|Year : 2018 | Volume
| Issue : 2 | Page : 97-100
Prolonged survival with anti-epidermal growth factor receptor therapy in head and neck squamous cell carcinoma: A case series
Pratik Patil, Vineet G Gupta, Ranga R Rangaraju, Waseem Abbas, Peush Bajpai
Department of Medical Oncology, Max Super Speciality Hospital, Shalimar Bagh, New Delhi, India
|Date of Web Publication||31-Dec-2018|
Vineet G Gupta
Department of Medical Oncology, B-2 Basement, Max Super Speciality Hospital, Shalimar Bagh, New Delhi
Source of Support: None, Conflict of Interest: None
Head and neck cancer (HNC) is the sixth most common cancer worldwide, with approximately 650,000 patients newly diagnosed annually. In the late 1990s, surgery followed by postoperative radiotherapy (RT) or RT alone was the standard therapeutic modality for locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC). As chemotherapeutic agents were identified to have additional effects when combined with RT, chemoradiotherapy has become the standard treatment over the last decade for patients with LA-HNSCC who were not candidates for surgery. Despite the heterogeneity of both tumor location and genetic aberrations, 90% of HNCs are histologically squamous cell carcinomas. Hereby, we present a case series of patients with HNSCC who were benefited with anti-epidermal growth factor receptor therapy with a prolonged survival.
Keywords: Chemoradiotherapy, head and neck cancer, head and neck squamous cell carcinoma, radiotherapy
|How to cite this article:|
Patil P, Gupta VG, Rangaraju RR, Abbas W, Bajpai P. Prolonged survival with anti-epidermal growth factor receptor therapy in head and neck squamous cell carcinoma: A case series. J Curr Oncol 2018;1:97-100
|How to cite this URL:|
Patil P, Gupta VG, Rangaraju RR, Abbas W, Bajpai P. Prolonged survival with anti-epidermal growth factor receptor therapy in head and neck squamous cell carcinoma: A case series. J Curr Oncol [serial online] 2018 [cited 2019 Mar 20];1:97-100. Available from: http://www.journalofcurrentoncology.org/text.asp?2018/1/2/97/249059
| Introduction|| |
Head and neck cancer (HNC) is the sixth most common cancer worldwide, with approximately 650,000 patients newly diagnosed annually. In the late 1990s, surgery followed by postoperative radiotherapy (RT) or RT alone was the standard therapeutic modality for locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC). As chemotherapeutic agents were identified to have additional effects when combined with radiation therapy, combined chemoradiotherapy (CRT) has become the standard treatment over the last decade for patients with LA-HNSCC who were not candidates for surgery. Clinical trials have shown that combined chemoradiation therapy can improve overall survival (OS) compared with RT alone. Despite the heterogeneity of both tumor location and genetic aberrations, 90% of HNCs are histologically squamous cell carcinomas (HNSCCs). At the time of diagnosis, most patients with HNSCC have locoregionally advanced disease, which requires a multimodality therapy.
The epidermal growth factor receptor (EGFR) is expressed in approximately 80% of patients with HNSCC. EGFR overexpression has been found to be an independent factor associated with unfavorable prognosis in these patients. Anti-EGFR agents can block the EGFRs, thereby inhibiting its downstream function, whereas radiation increases EGFR expression in cancer cells, blockade of EGFR signaling makes cancer cells more sensitive to radiation. As a randomized phase III trial showed survival benefit from the combination of cetuximab and RT compared with RT alone, trials have further evaluated other agents such as panitumumab, which are similar to cetuximab and also some other agents in the concurrent setting. The good results in concurrent setting also led to trials evaluating the addition of targeted therapy along with chemotherapy and RT.
| Case Report|| |
A 32-year-old man who consumed moderate amounts of alcohol, since the last 10 years of his life, presented with chief complaints of pain in the left ear and minimal discharge with decreased hearing from left ear since the last 2 months. Biopsy of external auditory canal was suggestive of squamous cell carcinoma. Whole body positron emission tomography–computed tomography (PET-CT) scan showed hypermetabolic active disease at the site of known primary (left external auditory canal). He underwent wide local excision of left external auditory canal mass with left extended parotidectomy. On histopathological examination, all margins were found to be free; overall features were in favor of squamous cell carcinoma left external ear pT2N0M0. On immunohistochemistry (IHC), tumor cells were creatinine kinase +5/6, p63+, epithelial membrane antigen +, carcinoembryonic antigen, polyclonal, and focal positive. He underwent radiation therapy to left external auditory canal and posterior mastoid at a dose of palnning target volume (PTV) 45:4500 cGy in 25 fractions + PTV 60:6000 cGy in 30 fractions. Follow-up scans revealed a complete response until 36 months after the RT, followed by progression with multiple lung metastasis with meditational lymph node metastasis. CT-guided right lung mass biopsy suggested squamous cell carcinoma. This patient was started on carboplatin with paclitaxel for six cycles, showing a stable disease. Following which, he was started on gefitinib (250mg) as a maintenance regimen, which had a very good response without any progression till date with a progression free survival of 16 months.
A 48-year-old patient who was a known hypertensive since the last 7 years and on treatment with no history of any addictions presented with the chief complaint of ulcer over the left margin of tongue since 1 month. Magnetic resonance imaging (MRI) of neck and tongue was suggestive of enhancing lesion in left lateral border with enlarged lymph nodes. Histopathological evaluation revealed well-differentiated squamous cell carcinoma, left lateral border of tongue infiltrating muscle, and nodes: negative, T2N0M0. He underwent wide excision glossectomy. On frozen section, all the borders were free of tumor cells. Postoperative glossectomy after 3 months, the patient started complaining of pain in the left side of the face and ear though local examination was within normal limits. Pain started increasing over left side of face, submental region, experiencing difficulty in chewing. Whole body PET-CT showed metabolically active large heterogeneously enhancing soft tissue seen involving the floor of the mouth, extending along the left tonsillo-linguinal sulcus into the left tonsil fossa involving the left valleculla and causing erosion of the left half of the hyoid bone and was suggestive of disease recurrence. The patient received three cycles of chemotherapy with cetuximab + abraxane + carboplatin, which showed a partial response on a follow-up scan, followed by external beam radiation therapy (EBRT) by image-guided radiotherapy technique to head and neck followed by evidence of disease progression. He was then started with maintenance therapy on cetuximab for 112 weeks with intermediate scans suggestive of near complete response and a stable disease till date making a progression free survival (PFS) of 23 months.
A 47-year-old man with no known comorbidities and no addictions presented with complaints of difficulty in swallowing and change in the voice since last 2 months. Examination revealed edema in the left aryepiglottic fold with decreased movements of the left vocal cord. CT of neck revealed a mass in the left pyriform sinus, involving left aryepiglottic fold and false cord. Enlarged lymph nodes were observed in left upper mid and lower deep cervical regions. Fine needle aspiration cytology of neck nodes was positive for malignant cells. He received CRT to his face and neck with cisplatin. Whole body PET-CT revealed metabolically active residual disease in the left pyriform fossa with metabolically active lymphadenopathy. He received three cycles of chemotherapy with paclitaxel and cisplatin with tablet gefitinib (250mg). Whole body PET-CT showed no metabolically active residual/ recurrent disease suggesting excellent response to chemotherapy.
After 5 years, the disease recurred, for which he underwent excision biopsy from the disease site (left vocal cord), which revealed invasive moderately differentiated keratinizing squamous cell carcinoma with clear resection margins. He was started on mitotax and carboplatin, followed by EBRT by three-dimensional conformal radiotherapy technique to head and neck with concurrent cisplatin. Two months post-CRT, MRI of neck with contrast revealed postoperative changes with homogenously enhancing mass involving the right half of tongue, crossing the midline toward left side and contiguously infiltrating the floor of mouth with involvement of the body of mandible anteriorly. MRI of brain was normal. After this, the patient was started on gemcitabine and carboplatin, which gave a complete response. After eight cycles of chemotherapy, MRI of neck revealed disease recurrence. Then the patient was started on gefitinib (250mg, od), achieving partial response with a stable disease on interval scans till date, making a PFS of 22 months.
| Discussion|| |
Activation of the proto-oncogene EGFR is an early event in head and neck carcinogenesis. EGFR micro-ribonucleic acid is highly expressed in HNSCC and contributes to the pathogenesis of this disease. High levels of EGFR protein expression, as detected by IHC, have been seen in up to 90% of head and neck squamoud cell carcinoma (HNSCC) tumors and are associated with poor prognosis. The loss of growth control in HNSCC is characterized by acquisition of an autocrine regulatory pathway involving the EGFR. The primary rationale for the design of EGFR-targeting strategies has been based on the increased EGFR expression levels detected on tumor cells, although evidence suggests that constitutive EGFR activation can occur in the absence of increased expression. In addition to the importance of EGFR expression in human HNSCC, many studies have reported antitumor effects when EGFR-targeting strategies were used in preclinical HNSCC models.
EGFR inhibitors have been shown to abrogate the growth of HNSCC cell lines and xenografts when administered alone or in combination with standard therapy such as chemotherapy and/or radiation. The EGFR monoclonal antibody cetuximab has been combined with cisplatin in patients with platinum-refractory HNSCC in a phase III trial supported by the Eastern Cooperative Oncology Group that showed enhanced response rates when subjects received the combined treatment regimen (median PFS was 2.7 months for combined arm and 4.2 months for placebo). The hazard ratio for progression of combined arm to placebo was 0.78 (95% confidence interval [CI], 0.54–1.12). Median OS was 8.0 months for combined arm and 9.2 months for placebo arm (P = 0.21). The hazard ratio for survival by skin toxicity in cetuximab-treated patients was 0.42 (95% CI, 0.21–0.86). Objective response rate was 26% for combined arm and 10% for placebo arm (P = 0.03). Enhancement of response was greater for patients with EGFR staining present in less than 80% of cells. The Food and Drug Administration approved the use of cetuximab for HNSCC in 2006 based on the results of a phase III trial showing prolonged survival when cetuximab was administered in conjunction with radiation. This was the first phase III trial to show a survival advantage using a molecular targeting agent combined with radiation. In addition, the combination of radiation and cetuximab did not significantly increase the toxicity profile or compromise the effective delivery of full course EBRT. It is noteworthy that cetuximab was the first new drug approved for use in this cancer in 45 years. Although the combination of cetuximab and radiation increased survival compared with radiation alone, cetuximab did not reduce the incidence of distant metastases nor did it completely prevent local-regional failure. These facts indicate the persistence of oncogenic signaling pathways.
Bonner et al. reported improved locoregional disease control, PFS, and OS with the addition of cetuximab to radiation in patients with locally advanced HNSCC. Chemoradiation is currently considered optimal therapy for this group of patients. However, concurrent chemotherapy is not only associated with additional adverse effects such as nausea, vomiting, and neutropenia but also with severe oropharyngeal mucositis in more than 50% of patients. This latter adverse event represents a serious challenge to quality of life costs and management in these patients. A large meta-analysis of individual patient data has also reported that concurrent chemotherapy is not associated with an improvement in OS in patients over the age of 70 years. It is unclear whether this lack of efficacy is a result of one or some combination of reduced efficacy of treatment, increased mortality of treatment, and effects of competing risks. The addition of cetuximab to radiation was not associated with chemotherapy-specific toxicities or an increase in the frequency of severe mucositis beyond that seen with radiation alone. The most common and significant effect was skin rash, which occurred in 87% of patients. The rash was severe in 17% of patients. Acute infusion reactions also occurred in 3% of patients. Overall quality of life was neither improved nor diminished by the addition of cetuximab to radiation.
EGFR-specific tyrosine kinase inhibitors such as erlotinib have also been explored as antitumor agents in HNSCC, although phase III data are lacking. Several ongoing US and international clinical trials are exploring the combination of CRT with EGFR targeting as a curative treatment strategy. Also, the response rates and survival times of patients who received gefitinib as a first-line therapy were not significantly different to those of patients who had received prior chemotherapy. Overall, the median time to progression and death were 3.4 and 8.1 months, respectively, with an estimated 1-year survival of 29%. These results were more favorable than those achieved with chemotherapy in this setting but with the additional benefit of reduced treatment-related toxicity. There was only a single case of grade 4 toxicity (hypercalcemia), a 4%–6% incidence of grade 3 toxicity (anorexia, diarrhea, nausea, and hypercalcemia), grade 1 or 2 skin rash in 48%, and grade 1 or 2 diarrhea in 50%.
Other questions that remain to be answered include the timing of radiation or chemotherapy delivery with EGFR-targeted therapies and the role of other targets, in addition to EGFR. To date, no evidence of an association between human papilloma virus status of the tumor and response to EGFR targeting is available. An improved understanding of EGFR-signaling interactions with other oncogenic pathways should facilitate the design of more effective targeting strategies by elucidating the critical proliferative and survival pathways that persist in the setting of EGFR blockade.
| Conclusion|| |
In conclusion, this case series shows that the addition of an anti-EGFR agent to conventional RT or CRT does improve the clinical outcomes compared with CRT in patients with HNSCC. These results indicate that anti-EGFR agents prolong the survival and clinical course of patients with HNSCC, though advanced studies on EGFR-signaling interactions with other oncogenic pathways are required for better study of these agents and its clinical application.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2015;1:E359-86. doi: 10.1002/ijc.29210. Epub 2014 Oct 9.
Pignon JP, le Maître A, Maillard E, Bourhis J, MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009;92:4-14.
Mohanti BK, Nachiappan P, Pandey RM, Sharma A, Bahadur S, Thakar A. Analysis of 2167 head and neck cancer patients’ management, treatment compliance and outcomes from a regional cancer centre, Delhi, India. J Laryngol Otol 2007;121:49-56.
Iberri DJ, Colevas AD. Balancing safety and efficacy of epidermal growth factor receptor inhibitors in patients with squamous cell carcinoma of the head and neck. Oncologist 2015;20:1393-403.
Zimmermann M, Zouhair A, Azria D, Ozsahin M. The epidermal growth factor receptor (EGFR) in head and neck cancer: Its role and treatment implications. Radiat Oncol 2006;1:11.
Liang K, Ang KK, Milas L, Hunter N, Fan Z. The epidermal growth factor receptor mediates radioresistance. Int J Radiat Oncol Biol Phys 2003;57:246-54.
Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al
. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:567-78.
Soulieres D, Senzer NN, Vokes EE, Hidalgo M, Agarwala SS, Siu LL. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol 2004;22:77-85.
Chung CH, Wang SJ, Chang YC, Wu SS. Reconstruction of the coronoid process with iliac crest bone graft in complex fracture-dislocation of elbow. Arch Orthop Trauma Surg 2007;127: 33-7.
Grandis JR, Chakraborty A, Zeng Q, Melhem MF, Tweardy DJ. Downmodulation of TGF-alpha protein expression with antisense oligonucleotides inhibits proliferation of head and neck squamous carcinoma but not normal mucosal epithelial cells. J Cell Biochem 1998;69:55-62.
Lui VW. EGFR-mediated cell cycle regulation. Grandis JR Anticancer Res 2002;22:1-11.
Thomas SM, Grandis JR. Pharmacokinetic and pharmacodynamic properties of EGFR inhibitors under clinical investigation. Cancer Treat Rev 2004;30:255-68.
Huang SM, Bock JM, Harari PM. Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res 1999;59:1935-40.
Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA; Eastern Cooperative Oncology Group. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: An Eastern Cooperative Oncology Group study. J Clin Oncol 2005;23:8646-54.
Cohen EE, Rosen F, Stadler WM, Recant W, Stenson K, Huo D, et al
. Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2003;21:1980-7.