BED) to 28 Gy at 2 Gy per fraction, 5 fractions per week. Patients in both the arms were assessed at nearly 4 weeks for response and toxicities. Patients in both the arms were taken for further radical treatment [FRT] only if they had at least a partial response after short course RT or chemo-RT. Patients eligible for FRT were administered RT as 2 Gy/fraction/day completing a total radiobiological equivalent dose of 70 Gy, in both the arms. In arm B, concurrent cisplatin at a dose of 40 mg/m2/week was administered along with RT. Radiation planning and optimization were done using 2D or 3D-CRT techniques. Treatment field encompassed primary disease, neck nodes and area of potential microscopic spread in the first phase. Cord sparing was accomplished after delivery of external beam radiotherapy (EBRT) up to 44 Gy. Gross primary and nodal disease were boosted by shrinking field technique after EBRT up
to 56 Gy. Gross posterior neck disease after cord sparing was boosted with electrons of suitable energy. All subjects received best supportive care as and when needed. Proper oral intake was maintained and Ryle’s tube was inserted if required. Primary endpoints were (1) to compare proportion of patients eligible for radical treatment in each arm and (2) to assess loco-regional disease control at 6 months between two arms. Secondary end points were to compare (1) progression free survival (PFS), (2) overall survival (OS), (3) to assess and compare the degree of symptom relief, palliation and quality of life (QOL) and (4) to compare toxicity between two arms. Response assessment Response assessment was done at 1 and 6 months. Subjective response was assessed by degree of symptomatic relief & palliation expressed by study subjects. Clinical evaluation including indirect laryngoscopy was carried out at each visit. CECT of face and neck was also done at 1 and 6 months for response assessment. Quality of life assessment was done at the base line, 1 and 6 months for all available patients by EORTC QLQ-C15-PAL and HN35 questionnaire. It was evaluated by the primary clinician himself. Toxicity was assessed at each visit by CTACE version 3. Statistical methods Rates of conversion to radical treatment, loco-regional disease control, symptom assessment, toxicity between the two arms were compared using the chi-square test. Survival curves were plotted using Kaplan Meier survival analysis. QOL within a group was compared using a paired t test and change in score for the different parameters of QOL assessment at 1 and 6 months from the baseline between the two groups were compared using wilcoxon rank-sum test. All statistical analysis was done using Stata 12.1. A p value of <0.05 was considered statistically significant. Results One hundred and fourteen patients (57 in each arm) were randomized between March 2012 and October 2013. There was no significant difference between 2 groups regarding baseline presentations, sites, stages, etc. (Table 1). Three patients were excluded from analysis. Two patients in arm A (abdominal metastasis was detected in one of the patient and the other had deranged renal functions at the baseline) and one patient in arm B (had stable disease post palliative CTRT but still taken for FRT in view of young age and good PS). Hence final analysis was done on 55 patients in arm A and 56 patients in arm B. At presentation, pain was the most common symptom in both the groups (98.18% and 94.55% in arms A and B respectively) followed by dysphagia and swelling. Trismus was more common in arm B (60% in arm B and 48.15% in arm A; p – 0.21) (See Fig. 1). Response assessment post 1 month of palliative treatment showed that 15 (27.27%) patients in arm A and 28 (50%) patients in arm B had either CR or PR (p = 0.01) (Table 2). One patient in each arm could not be taken for FRT due to poor PS and 1 patient in arm B developed fistula in cheek post one week of palliative CTRT. Hence 14 (25.45%) patients in arm A and 26 (46.42%) patients in arm B were taken for FRT (p = 0.02) (Table 2). Locoregional disease control i.e. (CR + PR) at 6 months was seen in 9 (16.36%) patients in arm A versus 18 (32.14%) patients in arm B (p = 0.15). Twenty four patients in arm A and 32 patients in arm B were alive at 6 months. Median PFS in arm A was
A. Kumar et al. / Radiotherapy and Oncology 117 (2015) 145–151 Table 1 Demographic details. RT (n = 55) n (%)
CTRT (n = 56) n (%)
p value
Age Mean ± SD
55.27 ± 12.40
53.41 (±11.16)
0.40
Sex Male Female
47 (85.45) 8 (14.55)
49 (87.50) 7 (12.50)
0.75
ECOG PS 0 1 2 3
5 (9.09) 20 (36.36) 27 (49.09) 3 (5.45)
4 (7.14) 23 (41.07) 21 (37.50) 8 (14.29)
SITE Oral cavity Oro pharynx Hypo pharynx
18 (32.73) 32 (58.18) 5 (9.09)
19 (33.93) 36 (64.29) 1 (64.29)
0.23
1 (1.82) 24 (43.64) 30 (54.55)
2 (3.57) 31 (55.36) 23 (41.07)
0.34
Histopathology (differentiation) Well 12 (21.82) Moderate 31 (56.36) Poor 1 (1.82) Not known 11 (20)
7 (17.27) 36 (60.91) 6 (10.91) 6 (10.91)
Serum albumin <3.5 >3.5
8 (14.54) 47 (85.45)
9 (16.07) 47 (83.92)
0.82
Addiction to tobacco Smoking Chewing Alcohol
31 (56.36) 18 (34) 21 (39)
38 (67.86) 14 (26) 24 (43)
0.21 0.33 0.61
Stage 3 Stage 4a Stage 4b
0.34
147
3.2 months and arm B was 6.2 months (Hazard ratio {HR} – 0.6%, 95% Confidence Interval {CI} 0.38–0.92; p = 0.02, Fig. 2a). Median OS in arm A was 5.9 months compared to 10.1 months in arm B (HR – 0.62, CI – 0.40–0.96; p = 0.03, Fig. 2b, Table 2). Among those patients in the RT arm who underwent FRT versus those who didn’t PFS (HR – 0.19, CI – 0.8–0.42; p 6 0.001) and OS (HR – 0.25, CI – 0.11–0.56. p = 0.001) were highly significant. Similarly, in the CTRT arm among those patients who underwent FRT versus those who didn’t PFS (HR – 0.21, CI – 0.1–0.44; p 6 0.001) and OS (HR – 0.4, CI – 0.2–0.78; p = 0.007) were significant. Except difficulty in tongue protrusion (suggesting involvement of deep muscles of the tongue at 1 month), all other symptoms were better controlled in arm B, both at 1 and 6 months. Pain was better controlled in arm B as compared to arm A (45.83% in arm A versus 67.92% patients in arm B had >50% reduction from base line; p = 0.02). Forty seven percent patients in arm A and 85.19% patients in arm B had >50% reduction of trismus at 6 months compared to baseline; p = 0.007). We have not carried out any separate analysis as regards response or toxicity to 2-D versus 3-D based radiotherapy delivery.
0.08
Toxicity assessment Mostly Grade 1 or 2 toxicity was present at any time point. Post 1 week of palliative treatment, one patient died due to pneumonia and sepsis in the CTRT arm but there was no toxic death in the RT arm. Post radical treatment there was 1 toxic death in the RT arm due to radiation induced late grade 3 dryness and mucosal edema. In the CTRT arm 1 patient died secondary to grade 3/4 mucositis and renal failure and another patient died due to sudden
Assessed for eligibility (n= 136)
Excluded (n = 22) Not meeng inclusion criteria (n = 14) Refused to parcipate (n = 5). Other reasons (n=3)
Randomized (n = 114)
Randomized to arm A {RT} (N=57) ST
Received allocated 1 week of Rx (n= 56). One paent defaulted aer 2 days of RT.
Randomized to arm B {CTRT} (N=57) Received allocated 1ST week of Rx (n= 55). Two paents defaulted one day of concurrent CDDP in first phase.
Paents evaluable at 1 months (n=53).
Paents evaluable at 1 months (n=57).
Radical Rx received (n=14)
Radical Rx received (n=26)
Toxic death aer 1 week of Rx (n=0)
Toxic death aer 1st week of Rx (n=1)
Toxic death aer/during radical Rx (n=1)
Toxic death aer/during radical Rx (n=3)
Lost to follow up (n=2)
Lost to follow up (n=2)
Alive at 6 months (n=24)
Alive at 6 months (n=32)
st
Analyzed (n = 55)
Analyzed (n = 56)
Excluded from analysis (n = 2) (abdominal metastasis was detected in one of the patient and the another had deranged renal functions at baseline)
Excluded from analysis (n = 1)( Had stable disease post palliative CTRT but still taken for radical treatment.)
Fig. 1. Consort diagram of the study.
148
short course RT Vs Chemo RT for unresectable head and neck cancer
Table 2 Response and survival results between the two treatment arms.
CR or PR at 1 month of palliative treatment Radical treatment received CR + PR at 6 months Median PFS Median OS
Discussion
RT arm
CTRT arm
p value
15 (27.27%)
28 (50%)
0.01
14 (25.45%) 9 (16.36%) 3.2 5.9
26 (46.42%) 18 (32.14%) 6.2 10.1
0.02 0.15 0.02 0.03
CR – complete response, PR – partial response, PFS – progression free survival, OS – overall survival.
aspiration. The third patient in the CTRT arm had a sudden rupture of carotid vessels post neck dissection for residual node after FRT. There was no incidence of grade 3 or 4 renal toxicity post 1 week of palliative CTRT. Grade 3 and 4 dysphagia was more in arm B during radical treatment (7.69% in arm A versus 68% in arm B, p 6 0.001). But at the 6 month grade 3 and 4 dysphagia between two arms were not significantly different. Quality of life assessment
0.00
0.00
0.25
0.25
0.50
0.50
0.75
0.75
1.00
1.00
At 1 month QLQ was missing in 9 patients (1 set of questions lost, 6 patients didn’t attend OPD and in 2 patients QLQ was not taken). Questions related to sexual issues were missing the most (nearly 2.5%). In the C15-PAL questionnaire, at one month statistically significant improvement in the CTRT arm was seen in emotional functioning (p = 0.009), global health status (p = 0.04), pain (p = 0.01) and insomnia (p = 0.01) (Table 3). At 6 months improvement was still seen in the CTRT arm in emotional functioning, global health status, and pain though it was not significant. At 6 months there was significantly more improvement in fatigue in the CTRT arm as compared to the RT arm (p = 0.03). At 6 months there was a non significant improvement in appetite in the RT as compared to CTRT arm (p = 0.20). There was deterioration of symptoms for fatigue, vomiting and constipation in both the arms at 1 month but more so in the RT arm (p value not significant). Similarly there was deterioration in physical functioning, dyspnea and constipation in both the arms at 6 months but more so in the RT arm (p value not significant) (Table 4). In the HN-35 questionnaire, at 1 month (Table 5) significant improvement was noted in the CTRT arm as compared to the RT arm for pain (p = 0.006), speech (p = 0.03), social contact (p = 0.03), dental complaints (p = 0.01) and mouth opening (0.03). Even at 6 months (Table 6), improvement was noted in the CTRT arm for pain (p = 0.02), swallowing (p = 0.05), social contact (p = 0.01), dysphagia (p = 0.04) and dental problems (p = 0.02).
0 Number at risk arm = RT arm = CTRT
NCCN guidelines recommend concurrent chemo-radiation for advanced head and neck cancer with performance status of PS 0/1 [6]. Induction chemotherapy followed by CTRT or definitive RT+/-concurrent CT is preferred if PS drops to 2. Combined modality treatment is not recommended with patients of PS 3 or more. In many countries including India HNSCC presents in an advanced and incurable state in a major proportion of cases which is different than Western countries [3,7,8]. Ironically we don’t have definitive treatment plan for such patients. A number of treatment options are described, which include radiotherapy, chemotherapy and targeted agents either singly or in combinations [9–12]. Inspite of having dismal prognosis even after aggressive treatment we are still tempted to address such patients with radical and aggressive treatment which may worsen their quality of life. In a study comparing treatment versus best supportive care Carvalho et al. showed a significant improvement in survival in the treated group versus not treated group (p < 0.00001). However, there was no difference in survival between different treatment groups (p = 0.706). It was reported that patients responding to treatment had a better survival outcome (p = 0.00002) [13]. Hitt et al. have reported that neoadjuvant chemotherapy prior to chemo-radiation doesn’t improve outcome in advanced/unresectable HNSCC [14]. In a study reported in 2003 it was shown that concurrent chemoradiation is better than radiation alone in unresectable HNSCC [15]. Our standard practice is to give palliative radiation in unresectable HNSCC. Mohanti et al. did a study in incurable HNSCC in which radiotherapy was given in two stages. In the first phase palliative RT of 20 Gy was given and in the second phase only responding patients were taken for radical RT [5]. Responding patients got the benefit of radical RT and toxicities of radical RT were omitted from non responding patients. The present study had been designed to address the benefit of adding cisplatin to RT on the background of previous study from this center reported by Mohanti et al. In a study reported by Ma et al. iv bolus, 3 h and 20 h infusion of CDDP had non-significant differences in the magnitude of the area under the concentration-time curve of unbound CDDP between the three dose-input functions and also the area under the CDDP-DNA adduct–time curves suggesting that either of the three modalities of administration had equal efficacy [16]. First phase of palliative CTRT showed a significant conversion to FRT as compared to palliative RT alone (46.42% versus 25.45%, p = 0.02) with a similar toxicity profile. Mohanti et al. had shown
53 56
3 28 37
6 9 analysis time 16 25 arm = RT
8 17
12 5 12
15 3 7
arm = CTRT
Fig. 2a. Progression free survival (PFS) of the patients between two treatment arms. X-axis: time in months. Y-axis: progression free survival (proportion). Median PFS in favor of CTRT arm; HR – 0.6 (95% CI, 0.38–0.92); p = 0.02. HR – Hazard ratio. CI – Confidence Interval.
Number at risk arm = RT arm = CTRT
0
3
6
9 analysis time
12
15
18
55 56
46 48
27 33
14 26
8 21
5 9
3 6
arm = RT
arm = CTRT
Fig. 2b. Overall survival (OS) of the patients between the two treatment arms. Xaxis: time in months. Y-axis: overall survival (proportion). Median OS in favor of CTRT arm; HR – 0.62 (95% CI, 0.40–0.96); p = 0.03. HR – Hazard ratio. CI – Confidence Interval.
149
A. Kumar et al. / Radiotherapy and Oncology 117 (2015) 145–151 Table 3 QLQ-C15-PAL at base line and at 1 month between the two groups. Characteristic
Physical functioning+ Emotional functioning Global Fatigue+ Pain Dyspnea Insomnia Appetite Vomiting+ Constipation+
RT (N = 43)
RT + CT (N = 47)
Baseline (mean ± SD)
1 month (mean ± SD)
p
Baseline (mean ± SD)
1 month (mean ± SD)
p
90.58 ± 13.85 65.18 ± 28.82 28.03 ± 20.88 37.40 ± 26.86 42.22 ± 26.73 11.59 ± 25.54 25.75 ± 32.83 19.25 ± 27.04 6.66 ± 18.25 14.72 ± 22.18
81.64 ± 30.74 62.22 ± 35.24 51.13 ± 36.72 51.48 ± 32.53 36.29 ± 31.64 10.14 ± 23.16 24.24 ± 34.74 21.48.±31.90 10.36 ± 24.43 23.25 ± 32.14
0.21 0.39 0.005 0.01 0.22 0.48 0.8 0.44 0.25 0.05
91.88 ± 13.76 64.74 ± 32.44 27.77 ± 19.34 31.73 ± 26.04 48.07 ± 27.14 12.17 ± 18.70 30.76 ± 31.54 20.97 ± 28.21 4.48 ± 13.24 11.76 ± 21.93
89.74 ± 19.90 78.84 ± 27.03 65.03 ± 30.95 35.57 ± 25.35 25.32 ± 29.42 4.48 ± 11.48 13.46 ± 23.11 15.68 ± 24.35 5.12 ± 12.14 17.64 ± 26.11
0.64 0.002 <0.001 0.14 <0.0001 0.007 0.002 0.13 0.59 0.21
Difference in reduction (CTRT – RT) (mean ± SE)
p
6.8 ± 5.03 17.06 ± 7.2 14.14 ± 6.83 10.22 ± 6.35 16.83 ± 6.42 6.24 ± 4.30 15.79 ± 7.34 7.50 ± 7.00 3.06 ± 3.64 2.64 ± 5.36
0.53 0.009 0.04 0.16 0.01 0.12 0.01 0.12 0.72 0.52
SD – standard deviation, SE – standard error. + RT arm is having more deterioration in symptoms than in the CTRT arm.
Table 4 QLQ-C15-PAL at the base line and at 6 months between the groups. Characteristic
Physical functioning+ Emotional functioning Global Fatigue Pain Dyspnea+ Insomnia Appetite## Vomiting Constipation+
RT (n – 13)
RT + CT (n – 15)
Baseline
6 months
p
Baseline
6 months
p
91.45 ± 14.45 66.66 ± 32.68 30.76 ± 26.21 29.48 ± 32.74 38.88 ± 30.42 7.69 ± 19.96 15.38 ± 29.23 25.63 ± 30.89 0 10.25 ± 16.01
73.50 ± 40.70 65.47 ± 40.01 57.69 ± 37.64 57.69 ± 38.25 37.5 ± 37.68 17.94 ± 37.55 12.81 ± 25.59 5.12 ± 12.51 5.12 ± 12.51 20.51 ± 32.02
0.21 0.57 0.04 0.09 0.78 0.57 0.71 0.05 0.15 0.41
95.67 ± 8.63 70.45 ± 25.68 34.09 ± 20.87 29.85 ± 25.99 41.30 ± 29.67 7.24 ± 14.05 20.28 ± 26.08 17.39 ± 24.34 4.54 ± 15.58 12.12 ± 26.31
90.74 ± 19.89 79.54 ± 32.50 71.96 ± 32.68 19.44 ± 21.79 24.63 ± 28.81 11.59 ± 21.57 14.49 ± 28.11 11.59 ± 21.57 4.54 ± 11.70 13.63 ± 28.46
0.58 0.19 <0.003 0.14 0.04 0.44 0.26 0.33 0.70 0.92
Difference in reduction (CTRT – RT) (mean ± SE)
p
5.03 ± 11.66 12.50 ± 13.69 19.54 ± 12.35 38.62 ± 12.73 23.18 ± 14.51 10.57 ± 11.00 11.42 ± 13.40 14.71 ± 10.69 7.14 ± 6.01 7.73 ± 12.36
0.98 0.18 0.13 0.03 0.15 0.47 0.35 0.31 0.26 0.54
SD – standard deviation, SE – standard error. + RT arm is having more deterioration in symptoms than in the CTRT arm. ## Improvement in symptoms in RT arm as compared to the CTRT arm.
Table 5 HN–35 at the baseline and at 1 month between the two groups. Characteristic
Pain Swallowing Sense+ Speech Dysphagia Social contact Sex Teeth Mouth opening Dryness++ Salivary gland+ Cough Felt ill
RT (n – 45)
RT+CT (51)
Baseline (mean ± SD)
1 month (mean ± SD)
p
Baseline (mean ± SD)
1 month (mean ± SD)
p
32.58 ± 21.23 29.43 ± 24.14 8.5 ± 16.52 27.35 ± 28.89 35.14 ± 27.73 19.99 ± 23.09 62.49 ± 41.31 15.55 ± 27.15 35.55 ± 39.82 19.25 ± 27.04 31.10 ± 29.64 14.81 ± 28.02 47.40 ± 32.94
30.17 ± 25.76 33.03 ± 29.51 21.11 ± 26.44 28.97 ± 32.36 34.62 ± 34.22 27.62 ± 34.63 56.43 ± 44.34 17.77 ± 24.20 31.85 ± 37.57 31.10 ± 26.96 35.55 ± 32.09 19.99 ± 33.63 39.99 ± 41.19
0.5 0.54 0.001 0.7 0.76 0.09 0.4 0.65 0.44 0.01 0.45 0.29 0.17
40.47 ± 23.78 28.90 ± 26.00 9.79 ± 18.60 31.71 ± 29.42 33.29 ± 33.03 22.08 ± 25.03 67.54 ± 41.34 28.10 ± 37.34 34.18 ± 36.04 20.25 ± 29.11 31.56 ± 32.09 13.26 ± 22.11 42.19 ± 35.93
23.84 ± 17.72 23.84 ± 25.65 17.86 ± 19.69 21.1 ± 26.29 26.78 ± 31.11 15.68 ± 23.54 60.20 ± 43.54 13.72 ± 22.28 21.91 ± 27.45 36.59 ± 25.16 34.63 ± 23.99 10.45 ± 20.53 26.66 ± 30.11
<0.001 0.24 0.009 0.01 0.22 0.12 0.30 0.007 0.003 0.005 0.57 0.39 0.006
Difference in reduction (CTRT – RT) (mean ± SE)
p
14.21 ± 4.93 7.65 ± 6.09 4.52 ± 4.62 12.22 ± 6.01 5.99 ± 7.07 14.03 ± 6.04 1.28 ± 10.14 16.60 ± 7.21 9.56 ± 6.38 4.48 ± 7.4 1.37 ± 7.9 8 ± 5.75 8.12 ± 7.69
0.006 0.24 0.68 0.03 0.37 0.03 0.20 0.01 0.03 0.4 0.57 0.15 0.18
SD – standard deviation, SE – standard error. + RT arm is having more deterioration in symptoms than in the CTRT arm. ++ CTRT arm is having more deterioration in symptoms than in the RT arm.
in their retrospective analysis that OS in such a group of patients treated with palliative treatment was only 3.2 months [3]. In the present study OS in the RT arm was 5.9 months and in the CTRT arm was 10.13 months. Adelstein et al. had showed a median OS of 12.6 months in the RT arm versus 19.1 months in the CTRT arm in advanced and unresectable head and neck cancers. In that study they included only ECOG PS of 0 or 1 patients whereas in present study we have included ECOG I–III [15]. Patients who received further treatment (RT or CTRT) did better than those
who did not. This suggests an initial response helped in identifying responding patients who would benefit from subsequent further treatment and non responding patients were spared toxicity of radical treatment. However, a larger and adequately powered phase III study should be able to answer this in a definite manner. Grade 3/4 mucositis during radical treatment in RT arm was 30.77% that corresponds to available literature of 20–34% with conventional RT schedule [17,18]. Grade 3/4 mucositis during radical treatment in the CTRT arm was 52% that is higher than available
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short course RT Vs Chemo RT for unresectable head and neck cancer
Table 6 HN-35 at the baseline and at 6 months between the two groups. Characteristic
Pain Swallowing Sense++ Speech Dysphagia Social contact Sex Teeth Mouth opening Dryness+ Salivary gland## Cough+ Felt ill
RT (N = 13)
RT + CT (N = 17)
Baseline (mean ± SD)
6 months (mean ± SD)
p
Baseline (mean ± SD)
6 months (mean ± SD)
p
26.91 ± 20.17 29.47 ± 29.58 5.12 ± 10.50 25.58 ± 30.53 25.50 ± 18.91 11.28 ± 12.58 66.66 ± 43.22 12.82 ± 28.99 17.94 ± 32.24 23.07 ± 25.03 28.20 ± 26.68 20.51 ± 37.36 41.02 ± 36.39
32.04 ± 24.73 41.91 ± 27.61 16.66 ± 15.21 43.55 ± 36.38 38.19 ± 32.21 32.81 ± 35.42 80.55 ± 36.12 28.20 ± 32.90 17.94 ± 32.24 51.27 ± 32.24 25.63 ± 14.61 41.02 ± 36.39 46.15 ± 51.88
0.44 0.25 0.04 0.14 0.18 0.06 0.42 0.02 1 0.009 0.75 0.15 0.76
40.67 ± 28.85 23.52 ± 25.72 6.86 ± 14.50 26.08 ± 29.65 27.44 ± 34.45 23.13 ± 24.84 68.88 ± 40.76 29.41 ± 38.87 23.52 ± 30.65 19.60 ± 26.50 31.37 ± 39.91 11.76 ± 20.20 50.97 ± 37.48
20.08 ± 17.69 14.69 ± 18.28 25.49 ± 30.68 18.92 ± 22.10 18.12 ± 27.83 8.62 ± 16.45 52.22 ± 45.80 15.68 ± 23.91 6.46 ± 26.65 41.17 ± 25.08 29.40 ± 30.91 13.72 ± 16.90 29.41 ± 37.04
0.01 0.1 0.02 0.43 0.36 0.04 0.21 0.16 0.21 0.02 0.87 0.71 0.11
Difference in reduction (CTRT – RT) (mean ± SE)
p
25.72 ± 9.87 21.26 ± 12.30 7.09 ± 10.01 25.12 ± 14.36 22.01 ± 13.99 36.04 ± 12.02 30.55 ± 20.64 29.10 ± 12.13 7.84 ± 10.13 6.63 ± 12.62 0.60 ± 15.37 18.55 ± 13.13 26.69 ± 20.70
0.02 0.05 0.61 0.02 0.04 0.01 0.20 0.02 0.42 0.57 0.8 0.05 0.17
SD – standard deviation, SE – standard error. + RT arm is having more deterioration in symptoms than in the CTRT arm. ++ CTRT arm is having more deterioration in symptoms than in the RT arm. ## Improvement in symptoms in the RT arm as compared to the CTRT arm.
literature of 43% [19]. This in turn resulted in higher incidence of grade 3/4 dysphagia in the CTRT as compared to the RT arm (68% versus 7.69% p 6 0.001). This is due to more of treatment related mucositis, submucosal fibrosis and functional loss of pharyngeal constrictor muscle in CTRT than in RT only mode of treatment. In Mohanti et al. study, 37% of the patients had at least PR as compared to 27.27% of patients in RT arm in the present study. Maximum response was seen in laryngeal cancers (43%) in Mohanti et al. study but in the present study laryngeal cancers were excluded. If we exclude laryngeal cancer from Mohanti et al. study then 28.72% had at least PR which is comparable to 27.27% in the RT arm in the present study. In the quality of life assessment we noticed an improvement in most of the symptoms and functional score at 1 and 6 months in the CTRT arm as compared to the RT arm with significant improvement in some of the parameters. Apart from primary symptom control proper care should be taken for cough, constipation, and insomnia at each visit. Compliance to OPD visit is a major problem in any palliative study. Patients enrolled in this study came from as far as 1500 km from the study center and once they were kept in best supportive group then they rarely came for regular OPD visits. About 16% of the patients didn’t attend even a single OPD post the decision to keep them in best supportive care. Quality of life should have been taken by an independent investigator. In the first week and post 1 month of palliative treatment nearly 15% of value for few of the hematological parameters was either missing or not done. This should have been minimized as much as possible.
Conclusion This phase 2 randomized study has shown that a short course of palliative CTRT over palliative RT alone leads to more partial responses and helps in identifying patients who may be offered radical treatment. It also leads to improvement in PFS and OS. Quality of life assessment also showed improvement in the CTRT arm and in any incurable cancer quality of life assessment is as important as survival analysis. The entire study can be summarized as this type of study design and its results aim to add the benefit of radical treatment in responders and subtract the toxicity of radical treatment in non responders.
Disclaimers Nil. Funding None. Conflict of interest None. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.radonc.2015.07. 026. References [1] Wei WI. Commentary: head and neck carcinomas in the developing world. BMJ 2002 Oct 12;325:827. [2] GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from:
A. Kumar et al. / Radiotherapy and Oncology 117 (2015) 145–151 [10] Gibson MK, Li Y, Murphy B, et al. Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol Off J Am Soc Clin Oncol. 2005 May 20;23:3562–7. [11] Tan IB, Dolivet G, Ceruse P, Vander Poorten V, Roest G, Rauschning W. Temoporfin-mediated photodynamic therapy in patients with advanced, incurable head and neck cancer: a multicenter study. Head Neck 2010 Dec;32:1597–604. [12] Mehra R, Cohen RB, Burtness BA. The role of cetuximab for the treatment of squamous cell carcinoma of the head and neck. Clin Adv Hematol Oncol HO 2008 Oct;6:742–50. [13] Carvalho AL, Salvajoli JV, Kowalski LP. A comparison of radiotherapy or radiochemotherapy with symptomatic treatment alone in patients with advanced head and neck carcinomas. Eur Arch Oto-Rhino-Laryngol Off J Eur Fed Oto-Rhino-Laryngol Soc EUFOS Affil Ger Soc Oto-Rhino-Laryngol - Head Neck Surg. 2000;257:164–7. [14] Hitt R, Grau JJ, López-Pousa A, et al. A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer. Ann Oncol Off J Eur Soc Med Oncol ESMO 2014 Jan;25:216–25.
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[15] Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2003 Jan 1;21:92–8. [16] Ma J, Verweij J, Kolker HJ, van Ingen HE, Stoter G, Schellenss JH. Pharmacokinetic-dynamic relationship of cisplatin in vitro: simulation of an i.v. bolus and 3 h and 20 h infusion. Br J Cancer 1994 May;69:858–62. [17] Sharma A, Mohanti BK, Thakar A, Bahadur S, Bhasker S. Concomitant chemoradiation versus radical radiotherapy in advanced squamous cell carcinoma of oropharynx and nasopharynx using weekly cisplatin: a phase II randomized trial. Ann Oncol Off J Eur Soc Med Oncol ESMO 2010 Nov;21:2272–7. [18] Trotti A, Bellm LA, Epstein JB, et al. Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review. Radiother Oncol J Eur Soc Ther Radiol Oncol 2003 Mar;66:253–62. [19] Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003 Nov 27;349:2091–8.