AHNS Virtual Education Series
Presented by the Reconstructive Head & Neck Section

Recon ‘Round the World: INDIA
“Management of Complex Oral Cavity Reconstruction”

Thursday, June 1, 2023
6:30 AM Pacific US/Canada / 9:30 AM Eastern US/Canada
7:00 PM India Standard Time

 

Learning Objectives:
1. Discuss the epidemiology and current treatment paradigms for hypopharyngeal and nasopharyngeal cancer
2. Compare and contrast preferred reconstruction techniques and brainstorm difficult patient situations
3. Explore solutions for management of the hypopharynx and nasopharynx with regard to function (voice, swallow) and innovations in reconstruction.

Host:
Matthew Old, MD – Vice-Chair AHNS Reconstructive Head & Neck Surgery Section – The Ohio State University, Columbus, Ohio

Moderators:
Rodrigo Bayon, MD, FACS – University Of Iowa Hospitals & Clinics – Iowa City, Iowa

Panelists:
Daniel G. Deschler, MD, FACS – Massachusetts Eye and Ear – Boston, Massachusetts
Nicole M. Fowler, MD – University Hospitals Cleveland Medical Center – Case Western Reserve University School of Medicine – Cleveland, Ohio
Dr. Dushyant Jaiswal – Tata Memorial Centre – Mumbai, India
Dr. Subramania Iyer K., MCh, MS – Amrita Vishwa Vidyapeetham – School of Medicine, Kochi, India

One-hour session is free to all registrants!

AHNS Virtual Education Series
Presented by the AHNS Mucosal Malignancy Section
“HPV Liquid Biopsies: Ethical and Practical Considerations”
May 31, 2023 at 7:00 PM Eastern Time

 

Learning Objectives:
Discuss the limitations of existing HPV liquid biopsy tests and how these can confound interpretation.
Understand the complex ethical dilemmas which can arise from utilizing new diagnostic assays without standardized approaches.
Articulate the impact of false negative and false positive test results on patient care and well-being.

Moderators:
Andrew G. Shuman, MD FACS – University of Michigan Medical School
Daniel Faden, MD, FACS – Mass Eye and Ear/Mass General Hospital – Broad Institute

Panelists:
David Routman, MD – Mayo Clinic, Rochester, MN
Chiara Mannelli, PhD – Italian National Institute of Health
Carole Fakhry, MD, MPH – Johns Hopkins Head and Neck Cancer Center

One-hour session is free to all registrants!

 

AHNS Virtual Education Series
Presented by the AHNS Cutaneous Cancer Section
“Exploring Controversies in Management of Cutaneous
Malignant Melanoma of the Head and Neck”
May 17, 2023 at 7:00 PM Eastern Time

Many advances have been made in the management of cutaneous malignant melanoma of the head and neck over the last decade with results from the MSLT I and II trials guiding our surgical management and increased utilization of immunotherapy for advanced stage melanoma. However, there is variability in how physicians apply this to the head and neck cohort, such as differences in the management of positive sentinel lymph node with completion lymphadenectomy versus observation, when to consider neoadjuvant or adjuvant immunotherapy, or the safe utilization of Mohs micrographic surgery for management of melanoma. This webinar will provide a lively discussion of relevant real-life cases that cover the breadth of these controversies to discuss best practices and evidence-based management of these patients.

Moderator:
Karen Y. Choi, MD, FACS

Panelists:
Mary Stevenson, MD – Mohs Dermatology – NYU (New York University)
Kelly Malloy, MD – Head and Neck Surgery – University of Michigan
Kerwin Shannon, FRACS – Head and Neck Surgery – Melanoma Institute Australia
Leslie Fecher, MD – Medical Oncology, University of Michigan
Devarati Mitra, MD, PhD- Radiation Oncology – MD Anderson Cancer Center
Jane Messina, MD – Dermatopathology – Moffitt Cancer Center

One-hour session is free to all registrants!

From the Authors Alia Tayara, BS¹, Anne C. Kane, MD FACS²

¹University of Mississippi Medical Center School of Medicine, Jackson, MS
²Department of Otolaryngology – Head and Neck Surgery, University of Mississippi Medical Center, Jackson, MS

Merkel Cell Carcinoma (MCC) is a rare, highly aggressive neuroendocrine skin malignancy. There is rising incidence of MCC worldwide with head and neck being the most common primary site. At diagnosis, a significant proportion of patients are known to have metastasis to secondary locations at diagnosis with nodal metastases in 15-32% of patients and 5-12% with metastasis at distant sites^1-5.MCC maintains a three-fold higher disease mortality than melanoma, with a predilection for patients who are elderly, immunosuppressed, and have history of significant sun exposure. 80% of MCC tumors are caused by Merkel Cell Polyoma Virus (MCPyV), a commensal virus of the human skin with the other major causative factor being UV light exposure⁶. The tendency for progression and early metastasis emphasizes the need for early detection, early diagnosis, and prompt initiation of treatment for this disease pathology^6-7.

Due to the rarity of this pathology, there is a lack of prospective randomized clinical trials (RCTs) comparing treatment approaches and most of the data is retrospective in nature and therefore low-level evidence. NCCN guideline recommendations for clinically localized MCC is complete excision of primary lesion with 1-2cm margins and sentinel lymph node biopsy (SLNB). Mohs surgery may be utilized for lesion excision in appropriate circumstances. Patients with clinical evidence of nodal metastases may undergo ultrasound and fine needle aspiration to detect lymph node metastases preoperatively and should be recommended to undergo nodal dissection and/or radiation therapy⁸.

While imaging is encouraged in most cases of MCC, there is no consensus on what appropriate imaging should be with options including regional ultrasound, CT scan(s) and whole-body PET/CT⁸. The importance of baseline imaging has been shown in several studies, including Singh et al. who found that occult metastatic disease resulted in upstaging in 12-20% of patients with MCC presenting without suspicious H&P findings⁹. Several studies have indicated that whole body PET is more sensitive for detecting occult metastatic disease at baseline¹⁰. Zijlker et al. evaluated ultrasound and PET/CT as baseline imaging and found that 23% of patients in their study group with clinically localized MCC were upstaged to stage III disease with PET/CT and 3% were upstaged to stage IV disease. Therapeutic management was altered by 22% due to PET/CT imaging¹¹. While this modality can provide a high rate of upstaging, sentinel lymph node biopsy (SLNB) remains the most reliable tool to identify subclinical nodal disease in patients with negative preoperative imaging^4,12.

MCC has been shown to be a radiosensitive tumor and radiation therapy (RT) should be considered post-operatively in cases with high-risk features, close or positive margins or as an alternative to surgery in patients who are poor candidates⁸.  Radiation has been utilized as a primary modality of treatment in Australia and New Zealand with growing retrospective evidence showing relatively high local and regional control rates¹³. Use of adjuvant RT has been shown to improve rates of local control and overall survival in several retrospective studies regardless of tumor stage. Because of this, some advocate for consideration of adjuvant radiation after surgical excision in all cases of this high-risk pathology^14-15. In contrast, a RCT of 83 patients with Stage I MCC found that was no improvement in overall survival (OS) or progression free survival (PFS) in patients undergoing adjuvant RT versus those undergoing clinical observation after surgical excision without high-risk features. However, there was a decreased rate of regional recurrence in the adjuvant RT group¹⁶.

MCC patients with distant metastatic disease represent a challenging cohort of patients that has traditionally had fairly dismal survival when treated with cytotoxic chemotherapy, with a median progression-free survival of approximately 3 months and progressive disease developing in 90% of patients within 10 months¹⁷. Immune checkpoint inhibitors (ICIs), in particular PD1/PDL1 inhibitors, have demonstrated potential to provide improved progression-free and overall survival compared to chemotherapy in MCC with distant metastatic disease. Virus-associated cancers, wherein viral antigens serve as tumor-specific antigens, have been proposed as a mechanistic marker than can predict response to anti-PD-1 therapy¹⁸. Several studies have shown that approximately 50% of Merkel cell carcinomas express PD-1 on tumor-infiltrating lymphocytes and express PD-L1 on tumor cells or infiltrating macrophages in an “adaptive resistance” pattern^19-22.

JAVELIN Merkel 200 Phase II trial results demonstrated an overall response rate (ORR) of 62.1% using Avelumab as first-line therapy in patients with metastatic MCC, with a duration of response for over six months in 83% of responders. When used as a second-line therapy in patients with metastatic disease after failure of ³1 line of prior chemotherapy, the ORR was 33%, which is higher than ORRs reported in recent observational studies of second line chemotherapy²³. Responses were shown to be durable in this population as well with estimated proportion of responses lasting greater than one year at 74%. This landmark trial led to the approval of Avelumab for MCC treatment in 2017²⁴. A Phase II trial of first-line therapy with pembrolizumab in 26 patients with advanced Merkel-cell carcinoma was found to have an ORR of 56%. Tumor regression appeared to be durable within an observation period of up to 9.7 months after initial documentation of response with progression free survival of 67% at 6 months. Responses were observed in both patients with virus-positive and virus-negative tumors and responses were not found to be correlated with PD-L1 expression¹⁸.  Treatment of advanced MCC with immunotherapy shows promising potential for long-term benefit not previously achieved with chemotherapy.

Immunotherapy as also been evaluated in the neoadjuvant setting. In the CheckMate 358 study, 39 patients received nivolumab for approximately 4 weeks prior to planned surgical resection, of which, 36 underwent surgery. There were high rates of pathologic complete response (pCR 47.2%) and radiographic response (54.5%) with responders having prolonged recurrence-free survival and no patients with pCR experiencing a tumor relapse within 19.3 months of mean follow up postoperatively²⁵. This study has demonstrated that immunotherapy should be further explored as a potential adjunct to surgery in patients with MCC.

Understanding optimal duration of immunotherapy treatment in patients with metastatic MCC is essential. A study of 40 patients with metastatic MCC found that 35% of patients experienced progressive disease within a median of 12.3 months after immunotherapy discontinuation, including 26% of patients with a complete response, 57% of patients with a partial response and in 100% of those with stable disease. PFS after treatment cessation was 21 months. Of those who were able to be restarted on immunotherapy after progressive disease, response rate was 75%²⁶. While the rate of progressive disease was lower in patients with complete response, this data is directly in contrast to the data for metastatic melanoma, where patients who cease treatment in a CR setting have durable remissions and a low incidence of relapse indicating that the same does not hold true for metastatic MCC. Despite this, it is promising that a high response rate remained in patients who progressed once they reinitiated ICI treatment.

Unfortunately, once ICIs have failed in the setting of advanced MCC, patients are left with very limited treatment options. Preliminary translational investigation has shown antineoplastic effects of dimethyl fumarate (DMF) in melanoma which Gambichler et al. sought to evaluate in MCC. Three different MCC virus negative cell lines were exposed to varying doses of DMF and all three showed significant reduction in cell viability and proliferation. This preliminary data warrants further exploration²⁷.

Circulating tumor DNA has emerged as a predictive and prognostic tool for evaluating treatment response and early detection of relapse in several different forms of cancer^28-30. There is emerging evidence for the utilization of this technology in MCC. In a pilot study, Park et al. demonstrated that ctDNA is both a sensitive biomarker of minimal residual disease and early relapse after definitive treatment. They also found that serial ctDNA testing may also be able to be used to risk-stratify patients who are more or less likely to respond to ICIs³¹. Akaike et al. performed a prospective study on 328 blood samples from 125 patients and further demonstrated support for this testing as a marker of early recurrence³². Future studies are needed to ascertain the role of ctDNA in MCC management, however it holds promise as a potential prognostic indicator and as a marker of early recurrence.

As MCC occurs most frequently in the head and neck region, it is crucial that we are aware of its rising incidence and new treatment potentials on the horizon. While ICIs have emerged as a promising treatment tool for advanced stage MCC, further research and clinical trials are needed to refine optimal treatment regimens in this aggressive disease pathology.

 

References

1. Harms KL, Healy MA, Nghiem P, et al. Analysis of Prognostic Factors from 9387 Merkel Cell Carcinoma Cases Forms the Basis for the New 8th Edition AJCC Staging System. Ann Surg Oncol. 2016;23(11):3564-3571. doi:10.1245/s10434-016-5266-4
2. Bleicher J, Asare EA, Flores S, Bowles TL, Bowen GM, Hyngstrom JR. Oncologic outcomes of patients with Merkel Cell Carcinoma (MCC): A multi-institutional cohort study. Am J Surg. 2021;221(4):844-849. doi:10.1016/j.amjsurg.2020.08.013
3. van Veenendaal LM, van Akkooi ACJ, Verhoef C, et al. Merkel cell carcinoma: Clinical outcome and prognostic factors in 351 patients. J Surg Oncol. 2018;117(8):1768-1775. doi:10.1002/jso.25090
4. Zijlker LP, Bakker M, van der Hiel B, et al. Baseline ultrasound and FDG-PET/CT imaging in Merkel cell carcinoma. Journal of Surgical Oncology. 2023;127(5):841-847. doi:10.1002/jso.27193
5. Fitzgerald TL, Dennis S, Kachare SD, Vohra NA, Wong JH, Zervos EE. Dramatic increase in the incidence and mortality from Merkel cell carcinoma in the United States. Am Surg. 2015; 81:802–06. [PubMed: 26215243]
6. Silling S, Kreuter A, Gambichler T, Meyer T, Stockfleth E, Wieland U. Epidemiology of Merkel Cell Polyomavirus Infection and Merkel Cell Carcinoma. Cancers (Basel). 2022;14(24):6176. doi:10.3390/cancers14246176
7. Wang AJ, McCann B, Soon WCL, et al. Merkel cell carcinoma: a forty-year experience at the Peter MacCallum Cancer Centre. BMC Cancer. 2023;23(1):30. doi:10.1186/s12885-022-10349-1
8. Bichakjian CK, Olencki T, Aasi SZ, et al. Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network. 2018;16(6):742-774. doi:10.6004/jnccn.2018.0055
9. Singh N, Alexander NA, Lachance K, et al. Clinical benefit of baselineimaging in merkel cell carcinoma: analysis of 584 patients.J Am AcadDermatol. 2021;84(2):330‐339.
10. Treglia G., Kakhki V.R.D., Giovanella L., Sadeghi R. Diagnostic Performance of Fluorine-18-Fluorodeoxyglucose Positron Emission Tomography in Patients with Merkel Cell Carcinoma: A Systematic Review and Meta-Analysis. Am. J. Clin. Dermatol. 2013;14:437–447. doi: 10.1007/s40257-013-0040-x.
11. Zijlker, LP et al. Baseline ultrasound and FDG-PET/CT imaging in Merkel cell carcinoma. J Surg Oncol 2023;127:841-847.
12. George A, et al. Nucl Med Commun 2014;35:282-290; Hawryluk EB, et al. J Am Acad Dermatol 2013;68:592-599; Siva S, et al. J Nucl Med 2013;54:1223-1229
13. Kok DL et al. The changing paradigm of managing Merkel cell carcinoma in Australia: An expert commentary. Asoa-Pac J Clinic Once 2020;16:312-319.
14. Mojica P, Smith D, Ellenhorn JD. Adjuvant radiation therapy is associated with improved survival in Merkel cell carcinoma of the skin. J ClinOncol. 2007;25(9):1043-1047.
15. Harrington C, Kwan W. Radiotherapy and conservative surgery in the locoregional management of Merkel cell carcinoma: the British Columbia Cancer Agency Experience. Ann Surg Oncol. 2016;23(2):573-578.
16. Jouary T et al. Adjuvant prophylactic regional radiotherapy versus observation in stage I Merkel cell carcinoma: a multi centric prospective randomized study. Ann Once. 2012 Apr;23(4):1074-80.
17. Iyer J, Blom A, Doumani R, et al.. Response rate and durability of chemotherapy for metastatic Merkel cell carcinoma among 62 patients. J Clin Oncol 2014;32:52.
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19. Afanasiev OK, Yelistratova L, Miller N, et al. Merkel polyomavirus-specific T cells fluctuate with Merkel cell carcinoma burden and express therapeutically targetable PD-1 and Tim-3 exhaustion markers. Clin Cancer Res. 2013;19:5351–5360.
20. Taube JM, Anders RA, Young GD, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012;4:127ra37. [PMC free article] [PubMed] [Google Scholar]
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25. Topalian SL, Bhatia S et al. Neoadjuvant Nivolumab for patient with Resectable Merkel Cell Carcinoma in the CheckMate 358 Trial. J Clin Oncol 38:2476-2487.
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28. Powles T et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature. 2021;595(7867):432-437. https://doi.org/10.1038/s41586-021-03642-9
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31. Park, S.J. et al. Circulating Tumor DNA as a Predictive Biomarker in Merkel Cell Carcinoma. J. Am. Acad. Dermatol. 2022, 87, 1209–1211.
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AHNS Virtual Education Series
Presented by the AHNS Cutaneous Cancer Section
“Exploring Controversies in Management of Cutaneous
Malignant Melanoma of the Head and Neck”
May 17, 2023 at 7:00 PM Eastern Time

Many advances have been made in the management of cutaneous malignant melanoma of the head and neck over the last decade with results from the MSLT I and II trials guiding our surgical management and increased utilization of immunotherapy for advanced stage melanoma. However, there is variability in how physicians apply this to the head and neck cohort, such as differences in the management of positive sentinel lymph node with completion lymphadenectomy versus observation, when to consider neoadjuvant or adjuvant immunotherapy, or the safe utilization of Mohs micrographic surgery for management of melanoma. This webinar will provide a lively discussion of relevant real-life cases that cover the breadth of these controversies to discuss best practices and evidence-based management of these patients.

Moderator:
Karen Y. Choi, MD, FACS

Panelists:
Mary Stevenson, MD – Mohs Dermatology – NYU (New York University)
Kelly Malloy, MD – Head and Neck Surgery – University of Michigan
Kerwin Shannon, FRACS – Head and Neck Surgery – Melanoma Institute Australia
Leslie Fecher, MD – Medical Oncology, University of Michigan
Devarati Mitra, MD, PhD- Radiation Oncology – MD Anderson Cancer Center
Jane Messina, MD – Dermatopathology – Moffitt Cancer Center

One-hour session is free to all registrants!