Introduction

With the use of combined modality therapy, clinical outcomes for locally advanced head and neck cancer (HNC) have improved dramatically over the past two decades. Unfortunately, the use of aggressive combined modality therapy is associated with increased acute toxicities. Some of the most common acute toxicities associated with chemoradiation include mucositis, xerostomia, dysphagia and nutritional deficits. With the increased use of targeted agents, the acute toxicity profile appears to be changing. In addition to acute toxicities, the late effects of therapy have begun to garner increased attention as more patients are surviving their disease process. Function preservation remains one of the most important late outcome measures in the head and neck patient population. Several abstracts presented this year at the American Society of Clinical Oncology (ASCO) provided further insight into the well recognized acute and late effects of therapy as well as the novel toxicities associated with targeted agents.

Cetuximab Toxicities

Cetuximab has been FDA approved for two indications in the head and neck cancer population: 1) as a radiation sensitizing agent for patients undergoing primary radiation based treatment, and 2) for patients with recurrent or metastatic disease. As the role of cetuximab in the treatment of head and neck cancer evolves, it is important to understand the toxicities of this novel targeted agent. Several abstracts presented this year in the Head and Neck and Supportive Care Sessions addressed the issues of cetuximab toxicity.

The seminal clinical trial evaluating cetuximab in combination with radiation therapy demonstrated enhanced tumor control without a significantly increased incidence of grade 3 and 4 toxicities.¹ Of particular note, there was no reported increase in mucositis. Because of the apparent lack of additive toxicity when used in combination with radiation therapy, investigators have begun to evaluate the use of cetuximab as a part of multi-agent radiation sensitizing regimens for patients with locally advanced head and neck cancer. A note of caution was sounded when Pfister reported the results of a Phase II study using a cetuximab and cisplatin based combination chemoradiation regimen.² The study was closed early due to unexpected acute toxicities. Whether the toxicity was due to the treatment itself or the expected and inherent complications associated with treating head and neck cancer patients was unclear. Investigators have continued to push forward with the evaluation of cetuximab-based combination regimens. Given the Pfister report, careful monitoring of toxicity of cetuximab-combination regimens is indicated.

Merlano and colleagues conducted a Phase II trial of cetuximab, plus alternating radiation and chemotherapy in patients with locally advanced HNC.³ Chemotherapy consisted of cisplatin 20mg/m2 per day and bolus 5-FU 200mg/m2 per x 5 days repeated days 22 and 43. Radiation at 200cGy fractions was administered on alternate weeks of chemotherapy and after chemotherapy completed until a total dose of 7000 Gy. Thirty-five of a planned forty-five patients had been enrolled at the time of the report. Twenty-four patients were eligible for toxicity reporting. Grade 3 and 4 toxicities included the following: 18 dermatitis, 16 stomatitis, 6 neutropenia, 4 diarrhea, and 3 hypomagnesemia. Based on prior experience, the frequency and severity of skin toxicity was unexpected.

An allergic reaction is a known potential toxicity of cetuximab; however, the initial studies reported that this occurred in a small percentage of patients (3%). An increase in the rate of allergic reactions has been noted by physicians in the Southeastern United States. To confirm this observation, investigators from three research sites in the Southeast reported the incidence of grade 3 or 4 allergic reactions to cetuximab.⁴ The first cohort consisted of 88 patients on clinical trials and an additional 55 patients treated off study in Tennessee. Patients had a variety of cancers; however, colon and lung predominated. The incidence of grade 3 or 4 hypersensitivity reaction was 21.6%. The allergic reaction occurred with the first dose. Pre-medication with steroids and anti-histamines did not protect against the allergic reaction. Investigators subsequently reviewed records of 90 patients treated with cetuximab at the University of North Carolina. Fouteen percent of patients experienced a grade 3 or 4 hypersensitivity reaction. Patients with a severe reaction were more likely to report prior allergy as defined by one of the following: prior H1 use, drug allergy, bee sting allergy, eczema, reactive airways disease, or food allergy. The data confirms the increased incidence of sever hypersensitivity reactions associated with cetuximab in the Southeastern United States.

The mechanism for the allergic reaction was assessed by Chung and colleagues at Vanderbilt University.⁵ Serum was obtained from two cohorts: 71 pre-treatment samples from patients who subsequently received cetuximab and 69 healthy controls from the Nashville community. Samples were analyzed for total, cetuximab-specific and mouse-specific IgE. Of the 71 patients who received cetuximab, 24 had a hypersensitivity reaction, 21 of which were severe as graded by the CTCAE 3.0. Fifteen patients had cetuximab specific IgE and all 15 experienced a severe hypersensitivity reaction and thus were not re-challenged. Six patients experienced a hypersensitivity reaction, but were cetuximab specific IgE-negative. Four of these patients were rechallenged and tolerated further infusion without incident. Mouse specific IgE was not detected in any samples. Patients with cetuximab specific IgE tended to have higher levels of total IgE. The serum samples from healthy volunteers, were 21.7% (15/69) positive for cetuximab specific IgE. This data suggest that in the Southeastern United States, approximately 20% of patients have a pre-existing cetuximab-specific IgE. The presence of cetuximab-specific IgE is predictive for a severe allergic reaction. Of note, not all allergic reactions appear to be IgE mediated. In those patients without a cetuximab specific IgE, rechallenge may be feasible.

The EGFR pathways are responsible for maintaining skin, hair and nail integrity. When these pathways are blocked, the normal reparative pathways are inhibited. Thus, patients treated with cetuximab manifest skin, hair and nail toxicities. While these toxicities are usually modest and frequently cosmetic in nature, they are unsightly and bothersome to patients. Investigators at the North Central Cancer Group conducted a randomized trial to determine whether tetracycline could prevent or palliate EGFR inhibitor associated acneiform rash.⁶ Sixty-one patients were randomized to tetracycline 500mg po bid x 4 weeks versus placebo. Patients were followed for eight weeks. Outcome measures included: a weekly rash diary, a quality of life questionnaire (SKINDEX-16) and an EGFR inhibitor compliance log. The primary outcome of the study was rash incidence. Thirty patients per arm were needed to detect a 40% difference in the incidence of rash. There was no improvement in rash incidence between the treated arm and placebo(see table1). There was, however a decrease in the severity of rash at week four (see table 2). This benefit was lost by week eight.

Xerostomia

Xerostomia remains one of the most significant acute and late effects of radiation therapy. Although chemotherapy may in and of itself result in modest levels of xerostomia, the xerostomia secondary to radiation is more severe and long lasting.⁷ It occurs shortly after the institution of radiation therapy and results in profound and often permanent damage to salivary function. Data would indicate that salivary loss is related to the dose of radiation delivered to the salivary gland. Thus, investigators have hypothesized that radiation techniques that limit dose to the salivary gland may result in decreased loss of salivary function.

The authors presented data that adds to the growing literature that confirms the ability of IMRT to effectively limit radiation to the salivary gland thereby limiting permanent loss of salivary gland function.⁸ Eligible patients had T2N0-1M0 nasopharyngeal carcinoma. Eighty-four patients were randomized to IMRT or conventional radiation. Twenty-five patients in each arm were asked to participate in a prospective salivary function assessment. Participating patients were tested for whole and stimulated salivary flow at baseline, and 2, 6, and 12 months post treatment. Results demonstrated decrease in salivary flow after completion of treatment with both IMRT and conventional radiation. By 12 months post-treatment, patients treated with IMRT had return of whole and stimulated salivary flow to 26% and 114% of baseline levels respectively. For patients treated with conventional radiation therapy, the 12 month post treatment whole and stimulated salivary flow was 5% and 0% of baseline. The difference was statistically significant at all post treatment time points favoring IMRT.

Mucositis

Mucositis is one of the most devastating acute effects of radiation-based therapy for head and neck cancer. With the increasing use of concurrent chemoradiation, the rates of mucositis have increased dramatically.⁹ Unfortunately, data on the economic impact and clinical consequences of mucositis in the head and neck population are scant. Although clinical trials report the maximum grade toxicity, they do not report key acute effects of mucositis such as treatment delays, hospitalizations and supportive medication utilization.¹⁰ In order to address this deficit, the Multinational Association for Supportive Care in Cancer initiated a prospective study to characterize the clinical and economic effect of mucositis injury. Inclusion criteria included: 1) squamous carcinoma, 2) planned full course radiation with either IMRT or conventional fractionation, and 3) concurrent chemotherapy was allowable. Patients completed the Oral Mucositis Daily Questionnaire from the start of treatment until radiation was completed.¹¹ The OMDQ is a validated measure that assesses mucositis related pain and resulting function loss.

Results were reported for the first 61 patients. As expected, a high percentage of patients experience significant mouth and throat soreness (see Graph 1). Patients with oropharyngeal and oral cavity primaries had worse symptoms than patients with laryngeal or hypopharyngeal primaries, however the difference was not statistically significant (p=0.12). Furthermore, patients with increased levels of pain required increased use of health care resources (see Graph 2).¹²

Graph 1: The graphs depicts the maximium pain score reported by each patient. Scale: 0 - none to 4 – severe. OC=oral cavity, OP=oral phyarynx, L=larynx, HP=hypopharynx, H&N=head and neck total

Graph 2: The graph depicts the effect of mouth and throat soreness on important clinical outcomes. Note that patients with worse mucositis related mouth and throat soreness have worse clinical outcomes.

Growth Factors

Patients with head and neck cancer frequently present with anemia. Numerous studies in head and neck cancer patients have demonstrated that pre-treatment anemia is associated with decreased survival.¹⁰ In addition, patients treated with radiation therapy may develop anemia over the course of therapy. This is most prominent in patients receiving concurrent chemotherapy. Thus, erythroid stimulating agents have been investigated to determine whether they can decrease anemia, decrease transfusions, and most importantly, increase survival. Recently reported studies, including a randomized Phase III trial in head and neck cancer patients, demonstrated a potential adverse impact of aggressive use of erythroid stimulating agents on disease control and survival.¹³ This has resulted in a re-examination of the role of erythroid stimulating agents and further interest in identifying potential mechanisms by which adverse effects might be mediated.

Lo Nigro and colleagues conducted a study in a head and neck cell line (SCCH-N CAL-166) to assess the effect of hypoxia, reoxygenation, and erythropoietin administration on cell survival, and mRNA and protein expression.¹⁴ The results indicated that after a single dose of 10Gy, 1) hypoxia resulted in an increased fraction of surviving cells when compared to normoxia (at 24 hours: 64.7 vs 45.2, p<0.001); 2) erythropoietin did not alter the effect of RT in either hypoxic or nomoxic cells; 3) reoxygenation of cells resulted in reversal of radioresistance; 4) reoxygenation of hypoxic cells treated with erythropoietin did not result in reversal of radioresistance.

Function Preservation

Function preservation is an important goal for patients with laryngeal primaries. The use of radiation with concurrent chemotherapy has demonstrated an increase in organ preservation when compared to radiation as a single modality. Several issues remain to be clarified. Of note, the role of chemoradiation in locally advanced tumors remains unclear. In particular, concern has been expressed that patients with T3 or T4 primaries may have a decrease in local control. Investigators at the Cleveland Clinic conducted a retrospective study of 115 patients treated with concurrent radiation and chemotherapy with 5-FU/cisplatin in order to identify predictors of larynx preservation. Results demonstrated that 83% (96/115) of patients had local control. Of the 19 patients who had persistent or recurrent local disease, 13 underwent successful salvage surgery. Local control with surgery was 93%. Of the 96 patients with local disease control, nine patients were feeding tube or tracheostomy tube dependent. Thus, 75.7% of patients had both anatomic and functional larynx preservation.¹⁵ In a multivariate analysis, age and smoking status predicted for survival; T stage and smoking status predicted for laryngectomy-free survival. Patients with T3-4 primaries had an increased risk for local recurrence, however, the local control without surgery was 75%. For those patients with local recurrence salvage surgery was highly effective.

Conclusion

Several important findings related to the acute and late toxicities of head and neck caner therapy were reported this year at ASCO. First, within the Southeast, cetuximab is associated with a 15-20% hypersensitivity reaction. This reaction is secondary to preexisting cetuximab specific IgE. Efforts are underway to develop a serum test so that patients can be tested prior to treatment to exclude the presence of cetuximab specific IgE. In addition, preliminary data was presented indicating that a multi-agent cetuximab containing concurrent regimen was associated with increased radiation dermatitis. Thus, this potential toxicity bears further scrutiny. A prospective trial was presented which adds to the growing data that IMRT is effective in ameliorating late xerostomia. In addition, data was presented that prospectively assessed the symptom burden and economic cost of mucositis. Investigators demonstrated the high incidence of severe pain associated with mucositis. Furthermore, higher grades of mucositis were associated with marked increase in resource utilization. Finally, investigators conducted a retrospective study to determine predictors of function preservation. Patients with T3 and T4 primaries were at increased risk for recurrence, however, the local control rate without surgery was 75% and salvage surgery for local recurrence was highly effective. The data therefore argues against excluding patients with large primary tumors from a function sparing radiation-based approach.

References

¹ Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. New England Journal of Medicine.2006; 354:567-78.

² Pfister DG, Su YB, Kraus DH, et al. Concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: A pilot phase II study of a new combined-modality paradigm. Journal of Clinical Onlcology. 2006; 24:1072-1078.

³ Merlano MC, Numico G, Russi EG, et al. Cetuximab (C-mab) and chemo-radiation (CT-RT) for loco-regional advanced squamous cell carcinoma of the head and neck (HNC): A phase II study. Proceeding from the American Society of Clinical Oncology Conference. Chicago, IL. 2007. Abstract # 6043.

⁴ Allen RM, Goldberg RM, Berlin J, et. Al. Unusually high rates of hypersensitivity to cetuximab in the middle-southern United States: Association with atopic phenotype. Proceedings from American Society of Clinical Oncology Conference. Chicago, IL. 2007. Abstract # 9051.

⁵ Chung CH, Chan E, Berlin J, et al. Cetuximab-related hypersensitivity reactions associated with pre-existing cetuximab-specific IgE antibody. Proceedings from American Society of Clinical Oncology Conference. Chicago, IL. 2007. Abstract # 9097.

⁶ Jatoi A, Rowland Jr K, Sloan JA, et al. Does tetracycline prevent or palliate epidermal growth factor receptor (EGFR) Inhibitor-induced skin rash? Results of a phase III trial from the North Central Cancer Treatment Group (NO3CB). Proceedings from the American Society of Clinical Oncology Conference. Chicago, IL. 2007. LBA # 9006.

⁷ Chambers MS, Garden AS, Kies MS, Martin JW: Radiation-induced xerostomia in patients with head and neck cancer: pathogenesis, impact on quality of life, and managment. Head Neck. 2004; 26:796.

⁸ Kwong DL, McMilan A, Pow E, et al. Value of intensity modulated radiotherapy for local control and salivary flow compared with conventional radiotherapy for stage II nasopharyngeal carcinoma. Proceedings from the American Society of Clinical Oncology Conference. Chicago, IL. 2007. Abstract # 6036.

⁹ 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. Radiotherapy Oncology. 2003; 66:253-262.

¹⁰ Trotti A: Toxicity in head and neck cancer: a review of trends and issues. International Journal of Radiation Oncology, Biology, and Physics. 2000; 47:1-12.

¹¹ Epstein JB, Beaumont JL, Gwene CK, et al. Evaluation of the Oral Mucositis Weekly Questionnaire - Head and Neck Cancer, A Patient Reported Outcome Questionnaire. Cancer. 2006; 109: 914-1922.

¹² Keefe DM, Garden A, Barasch A, et al. Brigham and Women’s Hospital, Boston, MA; Oral mucostitis is associated with increased resource use among patients receivng treatment for cancers of the hear and neck. Proceedings from the American Society of Clinical Oncology Conference. Chicago, IL. Abstract # 6070.

¹³ Henke M, Laszig R, Rube C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: Randomised, double-blind, placebo-controlled trial. Lancet. 2003; 326.

¹⁴ Lo Nigro C, Maffi M, Fischel J, et al. Impact of erythropoietin (EPO) on irradiation effect on the EPO receptor-positive head and neck cancer. Proceedings from the American Society of Clinical Oncology Conference. Chicago, IL. Abstract # 6058.

¹⁵ Rodrijuiz CP, Adelstein DJ, Rybicki L, et al. Clinical predictors of larynx preservation (LP) after multiagent concurrent chemoradiotherapy. (MCCRT). Proceedings from the American Society of Clinical Oncology Conference. Chicago, IL. 2007. Abstract # 6075.