Felix M. Chinea, MD

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

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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