Should HPV status guide treatment in oropharyngeal carcinoma?
Ron J. Karni, MD
Associate Professor & Chief
Over the past decade, a rise in the incidence of oropharynx cancer has been associated with HPV positivity. This shift in the demographics of head and neck cancer may be related to a decreasing population of patients with tobacco exposure, better molecular detection of HPV markers, and increasing HPV exposure. Early studies describing the rising incidence of HPV markers in oropharynx cancer also demonstrated a survival advantage for patients with HPV-positive malignancies who undergo traditional treatment using chemoradiation.
In order to understand the improved survival of HPV-related oropharynx cancer, one must examine the evolution of current treatment paradigms for this site. After the introduction of safe and reliable anesthesia in the early 20th century, surgery was considered the primary (and often the only) modality for locally-advanced head and neck cancer of all sites. Survival rate was predictably low with this approach and mutilating functional outcomes were not uncommon.
A role for radiation therapy in the treatment of head and neck malignancies came into standard use in the 1970’s. At that time, tumor boards struggled with correctly prescribing a balance of surgery and radiation therapy for each individual tumor site. Certain anatomic sites such as the oral cavity seemed more amenable to a combination approach using surgery to remove all perceptible tumor in the primary site and neck and radiation therapy given in post-operative (lower) doses to maintain locoregional control. Incorporating surgery in the treatment of oral cavity cancers also permitted new innovations in surgical reconstruction (such as microvascular free tissue transfer) to positively affect functional outcomes in speech and swallow.
Treatment allocation between radiation and surgery for laryngeal cancer has a similar trajectory. Open surgical approaches to the larynx which preserve laryngeal function were described in the 1950’s to 1970’s. However, a radiotherapy-first option for the treatment of laryngeal cancer was also identified in the 1990’s, in part based on the unique ability of radiation-recurrent malignancies of the larynx to be successfully salvaged using total laryngectomy (VA Larynx Trial of 1991). Soon after, chemotherapeutic agents with notable cytoreductive qualities in head and neck cancer were added to radiation therapy regimens. Improvements in radiotherapy techniques such as IMRT were also incorporated in standard head and neck regimens.
While surgical approaches were able to maintain key advantages over primary radiation therapy in the oral cavity and larynx, other sites in the head and neck such as the nasopharynx and oropharynx were relegated to a strictly radiation-based approach. This is due, in large part, to the inherent anatomic limitations in accessing large areas of the oropharynx and nasopharynx without disassembling vital components of the musculoskeletal framework and causing irreparable damage to swallow and other functional outcomes. A classic example is the “commando” operation for lateral oropharyngeal tumors which fell out of favor in the era of chemoradiation.
In the late 1980’s, the advantages of laparoscopic and minimally-invasive techniques in other surgical disciplines soon became apparent among head and neck oncologic surgeons. Steiner and others described new approaches to tumors of the oropharynx using Transoral Laser Microsurgery (TLM) .1, 2 The ability to use remote (not hand-held) cutting tools such as the CO2 laser, coupled with the improving visualization of the microscope and fiberoptic cameras, quickly led to a body of literature supporting TLM with neck dissection as a viable alternative to chemoradiation as primary modality for the oropharynx.
Both in terms of oncologic outcomes and functional preservation, TLM-based approaches to oropharyngeal cancer have shown marked improvements over traditional chemoradiation. Several studies have shown that patients who undergo TLM with neck dissection and post-operative (lower) doses of radiation enjoy unparalleled functional outcomes, with long-term gastrostomy tube dependence as low as 3%. 3 Survival outcomes are also markedly improved in TLM studies over almost all contemporary cohorts for the treatment of oropharynx cancer using chemotherapy with radiation.
Building on the success of TLM, robotic approaches to the treatment of oropharynx tumors were described in the last five years. Trans-Oral Robotic Surgery (TORS) improves surgical access, visualization, and precise cutting. Early results using robotic transoral techniques for the treatment of oropharynx cancer have further illustrated the distinct functional and survival advantages of surgical treatment in these patients .4
Tumor Boards must now contend with a volume of important data points and treatment options in determining the best possible therapy for patients with oropharynx cancer. One of these data points is HPV-status. However, there is much confusion about whether HPV positivity confers a survival advantage for radiation-based treatments over surgical treatments. A common misconception is that HPV-positive tumors should be treated with chemoradiation independent of whether they would be good candidates for a minimally-invasive surgical approach (TLM or TORS). This misconception has propagated because the landmark studies identifying the survival advantage for HPV-related tumors were described in patients undergoing mostly chemoradiation (and before the era of TLM and TORS).
There are several authors that have recently evaluated the significance of HPV positivity in patients undergoing surgery as primary modality for oropharynx cancer. Interestingly, HPV positivity confers a similar survival advantage in patients treated surgically and in patients treated with chemoradiation. 5,6 This suggests that the survival advantage imparted by HPV has more to do with the host-cancer interactions (immune system) than with specifically favorable interactions between HPV and chemoradiation. A recent Swiss study evaluated this issue by reviewing survival outcomes according to HPV status and surgery versus chemoradiation. The cohort of patients who were HPV positive and underwent surgery as primary modality had the best oncologic outcomes (p=0.067). 6
In summary, the discovery that HPV positivity confers a similar survival advantage for the treatment of oropharynx cancer with surgery as it does with traditional chemoradiation suggests that HPV positivity should not play a role in tipping the balance towards or away from surgery as a primary modality. More importantly, the basic principles of oncologic therapeutics need to be revisited with every new patient. Nodal stage is oft forgotten but is clearly the most important predictor of survival outcomes in head and neck cancer. Because greater than 80% of patients with oropharyngeal tumors have advanced nodal stages, a primary consideration for treatment is the aggressive and multimodality treatment of the neck. The addition of TLM or TORS to the armamentarium of the head and neck cancer surgeon allows for additional treatment of the primary site and concurrent neck dissection at little or no functional cost to the patient. In turn, patients can simultaneously benefit from lower (post-operative) doses of radiation therapy, better functional outcomes (swallow), multimodality treatment of the primary site and neck and improved survival.
- Steiner W, Fierek O, Ambrosch P, Hommerich CP, Kron M. Transoral laser microsurgery for squamous cell carcinoma of the base of the tongue. Arch Otolaryngol Head Neck Surg. 2003 Jan;129(1):36-43.
- Holsinger FC, McWhorter AJ, Ménard M, Garcia D, Laccourreye O. Transoral lateral oropharyngectomy for squamous cell carcinoma of the tonsillar region: I. Technique, complications, and functional results. Arch Otolaryngol Head Neck Surg. 2005 Jul;131(7):583-91.
- Rich JT, Milov S, Lewis JS Jr, Thorstad WL, Adkins DR, Haughey BH. Transoral laser microsurgery (TLM) +/- adjuvant therapy for advanced stage oropharyngeal cancer: outcomes and prognostic factors. Laryngoscope. 2009 Sep;119(9):1709-19.
- Weinstein GS, O’Malley BW Jr, Cohen MA, Quon H. Transoral robotic surgery for advanced oropharyngeal carcinoma. Arch Otolaryngol Head Neck Surg. 2010 Nov;136(11):1079-85.
- Haughey BH, Hinni ML, Salassa JR, Hayden RE, Grant DG, Rich JT, Milov S, Lewis JS Jr, Krishna M. Transoral laser microsurgery as primary treatment for advanced-stage oropharyngeal cancer: A united states multicenter study. Head Neck. 2011 Jan 31.
- Fischer CA, Zlobec I, Green E, Probst S, Storck C, Lugli A, Tornillo L, Wolfensberger M, Terracciano LM. Is the improved prognosis of p16 positive oropharyngeal squamous cell carcinoma dependent of the treatment modality? Int J Cancer. 2010 Mar 1;126(5):1256-62.