Oropharyngeal Cancer Management (Tonsil Cancer, Base of Tongue Cancer, Soft Palate Cancer, Pharyngeal Wall Cancer) - Cancer of the Oropharynx

Hoffman H, Anderson C, Buatti J, Bayon R, Pagedar N

return to: Cancer Care Principles

see update 3-28-2015: Oropharyngeal Cancer, HPV, and Patient Counseling; Transoral Robotic Surgery

Note: last updated before 2016

The following discussion addresses squamous cell carcinoma of the oropharynx. Lymphoma and other cancer types occur in the oropharynx but are not part of this discussion. Oropharyngeal cancers most commonly arise in the tonsil or base of tongue. Other sites of the oropharynx less commonly involved are the soft palate, uvula, and posterior pharyngeal wall. The following management plan is under continued reassessment and revision and reflect the current (May 2011) opinion of the coauthors.

Background

Oropharyngeal cancer has become more common over the past two decades and occurs in a male/female ration of 3/1.  The majority of oropharyngeal cancers are currently associated with human papillomavirus (HPV) infection. Hammarsted et al (Hammarsted 2006) identified HPV DNA tonsil cancer infection into be increasing across the decades through study of archived tonsil cancer specimens. These researchers reported the HPV positive percentage (%) to increase from the 1970's (23%) to 1980's (28%) to 1990's (57%) to the period after 2000 (68%). Among the hundreds of subtypes of HPV, the most common to be associated with oropharyngeal cancer is HPV 16 -- and was identified in 87% of oropharynx cancer specimens by Kreimer et al (Kreimer 2005). Analysis of tumor specimens for the presence of HPV infection is confounded by the hypersensitivity of the polymerase chain reaction (PCR) to detect HPV. Other methods for HPV detection include 'type specific HPV DNA in situ hybridization' and 'QRT-PCR' (quantitative reverse transcriptase PCR).

Limitations in the evaluation for HPV has led to use of immunohistochemistry staining for p16 as another approach to identify HPV infection in a tumor specimen. p16 accumulates within tumor tissue as a byproduct of HPV-related tumorigenesis and therefore may serve as a surrogate for HPV infection (Gillespie 2009).

Traditionally, most cases of oropharyngeal cancer were associated with chronic tobacco and alcohol use.  This exposure resulted in the mutational loss of the p16 and p53 genes. Decreased use of tobacco coupled with an increase in the HPV+'ve oropharyngeal (OP) cancer cases has shifted the majority of OP cancers to now occur more commonly in non-smokers.  An 'epidemic' of HPV related oropharyngeal cancer has been identified and attributed to HPV+'ve disease in many cases thought to result from oral genital contact (Ernster 2007).

Although the NCCN guidelines (as of 5-07-11) identify value in HPV testing solely for prognostic purposes and not to direct therapy, other investigators (Gillespie 2009) have suggested value in HPV testing to:

1. Assess patient prognosis
2. Optimize treatment selection
3. Determine site of origin of occult neck metastasis
4. Offer patient education
5. Determine eligibility for future therapy

Differences in behavior between HPV+ and HPV- oropharyngeal cancers have supported segregation of these tumor types as distinctly separate entities.

1. HPV+'ve patients have better survival. Fakhry et al (ref Fakhry 2008) in a prospective study of 96 stage III and IV oropharyngeal and laryngeal cancer patients treated with chemo-radiation identified a much better two-year overall survival in the HPV+ group (95%) than the HPV- group (62%).
2. HPV+'ve patients are at lower risk for second primary cancers compared to HPV-'ve patients (Licitra 2006 and Hafkamp HC 2008).
3. HPV+'ve patients have different epidemiological factors compared to HPV-'ve
   1. HPV+'ve are less likely to smoke tobacco and less likely to use alcohol heavily
   2. HPV+'ve have better dentition
   3. HPV+'ve have higher incidence of oral sex practice
   4. HPV+'ve present at a younger age and higher socioeconomic status
   5. HPV+'ve show increasing incidence

Miller et al (Miller 2001) estimated that 10% of the general population harbor HPV DNA in the upper aerodigestive tract. Despite the known association between HPV infection with high risk subtypes (HPV16/18) and cancer, Gillespie et al (Gillespie 2009) relate that currently "there is no evidence that HPV-cancer can be spread from one partner to another, and therefore patients and their partners can be reassured in this regard."

Initial Evaluation (consistent with current NCCN guidelines ref below: NCCN 5-07-2011)

1. Physical Examination
   1. Include flexible fiberoptic transnasal imaging of pharynx and larynx
      1. Include transoral examination employing tongue depressor to image faucial arches/tonsils/posterior pharyngeal wall
      2. Ideally done with video and still digital recordings for repeated reference to anatomic images
   2. Deep palpation of the tonsils and base of tongue
   3. Palpation of the neck
   4. Complete head and neck exam
2. Biopsy
   1. Include HPV/p16 analysis
   2. Not yet established that HPV/p16 status should impact on management choices. Ongoing evaluation is considering more limited use of chemotherapy in the HPV+'ve tumors – considered to generally be more radiosensitive than the HPV-'ve tumors.
3. Radiographic imaging
   1. Dental evaluation to include panorex
   2. CT and or MRI of pharynx and neck
   3. PET for stage III / IV disease (note more liberal use generally employed at U of Iowa for most oropharyngeal cancers)
   4. Imaging of the chest (is included when PET imaging is done via accompanying CT)
   5. Likely useful to routinely obtain "OPMS" = "oropharyngeal motility study" (aka "cookie swallow") done with Speech Pathology in attendance
4. Consultations
   1. Radiation Oncology
   2. Medical Oncology (depending on patient preference and expected treatment, medical oncology involvement may be limited to tumor board discussion if the patient has early stage disease targeted for treatment without chemotherapy)
      1. Consider audiogram if chemotherapy is part of treatment plan
   3. Dental evaluation
   4. In addition to speech pathology involvement with "OPMS" (above) consider nutrition evaluation and speech pathology assessment separate from swallowing evaluation (if relevant: impaired speech, need for counseling re: "life w/o the larynx")

Management Philosophy

1. Initial choice of treatment is dependent primarily on patient preference, tumor size, tumor location, and co-existing comorbidities.
2. Decision making at the University of Iowa is made through multidisciplinary care focused on a weekly tumor board discussion. Consultations with the specialties involved in caring for the patient (see above initial evaluation) are important to permit a dialogue at tumor board leading to a list of possible management approaches. These options are presented to the patient by the primary oncologist (surgical oncologist, radiation oncologist and/or medical oncologist) as a discussion from tumor board. The final recommendation is made by the treating physician. The final choice is made by the patient.
3. The 'first choice' of management suggested by the tumor board for similarly staged tumors in similar patients has changed across the years and will likely continue to change with medical advances. The alternative second choice (and third, fourth etc) are presented in the context of the discussion at tumor board. It is not uncommon for a patient to chose a treatment choice that had been ranked something other than 'first choice' at tumor board.
4. Management at the University of Iowa focuses on offering the highest possible chance for cure in the context of limiting morbidity from treatment. A current focus on diminishing the toxicity of chemotherapy is entertained with the understanding that use of adjuvant chemotherapy in appropriately selected patients improves survival (Furness - Cochrane analysis 2011). Additional emphasis on decreasing the morbidity from open approaches requiring mandibulotomy (see: Mandibulotomy) or mandibulectomy has led to a more liberal use of transoral surgical resection as initial treatment. The following broad summary expresses this approach: 
   1. Recommendations are currently more liberally made for treatment with transoral surgery either alone or with postoperative radiation for small (T1 or T2) tumors that are amenable to transoral resection
      1. Transoral resection with or without robotics coupled with neck dissection
         1. Widely clear margins and limited neck disease may permit observation without post-operative adjuvant therapy
         2. Aggressive features at the primary site or presence of nodal metastases may warrant the addition of postoperative radiation
         3. Positive margins at the primary site and/or extracapsular spread in neck metastases may warrant postoperative treatment with chemoradiation
   2. Consideration for radiation as single modality therapy for small (T1 or T2) tumors not amenable to transoral resection (midline base of tongue, poor surgical access, comorbidities limiting surgical option) with limited (N0 or N1) neck disease.
   3. Standard treatment with chemoradiation for larger (T3 or T4) tumors or with extensive neck metastases.

Radiotherapy at the University of Iowa

Our radiation oncology department is one of the few in the nation with CT, PET and MRI simulation capabilities. This allows us to more accurately define the tumor extent in the treatment position using information from multiple imaging modalities. We use intensity modulated radiation therapy (IMRT) planning to conform to tumor volumes and spare normal tissues. A daily conebeam CT on the treatment machine results in greater reproducibility in patient position. All of these components in the expert hands of our head and neck radiation oncologists result in a radiation plan that is tailored to optimize each patient’s outcome.

References

NCCN 5-07-2011: on-line access to NCCN guidelines (version 2.2011) Cancer of the Oropharynx

Gillespie MB, Rubinchik S, Hoel B, Sutkowski N: Human Papilomavirus and Oropharyngeal Cancer: What Nee to Know in 2009. Current Treatment Options in Oncology (200) 10:296-307

Fisher CA, Zlobec I, Green E et al: Is the improved prognosis of p16 positive oropharyngeal squamous cell carinoma dependent of the reatment modality? Int. J. Cancer: 126, 1256-1262 (2010)

Kreimer AR, Clifford GM, Boyle P, and Franceschi S: Human papilomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkesr Prev 2005,14:467-475

Fakhry C, Westra W, Li S, et al: IMproved surivval of patients iwth human papillomvirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 2008,100:261-269.

Licitra L, Perrone F, Bossi P, et al:High-risk human papillomavirus affects prognosis in patients iwth surgically treated oropharyngeal squajous cell carincaom. J Clin oncol 2006, 24:5630-5636

Hafkamp HC, Manni JJ, Haesevoets A, et al: Marked differences in survival rates between smokers and nonsmokers and HPV 16-associated tonsillar carcinomas. Int J Cancer 2008, 122:2656-2664

Miller CS, Johnstone BM: HUman papillomavirus as a risk factor for oral squamous cell carincoma: a meta-analysis, 1982-1997. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001, 91:622-635

Hammarstedt L, Lindquist D, Dahlstrand H, et al: Human papillomavirus as a risk factor for the increase in incidence of tonsillar cnacer. Int J Cancer 2006, 119:2620-2623.

Furness S, Glenny AM, Worthington HV, Pavitt S, Oliver R, Clarkson JE, Macluskey M, Chan KK and Conway DI: Interventions for the treatment of oral cavity and oropharyngeal cancer: chemotherapy. Cochrane Database Syst Rev. 2011 Apr 13;4:CD006386

Ernster JA, Sciotto CG, O'Brien MM, Finch JL, Robinson LJ, Willson T, and Mathews M: Rising Incidence of Oropharyngal Cancer and the Role of Oncogenic Human Papilloma Virus. Laryngoscope, 117, 2115-2128, 2007

Smith EM, Rubenstein LM, Hoffman H, Haugen TH and Turek: Human papillomavirus, p16 and p53 expression associated with survival of head and neck cancer. Infectious Agents and Cancer 2010, 5:4

Smith EM, Ritchie JM, Summersgill KF, Hoffman HT, Wang DH, Haugen TH, Turek LP: Human papillomavirus in oral exfoliated cells and risk of head and neck cancer. J Natl Cancer Inst. 2004 Mar 17,96(6):449-55

Weinstein GS, Quon H, O'Malley BW, Kin GG and Cohen MA: Selective Neck Dissection and Deintensified Postoperative Radiation and Chemotherapy for Oropharyngeal Cancer: A Subset Analysis of the University of Pennsylvania Transoral Robotic Surgery Trial. Laryngoscope 120:1749-1755,2010  note: selective neck dissection identified ECS pathologically in 29% overall -- in 70% with pN2b; 14% with pN1   hh

Haughey BH, Hinni ML, Salassa JR, Hayden RE, Grant DG, Rich JT, Milov S, Lewis JS and Krishna M: Transoral Laser Microsurgery as Primary Treatment for Advanced-STage Oropharygneal cancer: A United STates Multicenter Study. Head & Neck  accepted 4 October 2010 on-line DOI:10.1022/hed.21669 note: selective neck dissection identified ECS in 64% overall   hh 

Dahlstrom KR, LI G, Tortoler-Luna G, Wei Q and Sturgis EM: Differences in  History of Sexual Behavior Between Patients with Oropharyngeal Squamous Cell Carcinoma and Patients with Squamous Cell Carcinoma at other Head and Neck Sites. Head and Neck vol 33 no. 6 June 2011 pp 847 - 855