Ten Years of Progress in Head and Neck Cancers

Squamous cell carcinoma of the head and neck (HNSCC) is a heterogenous disease characterized by complex clinical and pathologic presentations comprising approximately 90% of all head and neck cancers. The past decade has seen important advances in our understanding of the epidemiology, pathogenesis, and management of HNSCC. It is a disease increasingly managed by a multi-disciplinary team of providers, as reflected in the updates of NCCN Clinical Practice Guidelines in Oncology for head and neck cancer (view the most recent version of the guidelines at the NCCN Web site at www.NCCN.org).

Epidemiology

The incidence of HNSCC has remained relatively stable over the past 10 years in the United States, despite declining rates of smoking, the major risk factor for HNSCC.^1,2 This discrepancy is at least partially explained by the emerging role of infection with high-risk subtypes of human papillomavirus (HPV), a risk factor for cancer of the oropharynx.^3,4 HPV viral oncogenes E6 and E7 inactivate tumor suppressor genes p53 and Rb, respectively.⁵ A substantial and growing proportion of oropharynx cancers – for example, an increase in HPV-positive tonsillar cancer in a Swedish Cancer Registry study from 23.3% in the 1970s to 68% approximately 30 years later - are now attributed to high-risk subtypes of HPV.^6,6a The NCCN recommends that all oropharynx tumors be tested for HPV using immunohistochemical (IHC) staining for p16 overexpression, a reliable marker for HPV gene integration,^7,8 or in-situ hybridization testing for detection of virus.

Numerous studies have shown that patients with HPV-related oropharynx SCC show an improved response to treatment and overall survival, after adjusting for traditional prognostic factors. However, smoking remains an independent predictor; patients with an HPV-related tumor and a smoking history (10 pack-years was the cut off used in a recent important study) have a worse prognosis than patients with HPV-related tumors and no smoking history. ^9–11 In an analysis of patients with Stage III or IV, M0 disease treated on RTOG 0129, patients with HPV-related HNSCC had 3-year overall survival rates of 82.4% compared with 57.1% in patients with HPV negative tumors (P < .001).

This trend has led investigators to research de-escalation of treatment for patients with HPV-related HNSCC. For example, a phase III trial (RTOG 1016) is currently underway randomizing patients with locally or regionally advanced disease to concurrent chemoradiation with cisplatin versus cetuximab in HPV-positive patients. Although HPV status of the tumor is considered in the management of occult primary cancers, treatment recommendations in the NCCN guidelines for the most part are currently based on stage and anatomic location of the tumor. However, the results of on-going trials will hopefully enable future integration of HPV status into treatment algorithms in a more substantial way.

Novel Therapeutics

Advances in our understanding of the genetic instability and the progression of disease in HNSCC are identifying new prognostic markers and therapeutic targets. On going studies are examining inhibitors of the vascular endothelial growth factors (VEGF), platelet-derived growth factors (PDGF), inhibitors of the mammalian target of rapamycin (mTOR), and other cellular pathways, either as single agents or in combination with cytotoxic chemotherapy.

In 2006, the U.S. FDA approved cetuximab, a human-mouse chimeric monoclonal antibody targeting the epidermal growth factor receptor (EGFR), as a single agent in patients with recurrent or metastatic HNSCC who had undergone prior platinum-based therapy. It was also approved for concomitant use with radiation in the primary treatment of locally or regionally advanced HNSCC. In a phase III study, cetuximab and concurrent radiation prolonged median overall survival by 19.7 months when compared with radiation alone in patients with locoregionally advanced tumors (P = .03); the estimated 5-year survival rate improved by 9.2% on the cetuximab arm.^12,13 Among patients treated with cetuximab, the development of a grade 2 or greater acneiform rash was associated with improved overall survival (P = .002).

The FDA expanded the indication of cetuximab to include its combination with chemotherapy for patients with recurrent or metastatic disease based on the results of the EXTREME study.¹⁴ In that study, patients with recurrent or metastatic disease were randomized to receive either the combination of cetuximab with chemotherapy (cisplatin or carboplatin and 5-fluorouracil) or chemotherapy alone. Patients receiving cetuximab with chemotherapy lived, on average, 10.1 months, compared with 7.4 months for those receiving chemotherapy only (P = .04).¹⁴ The identification of molecular and clinical predictors of response to anti-EGFR based therapy is an active area of investigation.

A small minority (< 5%) of patients receiving cetuximab experience a severe hypersensitivity reaction, typically with the first dose. In this regard, higher rates of hypersensitivity reactions have been identified in patients living in certain states, particularly in the Southeast United States, and appear associated with the pretreatment presence of IgE antibodies against galactose-α-1,3-galactose.¹⁵ The regional exposure that might explain the development of this antibody is not yet clearly defined.

Chemotherapy

The results of a meta-analysis combining the outcomes of 87 trials and 16,485 participants helped clarify the role of chemotherapy as part of definitive treatment for HNSCC.¹⁶ The hazard ratio of death was 0.88 (P < .0001) with an absolute benefit for chemotherapy of 4.5% at 5 years. A significant interaction (P < .0001) was seen between chemotherapy timing (adjuvant, induction, or concomitant) and outcomes. In trials studying the addition of concurrent chemotherapy to radiation, the hazard ratio was 0.81 (P < .0001) with an absolute benefit of 6.5% at 5 years. A decreasing effect of chemotherapy was seen with age.

In 2004, the results of two pivotal trials evaluating concurrent chemoradiation in the adjuvant setting for locally or regionally advanced, resected tumors were published. Both the RTOG 9501 and EORTC 22931 studied the impact of concurrent cisplatin 100 mg/m² on days 1, 22, and 43 with postoperative radiation versus radiation alone, following resection of locally advanced disease with high-risk surgical or pathologic features.^17,18_ENREF_14 In a meta-analysis combining these study results, the authors noted that patients with pathologic evidence of extra-capsular extension or positive surgical margins had a statistically significant improvement in both locoregional control and overall survival when treated with adjuvant concurrent chemoradiation compared to radiation alone.¹⁹ Patients who had neither of these factors did not appear to benefit from adjuvant chemoradiation (EORTC trial 22931, P = .33; RTOG trial 9501, P = .78). No significant impact on distant control was seen in either study, and the addition of cisplatin did increase acute severe adverse events.

The debate regarding the role of induction chemotherapy continues. Randomized phase III studies have shown that the addition of docetaxel to cisplatin and 5-FU as induction therapy before locoregional treatment can improve locoregional control, larynx preservation, and overall survival compared with the use of cisplatin and 5-FU alone as an induction regimen.^20–22 The regimen of paclitaxel, cisplatin, and 5-FU also appears to have added efficacy compared with cisplatin and 5-FU alone, but this combination is less well studied.²³ However, concerns regarding the potential negative impact of induction chemotherapy on the delivery of definitive concurrent chemoradiation remain, as does uncertainty as to whether its incorporation improves survival compared with use of state of the art concurrent chemoradiotherapy alone. In 2010, the preliminary results of a 3-arm phase III study evaluating chemoradiation alone versus two different induction chemotherapy regimens followed by chemoradiation were presented in abstract form. Although the study found improved time to progression in the induction arms, no overall survival benefit was seen, and methodological flaws preclude firm conclusions regarding the efficacy and tolerability of induction chemotherapy in that study.²⁴ Two recently presented phase III studies similarly failed to demonstrate improved overall survival, with the incorporation of induction chemotherapy prior to concurrent chemoradiation when compared to concurrent chemoradiation alone.^{24a, 24b}

Innovations in Surgery and Radiation Therapy for HNSCC

Head and neck surgery has also evolved over the past decade. For example, use of transoral resection robotic surgery (TORS) using the daVinci surgical robot for the resection of oropharynx tumors is growing.²⁵ The goal of minimally invasive procedures is to decrease surgical morbidity, reduce hospitalizations with the same overall survival as traditional open surgery and organ-preserving, nonsurgical treatments. Although minimally invasive procedures have been shown to be feasible, clinical trials are needed to assess which patients benefit from less-invasive surgical approaches and to compare outcomes to standard therapeutic options.²⁶ Given the high degree of skill necessary, robotic procedures should be performed at high-volume centers by experienced physicians.

Head and neck reconstruction has also seen significant advances, allowing for improved functional and quality of life outcomes. Some of the major advances in reconstructive surgery include newer techniques for free tissue transfer, integrated bone and dental rehabilitation, and motorized tissue transfer. Surgical advances will require more complex discussions with patients regarding all available therapeutic options and expected outcomes, recognizing that the data to guide these decisions are currently incomplete.

Advances in radiation oncology are aimed at improving or maintaining tumor control while minimizing the dose of radiation to surrounding normal tissue. In HNSCC in particular, the use of intensity-modulated radiation therapy (IMRT) is the major innovation in radiation delivery over the last decade. IMRT provides more conformal delivery of radiation to tumor target volumes and improved sparing of normal tissues.^26a In a multi-institutional phase III study, patients with pharynx cancers treated with parotid-sparing IMRT had lower rates of xerostomia than patients treated with conventional radiation (P = .005).²⁸ At 12 months, the rates of local tumor control appeared equivalent, but long-term outcomes with IMRT versus conventional radiation are pending. Questions remain as to whether the aggressive sparing of normal tissue may contribute to the occurrence of marginal failures caused by undertreatment of high-risk volumes.

At the same time, advancements in normal tissue sparing can allow for better tumor control through improved coverage of tumor target volumes and potentially dose-escalation, because compromises for normal tissue dose limitations are avoided (e.g., limiting spinal cord dose to prevent myelopathy). An alternative treatment approach that is attractive in head neck cancer is proton therapy, which could further decrease normal tissue doses compared with standard photon-based treatments, including IMRT. Published experience with proton therapy from the limited number of centers is growing, and availability is also expected to grow.²⁹ The results from multi-institutional studies will aid in clarifying the benefits of this newer, more expensive technique.

Conclusions

Head and neck cancer is a heterogeneous disease with a changing epidemiology. Important progress in therapeutic options has occurred over the past decade. Effective therapy requires coordination, communication, and individualized care delivered by multidisciplinary oncology and other providers. In the next 10 years, as our understanding of the molecular pathogenesis of cancer deepens, the need for clinical trials to identify optimal therapy will only increase. These studies will be critical to identifying further advances in care and deserve our support.