November - December 2017
Management of Papillary Thyroid Cancer
Vlad C. Sandulache, M.D., Ph.D.
Dec. 25 - 29, 2017
Specific question: How should we think about nodal metastasis in papillary thyroid cancer?
Differentiated thyroid carcinoma (DTC) is increasing in incidence. Although this phenomenon was initially thought to be driven primarily by increased patient screening (which is not recommended by the U.S. Preventive Services Task Force), newer evidence suggests that the actual incidence of this disease is rising. Papillary thyroid carcinoma (PTC) comprises approximately 80 percent of new DTC cases in the United States. In contrast to other malignancies such as head and neck squamous cell carcinoma (HNSCC), PTC displays a somewhat paradoxical behavior. On one hand, PTC can be cured with surgery alone in most patients, resulting in excellent 10 and 20 year overall survival. On the other hand, PTC is associated with a very high rate of nodal metastasis (20-40% depending on the study and the method of identification). Because most head and neck surgeons are trained to consider nodal metastasis in the management of head and neck cancer, selecting an optimal algorithm for management of cervical basins during PTC surgery remains challenging and continues to be the subject of heated debates within the field.
Fritze and Doherty (2010) summarize data regarding this clinical dilemma in a comprehensive manner. The incidence of microscopic PTC metastases in the absence of radiologic evidence of nodal metastasis can vary widely. The rate of central compartment micrometastasis can be as high as 80%, with lateral compartment (levels II-V) levels between 20-60 percent depending on the study. From a purely statistical perspective, these values clearly cross the threshold routinely utilized to justify elective neck treatment for HNSCC (20 percent). However, since the clinical behavior of PTC is decidedly more benign than that of HNSCC, the risk associated with occult metastasis cannot be viewed in a similar fashion across the 2 histologies. There is some correlation between primary disease location (superior vs inferior) and location of nodal metastasis and tumor size does correlate with metastatic risk. However, because the precise values vary widely between studies, and because skip metastasis can be identified in up to 10% of patients, constructing a consistent algorithm can be difficult.
Asimakopoulos et al (2017) provide an update on the earlier study with many similar conclusions. Importantly however, this group addresses a critical question related to neck dissection: technique. Data from multiple institutions indicate that elective neck dissections are associated with greater morbidity than is generally expected. In addition, the relative comprehensiveness of a neck dissection (i.e. level IIb for lateral dissections, high-risk areas for central dissections) can vary widely in the elective setting and therefore may not generate the expected improvement in disease control.
Although nodal metastasis may not portend the same dramatic decrease in survival associated with HNSCC, nodal metastasis has been shown to impact overall, but more frequently disease specific survival, in multiple institutional and national patient series. Combined with the data summarized above, this leads most head and neck surgeons to address the clinically evident locoregional disease first, and then address high risk basins on the basis of personal and institutional practice patterns and outcomes.
HIV and Head and Neck Cancer
David J. Hernandez, M.D.
Dec. 4 - 8, 2017
Specific Question: Are HIV patients at increased risk of head and neck cancer?
Management of the HIV patient with head and neck cancer is more common as these patients are living longer in the era of highly active anti-retroviral therapy (HAART). HIV infected individuals have an increased risk of a number of difference cancers, both viral-related (HPV) and alcohol/tobacco related. While the incidence of non-HPV related head and neck cancers is decreasing largely due to the decreased prevalence of smoking in the general population, smoking prevalence remains high among HIV+ patients (40-60% vs 17%). HPV 16 infection is also increased in the HIV population compared to the general population (2-7% vs 1%). Thus, the HIV population has a number of risk factors that are important in the carcinogenesis of head and neck cancer: smoking and alcohol use, HPV, and potentially immunodeficiency. Overall, there is a modestly increased risk of head and neck cancer for these patients (1.7-4-fold increased risk).
Beachler et al and D’Souza et al both suggest that a CD4 count nadir (and the immunosuppressed state resulting) preceding the diagnosis of head and neck cancer may be related to HPV infection persistence and progression to cancer. Additionally, low CD4 count at diagnosis was found to be associated with a poor prognosis, and survival improved with increased CD4 count (15 months for CD4350). This speaks to the importance of appropriate HIV management with HAART for patients with HIV, particularly those with head and neck cancer. These patients will continue to present with head and neck cancer in our clinics, with both HPV-related and HPV-unrelated head and neck malignancies, due to the combination of “traditional” and HPV risk factors in this unique population.
Daniel C. Beachler, Alison G. Abraham, Michael J. Silverberg, Yuezhou Jing, Carole Fakhry, M. John Gill, Robert Dubrow, Mari M. Kitahata, Marina B. Klein, Ann N. Burchell, P. Todd Korthuis, Richard D. Moore, Gypsyamber D’Souza, On behalf of the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of IeDEA. Incidence and risk factors of HPV-related and HPV-unrelated Head and Neck Squamous Cell Carcinoma in HIV-infected individuals. Oral Oncol. 2014 Dec;50(12):1169-76. PMID: 25301563
Gypsyamber D’Souza, Thomas E. Carey, William N. William Jr., Minh Ly Nguyen, Eric C. Ko, James Riddell IV, Sara I. Pai, Vishal Gupta, Heather M. Walline, J. Jack Lee, Gregory T. Wolf, Dong M. Shin, Jennifer R. Grandis, and Robert L. Ferris, on behalf of the HNC SPORE HIV supplement consortium. Epidemiology of head and neck squamous cell cancer among HIV-infected patients. J Acquir Immune Defic Syndr. 2014 Apr 15;65(5):603-10. PMID: 24326607
Functional Outcomes after Head and Neck Cancer Treatment
Vlad C. Sandulache, M.D., Ph.D.
Nov. 25 - 29, 2017
Specific question: How do we monitor and predict function following treatment for head and neck cancer?
Oropharyngeal squamous cell carcinoma (OPSCC) incidence is rapidly increasing in the United States, primarily due to the impact of the human papilloma virus (HPV). Although HPV vaccinations are likely to decrease the incidence of OPSCC in future decades, we can expect to encounter high levels of HPV associated (HPV+) OPSCC for the next 10-20 years. Fortunately, HPV+ OPSCC have been shown to demonstrate an excellent response to radiation and conventional chemotherapy, resulting in cure rates of >80% for early stage disease. Because of this excellent prognosis, HPV+ OPSCC patients are expected to live many decades following their initial diagnosis and treatment. As such, they will experience chronic radiation effects longer than we have ever previously seen. Although we have long known that radiation can generate profound effects on oropharyngeal function, namely swallowing, the advent of HPV+ OPSCC is rapidly creating a crisis in our ability to understand and manage long-term treatment-associated dysfunction.
Three lines of evidence exist that are beginning to inform our understanding of the relationship between radiation and swallowing function following cure of OPSCC. The first is driven by continued improvements in anatomic imaging, specifically MRI. Messer et al. discuss utilization of MRI during treatment to evaluate radiation-induced changes in swallowing structures such as the pharyngeal constrictors. Although this type of imaging-based analysis is still far from broad-based clinical implementation, it could theoretically inform treating clinicians of normal tissue radiation toxicity in real-time, in individual patients. This approach complements more empirically driven efforts to utilize intensity modulated radiotherapy (IMRT) to spare structures critical to swallowing such as the constrictors, by reducing the delivered dose. Feng et al. showed that such an approach can still achieve good oncologic outcomes for OPSCC while potentially improving post-treatment function. Finally, the introduction of better and more well-defined patient reported outcome (PRO) tools as recently reported by the MD Anderson Head and Neck Cancer Symptom working group (2017), provides increased patient input in a quantifiable and potentially reproducible manner.
The challenge for clinicians treating HPV+ OPSCC patients remains making the transition from research to clinical practice as it relates to functional outcomes. Current trials aimed at treatment de-escalation for HPV+ OPSCC will automatically reduce the dose delivered to critical structures and are likely to indirectly drive improved functional outcomes. However, concerted efforts across institutions are required to collect functional outcome data and advance the state of current clinical practice more rapidly. Institutions must define for themselves and their respective populations a series of PROs, objective functional measures (i.e. modified barium swallow) and dosimetric considerations, and continue to evaluate their impact in an iterative fashion. This will allow us to transition functional outcome studies from a research endeavor to a basic quality control and quality improvement one.
Messer JA, Mohamed AS, Hutcheson KA, Ding Y, Lewin JS, Wang J, Lai SY, Frank SJ, Garden AS, Sandulache V, Eichelberger H, French CC, Colen RR, Phan J, Kalpathy-Cramer J, Hazle JD, Rosenthal DI, Gunn GB, Fuller CD. Magnetic resonance imaging of swallowing-related structures in nasopharyngeal carcinoma patients receiving IMRT: Longitudinal dose-response characterization of quantitative signal kinetics. Radiother Oncol. 2016 Feb;118(2):315-22. doi: 10.1016/j.radonc.2016.01.011. Epub 2016 Jan 28. PMID: 26830697
Feng FY, Kim HM, Lyden TH, Haxer MJ, Worden FP, Feng M, Moyer JS, Prince ME, Carey TE, Wolf GT, Bradford CR, Chepeha DB, Eisbruch A. Intensity-modulated chemoradiotherapy aiming to reduce dysphagia in patients with oropharyngeal cancer: clinical and functional results. J Clin Oncol. 2010 Jun 1;28(16):2732-8. PMID: 20421546
MD Anderson Head and Neck Cancer Symptom Working Group, Eraj SA, Jomaa MK, Rock CD, Mohamed ASR, Smith BD, Smith JB, Browne T, Cooksey LC, Williams B, Temple B, Preston KE, Aymard JM, Gross ND, Weber RS, Hessel AC, Ferrarotto R, Phan J, Sturgis EM, Hanna EY, Frank SJ, Morrison WH, Goepfert RP, Lai SY, Rosenthal DI, Mendoza TR, Cleeland CS, Hutcheson KA, Fuller CD, Garden AS, Gunn GB. Long-term patient reported outcomes following radiation therapy for oropharyngeal cancer: cross-sectional assessment of a prospective symptom survey in patients ≥65 years old. Radiat Oncol. 2017 Sep 9;12(1):150. doi: 10.1186/s13014-017-0878-9. PMID: 28888224
Surgical Technique in the Treatment of Head and Neck Cancer
Vlad C. Sandulache, M.D., Ph.D.
Nov. 13 - 17, 2017
Specific question: Do surgical margins matter?
Each year, approximately 50,000 patients receive a diagnosis of head and neck squamous cell carcinoma (HNSCC) in the United States. Despite advances in targeted agents and more recently immunotherapy, there are 2 definitive, proven treatment modalities which are essential to achieving an oncologic cure for the vast majority of HNSCC patients: surgery and external beam radiation (EBRT). From the time of Billroth, head and neck surgeons have known that they play a critical role in the treatment of HNSCC. With continued advances in laser technology and robotics, that role has only increased over the last few decades. However, despite technological changes, the fundamental principle of surgical excision for HNSCC remain today as it was in Billroth’s time: complete surgical excision to negative margins.
The article from Byers et al. (1978) is a must read for all head and neck surgical oncologists. It not only addresses the impact of achieving negative margins, but also demonstrates the importance of communication between surgeon and pathologist with regard to specimen orientation and processing to insure appropriately pathological evaluation of tumor margins. The dataset summarized in this article is particularly important because it predates the routine implementation of adjuvant radiation in the post-operative setting as is common for most patients with advanced HNSCC today.
As summarized by Bernier and colleagues (2005) in their combined analysis of EORTC 22931 and RTOG 9501, the addition of chemotherapy to post-operative radiation can provide benefit in patients with positive margins. What is often lost in this analysis is the implicit understanding that positive margins have a negative impact on clinical outcomes. Although escalation of treatment through the addition of adjuvant radiation and/or chemotherapy can overcome some of the deficit of failing to achieve negative margins, we cannot forget that these gains come at the expense of both acute and long term treatment related toxicity. Today, as in 1873, achieving negative margins at the time of surgery is one of the most important things surgeons can do to maximize a patient’s chance of survival.
Bernier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, Ozsahin EM, Jacobs JR, Jassem J, Ang KK, Lefèbvre JL. 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 Oct;27(10):843-50. PMID: 16161069
Byers RM, Bland KI, Borlase B, Luna M. The prognostic and therapeutic value of frozen section determinations in the surgical treatment of squamous carcinoma of the head and neck. Am J Surg.1978 Oct;136(4):525-8. PMID: 707736