Patients with newly diagnosed head and neck cancer frequently seek us out directly or are referred to our medical oncology clinic by our colleagues in surgery or radiation oncology. Our initial approach will consist of a thorough evaluation of the patient by the multiple specialties that will need to participate in the patient‘s subsequent treatment. We frequently are able to accommodate patients on the same day, thus greatly facilitating and accelerating the work-up.
Staging and Diagnostic Work-up
Patients are staged with a CT scan of the head and neck and chest including the upper abdomen as well as a PET scan to better assess for possible synchronous second malignancies and to rule out metastatic spread beyond the head and neck area.
Patients then undergo panendoscopy by the head and neck surgeon with careful evaluation and mapping of the primary site and directed biopsies in patients with no obvious primary tumor.
The findings of this examination are carefully documented in a tumor map. Since organ preservation is a major goal of therapy, patients with locoreginally advanced disease (Stages III and IV) don‘t usually have surgery as their primary treatment modality. However, in patients with an unknown primary and limited neck disease, an initial modified neck dissection may be performed. Similarly, small oral lesions can be removed by initial surgery if that approach is likely to result in a lower subsequent radiation dose.
Standard pathologic evaluation will include histologic characterization and determination of tumor grade and presence of extra-capsular spread or lymphatic invasion (in patients who have undergone neck dissection).
Currently all tumors derived from oral pharyngeal primary sites are evaluated for HPV infection. Typically this is done by determining p16 status as a highly sensitive marker of HPV infection rather than HPV itself. The latter is limited to the specific HPV subtype tested while p16 will allow determination of HPV infection independent of specific viral subtype.
Prior to initiation of treatment, a review of all clinical and pathologic data by participating specialists from medical, radiation, and surgical oncology is performed. Thus, a comprehensive multimodality treatment plan is determined.
For patients with locoreginally advanced disease, currently there are three evidence-based treatment choices: concomitant chemoradiotherapy, induction chemotherapy, or the administration of cetuximab concurrently with radiotherapy.
I consider concurrent chemoradiotherapy to be the most solidly evidence-based choice, specifically the administration of single-agent cisplatin every three weeks during standard or concomitant boost radiotherapy.
This treatment has been shown to be superior to radiotherapy alone in multiple randomized trials in general study populations. It also seems to offer a particularly good prognosis for patients with HPV-related tumors.
A frequently utilized alternative at our institution is the combination of paclitaxel or docetaxel, infusional fluorouracil (5-FU), and oral hydroxyurea given every other week with twice daily radiation therapy (TFHX). The base regimen of 5-FU, hydroxyurea, and radiotherapy was found to be effective in a randomized Phase II trial conducted by RTOG.
Furthermore, subsequent trials at our institution using TFHX demonstrated high locoregional control and overall survival rates. In fact, locoregional control exceeded systemic control, indicating failure due to microscopic systemic disease and suggesting that administration of additional chemotherapy as induction therapy might be beneficial. As a consequence, a recently completed randomized trial comparing TFHX vs. two cycles of induction chemotherapy followed by TFHX was undertaken (the DeCIDE trial). Results are not yet available.
Induction chemotherapy has been studied for close to three decades in head and neck cancer. Meta-analyses have suggested that the combination of cisplatin and 5-FU can lead to increased survival rates. More recently, two randomized trials comparing the three-drug regimen of docetaxel, 5-FU, and cisplatin (TPF) vs cisplatin and 5-FU alone showed increased survival rates with the three-drug combination.
As a result, TPF can be considered as an evidence-based standard treatment option. It may be particularly attractive to offer patients who are not able to undergo immediate radiotherapy, be it due to comorbidity or other factors.
What is unknown at this time is how a modern combination of TPF would fair in direct comparison to concurrent chemoradiotherapy standards. Similarly, it is unknown whether the administration of both strategies in sequence as tested in the above mentioned DeCIDE trial might be superior to either approach by itself.
Cetuximab & RT
A third evidence-based option is the administration of cetuximab with concurrent radiation. However, this evidence is based on a single randomized trial that compared radiotherapy alone vs radiotherapy with concurrent weekly cetuximab and demonstrated a survival advantage for the combination.
While the trial is statistically positive, there has been concern that its control arm (radiotherapy alone) is not considered a current acceptable standard. It is unknown how the combination of cetuximab and radiotherapy would compare with either induction chemotherapy or standard concurrent chemoradiotherapy.
Furthermore, at this time it is unknown whether administration of cetuximab and radiation following induction chemotherapy or the addition of cetuximab to induction and/or concurrent chemoradiotherapy might be of further benefit. Clinical trials examining these questions are in progress. Of note, subset analysis of the randomized trial suggested that patients with small primaries, advanced lymph node stage, and oropharyngeal disease might in particular benefit from the addition of cetuximab.
These clinical characteristics are frequently seen in patients with HPV-related tumors. Of note, I am not aware of evidence that elderly or poor performance status patients benefit from cetuximab and radiotherapy.
Patients with advanced head and neck cancer need comprehensive team management and combined-modality therapy. Pathologic characterization of patients with oropharyngeal tumors needs to include HPV evaluation.
Three evidence-based combined modality therapy options are described. Of these I consider concurrent chemoradiotherapy as the best supported, since it has been found to be superior in many randomized clinical trials and meta-analyses.
Of note, all three strategies will allow for organ preservation. At our institution, surgery is reserved for patients with biopsy-proven residual disease following completion of chemoradiotherapy. Consideration can be given to performing a modified neck dissection in patients with advanced initial nodal stage, particularly bulky N2 or N3 disease. In recent years, we have been able to treat a great majority of our patients with such organ-preserving strategies and have found these to be feasible for patients with primary tumors of all head and neck cancer locations.
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From OT Clinical Advisory Editor for Oncology, Ramaswamy Govindan, MD
Over the past several years, the management of patients with squamous cell cancer of the head and neck has slowly shifted from radical operations to combined modality therapy. Even though progress is slow, the recognition that the Human Papilloma Virus (HPV) is involved in the pathogenesis in some patients with head and neck cancer and the demonstration that the addition of cetuximab to radiotherapy improves outcomes compared with radiotherapy alone represent significant advances. We asked Dr. Everett Vokes, a leading expert and a pioneer in the area of combined modality therapy in the treatment of head and neck cancer, to give his thoughts.