Indian Journal of Cancer Medknow Publications on behalf of Indian Cancer Society ISSN: 0019-509X EISSN: 1998-4774 Vol. 48, Num. 2, 2011, pp. 148-153

Indian Journal of Cancer, Vol. 48, No. 2, April-June, 2011, pp. 148-153

Mini Symposium

Cetuximab with radiotherapy in patients with loco-regionally advanced squamous cell carcinoma of head and neck unsuitable or ineligible for concurrent platinum-based chemo-radiotherapy: Ready for routine clinical practice?

JP Agarwal¹, T Gupta¹, N Kalyani¹, A Budrukkar¹, SG Laskar¹, V Murthy¹, P Kumar², V Narohna², P Pai³, P Chaturvedi³, AK D«SQ»cruz³

¹ Department of Radiation Oncology, Tata Memorial Hospital, Ernest Borges Marg, Parel, Mumbai, India
² Department of Medical Oncology, Tata Memorial Hospital, Ernest Borges Marg, Parel, Mumbai, India
³ Department of Surgical Oncology, Tata Memorial Hospital, Ernest Borges Marg, Parel, Mumbai, India

Correspondence Address: J P Agarwal Department of Radiation Oncology, Tata Memorial Hospital, Ernest Borges Marg, Parel, Mumbai India agarwaljp@tmc.gov.in

Code Number: cn11040

DOI: 10.4103/0019-509X.82872

Abstract

Keywords: Cetuximab, chemo-radiotherapy, cisplatin, cost-effectiveness, loco-regionally advanced squamous cell carcinoma of the head and neck

Introduction

Loco-regionally advanced squamous cell carcinoma of the head and neck (LASCCHN) is a leading cause of cancer morbidity and mortality in developing countries including India. ^[1] Radical surgery followed by post-operative adjuvant radiotherapy (RT) has traditionally been considered the treatment of choice for loco-regionally advanced disease. ^[2] Recent evidence supports the use of adjuvant chemo-radiotherapy for high-risk resected squamous cell cancers of the head and neck. ^[3] With current emphasis on organ and function preservation, definitive concurrent chemo-radiotherapy has emerged as the contemporary standard of care in the non-surgical management of LASCCHN, ^[4],[5] particularly those involving the larynx and pharynx. The most commonly used chemotherapeutic agent with RT for LASCCHN has been cisplatin, that has shown to be efficacious, ^[5] but can be associated with considerable acute and late toxicity, ^[6] particularly in a high-dose regimen. A small but significant proportion of the LASCCHN population such as those with impaired renal function, older age, poor performance status, and co-existent co-morbidities are unsuitable candidates for concurrent platinum-based chemotherapy and are offered RT alone, with suboptimal outcomes. Exploratory subgroup analysis from a large meta-analysis ^[5] has demonstrated decreasing benefit of concurrent chemotherapy for elderly patients (>70 years). Thus there is a real need to find out effective alternatives to cisplatin that can be safely combined with RT in this subgroup to improve outcomes.

Epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, is abnormally activated in several epithelial cancers, ^[7] including head and neck cancers ^[8] with high levels of expression being associated with poor clinical outcomes. ^[9],[10] Exposure to ionizing radiation increases the expression of EGFR in cancer cells; and blockade of EGFR signalling potentially sensitizes these cells to the effects of radiation, ^[11],[12] thus representing an attractive alternative strategy to offer higher therapeutic ratio compared to RT alone. Cetuximab (CMAB) is a chimeric monoclonal antibody that exclusively targets EGFR with high affinity, inhibiting endogenous ligand binding with resultant blockade of receptor dimerization, tyrosine kinase phosphorylation, and signal transduction. Recently, Bonner et al, ^[13],[14] have shown that the addition of cetuximab (CMAB) to RT significantly improves loco-regional control and survival, without consequent increase in major morbidity compared to RT alone. However, its value compared with concurrent high-dose cisplatin remains largely unknown. The present analysis is a clinical audit and chart review of patients with LASCCHN ineligible for platinum-based concurrent chemo-radiotherapy planned and treated with CMAB-RT in an academic radiotherapy unit at a tertiary-care comprehensive cancer centre in India.

Materials and Methods

All patients referred for primary definitive or post-operative adjuvant radiotherapy are registered in a prospective head-neck cancer database maintained in an academic radiotherapy unit at the institute. Patients with LASCCHN planned for curative intent treatment but unsuitable or ineligible for platinum-based concurrent chemo-radiotherapy based on decision-making in a multi-disciplinary head-neck cancer joint clinic were considered eligible for inclusion, provided they were treated with CMAB concurrent with RT. Tumor extent was evaluated by physical examination, examination under anaesthesia whenever necessary, and appropriate imaging. Disease was staged as per the American Joint Committee on Cancer (AJCC) 2002 staging system. Patients treated with palliative intent or for loco-regionally recurrent or metastatic disease were excluded from the study cohort. Relevant data was extracted from the database and medical case records to determine the compliance, toxicity, and efficacy of CMAB-RT in this study cohort.

The planned study regimen consisted of a loading dose of CMAB (400 mg/m2) given as an intravenous infusion along with diphenhydramine prophylaxis 4-7 days prior to initiation of RT, and then once weekly (250 mg/m2) concurrently throughout the course of conventionally fractionated (200 cGy/fraction, 5 fractions/week) radiotherapy. RT was planned and delivered with conventional portals with shrinking fields or simple three-dimensional conformal radiotherapy (3D-CRT) on megavoltage equipment (either telecobalt or 6 MV photons on a linear accelerator). Patients were monitored during CMAB infusion for any infusion reactions and reviewed at least once weekly during the course of RT for documenting acute toxicity. Acute toxicity was graded as per the Common Terminology Criteria for Adverse Events version 3 (CTCAE v3.0). Patients were initially reviewed at 6-8 weeks from completion of CMAB-RT for documenting response. Subsequently patients were followed up at 3-monthly intervals for the first 2 years and 6-monthly intervals thereafter. Outcome measures for efficacy included response rates, loco-regional control and survival. Loco-regional failure was defined as persistence of disease or reappearance of disease either at the primary site and/or draining regional lymph nodes. Recurrence was defined as re-appearance of disease at either the primary, regional or distant site. The loco-regional control, disease-free survival, and overall survival were calculated using the product-limit method of Kaplan-Meier. All estimates were calculated from the date of initiation of therapy till the defined event if any or until last contact or death. The data was compared using the log-rank test. All analysis was done on SPSS version 16.0

Results

Patient characteristics

Between 2005 to 2009, 37 patients were planned and treated with CMAB-RT and constitute the study cohort. Pre-treatment patient characteristics are depicted in [Table - 1]. The median age of the cohort was 59 years (range 35-87 years) and their median Karnofsky score was 80 (range 70-90). Twenty seven (73%) patients had history of tobacco consumption. Primary sites included oropharynx (n=19), oral cavity (n=10), and others (n=8). Thirty (81%) patients were treated with primary definitive RT, while 7 (19%) patients (all with oral cancers) were treated in the post-operative adjuvant setting. Reasons for being unsuitable or ineligible for concurrent cisplatin-based chemo-radiotherapy included impaired renal function (n=22), old age (n=8) and major co-morbidities (n=9) either alone or in combination. No patient had received prior systemic chemotherapy or biological therapy.

Compliance to therapy

The median external beam radiation dose for the study cohort was 66 Gy (range 40-70Gy), 67 Gy in definitive RT group (n=30) and 60 Gy in the adjuvant RT group (n=7). The median overall treatment time for RT was 44 days (range 21-71 days), 46 days for definitive RT (n=30) and 42 days for adjuvant RT (n=7). Thirty two patients (86%) completed the planned course of RT without any interruption. Reasons for interruption were severe skin or mucosal toxicity (n=4) and social reasons (n=1). Radiotherapy dose was compromised in 2 patients due to severe acute dermatitis. Twenty nine patients (80%) received 6 or more cycles of CMAB. CMAB was stopped early in 6 patients (17%) due to severe skin or mucosal toxicity. None of the patients experienced any anaphylactic reactions with CMAB. Fifteen (40.5%) developed acute grade 3 dermatitis while 9 patients (25%) developed acute grade 3 mucositis during the CMAB-RT regimen. Acute skin toxicity resolved completely without obvious scarring in all patients at first follow-up 6-8 weeks after completion of therapy. Acute mucositis also subsided at first follow up in all patients. There were no significant differences in skin or mucosal toxicity between patients treated with primary definitive RT or in the post-operative adjuvant setting.

Outcome analysis

At first follow-up, done 6-8 weeks post completion of treatment, 14 (47%) of 30 patients treated with primary definitive RT had a complete response (complete disappearance of all measurable loco-regional disease), 15 (50%) partial response (>50% regression) and 1 (3%) stable residual disease on conventional assessment. Amongst node positive patients treated with primary definitive RT (n=19), 7 patients had complete response, while 12 patients had partial response. The median follow-up of the entire cohort was 16 months (inter-quartile range 12-23 months). For the entire cohort of 37 patients, 2-year loco-regional control was 35.5% after initial primary treatment [Figure - 1]a. Seven patients underwent salvage surgery while one patient received curative re-irradiation. The ultimate loco-regional control after salvage therapy was 40.7% at 2 years. The 2-year Kaplan-Meier estimate of disease-free survival [Figure - 1]b and overall survival [Figure - 1]c was 29.5% and 44.4% respectively.

AJCC stage grouping was a significant predictor of all the outcome measures of efficacy on univariate analysis [Table - 2]. The 2-year loco-regional control (56.3% vs 19%, P=0.01), disease-free survival (45% vs 17.9%, P=0.01) and overall survival (57.9% vs 20.6%, P=0.005) was significantly better for patients with stage II-III as compared to stage IV disease. Severe acute dermatitis also predicted for better outcomes. Patients developing grade 3 or worse skin reactions had significantly better loco-regional control (51.4% vs 24.2%, P=0.02) and disease-free survival (38.6% vs 22.7%, P=0.02), with a trend towards improved overall survival (68.6% vs 27.3%, P=0.152), compared to patients with milder skin toxicity. Age, site of primary, nodal status, performance status, or treatment parameters did not impact upon outcome.

Discussion

Cetuximab concurrently with radiotherapy is now considered a reasonable therapeutic option in patients with LASCCHN unsuitable or ineligible for systemic chemotherapy. In a landmark study, Bonner et al, ^[13] reported that the addition of CMAB to RT significantly improved loco-regional control (34% vs 47%, HR: 0.68, 95%CI: 0.52-0.89; P=0.005) and overall survival (45% vs 55%, HR: 0.74, 95%CI: 0.57-0.97; P=0.03) at 3-years as compared to RT alone with no appreciable increase in severe acute toxicity, excepting acne form rash and infusional reactions. Long-term results ^[14] corroborated these earlier findings with a 9% difference in absolute survival at 5-years in favor of CMAB-RT (36.4% vs 45.6%, HR: 0.73, 95%CI: 0.56-0.95; P=0.18). More interestingly, in patients receiving CMAB, development of prominent acne form rash (grade II or worse) was associated with improved overall survival (HR: 0.49, 95%CI: 0.34-0.72; P=0.002) compared to mild (grade I) or no rash. Subgroup analysis showed increased benefit of CMAB in patients with oropharyngeal tumors, early T-status, altered fractionation radiotherapy, better KPS, male gender, and age <65 years. This suggests that the benefit of CMAB may be limited in older, unfit patients, the very population for which CMAB is recommended instead of cisplatin.

This is perhaps the first report on the safety and efficacy of CMAB concurrently with RT in LASCCHN from a developing country in a negatively selected cohort of patients (with impaired renal function, old age, or major co-morbidities), data on which is rather limited. Compliance to planned treatment was good and comparable to previously published data, despite a high rate (39%) of in-field grade 3 cutaneous toxicity. It is quite possible that severe acute dermatitis (≥ grade 3) was relatively under-reported in Bonner′s study (23%), as later reports ^[15],[16] across the world have consistently shown this figure to be around 50% (ranging from 35-70%). The high incidence of such toxicity and its resultant impact on quality-of-life has prompted development of guidelines for diagnosing and treating such toxicity. ^[16] The probable association of rash with improved survival has been a subject of intense discussion, debate, and controversy. ^[17],[18]

Whether CMAB can replace cisplatin in the LASCCHN is an unanswered question, as both have not been directly compared head-to-head in a randomized controlled trial. In a retrospective analysis, Koutcher et al, ^[19] indirectly compared patients treated with cisplatin-RT (n=125) and CMAB-RT (n=49). There were significant differences in patient selection, with patients in the CMAB-RT group being significantly older with worse renal function. At a median follow-up of 22.5 months, the 2-year failure-free survival (87.4 vs 44.5%; P=0.0001) and overall survival (92.8 vs 66.6%; P=0.0003) favoured the cisplatin-RT arm. On multivariate analysis treatment with cisplatin-RT predicted for improved loco-regional control (P=0.0001) and survival (P=0.01). Interestingly there was no difference in severe late toxicity between the two regimens. An ongoing European multicentre phase II ^[20] study is currently randomizing patients with LASCCHN to radical definitive radiotherapy with either concurrent weekly cisplatin (40mg/m ² ) or CMAB (400mg/m ² loading dose followed by 250mg/m ² /week) using compliance, acute toxicity, loco-regional control, and survival as endpoints.

The role of CMAB in addition to concurrent chemo-radiotherapy also needs to be better defined. A previous phase II study ^[21] had to be stopped early due to severe adverse events, despite encouraging 3-year efficacy outcomes. A more recent study ^[22] combining weekly CMAB with rapidly alternating split-course chemo-radiotherapy (cisplatin-fluorouracil) demonstrated a very high rate of complete response, but unacceptably high incidence of severe acute dermatitis. The Radiation Therapy Oncology Group (RTOG) has recently completed accrual on a large randomized trial ^[23] comparing concurrent cisplatin-based chemo-radiotherapy to the same regimen plus CMAB in patients with LASCCHN, which should provide a definitive answer.

The current cost of CMAB is prohibitively high, making it largely unaffordable and unfeasible in the vast majority of patients in developing economies like India. The incremental cost-effectiveness ratio of CMAB plus RT is £6390 per additional quality-adjusted life-year (QALY) gained compared to RT alone in the treatment of LASCCHN. ^[24] Whether this is acceptable to an individual in particular and the society at large is generally a value-judgement based on several socio-economic-cultural considerations.

Conclusions

Concurrent CMAB with radiotherapy is a reasonable alternative in patients with LASCCHN ineligible for platinum-based chemotherapy with good compliance and acceptable short-term loco-regional control and survival. It however results in higher acute skin toxicity that can interfere with optimal delivery of planned radiotherapy. The value of this regimen compared to cisplatin based regimens remains largely unknown. Although efficacious, the prohibitively high cost of CMAB may preclude its use in routine clinical practice especially in low-resource setting in developing economies.

Summary

• Bonner′s randomised trial has established benefit of concurrent Cetuximab and radiotherapy in locally advanced head and neck cancer. However one of the major critiques of this landmark trial was that it included patients who were also eligible for platinum based chemotherapy which is the standard of care and cisplatinum was not offered to these patients.
• The data in literature is lacking regarding use of Cetuximab in patients who are ineligible for platinum based concurrent chemotherapy
• This study outlines use of concurrent Cetuximab in patients ineligible for platinum based chemotherapy in locally advanced head and neck cancer.

References

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