Source: www.cancernetwork.com
Authors: Daniel W. Bowles, MD et al.

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:
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:
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. 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.

Treatment of the first locoregional recurrence:
DR. BOWLES: Unfortunately, our patient had a rapid relapse at his primary site after he completed adjuvant radiation. Could you each comment on the treatment of his local relapse?

DR. WINE: Resection is the indicated treatment for a recurrence in the oropharynx. The resection likely involved a portion of the pharyngeal wall. This caused a through-and-through defect, and the free flap was required to obtain the best chance of healing in a radiated field.

DR. BOWLES: How would your surgical recommendations be different if he had received CRT initially rather than being treated with a neck dissection?

DR. WINE: Occult regional metastasis occurs in approximately 25% of irradiated necks in recurrent HNSCC.[19] The percentage of occult regional metastases may be around 10% if the neck is N0 prior to radiation therapy and remains N0 clinically and radiographically at the time of recurrence.[20] Thus, elective neck dissection is definitely indicated for recurrent HNSCC if initial staging is N1 or greater. When there is a recurrence at the primary site, in necks that are initially N0, evidence exists that observation may be appropriate.

DR. REDDY: Is there a role for re-irradiation (re-RT) in this setting?

DR. RABEN: First, we should say that we agree with Dr. Wine. For patients presenting with a resectable recurrence, salvage surgery is the preferred option and offers the greatest likelihood of long-term survival. While adjuvant RT following salvage surgery offers the potential for improved locoregional control, no consistent overall survival benefit has been observed with this approach. In a recent randomized trial, 130 patients with recurrent HNSCC treated with salvage surgery were randomly assigned either to treatment with re-RT to 60 Gy combined with chemotherapy or to observation; a significant improvement in disease-free survival but not overall survival was observed with immediate adjuvant therapy.[20] Delaying re-RT after salvage resection until subsequent locoregional failure spares unnecessary treatment-related morbidity/mortality in the small subset of patients who may be cured by surgery alone.

DR. CHEN: While controversial, re-RT following locoregional failure in HNSCC has been shown in numerous single- and multi-institutional studies to be a feasible treatment option for patients with unresectable disease. Compared to chemotherapy alone, re-RT offers the potential for more durable disease control in locoregional relapse. RTOG 9610 was the first prospective multi-institutional randomized trial evaluating re-RT for the management of recurrent HNSCC or a second primary tumor (SPT) arising in a previously irradiated field. RT was undertaken to 60 Gy in 1.5-Gy twice-daily fractions (along with weekly 5-FU and hydroxyurea), with a 2-year survival of 15.2%.[22] RTOG 9911 similarly employed twice-daily RT, concurrent with cisplatin(Drug information on cisplatin) and paclitaxel(Drug information on paclitaxel), and demonstrated a 2-year overall survival of 25.9% in patients with recurrent HNSCC or SPT.[23] Retrospective series have demonstrated more favorable response rates and long-term outcomes with re-RT. In the recently reported experience of the Dana-Farber Cancer Institute with IMRT-based CRT ± surgery for locally recurrent HNSCC, the 2-year locoregional control and overall survival were 48% and 67%, respectively.[24] Although the percentage of patients with HPV-positive cancers may have contributed to these more favorable outcomes even in the recurrent setting, it is not known how many patients were HPV-positive. Such studies have shown that, for a select favorable subset of patients presenting with locoregionally recurrent HNSCC, long-term survival may be an achievable goal.

DR. RABEN: Of course, improved disease control with re-RT comes at the cost of an increased risk for treatment-related toxicity, underscoring the importance of appropriate patient selection. In RTOG 9911, for example, 28% of patients had grade 4 or worse acute toxicity, including eight treatment-related deaths.[23] Similarly, in the re-RT experience at the Dana-Farber Cancer Institute, 91% of the 35 treated patients had at least one acute grade 3 toxicity and 46% had late grade 3 toxicity. Four late deaths occurred in patients with no evidence of disease.[24]

DR. REDDY: How do target delineation and dose/fractionation selection in the re-RT setting compare with the upfront setting? What data support the use of hypofractionation approaches for re-RT for HNSCC recurrences?

DR. RABEN: Re-RT is usually delivered only to the recurrent tumor plus margins and does not include prophylactic nodal coverage. Conformal techniques, such as three-dimensional (3D) conformal radiation and IMRT, are essential to improve target coverage while minimizing treatment volume and associated toxicity. With conventional fractionation, doses used for curative-intent re-RT should approach those employed for initial upfront treatment. Fractionated stereotactic radiosurgery (SRS)/stereotactic body radiotherapy (SBRT) has emerged as an appealing approach that can minimize the toxicity associated with re-RT. The University of Pittsburgh recently reported their experience with SBRT for recurrent HNSCC, in which 85 patients received SBRT to a mean dose of 35 Gy (range, 15 to 44 Gy) [25] A complete/partial response or stable disease was observed in 88% of cases, with 1- and 2-year local control of 51.2% and 30.7%, respectively. Unger et al used SRS to a median dose of 30 Gy (range, 21 to 35 Gy) in 2 to 5 fractions for re-RT, reporting 2-year overall survival and locoregional control of 41% and 30%, respectively, with a 54% complete response rate.[26]

DR. BOWLES: Does systemic therapy have a role in the first locoregional relapse?

DR. JIMENO: Chemotherapy can play a role with concurrent re-RT. However, chemotherapy alone is palliative, and the goal at this setting, however unlikely, remains cure. As our surgical and radiation oncology colleagues stated, the management in this case appeared standard. However, before de-escalation strategies are applied in HPV-positive patients, we need long-term data confirming their appropriateness and safety.

Treatment of the second locoregional recurrence:
DR. BOWLES: Sadly, we met our patient when he had a second local recurrence, which occurred less than one year after he concluded his first therapy. His disease manifested as a PET-avid lesion in the left retropharyngeal/parapharyngeal region and was deemed unresectable. What can be done at this point?

DR. JIMENO: This is a setting in which chemotherapy can play a significant role. Clearly, his prognosis after a second relapse is quite grim, so therapy should focus on prolonging survival and improving quality of life. For patients with very good performance status you could consider a TPF-like regimen. However, this comes with significant toxicity. Other options include a platinum-taxane doublet, platinum–5-FU doublet, or cetuximab(Drug information on cetuximab) doublet with either a platinum or taxane. Single-agent taxanes, platinums, or cetuximab could also be used. We elected to give our patient two cycles of TP since he was chemotherapy-naive. He presented with stridor at his initial visit to our clinic, and cisplatin-docetaxel relieved this symptom.

DR. REE: The follow-up PET/CT scan showed decreased fullness of the soft tissue at the left skull base, nasopharynx, and oropharynx, with the supporting secondary sign of interval resolution of the effacement of the left fossa of Rosenmüller. Despite these areas of improvement, there remained considerable abnormal tissue and metabolic activity.

DR. BOWLES: Is it useful to employ chemotherapy to reduce the size of a relapse and then attempt a resection?

DR. WINE: There is utility in reconsidering surgery after a locoregional recurrence has been downstaged with chemotherapy or radiotherapy. It has been shown that resection of HNSCC that was unresectable at initial presentation can be beneficial if margins are negative.[27] In the setting of locoregional recurrence, surgery may be reconsidered after downstaging, although the risks are higher after radiation (or re-RT). Because surgery would have more morbidity in this setting, the ability to achieve negative margins is of utmost importance when reconsidering resection. Thus, surgery should be considered only if there has been a significant response to chemotherapy or radiotherapy and it appears very probable that negative margin status can be achieved.

Role of Biologic Agents for Head and Neck Cancers:
DR. REDDY: Our patient had not received re-RT at this point. We discussed re-RT and re-CRT earlier but we did not address a potential role for biologic agents in this setting. Are there data to support the use of targeted biologic agents, such as cetuximab, concurrently with re-RT for locally recurrent HNSCC?

DR. CHEN: Molecularly targeted agents, including cetuximab and erlotinib (Tarceva), have demonstrated feasibility and acceptable levels of acute toxicities when administered concurrently with re-RT for recurrent HNSCC. Heron et al recently reported the results of a retrospective matched-cohort study of patients with locally recurrent HNSCC, in which SBRT alone was compared to SBRT with weekly cetuximab infusion. The addition of cetuximab to SBRT improved overall survival from 14.8 months to 24.5 months, without a significant increase in grade 3/4 toxicities.[28] A phase I dose-escalation trial of concurrent and maintenance erlotinib and re-RT at UCCC demonstrated the safety and feasibility of re-RT to 66 Gy in 30 fractions with concurrent daily erlotinib up to a dose of 150 mg daily, with a favorable acute toxicity profile compared with trials utilizing re-RT and cytotoxic chemotherapy, as well as similar late toxicity/treatment-associated mortality.[29] Although no randomized trials to date have compared the efficacy of targeted biologics concurrent with re-RT to that of traditional chemotherapy, the above studies demonstrate that such an approach in HNSCC patients certainly merits consideration. Future trials might incorporate DNA repair inhibitors as a way to enhance radiosensitivity.

DR. RABEN: Following 2 cycles of TP chemotherapy, we elected to treat this patient with SBRT to 25 Gy delivered in 5 fractions (Figure 2), with sensitizing cetuximab during therapy and for a month afterwards. He had stable disease during treatment, but his disease progressed 2 months after he finished therapy.

DR. BOWLES: Dr. Jimeno, what novel options are available to patients with locally recurrent or metastatic HNSCC?

DR. JIMENO: There are a number of completed or ongoing trials looking at systemic therapy for locally recurrent or metastatic HNSCC. Drugs targeting EGFR have been investigated with mixed results. A phase III study showed that panitumumab plus 5-FU was no better than cisplatin plus 5-FU.[30] Similarly, zalutumumab, another humanized anti-EGFR antibody, showed improved progression-free survival but not overall survival compared with best supportive care in platinum-refractory HNSCC.[31] In contrast, the EGFR-HER2 inhibitor BIBW 2992 showed improved clinical benefit compared with single-agent cetuximab.[32] We are conducting exciting phase I/II studies with PI3K inhibitors and cetuximab or conventional chemotherapy in an effort to target multiple mechanisms and thereby prevent trans-activation or bypass of key signaling pathways. We believe these and similar studies represent the next wave of rational combination strategies aimed at improving outcomes for patients with HNSCC.

Conclusion:
Management of head and neck squamous cell carcinoma in the primary and relapsed setting requires the coordinated efforts of head and neck surgeons, radiation oncology, and medical oncology in order to maximize clinical care. Unfortunately, our patient died 4 months after completing re-RT and only 16 months after he underwent his initial surgery. Multidisciplinary efforts must be strengthened and new research performed to improve the otherwise poor prognosis for patients with locally recurrent HNSCC.

Financial Disclosure:
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

Authors:
By Daniel W. Bowles, MD1, Krishna Reddy, MD, PhD1, Todd Wine, MD1, Alexander Ree, MD1, David Raben, MD1, Changhu Chen, MD1, Antonio Jimeno, MD, PhD1

Authors’ affiliation:
1University of Colorado Cancer Center and the University of Colorado School of Medicine, Aurora, Colorado

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