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Characteristics of response of oral and pharyngeal mucosa in patients receiving chemo-IMRT for head and neck cancer using hypofractionated accelerated radiotherapy
Radiotherapy and Oncology 97 (2010) 86–91
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Radiotherapy related morbidity
Characteristics of response of oral and pharyngeal mucosa in patients receiving chemo-IMRT for head and neck cancer using hypofractionated accelerated radiotherapy Shreerang A. Bhide a,b,⇑, Sarah Gulliford b, Jack Fowler c,d, Nicola Rosenfelder a, Katie Newbold a, Kevin J. Harrington a,b, Christopher M. Nutting a,b a
Royal Marsden Hospital; and b Institute of Cancer Research, Sutton, London, UK; c Department of Human Oncology; and d Department of Medical Physics, University of Wisconsin, Madison, USA
a r t i c l e
i n f o
Article history: Received 20 April 2010 Received in revised form 17 August 2010 Accepted 18 August 2010 Available online 7 September 2010 Keywords: Head and neck cancer Chemo-IMRT Radiobiology Hypofractionated Accelerated
a b s t r a c t Purpose: This study describes the acute response of oral and pharyngeal mucosa to chemo-IMRT schedules using different doses per fraction. Materials and methods: Patients, treated in prospective trials of concomitant chemo-IMRT with 2.17 Gy, 2.25 Gy and 2.4 Gy per fraction and identical dose of cisplatin, were included in this study. Acute toxicity was recorded prospectively using the CTCAE v2.0. We describe the incidence and prevalence of grade 3 oral mucositis and dysphagia over time and report the influence of overall treatment time (OTT). The association between the lengths of pharyngeal mucosa receiving 50 Gy (L50) and 60 Gy (L60) and grade 3 dysphagia was tested. Results: The incidence and the peak prevalence of grade 3 dysphagia were significantly higher in patients receiving 2.4 Gy per fraction. The peak prevalence of grade 3 dysphagia was higher and the recovery was slower in patients with lower OTT (median 38 days vs. 42 days) treatment. There was a significant correlation between L50, L60 and grade 3 dysphagia. A L50 and L60 greater than 8 cm resulted in greater than 60% and 70% incidence of grade 3 dysphagia, respectively. Conclusion: The length of pharyngeal mucosa receiving doses close to the prescription dose correlates with grade 3 dysphagia. It was observed that incidence of grade 3 dysphagia was lower and recovery from it was quicker in patients with greater OTT. Ó 2010 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 97 (2010) 86–91
Using induction and/or concomitant systemic chemotherapy and/or altered fractionation radiotherapy in advanced head and neck cancer treatment have been shown to improve survival and rates of organ preservation [2–4,14]. Hypofractionated accelerated radiotherapy is thought to improve outcomes by reducing the impact of tumour cell repopulation. Using the simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT), it is possible to escalate tumour dose using the hypofractionated accelerated approach, while minimising the dose to organs at risk (OARs). Often acute mucositis can be the dose-limiting toxicity when escalating the radiation dose [11,15]. It is, therefore, important to study the radiobiology of acute radiation damage to mucosa of the upper aero-digestive tract, which results in significant morbidity and altered quality of life (QOL) during radiotherapy [13]. Although several studies using altered fractionation have been described in the literature, there is a paucity of detailed data on acute ⇑ Corresponding author. Address: Royal Marsden Hospital, Fulham Road, London SW3 6JJ, United Kingdom. E-mail address: [email protected] (S.A. Bhide). 0167-8140/$ - see front matter Ó 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2010.08.013
toxicity. We have conducted Phase I dose-escalation trials to identify a maximum tolerated prescription dose and to investigate safety and efficacy of using hypofractionated accelerated IMRT in combination with chemotherapy. The incidence of acute toxicity has been described before [10]. In this study, we describe the acute response of oral and pharyngeal mucosa after chemo-IMRT using data from studies with three different doses per fraction.
Materials and methods Patient selection Patients were treated in two prospective trials of concomitant chemo-IMRT. The first trial was a Phase I trial of dose-escalation and accelerated radiotherapy for laryngeal and hypopharyngeal cancer. Patients with squamous cell carcinoma of the larynx/hypopharynx requiring primary radical chemo-radiation were included in the study. Two dose levels were tested. The second trial was a Phase II trial looking at the benefit of using IMRT to spare bilateral superficial parotid glands in oropharyngeal squamous cell
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S.A. Bhide et al. / Radiotherapy and Oncology 97 (2010) 86–91
carcinomas requiring irradiation to bilateral parapharyngeal spaces. The doses used in each trial including the dose/fraction have been described in Table 1. These trials will be referred to as the ‘dose-escalation trial’ and ‘midline trial’, respectively, in this manuscript. The trials were approved by the Committee for Clinical Research and the Local Research Ethics Committee. Treatment Induction chemotherapy was of two cycles of cisplatin (75 mg/ m2) on day 1 and 5-FU (1000 mg/m2) for days 1–4. Cisplatin (100 mg/m2) on days 1 and 29 was used for concomitant treatment. Identical chemotherapy regimens were used for both trials. Radiotherapy planning Patients were immobilized and contrast-enhanced CT scans were acquired at 2.5 mm intervals. Gross tumour volume (GTV), clinical target volumes (CTVs) for macroscopic disease (CTV1), areas at risk of harbouring microscopic disease (CTV2) and critical structures were outlined. The oral and pharyngeal mucosa was retrospectively outlined by a single observer (SB). The surfaces of the inner table of mandible, tongue, base of tongue, floor of mouth and palate were outlined as the oral mucosa (oral cavity) as per Eisbruch et al. [8]. The pharyngeal mucosa was outlined from inferior surface of the floor of the sphenoid sinus to inferior edge of cricoid cartilage. The Helios inverse planning module in EclipseÓ was used for all IMRT plannings. The IMRT planning technique (including dose constraints for OARs) used at our institution has been previously described [10]. Doses were prescribed to median dose-volume point on the PTV1 dose volume histogram (DVH). Doses prescribed to PTV1 and PTV2 in each of the studies are described in Table 1. Data collection Mean dose was used as a single descriptor point for DVHs which were generated separately for oral mucosa and pharyngeal mucosa from the individual patients’ treatment plan. Mean dose for each patient was converted into equivalent dose in 2 Gy fractions (MD2), using the Withers formula [18], for comparison between groups (Table 3). The length of pharyngeal mucosa receiving 50 Gy (L50) and 60 Gy (L60) equivalents in 2 Gy/fraction of radiation was determined from the treatment plans for each patient and correlated to acute toxicity. Length of mucosa irradiated correlates with volume of the pharynx which is quite small. Acute toxicity was prospectively recorded using Common Toxicity Criteria (CTCAE v2.0). Data were recorded before treatment and weekly during and for four weeks after radiation. Final data recording for acute toxicity was performed at eight weeks postradiation. Late toxicity monitoring on these patients continued until five years post-treatment. Observer-assessed oral mucositis was used as a toxicity endpoint for oral mucosa. Observer-assessed dysphagia was used as a surrogate marker for pharyngeal mucositis as it is clinically relevant and visual assessment of mucositis using nasoendoscopy is difficult during radiotherapy.
Data analysis Statistical analysis was performed using the Statistical Program for Social Sciences (SPSS Ó 2006 SPSS Inc. Chicago, Illinois) v 15.0. Prevalence of a particular grade of toxicity at a given time point was defined as the number of patients reporting that grade of toxicity at that time point divided by the total number of evaluable patients at that time point. Incidence of a particular grade of toxicity was defined as the number of patients reaching that grade of toxicity during the course of treatment divided by the total number of evaluable patients [1]. Rules for missing data were as per Bentzen et al. [1]. The significance of difference in the incidence and prevalence between the two groups was tested using Chi-Square tests for proportions. The overall treatment time (OTT) was calculated for each patient. Variation in length is due to the day of the week on which treatment is commenced. The patients were split into two groups depending on whether the OTT included an extra weekend or not. The median OTT was 38 days for those patients whose treatment course did not include an extra weekend and 42 days for those whose treatment course did. The prevalence of grade 3 toxicity at each week was then plotted for each group to estimate the effect of an extra weekend on toxicity. The L50 and L60 data were correlated to the maximum grade of toxicity using the Spearman rank correlation coefficient. The patients were binned into equal-sized groups, defined by mean L50 and L60. The incidence of grade 3 dysphagia in each dose bin was then calculated, as the number of patients with grade 3 dysphagia divided by the total number of patients in that bin and plotted against the mean L50 and L60 for that bin. Results The dose-escalation trial commenced in September 2002 and the midline trial commenced in July 2005. Thirty patients were entered into each dose level of the dose-escalation study. DVH data on 26 and 29 patients were available from DL1 and DL2, respectively. Thirty patients were entered into the midline trial. The DVH data were available for all patients The patient characteristics and staging information are provided in Table 2. Applying the rules for substitution of the missing data for the acute toxicity values, all the patients with DVH were evaluable for analysis. Incidence and prevalence Incidence of grade 3 mucositis was 34% in DL1 and 43% in DL2 of the dose-escalation trial and the midline trial (Table 3). The difference in the incidence of grade 3 mucositis between DL1, DL2 and the midline trial was not statistically significant. Incidence of grade 3 dysphagia was highest in DL2 of the dose-escalation study (Table 2). Difference between the incidence of grade 3 dysphagia in DL2 and the midline trial was statistically significant (p = 0.02), and between DL1 and DL2 of borderline significance (p = 0.05). Prevalence of acute grade 3 mucositis at different time points during and immediately after CRT is shown in Fig. 1A. In the dose-escalation trial the onset of grade 3 mucositis was first
Table 1 Prescribed doses to the PTVs for the two studies. Volume
PTV1 PTV2
Dose greys (Gy)
Total dose Dose per fraction Total dose Dose per fraction
Dose-escalation study
Midline study
Dose level I (DL1)
Dose level II (DL2)
63 Gy in 28 fractions 2.25 Gy 51.8 Gy in 28 fractions 1.8 Gy
67.2 Gy in 28 fractions 2.4 Gy 56 Gy in 28 fractions 2 Gy
65 Gy in 30 fractions 2.17 Gy 54 Gy in 30 fractions 1.8 Gy
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Responses of mucosa during head and neck chemo-IMRT
Table 2 Dose-escalation trial
Age Sex Stage
Median (range) Male Female I II III IV
Midline trial (N = 30)
Dose level 1 (N = 26)
Dose level 2 (N = 29)
57(34–84)
62(44–78)
59(32–82)
22 4 1 1 10 14
23 6 0 0 16 14
23 7 0 1 5 23
Table 3 Incidence of grade 3 mucositis and dysphagia in the study population. Incidence
Grade 3 oral mucositis Grade 3 dysphagia
Dose-escalation study
Midline study (%)
Dose level I (%)
Dose level II (%)
34
43
43
61
87
56
reported during week 3 of the treatment. In DL1 and DL2 the peak prevalence of 30% (95% CI 12-47) was reached at week 1 post-CRT and week 6 of CRT, respectively. Prevalence decreased after this time point and all patients had recovered by week 8 post-CRT. Grade 3 mucositis was first recorded at week 2 in the midline trial, reached a peak of 36% (95% CI 18-53) at week 6 and then decreased to zero at week 8 post-CRT. Prevalence of acute grade 3 dysphagia is shown in Fig. 1B. One patient in DL1 and DL2 had grade 3 dysphagia at diagnosis. In the remainder it commenced at week 3 of CRT after which the prevalence increased reaching the peak of 50% (95% CI 30-69) at week 2 post-CRT and 79% (95% CI 64-93) at week 6 during CRT, in DL1 and DL2, respectively. In the midline study none of the patients had grade 3 dysphagia until week 3 and the peak prevalence of 50% (95% CI 32–67) was reached at week 1 post-CRT.
The grade 3 dysphagia had not recovered at week 8 post-CRT in all three groups. Six patients (23%) in DL1 had grade 3 dysphagia at 8 weeks post-CRT, who recovered at six months after CRT. Eight patients (27%) in the DL2 had grade 3 dysphagia at 8 weeks postCRT. Swallowing function returned to normal in three patients at 3 months and in two patients at 9 months post-CRT. Two patients died of progressive disease at 3 months. One patient required pharyngo-laryngectomy at 1 year for a post-cricoid stricture. In the midline study, two patients (6%) had grade 3 dysphagia at 8 weeks post- CRT. One patient recovered swallowing function at 3 months post-CRT. The other patient developed a post-cricoid stricture at 9 months post-CRT and had to undergo dilatation. The time spent at grade 3 correlates with the late dysphagia. Out of the 16 patients who had grade 3 dysphagia for greater than 12 weeks, 12 (75%) had late dysphagia (at 6 months). Overall treatment time (OTT) Of the 85 patients, 48 had an extended median OTT of 42 days (range 40–44). This was due to patients not commencing treatment on the Monday if on a thirty fraction schedule or by commencing treatment on a Thursday or Friday on the 28 fraction schedule. Thirty-seven patients commenced treatment on a Monday with a median overall treatment time of 38 days (range 38– 40). Prevalence of grade 3 dysphagia for patients with longer vs. shorter OTT is shown in Fig. 2B. Both cohorts included patients who had dysphagia before commencement of CRT; therefore prevalence curves do not start at zero. The prevalence increased after week 2 for both cohorts, but at a slower rate for patients with longer OTT. The peak prevalences were 40% (week 6 of CRT) and 63% (week 1 after CRT) for longer vs. shorter OTT, respectively. The recovery of grade 3 dysphagia was slower for patients with shorter OTT. Similar effects of OTT were observed on grade 3 oral mucositis, but the magnitude of difference for patients with shorter vs. longer OTT was smaller (Fig. 2A). Pharyngeal length analysis The median (range) L50 and L60 values were 12 (6.7–12.5) cm and 8.7 (6–16.5) cm, respectively. There was a significant correlation between the L50 (Spearman’s Rho = 0.3, p = 0.01) and L60
Fig. 1. Prevalence of grade 3 oral mucositis (A) and grade 3 dysphagia (B) during and up to 8 weeks after CRT in the three patient groups (black – midline, dashed – dose level 1 and grey – dose level L2). Error bars represent one standard error. Legend: w – week, RT – radiotherapy, pw – post-radiotherapy week.
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Fig. 2. Prevalence of grade 3 oral mucositis (A) and grade 3 dysphagia (B) during and up to 8 weeks after CRT for patients who had an extra weekend during treatment (black) versus those that did not (dashed). Error bars represent one standard error. Legend: w – week, RT – radiotherapy, pw – post-radiotherapy week.
(Spearman’s Rho = 0.3, p = 0.009) and the maximum grade of toxicity. The plot of the mean L50 and L60, and the incidence of grade 3 dysphagia show an increase in incidence as the length increases (Fig. 3A and B). Patients who have L50 and L60 greater than 8 cm have 60% and 70% incidence of grade 3 dysphagia, respectively. Of the 85 patients, the number of patients with L50 and L60 greater than 8 cm were 78 and 56, respectively.
Discussion This study describes acute toxicity resulting from three different hypofractionated accelerated chemo-radiation regimens (Table 1) in the treatment of head and neck cancer. The prescription dose rate (dose/week) in each of the arms was: DL2 (12 Gy/week), DL1 (11.25 Gy/week) and midline (10.85 Gy/week). Thames et al. and Denham et al. reported that the upper aero-digestive tract can recover up to 1.8–2 Gy of radiotherapy per day, i.e. 9–10 Gy per week, when delivered in once daily fraction of 2 Gy [6,16]. These studies demonstrate that onset, severity and recovery from mucositis depend on the rate of dose accumulation.
The incidence of oral mucositis in DL2 and in the midline trial was equal, however, the prescription dose rate was higher in the DL2 group and the corollary was true for the MD2 dose accumulation (Table 4). The interpretation may lie in the fact that neither prescription nor mean dose truly describes the dose distribution especially when averaged over a cohort of patients. The prevalence of oral mucositis at each time point is not significantly different in any of the groups as is evident from the curves in Fig. 2. However the onset of oral mucositis in patients in the midline group is earlier at week 2 compared to week 4 in the other two groups. This is unexpected because the DL1 and DL2 are accel-
Table 4 Shows the MD2 for the three dose levels for oral and the pharyngeal mucosa. Volume
Average MD2 (95%CI) Dose-escalation Study
Oral mucosa Pharyngeal mucosa
Dose level I
Dose level II
28 (24.2–31.8) 51.4 (48.9–53.9)
34.2 (28.8–39.6) 58.8 (55.8–61.7)
Midline study
53.5 (51.6–55.6) 57.8 (56.6–59)
Fig. 3. Shows a plot of the mean length receiving 50 Gy (A) and 60 Gy (B) and the incidence of grade 3 dysphagia. The error bars represent one standard error.
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erated schedules and published research suggests that the mucositis manifests itself earlier in the accelerated schedules [6]. This discrepancy might be due to the fact that these patients had a much higher average MD2 (53.5 Gy) to the oral mucosa resulting from the different primary tumour site (oropharynx). Incidence of grade 3 dysphagia was significantly higher in the DL2 (87%), which is not unexpected as the average MD2 in this group was higher (Table 4). Peak prevalence and prevalence at each time point of grade 3 dysphagia was highest for the DL2. The plotted curve for DL2 can be explained by the higher rate of dose accumulation, for both the prescribed dose (12 Gy/week) and according to the MD2 (10.5 Gy/week). The curves for DL1 and the midline study are similar corresponding to the similar prescription (11.25 and 10.85 Gy/week, respectively) and the MD2 (9.2 and 9.6 Gy/week, respectively) dose accumulation rates in the two arms. Prevalence of grade 3 dysphagia does not return to zero in any of the patient groups, at eight weeks post-CRT. This delayed recovery could be explained by the dose rate of radiotherapy being higher than the 10 Gy/week threshold reported in previous studies [6,16]. However, the dose rate according to the MD2 is higher than 10 Gy/week only in the DL2. The delayed recovery may also be attributable to the effect of concomitant chemotherapy, which is known to increase the incidence of acute toxicity [17]. The time spent at grade 3 mucositis correlates with late dysphagia, keeping in line with the observations of Denham et al. and the supporting the notion of ‘‘consequential late reaction” in patients whose acute reaction is severe (failure to recover after 8 weeks) [5]. This study also considered the prevalence of acute reactions based on the overall treatment time. Prevalence of grade 3 oral mucositis commenced earlier, peaked at a higher rate and recovered more slowly for patients with shorter OTT and vice versa (Fig. 2). Patients who commenced treatment during the later part of the week had less damage to the mucosa during the first week, which was probably compensated for by the repopulation. Accelerated repopulation commences at the end of the first week as postulated by Dorr et al. [7] or even earlier, possibly, due to the effect of concomitant chemotherapy. A similar difference, but of a greater magnitude, is observed between the groups when considering grade 3 dysphagia. The greater magnitude could be due to the higher average MD2 to the pharynx and consequently a higher dose rate (Table 3). Since the patients in this study have been treated with IMRT, the dose to the structures at risk could vary across the patient groups and might be a confounding factor that accounts for the difference seen. However, there was no significant difference between the average MD2 for the group without the extra weekend and the one with the extra weekend for the oral mucosa (p = 0.18) or pharynx (p = 0.16). The favourable curves observed for patients with longer OTT, especially for dysphagia, suggest that the treatment should be delivered such that all patients have an extra weekend. However, this might be detrimental from the point of view of tumour control. Definite conclusions would not be possible by comparing the local control rates in the patients in these studies as the numbers are too small to detect any meaningful difference. Therefore, this study provides an interesting observation regarding the benefit of just one extra weekend (by not commencing on a Monday) on acute toxicity. This observation should be tested in a larger study specifically looking at the effect of a single extra weekend on local control. This study shows that there is a significant correlation between length of pharynx treated to 50 Gy (L50) and 60 Gy (L60) and incidence of grade 3 dysphagia. Correlation coefficients for L50 and L60 are 0.3, which demonstrate a moderate strength of association. However Fig. 3 clearly show that incidences of grade 3 dysphagia increase as the L50 and L60 increase. The moderate correlation could be due to the low number of patients having grade 1 dysphagia in this study. To our knowledge this is the only study that
correlates the length receiving a certain dose with the grade of mucositis and quantifies the relationship between the length and the incidence of mucositis. Bentzen et al. have correlated the relationship between the lengths of the radiation field and mucositis in the CHART trial [1]. The analysis from the CHART study showed that the incidence of grade 3 mucositis for a field length of 8 cm was greater than 40%. The present study shows that when the L50 and L60 exceed 8 cm the incidences are 60% and 70%, respectively. The higher incidence in our study is most likely due to use of concomitant chemotherapy, which was not used in the CHART trial. When converting the mean doses to EQD2 the effect of repopulation was not factored into the calculation. The reasons for this were multifold. There is currently no consensus on the exact time at which repopulation begins after the start of fractionated radiotherapy [6,7]. The estimates published in the literature do not factor in the effect of chemotherapy. The rates of repopulation in acute mucosa that have been reported in the literature are quite varied (range 0.25–0.98 Gy/day) [1,6,9,12,16]. Repopulation depends on dose rate (MD2/time) which was varied in our patients. Using a set value for repopulation rate would have been inaccurate. This study has documented the acute mucosal reactions that result from a concurrent chemo-radiation schedule, using IMRT for treatment delivery. Observer-assessed dysphagia was used as a surrogate for pharyngeal mucositis. Single institution participation ensured the management of radiation-induced dysphagia was uniform. This study has described characteristics of the response of the oral and pharyngeal mucosa to different fractionations and indicates that length of pharyngeal mucosa receiving doses close to the prescription dose is correlated with grade 3 dysphagia. In addition, it was observed that patients with longer OTT (an extra weekend) in their treatment schedule experience are less likely to experience grade 3 toxicity and report it for a shorter duration of assisted feeding during chemo-radiation, which is clinically relevant.
Conflicts of interest statement There are no potential conflicts of interests for any of the authors.
References [1] Bentzen SM, Saunders MI, Dische S, Bond SJ. Radiotherapy-related early morbidity in head and neck cancer: quantitative clinical radiobiology as deduced from the CHART trial. Radiother Oncol 2001;60:123–35. [2] Bhide SA, Ahmed M, Barbachano Y, Newbold K, Harrington KJ, Nutting CM. Sequential induction chemotherapy followed by radical chemo-radiation in the treatment of locoregionally advanced head-and-neck cancer. Br J Cancer 2008;99:57–62. [3] Bourhis JAC, Pignon J-P. Update of MACH-NC (Meta-Analysis of Chemotherapy in Head & Neck Cancer) database focused on concomitant chemoradiotherapy. J Clin Oncol 2004;22:5505. [4] Bourhis J, Overgaard J, Audry H, et al. Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet 2006;368: 843–54. [5] Denham JW, Peters LJ, Johansen J, et al. Do acute mucosal reactions lead to consequential late reactions in patients with head and neck cancer? Radiother Oncol 1999;52:157–64. [6] Denham JW, Walker QJ, Lamb DS, et al. Mucosal regeneration during radiotherapy. Trans Tasman Radiation Oncology Group (TROG). Radiother Oncol 1996;41:109–18. [7] Dorr W, Hamilton CS, Boyd T, Reed B, Denham JW. Radiation-induced changes in cellularity and proliferation in human oral mucosa. Int J Radiat Oncol Biol Phys 2002;52:911–7. [8] Eisbruch A, Kim HM, Terrell JE, Marsh LH, Dawson LA, Ship JA. Xerostomia and its predictors following parotid-sparing irradiation of head-and-neck cancer. Int J Radiat Oncol Biol Phys 2001;50:695–704. [9] Fowler JF. Apparent rates of proliferation of acutely responding normal tissues during radiotherapy of head and neck cancer. Int J Radiat Oncol Biol Phys 1991;21:1451–6.
S.A. Bhide et al. / Radiotherapy and Oncology 97 (2010) 86–91 [10] Guerrero Urbano T, Clark CH, Hansen VN, et al. A phase I study of doseescalated chemoradiation with accelerated intensity modulated radiotherapy in locally advanced head and neck cancer. Radiother Oncol 2007;85:36–41. [11] Jackson SM, Weir LM, Hay JH, Tsang VH, Durham JS. A randomised trial of accelerated versus conventional radiotherapy in head and neck cancer. Radiother Oncol 1997;43:39–46. [12] Kaanders JH, van Daal WA, Hoogenraad WJ, van der Kogel AJ. Accelerated fractionation radiotherapy for laryngeal cancer, acute, and late toxicity. Int J Radiat Oncol Biol Phys 1992;24:497–503. [13] Kelly C, Paleri V, Downs C, Shah R. Deterioration in quality of life and depressive symptoms during radiation therapy for head and neck cancer. Otolaryngol Head Neck Surg 2007;136:108–11. [14] Lefebvre JL. Laryngeal preservation in head and neck cancer: multidisciplinary approach. Lancet Oncol 2006;7:747–55.
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[15] Maciejewski B, Skladowski K, Pilecki B, et al. Randomized clinical trial on accelerated seven days per week fractionation in radiotherapy for head and neck cancer. Preliminary report on acute toxicity. Radiother Oncol 1996;40:137–45. [16] Thames HD, Bentzen SM, Turesson I, Van OvergaardM, den Bogaert W. Timedose factors in radiotherapy: a review of the human data. Radiother Oncol 1990;19:219–35. [17] 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 2003;66:253–62. [18] Withers HR, Thames Jr HD, Peters LJ. A new isoeffect curve for change in dose per fraction. Radiother Oncol 1983;1:187–91.
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Radiotherapy related morbidity
Characteristics of response of oral and pharyngeal mucosa in patients receiving chemo-IMRT for head and neck cancer using hypofractionated accelerated radiotherapy Shreerang A. Bhide a,b,⇑, Sarah Gulliford b, Jack Fowler c,d, Nicola Rosenfelder a, Katie Newbold a, Kevin J. Harrington a,b, Christopher M. Nutting a,b a
Royal Marsden Hospital; and b Institute of Cancer Research, Sutton, London, UK; c Department of Human Oncology; and d Department of Medical Physics, University of Wisconsin, Madison, USA
a r t i c l e
i n f o
Article history: Received 20 April 2010 Received in revised form 17 August 2010 Accepted 18 August 2010 Available online 7 September 2010 Keywords: Head and neck cancer Chemo-IMRT Radiobiology Hypofractionated Accelerated
a b s t r a c t Purpose: This study describes the acute response of oral and pharyngeal mucosa to chemo-IMRT schedules using different doses per fraction. Materials and methods: Patients, treated in prospective trials of concomitant chemo-IMRT with 2.17 Gy, 2.25 Gy and 2.4 Gy per fraction and identical dose of cisplatin, were included in this study. Acute toxicity was recorded prospectively using the CTCAE v2.0. We describe the incidence and prevalence of grade 3 oral mucositis and dysphagia over time and report the influence of overall treatment time (OTT). The association between the lengths of pharyngeal mucosa receiving 50 Gy (L50) and 60 Gy (L60) and grade 3 dysphagia was tested. Results: The incidence and the peak prevalence of grade 3 dysphagia were significantly higher in patients receiving 2.4 Gy per fraction. The peak prevalence of grade 3 dysphagia was higher and the recovery was slower in patients with lower OTT (median 38 days vs. 42 days) treatment. There was a significant correlation between L50, L60 and grade 3 dysphagia. A L50 and L60 greater than 8 cm resulted in greater than 60% and 70% incidence of grade 3 dysphagia, respectively. Conclusion: The length of pharyngeal mucosa receiving doses close to the prescription dose correlates with grade 3 dysphagia. It was observed that incidence of grade 3 dysphagia was lower and recovery from it was quicker in patients with greater OTT. Ó 2010 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 97 (2010) 86–91
Using induction and/or concomitant systemic chemotherapy and/or altered fractionation radiotherapy in advanced head and neck cancer treatment have been shown to improve survival and rates of organ preservation [2–4,14]. Hypofractionated accelerated radiotherapy is thought to improve outcomes by reducing the impact of tumour cell repopulation. Using the simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT), it is possible to escalate tumour dose using the hypofractionated accelerated approach, while minimising the dose to organs at risk (OARs). Often acute mucositis can be the dose-limiting toxicity when escalating the radiation dose [11,15]. It is, therefore, important to study the radiobiology of acute radiation damage to mucosa of the upper aero-digestive tract, which results in significant morbidity and altered quality of life (QOL) during radiotherapy [13]. Although several studies using altered fractionation have been described in the literature, there is a paucity of detailed data on acute ⇑ Corresponding author. Address: Royal Marsden Hospital, Fulham Road, London SW3 6JJ, United Kingdom. E-mail address: [email protected] (S.A. Bhide). 0167-8140/$ - see front matter Ó 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2010.08.013
toxicity. We have conducted Phase I dose-escalation trials to identify a maximum tolerated prescription dose and to investigate safety and efficacy of using hypofractionated accelerated IMRT in combination with chemotherapy. The incidence of acute toxicity has been described before [10]. In this study, we describe the acute response of oral and pharyngeal mucosa after chemo-IMRT using data from studies with three different doses per fraction.
Materials and methods Patient selection Patients were treated in two prospective trials of concomitant chemo-IMRT. The first trial was a Phase I trial of dose-escalation and accelerated radiotherapy for laryngeal and hypopharyngeal cancer. Patients with squamous cell carcinoma of the larynx/hypopharynx requiring primary radical chemo-radiation were included in the study. Two dose levels were tested. The second trial was a Phase II trial looking at the benefit of using IMRT to spare bilateral superficial parotid glands in oropharyngeal squamous cell
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carcinomas requiring irradiation to bilateral parapharyngeal spaces. The doses used in each trial including the dose/fraction have been described in Table 1. These trials will be referred to as the ‘dose-escalation trial’ and ‘midline trial’, respectively, in this manuscript. The trials were approved by the Committee for Clinical Research and the Local Research Ethics Committee. Treatment Induction chemotherapy was of two cycles of cisplatin (75 mg/ m2) on day 1 and 5-FU (1000 mg/m2) for days 1–4. Cisplatin (100 mg/m2) on days 1 and 29 was used for concomitant treatment. Identical chemotherapy regimens were used for both trials. Radiotherapy planning Patients were immobilized and contrast-enhanced CT scans were acquired at 2.5 mm intervals. Gross tumour volume (GTV), clinical target volumes (CTVs) for macroscopic disease (CTV1), areas at risk of harbouring microscopic disease (CTV2) and critical structures were outlined. The oral and pharyngeal mucosa was retrospectively outlined by a single observer (SB). The surfaces of the inner table of mandible, tongue, base of tongue, floor of mouth and palate were outlined as the oral mucosa (oral cavity) as per Eisbruch et al. [8]. The pharyngeal mucosa was outlined from inferior surface of the floor of the sphenoid sinus to inferior edge of cricoid cartilage. The Helios inverse planning module in EclipseÓ was used for all IMRT plannings. The IMRT planning technique (including dose constraints for OARs) used at our institution has been previously described [10]. Doses were prescribed to median dose-volume point on the PTV1 dose volume histogram (DVH). Doses prescribed to PTV1 and PTV2 in each of the studies are described in Table 1. Data collection Mean dose was used as a single descriptor point for DVHs which were generated separately for oral mucosa and pharyngeal mucosa from the individual patients’ treatment plan. Mean dose for each patient was converted into equivalent dose in 2 Gy fractions (MD2), using the Withers formula [18], for comparison between groups (Table 3). The length of pharyngeal mucosa receiving 50 Gy (L50) and 60 Gy (L60) equivalents in 2 Gy/fraction of radiation was determined from the treatment plans for each patient and correlated to acute toxicity. Length of mucosa irradiated correlates with volume of the pharynx which is quite small. Acute toxicity was prospectively recorded using Common Toxicity Criteria (CTCAE v2.0). Data were recorded before treatment and weekly during and for four weeks after radiation. Final data recording for acute toxicity was performed at eight weeks postradiation. Late toxicity monitoring on these patients continued until five years post-treatment. Observer-assessed oral mucositis was used as a toxicity endpoint for oral mucosa. Observer-assessed dysphagia was used as a surrogate marker for pharyngeal mucositis as it is clinically relevant and visual assessment of mucositis using nasoendoscopy is difficult during radiotherapy.
Data analysis Statistical analysis was performed using the Statistical Program for Social Sciences (SPSS Ó 2006 SPSS Inc. Chicago, Illinois) v 15.0. Prevalence of a particular grade of toxicity at a given time point was defined as the number of patients reporting that grade of toxicity at that time point divided by the total number of evaluable patients at that time point. Incidence of a particular grade of toxicity was defined as the number of patients reaching that grade of toxicity during the course of treatment divided by the total number of evaluable patients [1]. Rules for missing data were as per Bentzen et al. [1]. The significance of difference in the incidence and prevalence between the two groups was tested using Chi-Square tests for proportions. The overall treatment time (OTT) was calculated for each patient. Variation in length is due to the day of the week on which treatment is commenced. The patients were split into two groups depending on whether the OTT included an extra weekend or not. The median OTT was 38 days for those patients whose treatment course did not include an extra weekend and 42 days for those whose treatment course did. The prevalence of grade 3 toxicity at each week was then plotted for each group to estimate the effect of an extra weekend on toxicity. The L50 and L60 data were correlated to the maximum grade of toxicity using the Spearman rank correlation coefficient. The patients were binned into equal-sized groups, defined by mean L50 and L60. The incidence of grade 3 dysphagia in each dose bin was then calculated, as the number of patients with grade 3 dysphagia divided by the total number of patients in that bin and plotted against the mean L50 and L60 for that bin. Results The dose-escalation trial commenced in September 2002 and the midline trial commenced in July 2005. Thirty patients were entered into each dose level of the dose-escalation study. DVH data on 26 and 29 patients were available from DL1 and DL2, respectively. Thirty patients were entered into the midline trial. The DVH data were available for all patients The patient characteristics and staging information are provided in Table 2. Applying the rules for substitution of the missing data for the acute toxicity values, all the patients with DVH were evaluable for analysis. Incidence and prevalence Incidence of grade 3 mucositis was 34% in DL1 and 43% in DL2 of the dose-escalation trial and the midline trial (Table 3). The difference in the incidence of grade 3 mucositis between DL1, DL2 and the midline trial was not statistically significant. Incidence of grade 3 dysphagia was highest in DL2 of the dose-escalation study (Table 2). Difference between the incidence of grade 3 dysphagia in DL2 and the midline trial was statistically significant (p = 0.02), and between DL1 and DL2 of borderline significance (p = 0.05). Prevalence of acute grade 3 mucositis at different time points during and immediately after CRT is shown in Fig. 1A. In the dose-escalation trial the onset of grade 3 mucositis was first
Table 1 Prescribed doses to the PTVs for the two studies. Volume
PTV1 PTV2
Dose greys (Gy)
Total dose Dose per fraction Total dose Dose per fraction
Dose-escalation study
Midline study
Dose level I (DL1)
Dose level II (DL2)
63 Gy in 28 fractions 2.25 Gy 51.8 Gy in 28 fractions 1.8 Gy
67.2 Gy in 28 fractions 2.4 Gy 56 Gy in 28 fractions 2 Gy
65 Gy in 30 fractions 2.17 Gy 54 Gy in 30 fractions 1.8 Gy
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Table 2 Dose-escalation trial
Age Sex Stage
Median (range) Male Female I II III IV
Midline trial (N = 30)
Dose level 1 (N = 26)
Dose level 2 (N = 29)
57(34–84)
62(44–78)
59(32–82)
22 4 1 1 10 14
23 6 0 0 16 14
23 7 0 1 5 23
Table 3 Incidence of grade 3 mucositis and dysphagia in the study population. Incidence
Grade 3 oral mucositis Grade 3 dysphagia
Dose-escalation study
Midline study (%)
Dose level I (%)
Dose level II (%)
34
43
43
61
87
56
reported during week 3 of the treatment. In DL1 and DL2 the peak prevalence of 30% (95% CI 12-47) was reached at week 1 post-CRT and week 6 of CRT, respectively. Prevalence decreased after this time point and all patients had recovered by week 8 post-CRT. Grade 3 mucositis was first recorded at week 2 in the midline trial, reached a peak of 36% (95% CI 18-53) at week 6 and then decreased to zero at week 8 post-CRT. Prevalence of acute grade 3 dysphagia is shown in Fig. 1B. One patient in DL1 and DL2 had grade 3 dysphagia at diagnosis. In the remainder it commenced at week 3 of CRT after which the prevalence increased reaching the peak of 50% (95% CI 30-69) at week 2 post-CRT and 79% (95% CI 64-93) at week 6 during CRT, in DL1 and DL2, respectively. In the midline study none of the patients had grade 3 dysphagia until week 3 and the peak prevalence of 50% (95% CI 32–67) was reached at week 1 post-CRT.
The grade 3 dysphagia had not recovered at week 8 post-CRT in all three groups. Six patients (23%) in DL1 had grade 3 dysphagia at 8 weeks post-CRT, who recovered at six months after CRT. Eight patients (27%) in the DL2 had grade 3 dysphagia at 8 weeks postCRT. Swallowing function returned to normal in three patients at 3 months and in two patients at 9 months post-CRT. Two patients died of progressive disease at 3 months. One patient required pharyngo-laryngectomy at 1 year for a post-cricoid stricture. In the midline study, two patients (6%) had grade 3 dysphagia at 8 weeks post- CRT. One patient recovered swallowing function at 3 months post-CRT. The other patient developed a post-cricoid stricture at 9 months post-CRT and had to undergo dilatation. The time spent at grade 3 correlates with the late dysphagia. Out of the 16 patients who had grade 3 dysphagia for greater than 12 weeks, 12 (75%) had late dysphagia (at 6 months). Overall treatment time (OTT) Of the 85 patients, 48 had an extended median OTT of 42 days (range 40–44). This was due to patients not commencing treatment on the Monday if on a thirty fraction schedule or by commencing treatment on a Thursday or Friday on the 28 fraction schedule. Thirty-seven patients commenced treatment on a Monday with a median overall treatment time of 38 days (range 38– 40). Prevalence of grade 3 dysphagia for patients with longer vs. shorter OTT is shown in Fig. 2B. Both cohorts included patients who had dysphagia before commencement of CRT; therefore prevalence curves do not start at zero. The prevalence increased after week 2 for both cohorts, but at a slower rate for patients with longer OTT. The peak prevalences were 40% (week 6 of CRT) and 63% (week 1 after CRT) for longer vs. shorter OTT, respectively. The recovery of grade 3 dysphagia was slower for patients with shorter OTT. Similar effects of OTT were observed on grade 3 oral mucositis, but the magnitude of difference for patients with shorter vs. longer OTT was smaller (Fig. 2A). Pharyngeal length analysis The median (range) L50 and L60 values were 12 (6.7–12.5) cm and 8.7 (6–16.5) cm, respectively. There was a significant correlation between the L50 (Spearman’s Rho = 0.3, p = 0.01) and L60
Fig. 1. Prevalence of grade 3 oral mucositis (A) and grade 3 dysphagia (B) during and up to 8 weeks after CRT in the three patient groups (black – midline, dashed – dose level 1 and grey – dose level L2). Error bars represent one standard error. Legend: w – week, RT – radiotherapy, pw – post-radiotherapy week.
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Fig. 2. Prevalence of grade 3 oral mucositis (A) and grade 3 dysphagia (B) during and up to 8 weeks after CRT for patients who had an extra weekend during treatment (black) versus those that did not (dashed). Error bars represent one standard error. Legend: w – week, RT – radiotherapy, pw – post-radiotherapy week.
(Spearman’s Rho = 0.3, p = 0.009) and the maximum grade of toxicity. The plot of the mean L50 and L60, and the incidence of grade 3 dysphagia show an increase in incidence as the length increases (Fig. 3A and B). Patients who have L50 and L60 greater than 8 cm have 60% and 70% incidence of grade 3 dysphagia, respectively. Of the 85 patients, the number of patients with L50 and L60 greater than 8 cm were 78 and 56, respectively.
Discussion This study describes acute toxicity resulting from three different hypofractionated accelerated chemo-radiation regimens (Table 1) in the treatment of head and neck cancer. The prescription dose rate (dose/week) in each of the arms was: DL2 (12 Gy/week), DL1 (11.25 Gy/week) and midline (10.85 Gy/week). Thames et al. and Denham et al. reported that the upper aero-digestive tract can recover up to 1.8–2 Gy of radiotherapy per day, i.e. 9–10 Gy per week, when delivered in once daily fraction of 2 Gy [6,16]. These studies demonstrate that onset, severity and recovery from mucositis depend on the rate of dose accumulation.
The incidence of oral mucositis in DL2 and in the midline trial was equal, however, the prescription dose rate was higher in the DL2 group and the corollary was true for the MD2 dose accumulation (Table 4). The interpretation may lie in the fact that neither prescription nor mean dose truly describes the dose distribution especially when averaged over a cohort of patients. The prevalence of oral mucositis at each time point is not significantly different in any of the groups as is evident from the curves in Fig. 2. However the onset of oral mucositis in patients in the midline group is earlier at week 2 compared to week 4 in the other two groups. This is unexpected because the DL1 and DL2 are accel-
Table 4 Shows the MD2 for the three dose levels for oral and the pharyngeal mucosa. Volume
Average MD2 (95%CI) Dose-escalation Study
Oral mucosa Pharyngeal mucosa
Dose level I
Dose level II
28 (24.2–31.8) 51.4 (48.9–53.9)
34.2 (28.8–39.6) 58.8 (55.8–61.7)
Midline study
53.5 (51.6–55.6) 57.8 (56.6–59)
Fig. 3. Shows a plot of the mean length receiving 50 Gy (A) and 60 Gy (B) and the incidence of grade 3 dysphagia. The error bars represent one standard error.
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Responses of mucosa during head and neck chemo-IMRT
erated schedules and published research suggests that the mucositis manifests itself earlier in the accelerated schedules [6]. This discrepancy might be due to the fact that these patients had a much higher average MD2 (53.5 Gy) to the oral mucosa resulting from the different primary tumour site (oropharynx). Incidence of grade 3 dysphagia was significantly higher in the DL2 (87%), which is not unexpected as the average MD2 in this group was higher (Table 4). Peak prevalence and prevalence at each time point of grade 3 dysphagia was highest for the DL2. The plotted curve for DL2 can be explained by the higher rate of dose accumulation, for both the prescribed dose (12 Gy/week) and according to the MD2 (10.5 Gy/week). The curves for DL1 and the midline study are similar corresponding to the similar prescription (11.25 and 10.85 Gy/week, respectively) and the MD2 (9.2 and 9.6 Gy/week, respectively) dose accumulation rates in the two arms. Prevalence of grade 3 dysphagia does not return to zero in any of the patient groups, at eight weeks post-CRT. This delayed recovery could be explained by the dose rate of radiotherapy being higher than the 10 Gy/week threshold reported in previous studies [6,16]. However, the dose rate according to the MD2 is higher than 10 Gy/week only in the DL2. The delayed recovery may also be attributable to the effect of concomitant chemotherapy, which is known to increase the incidence of acute toxicity [17]. The time spent at grade 3 mucositis correlates with late dysphagia, keeping in line with the observations of Denham et al. and the supporting the notion of ‘‘consequential late reaction” in patients whose acute reaction is severe (failure to recover after 8 weeks) [5]. This study also considered the prevalence of acute reactions based on the overall treatment time. Prevalence of grade 3 oral mucositis commenced earlier, peaked at a higher rate and recovered more slowly for patients with shorter OTT and vice versa (Fig. 2). Patients who commenced treatment during the later part of the week had less damage to the mucosa during the first week, which was probably compensated for by the repopulation. Accelerated repopulation commences at the end of the first week as postulated by Dorr et al. [7] or even earlier, possibly, due to the effect of concomitant chemotherapy. A similar difference, but of a greater magnitude, is observed between the groups when considering grade 3 dysphagia. The greater magnitude could be due to the higher average MD2 to the pharynx and consequently a higher dose rate (Table 3). Since the patients in this study have been treated with IMRT, the dose to the structures at risk could vary across the patient groups and might be a confounding factor that accounts for the difference seen. However, there was no significant difference between the average MD2 for the group without the extra weekend and the one with the extra weekend for the oral mucosa (p = 0.18) or pharynx (p = 0.16). The favourable curves observed for patients with longer OTT, especially for dysphagia, suggest that the treatment should be delivered such that all patients have an extra weekend. However, this might be detrimental from the point of view of tumour control. Definite conclusions would not be possible by comparing the local control rates in the patients in these studies as the numbers are too small to detect any meaningful difference. Therefore, this study provides an interesting observation regarding the benefit of just one extra weekend (by not commencing on a Monday) on acute toxicity. This observation should be tested in a larger study specifically looking at the effect of a single extra weekend on local control. This study shows that there is a significant correlation between length of pharynx treated to 50 Gy (L50) and 60 Gy (L60) and incidence of grade 3 dysphagia. Correlation coefficients for L50 and L60 are 0.3, which demonstrate a moderate strength of association. However Fig. 3 clearly show that incidences of grade 3 dysphagia increase as the L50 and L60 increase. The moderate correlation could be due to the low number of patients having grade 1 dysphagia in this study. To our knowledge this is the only study that
correlates the length receiving a certain dose with the grade of mucositis and quantifies the relationship between the length and the incidence of mucositis. Bentzen et al. have correlated the relationship between the lengths of the radiation field and mucositis in the CHART trial [1]. The analysis from the CHART study showed that the incidence of grade 3 mucositis for a field length of 8 cm was greater than 40%. The present study shows that when the L50 and L60 exceed 8 cm the incidences are 60% and 70%, respectively. The higher incidence in our study is most likely due to use of concomitant chemotherapy, which was not used in the CHART trial. When converting the mean doses to EQD2 the effect of repopulation was not factored into the calculation. The reasons for this were multifold. There is currently no consensus on the exact time at which repopulation begins after the start of fractionated radiotherapy [6,7]. The estimates published in the literature do not factor in the effect of chemotherapy. The rates of repopulation in acute mucosa that have been reported in the literature are quite varied (range 0.25–0.98 Gy/day) [1,6,9,12,16]. Repopulation depends on dose rate (MD2/time) which was varied in our patients. Using a set value for repopulation rate would have been inaccurate. This study has documented the acute mucosal reactions that result from a concurrent chemo-radiation schedule, using IMRT for treatment delivery. Observer-assessed dysphagia was used as a surrogate for pharyngeal mucositis. Single institution participation ensured the management of radiation-induced dysphagia was uniform. This study has described characteristics of the response of the oral and pharyngeal mucosa to different fractionations and indicates that length of pharyngeal mucosa receiving doses close to the prescription dose is correlated with grade 3 dysphagia. In addition, it was observed that patients with longer OTT (an extra weekend) in their treatment schedule experience are less likely to experience grade 3 toxicity and report it for a shorter duration of assisted feeding during chemo-radiation, which is clinically relevant.
Conflicts of interest statement There are no potential conflicts of interests for any of the authors.
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