Multidisciplinary Consultations on Challenging Cases
The University of Colorado Denver School of Medicine faculty holds weekly second opinion conferences focusing on cancer cases that represent most major cancer sites. Patients seen for second opinions are evaluated by an oncologic specialist. Their history, pathology, and radiographs are reviewed during the multidisciplinary conference, and then specific recommendations are made. These cases are usually challenging, and these conferences provide an outstanding educational opportunity for staff, fellows, and residents in training.
The second opinion conferences include actual cases from genitourinary, lung, melanoma, breast, neurosurgery, gastrointestinal, and medical oncology.
E. David Crawford, MD
Thomas W. Flaig, MD
University of Colorado Denver School of Medicine
and University of Colorado Cancer Center
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.
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 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.
DR. 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 Rosenmller. 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.
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, 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. 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.
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. Alternative weekly regimens include cisplatin, 30 to 40 mg/m2; carboplatin plus 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, 75mg/m2; infusional 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. 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. 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, 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. ECOG is conducting a trial comparing induction chemotherapy with cisplatin, paclitaxel, and 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. 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. 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. 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.
1. Rich JT, Milov S, Lewis JS, Jr., et al. Transoral laser microsurgery (TLM) +/- adjuvant therapy for advanced stage oropharyngeal cancer: outcomes and prognostic factors. Laryngoscope. 2009;119:1709-19.
2. Boscolo-Rizzo P, Gava A, Baggio V, et al. Matched survival analysis in patients with locoregionally advanced resectable oropharyngeal carcinoma: platinum-based induction and concurrent chemoradiotherapy versus primary surgical resection. Int J Radiat Oncol Biol Phys. 2011;80:154-60.
3. Chen AY, Schrag N, Hao Y, et al. Changes in treatment of advanced oropharyngeal cancer, 1985-2001. Laryngoscope. 2007;117:16-21.
4. Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck. 2005;27:843-50.
5. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004;350:1945-52.
6. Daly ME, Le QT, Maxim PG, et al. Intensity-modulated radiotherapy in the treatment of oropharyngeal cancer: clinical outcomes and patterns of failure. Int J Radiat Oncol Biol Phys. 2010;76:1339-46.
7. Setton J, Caria N, Romanyshyn J, et al. Intensity-modulated radiotherapy in the treatment of oropharyngeal cancer: an update of the Memorial Sloan-Kettering Cancer Center experience. Int J Radiat Oncol Biol Phys. 2010 Dec 16. [Epub ahead of print]
8. Clavel S, Nguyen DH, Fortin B, et al. Simultaneous integrated boost using intensity-modulated radiotherapy compared with conventional radiotherapy in patients treated with concurrent carboplatin and 5-fluorouracil for locally advanced oropharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2011 Feb 1. [Epub ahead of print]
9. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003;349:2091-8.
10. Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med. 2007;357:1695-704.
11. Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med. 2007;357:1705-15.
12. Hitt R, Grau JJ, Lopez-Pousa A, et al. Final results of a randomized phase III trial comparing induction chemotherapy with cisplatin/5-FU or docetaxel/cisplatin/5-FU followed by chemoradiotherapy (CRT) versus CRT alone as first-line treatment of unresectable locally advanced head and neck cancer (LAHNC). J Clin Oncol. 2009;27(15s):Abstract 6003.
13. Kreimer AR, Clifford GM, Boyle P Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev. 2005;14:467-75.
14. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363:24-35.
15. Shoushtari A, Meeneghan M, Sheng K, et al. Intensity-modulated radiotherapy outcomes for oropharyngeal squamous cell carcinoma patients stratified by p16 status. Cancer. 2010;116:2645-54.
16. Hong AM, Dobbins TA, Lee CS, et al. Human papillomavirus predicts outcome in oropharyngeal cancer in patients treated primarily with surgery or radiation therapy. Br J Cancer. 2010;103:1510-7.
17. Kumar B, Cordell KG, Lee JS, et al. EGFR, p16, HPV Titer, Bcl-xL and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer. J Clin Oncol. 2008;26:3128-37.
18. Koutcher L, Sherman E, Fury M, et al. Concurrent cisplatin and radiation versus cetuximab and radiation for locally advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2010 Oct 13. [Epub ahead of print]
19. Solares CA, Fritz MA Esclamado RM. Oncologic effectiveness of selective neck dissection in the N0 irradiated neck. Head Neck. 2005;27:415-20.
20. Dagan R, Morris CG, Kirwan JM, et al. Elective neck dissection during salvage surgery for locally recurrent head and neck squamous cell carcinoma after radiotherapy with elective nodal irradiation. Laryngoscope. 2010;120:945-52.
21. Janot F, de Raucourt D, Benhamou E, et al. Randomized trial of postoperative reirradiation combined with chemotherapy after salvage surgery compared with salvage surgery alone in head and neck carcinoma. J Clin Oncol. 2008;26:5518-23.
22. Spencer SA, Harris J, Wheeler RH, et al. Final report of RTOG 9610, a multi-institutional trial of reirradiation and chemotherapy for unresectable recurrent squamous cell carcinoma of the head and neck. Head Neck. 2008;30:281-8.
23. Langer CJ, Harris J, Horwitz EM, et al. Phase II study of low-dose paclitaxel and cisplatin in combination with split-course concomitant twice-daily reirradiation in recurrent squamous cell carcinoma of the head and neck: results of Radiation Therapy Oncology Group Protocol 9911. J Clin Oncol. 2007;25:4800-5.
24. Sher DJ, Haddad RI, Norris CM, Jr., et al. Efficacy and toxicity of reirradiation using intensity-modulated radiotherapy for recurrent or second primary head and neck cancer. Cancer. 2010;116:4761-8.
25. Rwigema JC, Heron DE, Ferris RL, et al. Fractionated stereotactic body radiation therapy in the treatment of previously-irradiated recurrent head and neck carcinoma: updated report of the University of Pittsburgh experience. Am J Clin Oncol. 2010;33:286-93.
26. Unger KR, Lominska CE, Deeken JF, et al. Fractionated stereotactic radiosurgery for reirradiation of head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2010;77:1411-9.
27. Rivera F, Eugenia Vega-Villegas M, Lopez C, et al. Retrospective analysis of surgical resection after induction chemotherapy for patients with T4b squamous cell head and neck cancer. Acta Oncol. 2008;47:1584-9.
28. Heron DE, Rwigema JC, Gibson MK, et al. Concurrent cetuximab with stereotactic body radiotherapy for recurrent squamous cell carcinoma of the head and neck: a single institution matched case-control study. Am J Clin Oncol. 2011;34:165-72.
29. Rusthoven KE, Feigenberg SJ, Raben D, et al. Initial results of a Phase I dose-escalation trial of concurrent and maintenance erlotinib and reirradiation for recurrent and new primary head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2010;78:1020-5.
30. Vermorken JB, Stohlmacher J, Davidenko I, et al. Primary efficacy and safety results of SPECTRUM, a phase 3 trial in patients (pts) with recurrent and/or metastatic (R/M) squamous cell carcinoam fo the head and neck (SCCHN) receiving chemotherapy with or without panitumumab (Pmab). Ann Oncol. 2010;21:LBA26.
31. Machiels JH, Subramanian S, Ruzsa A, et al. An open-label, randomized, phase III trial of zalutumumab, a human monoclonal EGF receptor (EGFr) antibody, versus best supportive care, in patients with noncurable squamous cell carcinoma (SCCHN) of the head and neck who have failed standard platinum-based chemotherapy (ZALUTE) J Clin Oncol. 2010;28:LBA5506.
32. Seiwert TY, Clement PM, Cupissol D, et al. BIBW 2992 versus cetuximab in patients with metastatic or recurrent head and neck cancer (SCCHN) after failure of platinum-containing therapy with a cross-over period for progressing patients: Preliminary results of a randomized, open-label phase II study. J Clin Oncol. 2010;28:abstr 5501.