September - October 2017
Chemotherapy Use in Head and Neck Cancer
Vlad C. Sandulache, M.D., Ph.D.
Oct. 23 - 27, 2017
Specific question: Does timing of chemotherapy impact its effectiveness?
Conventional chemotherapy is often utilized in the treatment of advanced head and neck cancers. In general, chemotherapy can be administered prior to definitive treatment with radiation or surgery (induction) or during radiation (concurrent). Induction chemotherapy regimens can vary significantly between institutions, but they often include multiple agents, administered in several cycles prior to definitive treatment initiation. Once common induction chemotherapy regimen combines a (T)axane (i.e. docetaxel), with cis(P)latin (alkylating agent) and 5-(F)luorouracil (antimetabolite), administered every 21 days for up to 3 cycles. Concurrent chemotherapy more commonly consists of single agent regimens, among which cisplatin, administered weekly is one of the most commonly utilized. In addition to individual prospective clinical trials, there now exists large scale data addressing the relative impact of conventional chemotherapy on head and neck cancer outcomes.
Pignon et al. (2009) conducted a meta-analysis of ~16,000 patients enrolled in 87 trials and identified an absolute survival benefit from chemotherapy of 4.5% at 5 years. Their analysis favored concurrent chemotherapy over induction chemotherapy with respect to survival. However, a more detailed review of the data provides clues as to the differential impact of chemotherapy regimens on treatment failure. Whereas concurrent regimens demonstrate a significant improvement in the rate of local failure, induction regimens demonstrate their maximal effectiveness by decreasing the rate of distant failure. These data support institutional algorithms which favor induction chemotherapy in the setting of advanced loco-regional disease with a high risk of distant metastasis. The updated analysis completed in 2011 by the same group, provided additional granularity with respect to disease site, and identified a statistically significant impact for chemotherapy in laryngeal and oropharyngeal tumors.
The impact of chemotherapy on outcomes for head and neck cancer is real, measurable and statistically significant. It is also relative small (4-9 percent) depending on the disease site, manner of administration and specific regimen. Conversely, the toxicity associated with conventional chemotherapy is one of the primary drivers of current regimens and has been found to be significantly higher outside of the clinical trial setting. This is particularly true of induction chemotherapy regimens. As such, clinicians and patients must set and maintain reasonable expectations of effect size and relative toxicity for treatment regimens which include conventional chemotherapy.
Pignon JP1, le Maître A, Maillard E, Bourhis J; MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009 Jul;92(1):4-14. PMID: 19446902
Blanchard P, Baujat B, Holostenco V, Bourredjem A, Baey C, Bourhis J, Pignon JP; MACH-CH Collaborative group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site. Radiother Oncol. 2011 Jul;100(1):33-40. PMID: 21684027
Vlad C. Sandulache, M.D., Ph.D.
Oct. 16 - 20, 2017
Specific question: What drives salvage laryngectomy outcomes?
Laryngeal cancer is one of the most challenging diseases a head and neck surgeon can face. As the keystone of swallowing and phonation, it is one of the most difficult organs to sacrifice in the context of cancer treatment. This is cruelly ironic because laryngectomy is one of the most effective ablative procedures in the head and neck surgeon’s arsenal.
In large part because of the morbidity and stigma associated with laryngectomy and even partial laryngeal surgery, organ preservation approaches utilizing chemotherapy and radiation have become increasingly common over the last quarter century even for advanced laryngeal disease. Because patients with head and neck malignancies are at increased risk of developing second primary tumors, most head and neck surgeons will encounter increasing percentages of laryngeal cancer patients previously treated with radiation. As such, it is critical to understand the oncologic promise and potential pitfalls associated with salvage laryngectomy (STL). Two recent, complementary papers provide some insight into this issue.
Sandulache et al. evaluated 218 patients treated with STL following previous radiation-based treatment. The most significant drivers of outcomes following STL were found to be nodal status at the time of STL and the disease-free interval between completion of previous radiation and STL. This second factor was particularly interesting given that it may, in fact, represent a surrogate marker of disease biology (aggressive vs indolent disease). More recently, Birkeland et al. evaluated 244 patients treated with STL. This analysis confirmed the importance on the nodal status on STL outcomes, but also demonstrated a strong comorbidity impact on survival. Together, these large retrospective reviews from tertiary institutions suggest that STL outcomes are a function of both disease biology and patient-related factors. As such, both parameters must be carefully considered in counseling patients prior to STL. Consistent with previous work, both studies report overall survival following STL in the range of 50% and provide additional outcomes data which may be useful for trainees in setting appropriate expectations vis a vis peri-operative complications.
Birkeland AC, Beesley L, Bellile E, Rosko AJ, Hoesli R, Chinn SB, Shuman AG, Prince ME, Wolf GT, Bradford CR, Brenner JC, Spector ME. Predictors of survival after total laryngectomy for recurrent/persistent laryngeal squamous cell carcinoma. Head Neck. 2017 Sep 30. doi: 10.1002/hed.24918. PMID: 278963806
Sandulache VC, Vandelaar LJ, Skinner HD, Cata J, Hutcheson K, Fuller CD, Phan J, Siddiqui Z, Lai SY, Weber RS, Zafereo ME. Salvage total laryngectomy after external-beam radiotherapy: A 20-year experience. PMID: 26879395
Head and Neck Cancer Treatment
Vlad C. Sandulache, M.D., Ph.D.
Oct. 2 - 6, 2017
Specific question: Does treatment delivery impact clinical outcomes for head and neck cancer?
Despite decades of research, clinical outcome for patients with advanced head and neck squamous cell carcinoma (HNSCC) have remained nearly unchanged at multiple disease site including oral cavity, larynx and hypopharynx. As yet, no targeted agents have entered routine clinical practice with the exception of Cetuximab, an epithelial growth factor receptor (EGFR) antibody. Whether immunotherapy will prove efficacious in improving survival in patients with advanced HNSCC remains to be seen. As such in 2017, much like in 1987, most patient with advanced HNSCC will undergo a combination of surgery, radiation and conventional chemotherapy. What has become clear however over the last 25 years, is that the manner in which conventional treatments are delivered can greatly impact clinical outcomes.
The National Comprehensive Cancer Network (NCCN) guidelines recommend that patients should initiate adjuvant or post-operative radiation within 6 weeks of surgery. This recommendation is made in large part on the basis of older studies which demonstrated improved survival. In the modern era, Parsons and Rosenthal demonstrated that completion of surgical and post-surgical treatment (i.e. radiation +/- chemotherapy) within a total treatment package time of 100 days had a significant impact on survival. Despite this, Graboyes et al. found that at a population level, >50% of patients do not receive adjuvant radiation within 6 weeks post-surgery, resulting in decreased survival. Completion of the proscribed radiation course in a timely fashion has also become a well-accepted standard at most tertiary institutions. However, nearly 25% of patients in the US will experience delays or treatment breaks during their radiation course, resulting in decreased survival (Shaikh et al. 2016).
As we continue to search for novel treatments for HNSCC, it is important that we remember that doing the basic things well has been shown to have a great impact on survival for patients with this deadly disease.
Parsons JT, Mendenhall WM, Stringer SP, Cassisi NJ, Million RR. An analysis of factors influencing the outcome of postoperative irradiation for squamous cell carcinoma of the oral cavity. Int J Radiat Oncol Biol Phys 1997;39(1):137-48. PMID: 9300748
Rosenthal DI, Liu L, Lee JH, Vapiwala N, Chalian AA, Weinstein GS, Chilian I, Weber RS, Machtay M. Importance of the treatment package time in surgery and postoperative radiation therapy for squamous carcinoma of the head and neck. Head Neck. 2002 Feb;24(2):115-26. PMID: 11891941
Graboyes EM, Garrett-Mayer E, Ellis MA, Sharma AK, Wahlquist AE, Lentsch EJ, Nussenbaum B, Day TA. Effect of time to initiation of postoperative radiation therapy on survival in surgically managed head and neck cancer. Cancer. 2017 Aug 25. doi: 10.1002/cncr.30939. PMID: 28841234
Shaikh T, Handorf EA, Murphy CT, Mehra R, Ridge JA, Galloway TJ. The Impact of Radiation Treatment Time on Survival in Patients With Head and Neck Cancer. Int J Radiat Oncol Biol Phys. 2016 Dec 1;96(5):967-975. PMID: 27869097
Oral Cavity Cancer
Vlad C. Sandulache, M.D., Ph.D.
Sept. 11 - 15, 2017
Specific question: What is the role of sentinel node biopsy in early stage oral cavity cancer
Oral cavity squamous cell carcinoma has a high propensity for metastasis to cervical lymph nodes even at early stages. Classical teaching has held that elective neck dissection is warranted when the risk of cervical metastasis reaches 20 percent. Primarily retrospective data have indicated that this risk is a function of tumor biology, T stage and depth of invasion. Depending on the institution, elective neck dissections are generally considered and performed for depth of invasion >3-4mm. At some institutions, elective neck irradiation is substituted for elective neck dissection if the primary tumor presents with adverse features which warrant adjuvant radiation.
Although the morbidity of a selective neck dissection can be low in the hands of a well-trained head and neck surgeon, no surgeon can ever claim that a neck dissection is free of morbidity. In addition, although nodal patterns generally conform to those described by Byers in the 80s, some variability does exist in nodal spread of OSCC. As a result, an increasing number of head and neck surgeons have begun to employ sentinel node biopsy for staging purposes in early T stage OSCC. A sentinel node biopsy in the setting of T1-2 OSCC can take the place of an elective neck dissection in order to determine whether occult metastatic disease is present in cervical lymph nodes.
Civantos et al. evaluated the negative predictive value of sentinel node biopsy in 140 patients with OSCC and arrived at a value of 94 percent which increased with surgeon experience. Agrawal et al. evaluated the negative predictive value of sentinel node biopsy in 101 patients with OSCC and arrived at a value of 98 percent when using [99mTc] Tilmanocept. As in the context of melanoma, there is no substantial data regarding the therapeutic impact of a sentinel node biopsy, but its role as a staging tool is becoming increasingly clear. As most training programs routinely employ sentinel node biopsy in the treatment of melanoma, it is likely that an increasing number of head and neck surgeons will transition from elective neck dissection to sentinel node biopsy in the setting of early T stage OSCC, particularly in the case of midline lesions.
Civantos FJ, Zitsch RP, Schuller DE, Agrawal A, Smith RB, Nason R, Petruzelli G, Gourin CG, Wong RJ, Ferris RL, El Naggar A, Ridge JA, Paniello RC, Owzar K, McCall L, Chepeha DB, Yarbrough WG, Myers JN. Sentinel lymph node biopsy accurately stages the regional lymph nodes for T1-T2 oral squamous cell carcinomas: results of a prospective multi-institutional trial. J Clin Oncol. 2010 Mar 10;28(8):1395-400. PMID: 20142602
Agrawal A, Civantos FJ, Brumund KT, Chepeha DB, Hall NC, Carroll WR, Smith RB, Zitsch RP, Lee WT, Shnayder Y, Cognetti DM, Pitman KT, King DW, Christman LA, Lai SY. [(99m)Tc]Tilmanocept Accurately Detects Sentinel Lymph Nodes and Predicts Node Pathology Status in Patients with Oral Squamous Cell Carcinoma of the Head and Neck: Results of a Phase III Multi-institutional Trial. Ann Surg Oncol. 2015 Oct;22(11):3708-15. PMID: 25670018
Human Papilloma Virus Vaccination (HPV)
Vlad C. Sandulache, M.D., Ph.D.
Sept. 4 - 8, 2017
Specific question: What is the current status of HPV vaccination in the United States?
Head and neck squamous cell carcinoma has traditionally been associated with conventional risk factors such as alcohol and tobacco exposure. Over the last two decades, it has become clear that exposure to the human papilloma virus (HPV), particularly strains 16 and 18 is associated with an increased risk of head and neck squamous cell carcinoma, predominantly in the oropharynx (i.e. tonsils, base of tongue, pharyngeal wall). Over the last decade, we have witnessed a nearly epidemic increase in the incidence of oropharyngeal squamous cell carcinoma associated with HPV. Although conventional chemo-radiation strategies are very effective at achieving a cure in the setting of HPV+ disease, there are significant concerns about long-term, treatment-related toxicity and loss of function in cancer survivors.
Vaccination against HPV infection has provided a true breakthrough in the fight against HPV associated cervical cancer and is now available, with variable penetrance, in many countries around the world. Although no studies have definitively proven that HPV vaccination can lower the incidence of oropharyngeal squamous cell carcinoma, there is strong circumstantial evidence that vaccination generates effective titters which rise above those associated with an acute HPV infection. The review by Harper and DeMars (2017) provides an excellent overview of the existing vaccination options (Gardasil®, Gardasil® 9 and Cervarix®), discusses the relevant HPV subtype coverage for each vaccine, and the impact of vaccination schedules on serum titters. The authors also review existing evidence regarding the positive impact HPV vaccination has had on the incidence of cervical intraepithelial neoplasia (CIN) and carcinoma in situ. Unfortunately, as Barnard et al. 2017 explain, attitudes regarding the relative risk of HPV exposure are such that many young people underestimate their exposure risk. It is essential that clinicians, especially primary care providers give patients and parents accurate and timely information regarding HPV vaccination. Data from Warner et al. (2017) suggest that discussions regarding HPV vaccination be specific, detailed and to some degree repetitive, in order to insure appropriate patient and parental education.
Barnard M, George P, Perryman ML, Wolff LA. Human papillomavirus (HPV) vaccine knowledge, attitudes, and uptake in college students: Implications from the Precaution Adoption Process Model. PLoS One. 2017 Aug 7;12(8):e0182266. PMID: 28786994
Warner EL, Ding Q, Pappas L, Bodson J, Fowler B, Mooney R, Kirchhoff AC, Kepka D. Health Care Providers' Knowledge of HPV Vaccination, Barriers, and Strategies in a State With Low HPV Vaccine Receipt: Mixed-Methods Study. JMIR Cancer. 2017 Aug 11;3(2):e12. PMID: 28801303