Despite great strides forward in the organ preservation treatment of head and neck cancer, recurrent disease in the inoperable patient afflicted with squamous cell carcinoma of the head and neck (SCCHN) often remains challenging. Re-excision is usually limited by radiation effect of prior treatment, or a history of a prior resection. For these patients, systemic therapy, re-irradiation, and other supportive care are often the only available options.

Systemic therapy alone is typically considered the standard palliative treatment option for recurrent SCCHN patients. Re-irradiation of the head and neck can be fraught with hazards due to normal tissue tolerance saturation from prior radiation treatments. Little available normal tissue tolerance will often result in a sub-optimal treatment plan. Older palliative radiation regimens such as ”quad-shot“ therapy require considerable expertise in treating these types of patients in order to be administered safely.

This interesting single institutional study by Patel et al is contemporary as it addresses the use of low-dose fractionated radiation therapy (LDFRT) in addition to cetuximab and docetaxel in patients in this unique situation. The investigators used a regimen as follows: cetuximab 400mg/m2 was given as loading dose only on day 1 of week 1 and then, subsequently, in 250 mg/m

 weekly doses on day 1 of each following week (weeks 2 to 7). Docetaxel 20 mg/ m

 was administered weekly on day 1 from week 2 to 7. Radiotherapy consisted of 0.5 Gy/fraction twice a day at least 6 hours apart on days 2 and 3 of weeks 2 to 7 for a total dose of 12 Gy. Patel at al suggest that this regimen is well-tolerated, however the benefit may be marginal.

For this appropriate subset of patients, LDFRT and chemotherapy may offer transient palliation accompanied by low treatment related morbidity.

In this phase II study, cetuximab 400 mg/m

 was given in the usual loading dose only on day 1 of week 1 and then, subsequently, in 250mg/m

 weekly doses on day 1 of each following week (weeks 2-7). Docetaxel 20 mg/m

 was administered weekly on day 1 from week 2-7. Radiotherapy consisted of 0.5 Gy/fraction BID at least 6 hours apart on days 2 and 3 of weeks 2-7 for a total dose of 12 Gy.

Nine patients were screened, 5 patients were enrolled, and 4 patients were treated between October 2013 through February 2015. After completion of salvage treatment per protocol, at 1 month follow up, partial response was seen in 2 patients (50%), stable disease in 1 patient (25%), and progressive disease in 1 (25%) patient. By 6 months, all patients had progressive disease, 1 patient (25%) completed a full course of re-irradiation, and 1 patient (25%) received further chemotherapy for progression. Treatment-related morbidity was limited to diffuse grade 1 skin toxicity reported in all patients. The Data Safety and Monitoring Board suggested closing this protocol as clinical response approached the predefined futility endpoint for complete response.

Low-dose radiotherapy in addition to docetaxel and cetuximab was well tolerated although treatment effects were transient. More durable treatment options may exist for definitive treatment; however, this protocol may offer palliation to select patients.

Local/regional failure after definitive radiotherapy (RT) remains a significant problem particularly in advanced stage head and neck cancer.1-3 Approximately 50% to 60% of patients who fail initial definitive treatment will die as a direct consequence of locally or regionally recurrent disease.

Surgical salvage is sometimes successful, but not always feasible due to disease extent, location, or patient comorbidities.

For these patients, systemic therapy, re-irradiation, and supportive care may be the only remaining options.

Historically, prior to when re-irradiation was not yet commonly used, systemic therapy alone was considered the remaining palliative treatment option for inoperable patients with recurrent squamous cell carcinoma of the head and neck (SCCHN). Use of platinum-based chemotherapy has been associated with response rates of less than 50% and a median overall survival (OS) of 6-8 months.

 More recently, cetuximab therapy has demonstrated improved response rates and survival in platinum-refractory SCCHN compared with historical controls.

 In a study of 442 patients randomized to receive a platinum-based chemotherapy and fluorouracil with or without cetuximab, the addition of cetuximab significantly prolonged the median OS to 10.1 months versus 7.4 months in the control arm.

 Furthermore, the same authors reviewed 3 separate phase II trials in patients with recurrent or metastatic SCCHN who progressed on platinum-based therapies and found that the addition of cetuximab led to additional improvement in response rates from 10-13%.

 The authors concluded that cetuximab may prolong survival in patients with SCCHN who fail first-line therapy.

Re-irradiation of the head and neck may be fraught with difficulties in relation to concerns regarding normal tissue tolerance and, sometimes, tumor radioresistance.

 More recently, preclinical and clinical data have shown that re-irradiation is feasible and may provide improved disease control translating into superior survival in subsets of patients; albeit, in the setting of potentially high toxicity profile.

Various types of RT delivery, such as conventionally fractionated therapy, hyperfractionation, brachytherapy, and stereotactic body RT have been attempted with and without concurrent chemotherapy in this group of patients.

In appropriately selected patients who are able to undergo re-irradiation, there is usually an improved disease response compared to systemic therapy alone; however, there also continues to be a notable risk of treatment related morbidity with such combination therapy.

In contrast to the paucity of treatment options for patients in the loco-regionally recurrent and unresectable setting, there have been numerous developments in the primary treatment of SCCHN. Low-dose fractionated RT (LDFRT) is a novel approach that has been utilized in the treatment of loco-regionally very advanced SCCHN as a means of decreasing the toxicity of re-irradiation. LDFRT resulted in more effective cell-kill than was predicted by the linear quadratic model in preclinical studies, possibly, through both the hyper-radiation sensitivity (HRS) phenomenon and/or through potentiating the effect of chemotherapy.

 Early work by groups such as Joiner and colleagues showed an initial phase of HRS in head and neck cell lines that were exposed to doses less than 1 Gy, specifically around 0.5 Gy.

 In this low dose region there exists a paradoxical increase in tumor cell kill compared with higher doses. It is hypothesized that HRS does not cause the initiation of DNA repair mechanisms that would otherwise arrest these cells for repair in the G2 phase. As such, these damaged cells ultimately undergo cellular death.

The use of LDFRT along with chemotherapy has also demonstrated a chemo-potentiating role. In vitro data initially revealed that LDFRT potentiates the effects of the paclitaxel in both wild type and mutant 

 Furthermore, LDFRT in both cell lines caused an up-regulation in the pro-apoptotic protein, BAX, and a down-regulation in anti-apoptotic proteins, BCL-2 and NF-kB. The combined effects of LDFRT and docetaxel therapy on the growth of SCCHN were also evaluated in the nude mouse model to elicit the HRS phenomenon present in G2/M cell cycle.

 Combination therapy showed a significant improvement in both tumor regression and local control. Additionally, molecular analysis of resected tumor specimens demonstrated that Bax levels were elevated with concomitant increase in cytochrome c release to the cytosol in the LDFRT and docetaxel group. These findings strongly suggest that LDFRT can be used in combination with docetaxel to potentiate the effects of docetaxel on tumor regression through an apoptotic mode of death. As such, the G2/M cell cycle arrest by docetaxel appears to be an important component of the enhanced apoptotic effect of LDFRT + docetaxel combined treatment.

The aforementioned in vitro and in vivo studies also led to a clinical trial: Gleason et al evaluated 39 patients with loco-regionally advanced SCCHN in a phase II clinical trial treated with induction paclitaxel, carboplatin, and LDFRT every 21 days for 2 cycles.25 RT consisted of 80 cGy BID on days 1 and 2 to a total dose of 640 cGy. Initial results were promising and showed a response rate of 90% at the primary disease site and 69% at the nodal site.26 Five-year follow-up was similar to historical controls showing an OS of 62% and progression-free survival (PFS) of 58%. In this study, treatment-related toxicity was minimal.

Our novel approach to treat recurrent SCCHN was based on the following 5 hypotheses, extrapolated from the aforementioned data: 1) LDFRT would be utilized to sensitize chemotherapy 2) low dose HRS response would be significantly enhanced in docetaxel-induced G2/M cell cycle arrest, 3) LDFRT would render enhanced BAX activation mediated mode of apoptotic cell death 4) cetuximab would help arrest the cells in G1/G0 phase leading to p21-mediated mode of cell death, and 5) the toxicity profile would be expected to be minimal. The purpose of this study is to describe our initial exploratory experience with LDFRT in addition to docetaxel and cetuximab in the setting of recurrent SCCHN.

Study and patient characteristics / eligibility criteria This study was Institutional Review Board approved, Investigational New Drug exempt, and Health Insurance Portability and Accountability Act compliant. In addition to having loco-regional recurrence in the head and neck, all patients fulfilled all the following inclusion criteria: 1) Eastern Cooperative Oncology Group (ECOG) performance status of 0—2, 2) histo-pathologically confirmed recurrence of SCCHN, 3) not candidates for surgical salvage treatment due to unresectability, and 4) a period of at least 6 months from the completion of prior RT. Exclusion criteria included distant metastases outside the head and neck, primary in the nasopharynx or salivary glands, other invasive malignancies, or medical illnesses impairing ability to receive treatment.

The plan was to enroll 25 evaluable patients and follow them for a minimum of 2 additional years. The primary objective was to show an improvement of response rate of 40% with chemotherapy alone to 70% with the addition of LDFRT. Considering the possibility that 5% of study-eligible patients will not be evaluable, we aimed to enroll 27 patients to ensure an analysis set of 25 patients who would be evaluable for efficacy. This sample size would provide reasonable precision in estimating the overall response rate (ORR) as preliminary evidence that the proposed docetaxel-cetuximab-LDFRT treatment is efficacious in this population. ORR is defined as rate of patients achieving complete response (CR) or partial response (PR). Secondary objectives consisted of a safety profile along with an estimate of PFS and OS.

Cetuximab 400mg/m2 IV was administered as a loading dose 1 week prior to RT and then cetuximab 250mg/m

 IV was given weekly on day 1 of weeks 2 to 7. Docetaxel 20mg/ m2 IV was given weekly on day 1 of week 2 to 7. LDFRT consisted of 0.5 Gy/fraction BID via intensity modulated radiotherapy at least 6 hours apart on day 2 and 3 of weeks 2 to 7 for a total dose of 12 Gy. Total therapy lasted for a total of 7 weeks. Figure 1 reviews the treatment schema.

 Patients were assessed weekly in the Department of Radiation Oncology. Every week, complete blood counts, and chemistries were evaluated to evaluate hematologic toxicity. NCI-Common terminology criteria for adverse events (CTCAE) version 4.0 was utilized for documentation of toxicity.

Follow-up visits consisting of history and physical examination were performed at 1, 3, 6, and 9 months. Four weeks after treatment a CT or MRI of the head and neck were obtained. Response was evaluated by the treating physician defined as follows : CR was defined as disappearance of the target lesions, PR was defined as at least a 30% decrease in size of the lesion, progressive disease (PD) was defined as at least a 20% increase in the size of the lesion, and stable disease (SD) was defined as insufficient changes to qualify for the aforementioned end points of PR or PD. Patients that had less than a CR were recommended for further treatment with RT or chemotherapy at the discretion of the treating physician.

Proposals were set in place for the Data Safety Monitoring Committee (DSMC) to stop the trial bases on response or toxicity data. These guidelines were developed using Bayesian methods that could be applied at any phase of enrollment without advance specification of the number of interim analyses to be performed. Under these methods, a prior probability is assigned to possible values for response and toxicity data. As data on treated patients becomes available, the probability distributions are revised and the resulting posterior probability becomes the basis for recommending either continuation or termination of the study.

Patients Between October 2013 and February 2015, 9 patients were screened for this institutional study to receive LDFRT, cetuximab, and docetaxel. Four patients were found to be ineligible for the study as 1 patient had metastatic disease on further work up, 1 patient had a poor performance status, 1 patient elected hospice, and 1 patient died prior to enrollment.

Five patients were enrolled in this study; however, 4 patients were ultimately treated as 1 patient was found to have a poor performance status and was not recommended for further treatment at the discretion of the treating physician. Table 1 lists the characteristics of the patients included in this study. All patients were male. Primary disease sites were the larynx, in 2 patients, floor of mouth in 1 patient, and the tonsillar fossa in another. 

Only 1 patient received surgery as treatment for their primary tumor followed by RT consisting of 66 Gy whereas 3 patients received definitive chemoradiation consisting of cisplatin 100mg/m2 q3 weeks and RT dose of 70 Gy to their primary tumor. Time from end date of definitive primary treatment to therapy for recurrent disease ranged from 13 to 26 months. Four patients completed the reirradiation protocol and were able to tolerate treatment.

All the patients had grade 1 fatigue attributed to both chemotherapy and radiotherapy treatment. All patients had grade 1 rash ascribed to chemotherapy. There was no grade 2 or higher toxicity.

At 1 month follow up, PR was seen in 2 patients (50%), SD in 1 patient (25%), and PD in 1 (25%) patient. By 6 months, all patients had PD. One patient (25%) underwent a second course of re-irradiation consisting of 58 Gy in 2 Gy/ fraction as salvage treatment at progression and 1 patient (25%) underwent chemotherapy. Table 2 summarizes treatment response. Given that the accumulating data suggested that the ORR was no better than 40%, the DSMC recommended early discontinuation due to lack of efficacy as previously outlined.

To our knowledge, this is the first study to evaluate the use of LDFRT with chemotherapy in patients with recurrent SCCHN. The primary endpoint for assessing efficacy was overall response rate. The secondary objectives were treatment- related acute and long-term toxicities and estimate of PFS and OS. In this exploratory analysis, we found an initial 75% rate of stable or responsive disease. The treatment effect was transient, with all patients experiencing PD at 6 months. The treatment was tolerated well with all patients experiencing grade 1 fatigue and rash and no reported grade 2 or higher toxicity. The DSMC suggested closing this protocol early as results were approaching the predefined futility endpoint.

 In the setting of nonsurgical treatment options for patients with recurrent SCHHN, there is a paucity of randomized data evaluating the comparative benefit of treatment options. Provider treatment biases as demonstrated in part by selection of healthier patients into surgical series as well as the heterogeneity present in the remaining patient population may account for this dearth of comparative clinical data. Consequently, national phase III studies such as RTOG 0421, a randomized trial designed to evaluate concurrent re-irradiation and chemotherapy versus chemotherapy alone in patients with recurrent head and neck cancer, were closed early due to inadequate patient accrual. Even after overcoming the challenge of enrolling patients, there are numerous difficulties in maintaining a clinical trial within this select, chronically ill, and unstable population. Nine patients were originally screened, but only 4 were treated due to rapidly deteriorating functional status of the excluded patients. Furthermore, this trend of incomplete clinical trial data continues as this trial was closed early.

Prior to our protocol design, a study evaluating LDFRT, paclitaxel, and carboplatin in patients with primary locally advanced SCCHN was initially reported by Arnold et al.26 In their study, the response rate was initially high at the primary site and nodal site. Our study was in part motivated by these developments; however, more recently these originally promising results were published as a 5-year follow-up with the mature data matching historic data in respect to DFS and OS.25 In the recurrent SCHHN setting, the treatment effect with LDFRT and chemotherapy appears to be more transient as seen with our experience. This reason may be in part due to a lower threshold for DNA repair due to previous treatment or even an inherent and selected radioresistance in cells surviving a previous full course of radiotherapy.

Early work with LDFRT unveiled the concept of HRS in which low doses of radiation paradoxically increased tumor cell kill as compared to conventional doses.23 Hypothetically, HRS related damage is below the threshold of DNA repair initiation that would otherwise be recognized (eg, double strand damage that occurs after conventional doses). As such, the cell undergoes an apoptotic death.25 Depending on the study, this area of HRS is described as being in the <1 Gy range usually described broadly from 0.1—0.8 Gy region of the cell survival curve.22-24 Notably this area of HRS is swiftly followed by an area of increased radioresistance (IRR). IRR is thought to represent repair mechanism initiation after a dose active increase in ATM activity and G2 checkpoint function.27 As such, radiation induced damage triggers activation of repair mechanisms in the region of IRR. Some studies have described this area of IRR being present in the 0.3&mdash;1 Gy range.24,27 As such, it is plausible that 0.5 Gy may be too high of a dose to take advantage of HRS and may even conversely fall into an area of IRR.

This is also the first study to use cetuximab and docetaxel in conjunction with LDFRT in patients with recurrent SCCHN. We based the use of cetuximab on the favorable response seen in patient receiving cetuximab in the recurrent setting while docetaxel was chosen due to the potentiating effect of LDFRT based upon the aforementioned in vitro and in vivo clinical data.14,22,25,28 Although the potentiating effect of docetaxel is well described, there could be more of a potentiation role with other chemotherapeutic agents. It appears that LDFRT and both chemotherapeutic agents were very well tolerated compared to published experiences of multidrug chemotherapy regimens alone.10,11,29 From our single institutional experience, patients with loco-regionally recurrent unresectable SCCHN should be treated with more established RT techniques as they may not optimally benefit from this protocol.2,8 In patients with more limited options, as those presenting with metastatic disease, LDFRT with cetuximab and docetaxel may offer transient palliation with minimal morbidity.

Although there have been numerous improvements in the primary treatment of SCCHN, treatment of recurrent disease in inoperable patients is challenging. From our single- institutional experience, low-dose RT in addition to cetuximab and docetaxel is well-tolerated in patients with recurrent SCCHN. More long-term treatment options may exist in patients with recurrent SCCHN; however, for a select group of patients, LDFRT and chemotherapy may offer transient palliation in the setting of low morbidity.

Department of Radiation Oncology, University of Miami, Miami FL (VNP, HJN, MAS, LMF, NME, MCA). Department of Biostatistics, University of Miami, Miami FL (DK). Department of Otolaryngology, University of Miami, Miami, FL (CI). Department of Medical Oncology, University of Miami, Miami, FL (DW).

Supported by a research grant from the American Cancer Society (Grant # IRG9827710). Sylvester Comprehensive Cancer Center provided resources and the use of facilities to support this research investigation.

 Matthew C. Abramowitz, MD, Department of Radiation Oncology, Sylvester Comprehensive Cancer Center, 1275 NW 14th St. Miami, FL, 33136. E-mail: mabramowitz@med.miami.edu

Forastiere A, Koch W, Trotti A, Sidransky D. Head and neck cancer. 

Marur S, Forastiere AA. Head and neck squamous cell carcinoma: update on epidemiology, diagnosis, and treatment. 

. 2016;91(3):386-396. doi: 10.1016/j.mayocp.2015.12.017.

Strom T, Wishka C, Caudell JJ. Stereotactic body radiotherapy for recurrent unresectable head and neck cancers. 

Hong WK, Bromer RH, Amato DA, et al. Patterns of relapse in locally advanced head and neck cancer patients who achieved complete remission after combined modality therapy. 

Zafereo M. Surgical salvage of recurrent cancer of the head and neck. 

. 2014;16(5):386. doi: 10.1007/s11912-014-0386-0.

Strojan P, Corry J, Eisbruch A, et al. Recurrent and second primary squamous cell carcinoma of the head and neck: when and how to reirradiate. 

. 2015;37(1):134-150. doi: 10.1002/hed.23542.

Wong SJ, Machtay M, Li Y. Locally recurrent, previously irradiated head and neck cancer: concurrent re-irradiation and chemotherapy, or chemotherapy alone? 

Sacco AG, Cohen EE. Current treatment options for recurrent or metastatic head and neck squamous cell carcinoma. 

. 2015;33(29):3305- 3313. doi: 10.1200/JCO.2015.62.0963.

Ho AS, Kraus DH, Ganly I, Lee NY, Shah JP, Morris LG. Decision making in the management of recurrent head and neck cancer. 

. 2014;36(1):144- 151. doi: 10.1002/hed.23227.

Colevas AD. Chemotherapy options for patients with metastatic or recurrent squamous cell carcinoma of the head and neck. 

Colevas AD. Systemic Therapy for Metastatic or Recurrent Squamous Cell Carcinoma of the Head and Neck. 

Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. 

Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. 

. 2008;359(11):1116-1127. doi: 10.1056/NEJMoa0802656

Vermorken JB, Herbst RS, Leon X, Amellal N, Baselga J. Overview of the efficacy of cetuximab in recurrent and/or metastatic squamous cell carcinoma of the head and neck in patients who previously failed platinum-based therapies. 

. 2008;112(12):2710-2719. doi: 10.1002/cncr.23442.

Soltys B, Wiazzane N, Mirjolet C, et al. [Reirradiations of head and neck cancers: state of the concept and ways of development]. 

 2013;17(5-6):508-512. doi: 10.1016/j.canrad.2013.07.142.

Peponi E, Balta S, Tasiou I, et al. Reirradiation for recurrent head and neck carcinoma. 

Chen AM, Phillips TL, Lee NY. Practical considerations in the re-irradiation of recurrent and second primary head-and-neck cancer: who, why, how, and how much? 

. 2011;81(5):1211-1219. doi: 10.1016/j. ijrobp.2011.06.1998.

Cacicedo J, Navarro A, Alongi F, et al. The role of re-irradiation of secondary and recurrent head and neck carcinomas. Is it a potentially curative treatment? A practical approach. 

. 2014;40(1):178-189. doi: 10.1016/j.ctrv.2013.08.002.

Mouttet-Audouard R, Gras L, Comet B, Lartigau E. Evidence based and new developments in re-irradiation for recurrent or second primary head and neck cancers. 

. 2012;20(2):137-141. doi: 10.1097/MOO.0b013e3283506a52.

Riaz N, Hong JC, Sherman EJ, et al. A nomogram to predict loco-regional control after re-irradiation for head and neck cancer. 

. 2014;111(3):382-387. doi: 10.1016/j.radonc.2014.06.003.

Spring PM, Arnold SM, Shajahan S, et al. Low dose fractionated radiation potentiates the effects of taxotere in nude mice xenografts of squamous cell carcinoma of head and neck. 

Dey S, Spring PM, Arnold S, et al. Low-dose fractionated radiation potentiates the effects of Paclitaxel in wild-type and mutant p53 head and neck tumor cell lines. 

Joiner MC, Marples B, Lambin P, Short SC, Turesson I. Low-dose hypersensitivity: current status and possible mechanisms. 

Marples B, Collis SJ. Low-dose hyper-radiosensitivity: past, present, and future. 

. 2008;70(5):1310-1318. doi: 10.1016/j. ijrobp.2007.11.071.

Gleason JF, Jr., Kudrimoti M, Van Meter EM, et al. Low-dose fractionated radiation with induction chemotherapy for locally advanced head and neck cancer: 5 year results of a prospective phase II trial. 

Arnold SM, Regine WF, Ahmed MM, et al. Low-dose fractionated radiation as a chemopotentiator of neoadjuvant paclitaxel and carboplatin for locally advanced squamous cell carcinoma of the head and neck: results of a new treatment paradigm. 

Krueger SA, Collis SJ, Joiner MC, Wilson GD, Marples B. Transition in survival from low-dose hyper-radiosensitivity to increased radioresistance is independent of activation of ATM Ser1981 activity.

Specenier PM, Vermorken JB. Recurrent head and neck cancer: current treatment and future prospects. 

. 2008;8(3):375-391. doi: 10.1586/14737140.8.3.375.

Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. 

Articles

This study evaluates low dose radiotherapy in combination with docetaxel and cetuximab in patients with recurrent, unresectable squamous cell carcinoma of the head and neck initially treated with definitive chemo-radiation therapy.

Radiation for Chemo-Sensitization: A Phase II Trial of Cetuximab and Docetaxel With Low-Dose Fractionated Radiation for Recurrent Unresectable Locally Advanced Head and Neck Carcinoma

	The optimal fractionation for early glottic cancer is unclear. Prospective randomized data showing superiority of 2.25 Gy versus 2 Gy/fraction derive from only 1 trial. We analyzed our single-institutional experience to address the therapeutic ratio of 2.25 Gy vs. 2 Gy.

	One hundred patients with T1-T2 glottic carcinoma received radiation therapy (RT) between 2003-2013. Their records underwent retrospective analysis. Median age was 64 years. Seventy-six had T1 tumors; 24 had T2. Forty-eight received 2 Gy daily (conventional RT--CRT) and 52 received 2.25 Gy daily (hypofractionated RT--HRT). Median CRT dose was 66 Gy and HRT dose was 63 Gy. Logistic regression, t-test, log-rank test, and Cox proportional hazards regression were used and two-sided p-value was reported. Recurrence-free survival (RFS) was estimated using Kaplan-Meier method.

	Median follow-up was 28.8 months overall, with 54.7 months for CRT and 16.1 months for HRT, after excluding from local control analysis 9 patients with follow-up <3 months. CRT patients had less grade 2 dysphagia (

 < 0.001), and required less frequent administration of opiates (

 = 0.004). Rates of grade >2 radiation dermatitis (

 = 0.655) during treatment were similar. Complete response (CR) was 91.7% in the CRT group vs. 90.4% for HRT. RFS was comparable at 24 months (86.7% vs 86.6%, 

 = 0.988) and at 60 months (82.8% vs 78.8%,

-value of log-rank test for RFS was 0.797. Univariate analysis for the 76 T1 patients upheld the significance for all of the above findings, including CR and RFS, except grade 2 dysphagia (

	Our retrospective data suggest that treatment of early glottic cancer with 2.25 Gy/fraction may result in greater acute toxicity than 2 Gy/fraction without improved efficacy.

Early stage glottic cancers are a common malignancy of the head and neck, and may be treated effectively with radiotherapy (RT), surgery, or laser microsurgery.

 RT provides local control rates of 80-95%.

 Historically, conformal RT (CRT) used 2 Gy per fraction for 33 fractions. Some retrospective data have demonstrated that hypofractionated regimens (>2 Gy) with a shorter overall treatment time (OTT) improved local control. However, most reports used <2 Gy as the control.

 Few retrospective studies have evaluated 2 Gy vs. 2.25 Gy.

		Table 1: Patient and Tumor Characteristics

		* excluding 9 pts whose follow-up duration is less than 3 months

In 2006, Yamazaki published a prospective randomized trial demonstrating superior local control of 92% with HRT versus 77% with CRT.

 A limited discussion of toxicity indicated no significant differences in acute mucosal, skin or chronic adverse reactions. There are many differences in the techniques used in this study and in typical United States practice (beam energy, field size, dose prescription point, dose range). Biologic or cultural differences between a Japanese patient cohort and one from the United States may affect tumor control or toxicity outcomes. Since 2006, the Japanese randomized trial has not been replicated. For these reasons, the outcome and toxicity results from that study may not apply to patients treated in the United States at the University of Miami, we noted greater toxicity with HRT without apparent local control benefit compared to CRT. Therefore, we decided to re-examine this topic.

Retrospective data collection and analysis was approved by our Institutional Review Board. One hundred patients with histologically proven T1-2N0M0

 glottic carcinoma treated with RT at the University of Miami between 2003-2013 were identified. Patient and tumor characteristics are summarized in 

Treatment was delivered with 6 MV photons to opposed lateral or slightly oblique fields. A few patients prior to 2006 also received an additional anterior field. In both eras, patients were treated to an isodose line (usually 98% or 95%) with fields ranging from 5x5 to 6x6 cm. Bolus was used on some anterior commissure cases in the CRT era but not in the HRT era.

Prior to 2006, patients were prescribed CRT daily to 66 Gy for T1 tumors or 70 Gy for T2 tumors. After 2006, patients were prescribed HRT daily to 63.25 Gy for T1 tumors or 65.5 Gy for T2 tumors. Forty-eight patients received 2 Gy and 52 received 2.25 Gy. Median dose was 66 Gy for CRT and 63 Gy for HRT. No patients received systemic therapy. Treatment characteristics are summarized in 

SAS and R software were used for all statistical analyses (SAS Institute, Cary, NC and www.r-project.org). Logistic regression, t-test, log-rank test, and Cox proportional hazards regression were used to compare the two groups and two-sided P-value was reported. 

 <0.05 was considered statistically significant. Local control was defined at the primary site. Patients without CR at initial follow-up after radiotherapy were regarded local failures. Recurrence-free survival (RFS) was defined as no evidence of recurrence at any site and was estimated using Kaplan-Meier method.

 Complications were graded using CTCAE version 4.0.

Flexible laryngopharyngoscopy was performed at 6-12 weeks after radiotherapy to assess response. Rates of response and tumor progression were not statistically different for CRT and HRT groups (

		Figure I: Recurrence-Free Survival Rates: Left (n=91; T1+T2), Right (n=76; T1 only), 

RFS rates were similar at 12, 24, 36 and 60 months as shown in 

. The p-value of log-rank test for RFS was 0.797 (

). To account for the variable stage distribution of patients in the CRT and HRT groups, a multivariate analysis adjusted for AJCC stage confirmed that RFS of the two treatment groups is not significantly different: HR (hazard ratio) 1.147 and (95% CI; 

 =.953) by Cox proportional hazard regression. Univariate analysis for the 76 T1 patients upheld the significance for both CR rate and RFS. The 2-yr RFS was 87.3% for CRT and 88.9% for HRT (

). Cox proportional hazard regression showed that RFS of the two treatment groups are not significantly different: HR 0.382 and (95% CI; 

-value) (0.001, 106.6; 0.738) for the T1 patients.

There were 7 local failures in the CRT group, with 2/7 patients receiving less than the planned dose due to toxicity, and 1 of those 2 having a prolonged OTT of 55 days. The remaining 5 T1 patients with local failures in the CRT group received 66 Gy in 41—49 days. Median OTT in the CRT group was 46 days. Four patients had OTT > 49 days with one local failure as mentioned above.

Of the 6 failures in the HRT group, all patients completed the full prescribed dose of RT (63 Gy for T1 [n=4] and 65.25 Gy for T2 [n=2]) in 36-42 days. The T2 patient with OTT of 42 days and a CR to HRT failed locally and regionally and was pending surgical salvage at the most recent follow-up. Median OTT in the HRT group was 40 days. Three patients had an OTT >44 days with no local recurrences, and 1 patient received less than the prescribed dose without recurrence.

Early toxicity was determined by clinical and laryngoscopic exams performed during RT and at 6-12 week follow-up. Toxicities for all 100 patients were recorded as the maximum toxicity for each endpoint during this time.

-values of patient toxicity by grade is listed in 

. CRT patients had less grade 2 dysphagia, grade >2 hoarseness, grade >2 mucositis and required opiate analgesics less frequently. The rates of grade >2 radiation dermatitis, grade >2 laryngeal edema and weight loss were similar.

With the exception of grade 2 dysphagia (

 = 0.156), univariate toxicity analysis for the 76 T1 patients confirmed the significance for each specific area noted for the entire cohort. To account for the variable stage distribution of patients between treatment groups, logistic regression of toxicities by UVA and MVA confirmed the significance of these findings (

Nine patients were salvaged surgically including 6 in the CRT group and 3 in the HRT group. There were 6 deaths in the entire cohort: 5 in the CRT group and 1 in the HRT group; none attributable to laryngeal cancer.

Although radiotherapy for early glottic cancer is standard treatment for decades, the optimal dose-fractionation scheme to provide maximum local control with minimum treatment toxicity is not clearly established. While several studies have indicated an improvement in local control with HRT compared to lower daily fraction sizes,

 rarely have these studies directly compared HRT with CRT of 2 Gy fractions. Additionally, most studies have not reported acute treatment toxicity to allow for an accurate assessment of the therapeutic ratio of HRT.

Numerous retrospective series have demonstrated that local control with 2 Gy fractions (compared to 1.8 Gy fractions) was excellent, ranging from 95-100%.7-9 The University of Florida (UF) experience with hypofractionation using 2.25 Gy fractions developed in the late 1970s and was based on radiobiologic principles without a direct comparison (prospective or retrospective) with CRT using 2 Gy fractions. Mendenhall published the UF retrospective data showing a trend toward improved local control for 4 of 7 small patient cohorts, divided by T stage, who received higher doses per fraction.

 However, 3 of the 4 cohorts with the positive trend compared local control for patients receiving 205-230 cGy per fraction to patients receiving 180-199 cGy per fraction, which had previously been shown to be inferior.7-9, 11 Despite this, the UF experience influenced many other institutions including Yamazaki, who performed the only randomized comparison of 2 vs. 2.25 Gy fractions.

Of note, the only two published retrospective comparisons of CRT to HRT were from Yu12 and Kim.

 The Yu study utilized 2 Gy vs. either 2.25 or 2.5 Gy fractions and showed a local control advantage for hypofractionation. However, the local control rate for the 2 Gy arm was extremely poor at 65.6% at 5 years, approximately 20-30% lower than comparable series. Kim compared 2 vs. 2.25 Gy fractions and showed an advantage for hypofractionation. However, Kim used non-standard doses in the T1 group of 70 Gy for CRT and 67.5 Gy for HRT with prolonged OTT in both arms. In addition, the T2 group in this study showed no advantage to HRT compared to CRT. Importantly, none of the retrospective studies provided detailed analyses of acute treatment toxicity to sufficiently analyze the therapeutic ratio of HRT.

		Table e1. Logistic regression of toxicities: UVA I, UVA II (AJCC stage T1 only), and MVA (adjusted for AJCC stage)

In 2006, Yamazaki et al published a prospective randomized trial of radiation fraction size and OTT, which has since changed practice worldwide by demonstrating a superior local control rate with HRT (2.25 Gy) compared to CRT (2 Gy) with no reported differences in toxicity.

 In this study, 180 patients were randomly allocated to either HRT of 2.25 Gy daily to a total dose of 56.25 Gy for minimal tumors and 63 Gy for larger tumors or to CRT of 2 Gy daily to 60 Gy for minimal tumors and 66 Gy for larger tumors. Minimal tumors were defined as those involving two-thirds of the vocal cord or less. The 5-year local control was significantly improved for HRT (92%) versus CRT (77%) with no significant differences in overall toxicity measured by rates of acute mucosal, skin and chronic adverse reactions, although these toxicities were described in a very limited fashion.

Further criticism of the Yamazaki study includes 5-year local control of only 77% for CRT, well below published retrospective studies, including ours. If the CRT arm had achieved local control results consistent with other studies, there may not have been a significant control advantage with HRT. Regarding toxicity, Yamazaki presents only acute skin and mucosal toxicities, with no mention of hoarseness, dysphagia, pain, or need for narcotics. We found each of these toxicities to be significantly more frequent with HRT. The lack of detailed toxicity information limits analysis of the therapeutic ratio of HRT versus CRT from this single trial.

Several studies analyzing outcome in early glottic cancer by treatment variables have demonstrated that only OTT was significant for local control in MVA, unlike dose and fraction size.

 Fowler’s review article best summarizes this data and the relevant radiobiological principles.

 In our cohort, the patients receiving CRT consistently completed treatment within the OTT suggested by these studies, which may explain the similar outcomes of CRT to HRT in our study.

Several studies including a recent retrospective series from Japan have indicated that tumor control is inferior with lower total treatment doses.

 Importantly, the combination of overall dose and OTT can significantly influence outcomes. Le et al reported no local failures when the OTT was <50 days and the total dose was >65 Gy but described local failures in 54% of patients when the OTT was >50 days and the total dose was £ 65 Gy (4). A CRT plan of 66 Gy/33 fractions meets these parameters.

Our outcomes in this series compare favorably with the previously reported rates of local control for conventional fractions of <2 Gy and are similar to outcomes of several studies with a CRT arm of 2-Gy.

 Our study found no difference in complete tumor response or local control — described as RFS – rates in a cohort of 100 patients treated over the past decade with either HRT or CRT. This contrasts with the prospective randomized trial from Japan.

Despite the retrospective nature of this study, we have thoroughly analyzed early toxicity by measuring and reporting the maximal severity of toxicity for several key endpoints from the start of radiotherapy through the first follow-up exam at 6 to 12 weeks. Strikingly, our HRT patients developed more grade 2 dysphagia, grade >2 hoarseness, grade >2 laryngeal mucositis, and need for opiate analgesics. These acute toxicities were not routinely recorded or analyzed in the previous retrospective studies or the Japanese randomized study that led to the widespread adoption of HRT.

		Table e2. Toxicity (AJCC stage T1 only)

Limitations to our series include the retrospective structure and the absence of long-term toxicity data. Patient-reported quality of life data would be desirable, but has not been provided by any investigator in this area or by us. However, our series alone provides detailed information on the severity of acute toxicities of HRT and CRT and thus enables a comparative discussion of the therapeutic ratio of each technique.

We agree with Yamazaki that a multi-institutional prospective randomized trial is essential for HRT to be standard treatment, particularly when toxicity is considered with efficacy. Along with several other investigators, we advocate timely radiotherapy without treatment delay and insist that patients treated with CRT complete their radiotherapy in < 50 days from start of RT.

Our retrospective experience suggests that early glottic cancer treated with HRT results in a higher incidence of acute toxicity without improved control compared to CRT delivered in an appropriate OTT. Therefore, HRT may not provide a therapeutic advantage over CRT.

 From the Departments of Radiation Oncology (MTS, NE, MCA, AMM, MAS) and Biostatistics and Bioinformatics Core (WZ), Sylvester Comprehensive Cancer Center at the University of â€¨Miami Miller School of Medicine (AD), Miami, Florida.

Michael A. Samuels, MD, Department of Radiation Oncology, University of Miami Miller School of Medicine, 1475 NW 12th Avenue, Miami, FL 33136. Tel: (305) 243-4210; Fax: (305) 243-4363; E-mail: msamuels2@med.miami.edu.

 The authors have no conflicts to disclose.

			Mendenhall WM, Werning JW, Hinerman RW, et al. Management of T1-T2 glottic carcinomas. 

			Mendenhall WM, Parsons JT, Million RR, et al. T1-T2 Squamous cell carcinoma of the glottic larynx treated with radiation therapy: relationship of dose-fractionation factors to local control and complications. 

			Burke LS, Greven KM, McGuirt WT, et al. Definitive radiotherapy for early glottic carcinoma: prognostic factors and implications for treatment. 

			Le QX, Fu KK, Kroll S, et al. Influence of fraction size, total dose, and overall time on local control of T1-T2 glottic carcinoma. 

			Chera BS, Amdur RJ, Morris CG, et al. T1NO to T2N0 squamous cell carcinoma of the glottic larynx treated with definitive radiotherapy. 

			Harwood AR, Hawkins NV, Rider WD, et al. Radiotherapy for early glottic cancer. 

			Schwaibold F, Scariato A, Nunno M, et al. The effect of fraction size on control of early glottic cancer. 

			Kim RY, Marks ME, Salter MM, et al. Early-stage glottic cancer: Importance of dose fractionation in radiation therapy. 

			Ricciardelli EJ, Weymuller EA, Koh W, et al. Effect of radiation fraction size on local control rates for early glottic carcinoma. 

			Fein DA, Lee WR, Hanlon AL, et al. Do overall treatment time, field size, and treatment energy influence local control of T1-T2 squamous cell carcinomas of the glottic larynx?

			Rudoltz MS, Benammar A, Mohiuddin M. Prognostic factors for local control and survival in T1 squamous cell carcinoma of the glottis. 

			Yu E, Shenouda G, Beaudet MP, et al. Impact of radiation therapy fraction size on local control of early glottic carcinoma. 

			Gultekin M, Ozyar E, Cengiz M, et al. High daily fraction dose external radiotherapy for T1 glottic carcinoma: treatment results and prognostic factors. 

			Yamazaki H, Nishiyama K, Tanaka E, et al. Radiotherapy for early glottic carcinoma (T1N0M0): results of prospective randomized study of radiation fraction size and overall treatment time. 

			Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. 

A retrospective experience suggests that early glottic cancer treated with HRT results in a higher incidence of acute toxicity without improved control compared to CRT delivered in an appropriate OTT. 

Michael A. Samuels, MD

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