Locoregional recurrences are a major source of morbidity and mortality for patients with squamous cell carcinomas of the head and neck (HNSCC). This article examines the multidisciplinary care of a patient with recurrent human papillomavirus (HPV)-positive squamous cell carcinoma of the tonsil.
Case Presentation
Case history
DR. DANIEL BOWLES: The patient was a 46-year-old man who presented to the University of Colorado Cancer Center (UCCC) for evaluation and treatment of a locoregionally recurrent squamous cell carcinoma (SCC) of the left tonsil. SCC was originally diagnosed one year earlier when a left tonsil mass was biopsied and determined to be a poorly differentiated HPV-positive SCC. The patient was a lifelong nonsmoker and drank alcohol(Drug information on alcohol) rarely. He chose surgery as his primary modality of care and underwent a tonsillectomy and left neck dissection. His primary mass was 3.1 cm x 2.5 cm x 1.3 cm, and 1 of 20 level 2A lymph nodes was positive, with a maximal dimension of 3.5 cm. His cancer was stage IVA (T2 N2a M0) based on the histology and a PET/CT scan that did not show evidence of metastatic disease. Surgical margins were negative, but he had evidence of both angiolymphatic and perineural invasion. Fluorescence in situ hybridization (FISH) was positive for high-risk HPV. He received adjuvant external beam radiation to 60 Gy to the primary tumor site and 54 Gy to the bilateral neck. He did not receive a systemic sensitizing agent. A PET/CT scan 2 months after the completion of adjuvant radiation showed no evidence of disease. However, a PET/CT scan 3 months later revealed a hypermetabolic lesion in the oropharynx within the surgical bed and radiation field. He underwent a salvage oropharyngeal resection with mandibular swing and left radial forearm flap placement. He was again found to have SCC, with an ulcerative mass 2.5 cm in size involving the submucosa and skeletal muscle. Perineural invasion was observed once again. Just 3 months following his salvage surgery he began to experience weight loss, dysphagia, and voice changes. Another PET/CT scan revealed a hypermetabolic mass in the left retropharyngeal/parapharyngeal region. At this time he established care at UCCC to investigate other treatment options.
Radiology review
PET/CT Images of the Second Relapse in a Patient With a Stage IVA HPV-Positive Squamous Cell Carcinoma of the Head and NeckDR. BOWLES: Dr. Ree, can you comment on the PET/CT scan at the time of the patient’s second relapse?
DR. ALEXANDER REE: There is asymmetric soft tissue fullness and metabolic activity at the skull base in the lateral retropharyngeal space that obliterates portions of the left longus capitis, the medial pterygoid muscle, and the posterior belly of the digastric muscle (Figure 1). There is abnormal fullness of the submandibular space, the hypopharynx, and the inferior aspect of the left nasopharynx, which results in asymmetric effacement of the overlying left fossa of Rosenmüller. There is no evidence of cortical disruption of the mandible or hyoid bone, or of erosions of the thyroid cartilage. Both the soft tissue fullness and abnormal PET activity extend into the region of the left tonsillar surgical bed.
Discussion
Initial therapy
DR. BOWLES: I think we should start our conversation by discussing the patient’s initial treatment. The comprehensive treatment plan for a patient with a stage IVA HNSCC requires input from head and neck surgery, radiation oncology, and medical oncology. Dr. Wine, could you please describe the role of surgery in the upfront management of this patient?
DR. TODD WINE: While it may not be possible to adequately address it in this forum, the role of upfront surgical resection for advanced oropharyngeal cancer is an important topic. Recently, there has been a resurgence of interest in the surgical management of oropharyngeal primary tumors that has been driven by the improved functional outcomes of transoral microsurgery and the late toxicities of chemoradiation. Numerous studies support oropharyngeal surgery with adjuvant treatment as an oncologically sound alternative to chemoradiation.[1,2] Unfortunately, there has not been a randomized controlled trial comparing the efficacy of chemoradiation to that of open or transoral oropharyngeal surgery with postoperative radiotherapy.
This patient had a stage IVA (T2 N2a M0) oropharyngeal cancer. While most advanced oropharyngeal cancers are treated with chemoradiation,[3] transoral resection and neck dissection with postoperative adjuvant therapy is a reasonable and accepted alternative to definitive chemoradiation. Of course, further randomized controlled comparisons of oncologic and functional outcomes of surgical and nonsurgical techniques in advanced oropharyngeal cancer are necessary before a more definitive conclusion can be reached.
DR. KRISHNA REDDY: Can you discuss the radiation therapy (RT) this patient received in the adjuvant setting?
DR. DAVID RABEN: Our patient had a stage IVA SCC of the tonsil and received a tonsillectomy and left neck dissection, which revealed both angiolymphatic and perineural invasion. Given the negative surgical margins and the lack of extracapsular extension, radiation treatment to 60 Gy was appropriate, based on the European Organisation for Research and Treatment of Cancer (EORTC)/Radiation Therapy Oncology Group (RTOG) re-analysis.[4] If extracapsular extension had been present in his single level 2A lymph node, a higher dose (64 to 66 Gy) might have been indicated, along with sensitizing chemotherapy. Of note, angiolymphatic and perineural invasion were considered high-risk features in the EORTC randomized study of RT alone vs RT plus high-dose cisplatin(Drug information on cisplatin).[5]
DR. CHANGHU CHEN: For a patient with a stage IVA tonsil cancer, definitive chemoradiation, rather than surgery followed by adjuvant therapy, would have been a very reasonable approach. We often prefer definitive chemoradiation as first-line therapy for stage III-IV oropharyngeal cancer. In this setting, radiation to 70 Gy with concurrent, sensitizing chemotherapy (CRT) is a great option, with surgery reserved for initial salvage. With intensity-modulated radiation therapy (IMRT), the 3-year locoregional control rates for stage III-IV oropharyngeal cancer have been reported to be greater than 90%, allowing many patients to forgo upfront surgery.[6-8]
DR. ANTONIO JIMENO: I agree with Dr. Chen. Certainly CRT is an excellent option for a patient with stage IVA SCC of the tonsil. The classic sensitizing regimen is cisplatin, 100 mg/m2, on days 1, 22, and 43.[9] Alternative weekly regimens include cisplatin, 30 to 40 mg/m2; carboplatin(Drug information on carboplatin) plus paclitaxel(Drug information on paclitaxel); and single-agent cetuximab (Erbitux). For patients with bulky N2/N3 disease or large primaries we often incorporate neoadjuvant chemotherapy with TPF (cisplatin, 75mg/m2; docetaxel(Drug information on docetaxel), 75mg/m2; infusional fluorouracil(Drug information on fluorouracil) [5-FU]) every 3 weeks. In the TAX 323 and 324 studies, outcomes in patients treated with three to four cycles of TPF followed by either radiation therapy or chemoradiation were superior to outcomes in those treated with neoadjuvant PF (cisplatin and infusional 5-FU).[10,11] A pivotal study presented in abstract by Hitt et al compared CRT, neoadjuvant PF followed by CRT, and neoadjuvant TPF followed by CRT; the study showed a doubling of progression-free survival in the TPF-containing arm.[12] However, 40% of the patients studied had cancers of the hypopharynx or larynx. Based on these studies and the unpublished TREMPLIN study, we often offer a risk-adapted approach—two to three cycles of TPF followed by CRT—if there is a good initial response to therapy. Patients with a poor initial response are offered resection.
Importance of HPV status in treatment design
DR. BOWLES: Right now, 25% to 30% of HNSCCs are HPV-positive, and HPV-positive cancers account for an increasing percentage of oropharyngeal cancers in recent studies.[13] Does the fact that this patient had an HPV-positive cancer change the recommendations for his initial management?
DR. CHEN: No, not yet. While patients with HPV-positive HNSCC are typically regarded as a cohort with a more favorable prognosis,[14] we do not yet know how this observation should affect our treatment decisions. Some have speculated that it may be possible to decrease dose intensity in HPV-positive patients; however, outside of a clinical trial we would not yet incorporate a less intense radiation plan in the curative-intent setting in our daily practice.[15] ECOG is conducting a trial comparing induction chemotherapy with cisplatin, paclitaxel, and cetuximab(Drug information on cetuximab) followed by 69.3 Gy in 33 fractions to 54 Gy in 27 fractions of RT with sensitizing cetuximab to help address this question. RTOG is also designing a trial to address this question.
DR. WINE: It is an excellent question. Whether treated with radiation or surgery as a primary modality, patients with HPV-positive cancers have a very good prognosis.[16] As survival with HPV-positive cancers increases, more focus must be placed on minimizing the morbidity of treatment, whether this consists primarily of surgery or radiation therapy.
DR. JIMENO: The fundamental issue is that HPV-positive cancers likely have a different biology than do HPV-negative cancers. For example, HPV-positive cancers are driven by the expression of viral oncoproteins and are associated with lower epidermal growth factor receptor (EGFR) levels than are HPV-negative cancers.[17] This has potential implications with regard to cetuximab sensitivity in HPV-positive tumors. A retrospective study out of Memorial Sloan-Kettering recently suggested that HPV-positive patients treated with cetuximab plus radiation have worse outcomes than patients treated with cisplatin and radiation.[18] It is imperative that current and future studies address specific therapies for HPV-positive and HPV-negative cancers; such studies need to focus on tumor biology, treatment intensity, and curability, and they need to acknowledge the fact that patients with HPV-positive tumors tend to be young and otherwise healthy—with the result that failures in this setting can be catastrophic.
