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ORIGINAL ARTICLE Increased local failure risk with prolonged radiation treatment time in head and neck cancer treated with concurrent chemotherapy Donald M. Cannon, MD,1* Heather M. Geye, MS,1,2 Gregory K. Hartig, MD,2 Anne M. Traynor, MD,3 Tien Hoang, MD,3 Timothy M. McCulloch, MD,2 Peggy A. Wiederholt, RN,1 Richard J. Chappell, PhD,4 Paul M. Harari, MD1 1 Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, 2Department of Surgery – Otolaryngology, Head and Neck Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, 3Department of Medicine – Medical Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, 4Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. Accepted 10 June 2013 Published online 27 November 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.23419 ABSTRACT: Background. Prolonged radiation treatment time (RTT) in head and neck squamous cell carcinoma (HNSCC) is associated with inferior tumor control in patients treated with radiation therapy (RT) alone. However, the significance of prolonged RTT with concurrent chemotherapy is less clear. Methods. We reviewed outcomes for 171 patients with primary HNSCC treated with curative intent RT and concurrent drug therapy from 2001 to 2009. The effects of RTT and other variables on local control and survival were analyzed. Results. Patients with RTT >7 weeks had a significantly increased risk of local failure (hazard ratio [HR], 2.6; p 5 .018) and death (HR, 1.9 INTRODUCTION Radiation therapy (RT) with concurrent chemotherapy has been embraced as a standard of care for the treatment for locally advanced head and neck squamous cell carcinoma (HNSCC) in appropriately selected patients. Compared to radiation alone, this approach has been associated with an approximately 6.5% improvement in overall survival,1 but at the expense of increased toxicity. Side effects in the form of mucositis, neutropenia, fatigue, and dehydration may occasionally require treatment breaks and therefore prolong treatment time. Although treatment breaks (planned or unplanned) may allow for some tempering of treatment toxicity, evidence from multiple retrospective studies has shown that prolonged treatment time is associated with inferior outcome in patients with HNSCC treated with RT alone.2–7 This has been attributed largely to accelerated repopulation of tumor clonogens.3 For patients with HNSCC treated with RT alone, prospective randomized clinical trials have *Corresponding author: D. M. Cannon, Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 600 Highland Ave K4/B100, Madison, WI 53792. E-mail: [email protected] This work was presented in part at the American Society for Radiation Oncology (ASTRO) 53rd Annual Meeting in Miami, Florida, October 2011. 1120 HEAD & NECK—DOI 10.1002/HED AUGUST 2014 p 5 .035). These results retained significance even after adjustment for tumor stage (age was not significant). Conclusion. For patients treated with concurrent chemoradiotherapy (chemoRT), prolonged RTT may compromise tumor control as has been established in the setting of RT alone. Symptoms of patients with HNSCC undergoing definitive chemoRT should be managed aggressively to limit C 2013 Wiley Periodicals, Inc. Head Neck 36: treatment interruptions. V 1120–1125, 2014 KEY WORDS: head and neck cancer, chemoradiotherapy, accelerated repopulation, treatment time, prognostic factors shown benefit to treatment acceleration in an effort to counter the effects of repopulation.8–10 In contradistinction to the setting of patients treated with RT alone, recent randomized controlled trials demonstrate no benefit to treatment acceleration in patients undergoing concurrent chemoradiotherapy (chemoRT) for locally advanced HNSCC.11,12 This result, however, does not necessarily exclude a detriment in outcome with prolonged treatment times for patients treated with chemoRT. Sher et al13 recently reported a post hoc analysis of data from the TAX-324 study evaluating induction chemotherapy followed by radiation with concurrent carboplatin in locally advanced HNSCC and found that prolonged radiation treatment time (RTT) was associated with a significantly inferior overall survival and locoregional control rate, independent of other prognostic factors. Beginning in the year 2000, the majority of medically fit patients at our institution undergoing definitive RT for locally advanced HNSCC were treated with concurrent chemotherapy. We sought to evaluate the impact of RTT on outcome in these patients as it has been our institutional practice to maintain treatment breaks to a strict minimum. We postulate that in patients with HNSCC receiving concurrent chemoRT, overall RTT remains an important variable that may influence ultimate clinical outcome. IMPACT MATERIALS AND METHODS Patient selection The University of Wisconsin Hospitals and Clinics Institutional Review Board approved this retrospective study. From 1990 to the present, a database of all consenting patients with head and neck cancer treated at the University of Wisconsin has been maintained and updated in a prospective fashion under institutional review board approval and with written patient consent. As mentioned above, concurrent chemotherapy has been recommended routinely for suitable patients at our institution from approximately 2000 forward. We limited our analysis to patients with stage III or nonmetastatic stage IV HNSCC treated with primary radiation and concurrent drug therapy (including cetuximab) between the years 2001 and 2009. The following disease subsites were included: oropharynx, nasopharynx, hypopharynx, and larynx. Specifically, patients with T1N0 or T2N0 tumors of the glottic larynx were excluded, as were patients with oral cavity tumors (the vast majority of whom were treated with primary surgery), unknown primary, those treated after radical surgery to the primary tumor, and patients with recurrent disease. Patients receiving palliative doses of radiation (ie, <60 Gy) were also excluded from the analysis. The p16 immunohistochemistry results were available for a subset of patients and were included in the analysis. Statistical analysis and definition of variables The RTT was defined as the duration in days of the entire course of radiotherapy. For comparison to prior reports,14 we calculated an average weekly dose (AWD), which was defined as D 3 7 4 RTT, where D is the total dose delivered to the primary tumor. For each patient we also defined DRTT as RTT minus the number of days that would be expected for the patient to complete their given fractionation schedule (assuming a Monday start). Local control of the primary tumor was the primary endpoint of the study, with the time to event of interest defined from initiation of RT. Death from any cause was analyzed as a secondary endpoint. Patients were censored at the time of their last follow-up at the cancer center. Estimates of local control and overall survival were obtained via the Kaplan–Meier method. A Cox proportional hazards model was used to analyze variables associated with local control and overall survival. RTT was analyzed as a continuous variable and as a dichotomous variable with cut points at the median and between the third and fourth quartile. This was done in similar fashion to Sher et al13 because of a very narrow distribution of RTT among patients with a difference between the first quartile and median RTT of only 1 day. Tests for imbalances among patient groups were performed using Fisher’s exact test for categorical variables or the t test for continuous variables. RESULTS Patient characteristics The characteristics of the 171 patients who met study criteria are summarized in Table 1 along with the distribution of the types of fractionation schedules used. The OF CONCURRENT RADIOCHEMOTHERAPY TREATMENT TIME IN HNSCC TABLE 1. Patient and tumor characteristics. Characteristic No. (%) Total no. of patients Age, y <60 60–70 >70 Sex Male Female Disease site Nasopharynx Oropharynx Hypopharynx Larynx Stage III IV T classification T1–2 T3–4 N classification N0–1 N2–3 Chemotherapy, drug* Cisplatin Cetuximab Other p16 status Positive Negative Not available Chemotherapy sequencing Concurrent Neoadjuvant and concurrent Fractionation scheme Six fractions/wk Concomitant boost Once daily 171 (100%) 109 51 11 (64) (30) (6) 139 33 (81) (19) 19 118 13 21 (11) (69) (8) (12) 20 151 (12) (88) 85 86 (50) (50) 31 140 (18) (82) 162 13 20 (94) (8) (12) 26 2 143 (15) (1) (84) 162 10 (94) (6) 6 34 131 (4) (20) (77) *Note that some patients received more than 1 type of drug with treatment, thus totals add to greater than 100%. median age was 57 years (range, 36–83 years). Median follow-up was 43 months (range, 4–110 months) and >75% of patients had follow-up more than 2 years. The majority of patients were treated with concurrent weekly cisplatin 30 mg/m2, and treated to doses of 65.6 to 74.4 Gy (median, 70 Gy) with the most common prescription dose being 70 Gy in 33 fractions (49% of patients).15 A significantly higher percentage of patients with N0 or N1 disease had advanced tumors (T3 or T4) compared with patients with N1 or N2 disease (84% vs 43%; p < .005). Patients who received drug therapy before radiation had similar average RTT compared to those without any prior drug therapy (47.4 vs 46.7 days; p 5 .48). Six of these 10 patients were treated with a single dose of bevacizumab before RT as part of an institutional clinical trial, whereas the others received only 1 or 2 cycles of chemotherapy before RT. The distribution of RTT among patients was relatively narrow, with a median RTT of 46 days (range, 39–58 days). The upper quartile consisted of 36 patients (21%) with an RTT >49 days, and only 3 patients (2%) had an HEAD & NECK—DOI 10.1002/HED AUGUST 2014 1121 CANNON ET AL. RTT >56 days. For the 131 patients (77%) treated with once-daily fractionation, the median RTT was 47 days (range, 42–58 days) whereas for the 34 patients (20%) treated with a concomitant boost fractionation schedule, median RTT was 44 days (range, 40–58 days). The 6 patients (4%) treated with 6 fractions per week on Radiation Therapy Oncology Group 0522 had a median RTT of 39 days (range, 39–41 days). No planned breaks were incorporated into any treatment schedules. effect of induction chemotherapy (p 5 0.69) or total dose (p 5 .88) but, interestingly, N2 or N3 nodal disease was a predictor for local control, which was not unusual given the less advanced T classification compared to N0 or N1 patients, as described above. There was a trend for patients treated with an AWD >10 Gy/week to be at decreased risk for local recurrence (p 5 .06). The parameter DRTT, intended to be a surrogate for treatment breaks, was not significant, but given its retrospective definition does contain some uncertainty in accurately accounting for all deviations from a prescribed radiation course. Adjusting for T classification, patients with RTT >49 days still had significantly higher risk for local failure (HR, 2.4; 95% CI, 1.07–5.2; p 5 .044) and the trend for increased risk with RTT as a continuous variable persisted but with diminished significance (HR, 1.09; 95% CI, 0.99–1.2; p 5 .07). When patients treated with induction drug therapy were excluded, the effect on worse local control with RTT >49 days persisted (HR, 2.3; p 5 .044). The p16 status was not included in the univariate analyses for local control and overall survival because only 2 of 28 patients with immunohistochemistry data were p16negative. However, an exploratory analysis showed that in the subset of 26 patients who were classified as p16positive, RTT >49 days was still significant for local failure (HR, 1.24; 95% CI, 1.3–33; p 5 .022), although RTT as a continuous variable was not significant (p 5 .13). When adjusting for all primary tumor subsites in a multivariate proportional hazards model, RTT >49 days was still significant for local failure at p 5 .031, although when analyzed as a continuous variable it was no longer significant (p 5 .067). Impact on local control Impact on overall survival A total of 26 patients (15%) experienced local failure, with a 5-year local control rate of 83% (95% confidence interval [CI], 77% to 90%). The distribution of RTT coded for local disease control is shown in Figure 1. Univariate analysis of factors potentially affecting local control showed that when RTT was analyzed as a continuous variable, there was an increased risk of local failure for each day of RTT (p 5 .049). As shown in Figure 2A, patients in the upper quartile of RTT (>49 days) had a higher local recurrence rate compared to those with RTT 49 days (p 5 .014 by log-rank test). With this grouping, there was no difference between the percentage of patients with advanced (T3 or T4) tumors (56% and 49% for RTT and >49 days, respectively; p 5 .57), mean age (p 5 .73), or those treated with induction chemotherapy (p 5 .69). For patients treated with RTT > median RTT (46 days), the trend for worse local control persisted, although was not statistically significant (hazard ratio [HR], 1.95; p 5 .097). Limiting the analysis to patients treated over a course of 7 weeks or less, there was no significant difference (p 5 .35) in risk for local failure in those treated within 6 weeks (42 days) versus those treated within 7 weeks (range, 43–49 days). A summary of the univariate analysis of local control is given in Table 3. As expected, more advanced tumor was associated with local failure (p 5 .002). There was no Overall survival at 5 years for the entire cohort was 74% (95% CI, 63% to 78%). The results of a univariate analysis describing risks of death from any cause are shown in Table 3. A significant increased risk was found in patients with RTT >49 days (Figure 2B; p 5 .035 by the log-rank test). For patients treated with RTT > median RTT, a similar trend was seen, but this was not statistically significant (p 5 .06). However, when RTT was modeled as a continuous variable, no significant association was seen (p 5 .49). Age, sex, and use of induction chemotherapy were not significantly associated with overall survival on univariate analysis, but advanced T classification was (p < .005). Both RTT >49 days and advanced T classification were independently associated with worse overall survival on multivariate analysis (p 5 .049 and < .005, respectively). FIGURE 1. Histogram of radiation treatment time (RTT) according to whether or not patients experienced a local failure or maintained primary tumor control after radiochemotherapy. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] 1122 HEAD & NECK—DOI 10.1002/HED AUGUST 2014 DISCUSSION The relationship between RTT and outcome in patients with HNSCC treated with RT and concurrent chemotherapy remains to be fully defined. A recent retrospective study suggested that an AWD >10.0 Gy (which combines total dose and the inverse of treatment time) was associated with improved locoregional control in patients treated with radiation alone but not in patients treated IMPACT OF CONCURRENT RADIOCHEMOTHERAPY TREATMENT TIME IN HNSCC FIGURE 2. (A) Local control according to radiation treatment time (RTT). Patients with RTT 49 days had a superior 3-year local control rate compared to those with RTT >49 days (88% vs 71%; p 5 .014 by log-rank test). (B) Overall survival according to RTT. Survival at 3 years was superior in patients with RTT 49 days (81% vs 58%; p 5 .032 by log-rank test). TABLE 2. Fractionation schedule characteristics. Fractionation scheme Representative schedules Median RTT, d (range) Median AWD, Gy (range) Six fx/wk (n 5 6) Concomitant boost (n 5 34) Once daily (n 5 131) 70 Gy/35 fx (6 wk) 72 Gy/42 fx (6 wk)* 70 Gy/33 fx (6.5 wk) 70 Gy/35 fx (7 wk) 39 (39–41) 44 (40–58) 47 (42–58) 12.6 (12–12.6) 11.4 (8.5–12.6) 10.4 (8.2–11.7) Abbreviations: RTT, radiation treatment time; AWD, average weekly dose; fx, fractions. *Using BID dosing for last 12 treatment days as per Radiation Therapy Oncology Group 9003 (1.8 Gy to large field followed by 1.5 Gy to boost field >6 hours afterward). TABLE 3. Univariate analysis of local control and overall survival. Local control Variables HR (95% CI) RTT, continuous (per d) RTT upper quartile (>7 wk) RTT > median DRTT, continuous (per d) AWD >10 Gy per wk Dose to primary (per Gy) T3 or T4 tumor N2 or N3 nodal disease Age at diagnosis > median (57 y) Sex (male vs female) Tumor subsite Oropharynx Nasopharynx Larynx Hypopharynx Altered fractionation* (vs once daily) Induction systemic therapy 1.1 (1–1.2) 2.6 (1.2–5.8) 1.95 (0.9–4.3) 1.04 (0.97–1.1) 0.48 (0.2–1.03) 1.02 (0.7–1.4) 4.9 (1.8–12.9) 0.44 (0.2–1.0) 1.6 (0.7–3.5) 1.4 (0.5–4.0) 1 2.6 (0.9–7.5) 1.4 (0.4–5.0) 4.0 (1.5–10.8) 0.9 (0.4–2.3) 1.3 (0.3–5.5) Overall survival p value HR (95% CI) p value .049 .018 .097 .29 .06 .88 .002 .057 .23 .55 1.02 (0.96–1.1) 1.9 (1.1–3.3) 1.7 (0.98–2.9) 1.02 (0.97–1.1) 0.6 (0.3–1.02) 1.2 (0.95–1.5) 3.4 (1.8–5.8) 0.58 (0.3–1.1) 1.54 (0.9–2.6) 0.9 (0.56–2.1) .47 .035 .058 .50 .06 .13 .0001 .073 .11 .81 NA .068 .59 .006 .89 .69 1 1.8 (0.8–3.9) 2.0 (0.98–4.2) 3.1 (1.5–6.5) 1.4 (0.8–2.4) 0.39 (0.05–2.8) NA .13 .057 .003 .25 .35 Abbreviations: HR, hazard ratio; CI, confidence interval; RTT, radiation treatment time; DRTT, RTT minus the number of days that would be expected for the patient to complete their given fractionation schedule; AWD, average weekly dose; NA, not applicable. *Altered fractionation includes concomitant boost technique or giving 6 fractions per week. HEAD & NECK—DOI 10.1002/HED AUGUST 2014 1123 CANNON ET AL. with concurrent chemoRT.14 Two older studies using split-course RT and concurrent chemotherapy found no significant detriment in outcomes despite longer treatment times.16,17 The report from the University of Chicago16 contained a multivariate analysis including duration of radiation and total radiation dose, with only total dose significant for local failure. However, the conclusion that radiation treatment duration was not significant for local control is confounded by the fact that 20 of 21 of the local failures were in patients with recurrent disease who were often treated to lower doses and with shorter treatment times. In this subset of patients, no predictor for local control could be found because of the exceptionally high risk for recurrence regardless of treatment duration or dose. It is appreciated, however, that excellent local control was found in the group with no prior therapy despite having treatment durations ranging from approximately 60 to 160 days. In contrast, the results of the present study provide support for the hypothesis that even in patients treated with concurrent chemotherapy, prolonged RTT is associated with inferior local control and possibly overall survival as well. In our cohort of patients, significant and independent predictors for local failure were advanced T classification and RTT >7 weeks. When RTT was analyzed as a continuous variable rather than using a cut-point of 7 weeks, it remained associated with a significant risk for local failure (p 5 .049). These results are congruent with those in the recent study by Sher et al13 in which data from the TAX 324 trial was analyzed retrospectively for an effect of treatment duration on outcomes. This was a phase III trial comparing docetaxel, cisplatin, and fluorouracil to cisplatin and fluorouracil as induction chemotherapy followed by radiotherapy with concurrent carboplatin in patients with newly diagnosed locally advanced HNSCC. Multivariable analysis showed that a prolonged radiotherapy course (modeled both as a continuous variable and with a cut-point at the upper quartile, or 8 weeks) was independently associated with an increased risk for locoregional failure and death. However, overall treatment time (defined as total duration of treatment including induction and chemoRT) was not. Results from retrospective analyses should be interpreted with an understanding of the possibility of hidden biases and confounding variables. For the present study, it is possible that prolonged RTT could be associated with patient medical comorbidity because of less physiological reserve to tolerate the rigors of treatment. We were not able to rigorously adjust for underlying medical comorbidity with the available data, but, as a surrogate, we observed that age did not vary significantly in patients in the upper quartile of RTT compared to the remainder of the cohort (p 5 .7) and was not a predictor for either overall survival or local control. We also cannot exclude that patients with shorter RTT had tumors with a more favorable biology. Patients with human papillomavirus (HPV)-positive HNSCC treated with definitive chemoRT have been shown to have superior locoregional control and overall survival.11 As risk factors and demographics in patients with HPV-positive tumors are known to differ from patients with 1124 HEAD & NECK—DOI 10.1002/HED AUGUST 2014 HPV-negative tumors,18,19 one can hypothesize that patients with HPV-negative tumors may have been more likely to have longer RTT because of medical comorbidity or less social support. We commenced routine HPV testing for all oropharyngeal patients in 2009 and thus did not have HPV data for this entire 2001 to 2009 cohort. However, 28 patients within our cohort had p16 status made available as part of a current research protocol. Despite small numbers, when our analysis was limited to the 26 confirmed p16-positive patients, the detrimental effect of prolonged RTT on local control persisted. This is consistent with the results of the Danish Head and Neck Cancer Group 6 and 7 study in which the effect of treatment time was independent of HPV status.20 Our data could also be viewed as resulting from the possibility that patients with larger tumors or more extensive nodal disease would have larger volumes of sensitive tissue receiving high-dose radiation and thus a given patient would be more susceptible to toxicity requiring treatment breaks. However, we did not find any significant difference in the distribution of T classification in patients with longer RTT. Interestingly, advanced nodal disease was inversely correlated with risk for local failure. However, this was likely because of a greater proportion of T3 and T4 tumors in patients with N0 and N1 disease (p < .005). Also, when adjusting for T classification, an effect on local control with RTT >49 days was still seen. Finally, some of our results were based on a cutoff at the upper quartile of RTT and could be interpreted as statistical artifacts of a post hoc analysis. This cutoff, however, was not arbitrary13 and analysis of RTT as a continuous variable also indicated an effect. Although our data are consistent with the results of randomized studies indicating that RT acceleration in the setting of concurrent chemotherapy is of no significant clinical benefit,11,12 the detriment seen with RTT >7 weeks can be used to inform selection of a fractionation schedule. Similar to others,15 our current institutional practice has been to prescribe a dose of 70 Gy in 33 fractions (2.12 Gy per fraction; 6.5 weeks) for the treatment of gross disease in HNSCC. This provides a measure of acceleration relative to a full 7-week course and allows for a cushion of a few days in the event of a missed treatment. CONCLUSION Despite select trials suggesting lack of benefit to accelerated fractionation in patients with HNSCC treated with concurrent chemoradiation, our results from 171 patients treated with definitive chemoradiation suggests that prolonged radiation treatment time may still be associated with an adverse impact on local control and overall survival. For patients with HNSCC treated with curative intent chemoradiation, attention to treatment time and strict limitation of treatment interruption seems to be warranted. REFERENCES 1. Pignon JP, le Ma^ıtre A, Maillard E, Bourhis J; MACH-NC Collaborative Group. 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