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What are the Ongoing Therapeutic Challenges in Recurrent Squamous Cell Cancer of the Head and Neck?

What are the Ongoing Therapeutic Challenges in Recurrent Squamous Cell Cancer of the Head and Neck?

A medical oncologist, a radiation oncologist, and a surgeon share pearls and pitfalls in their specialized approaches to managing recurrent disease.

More than half of patients with squamous cell carcinoma of the head and neck will experience disease relapse. Locoregional recurrence is most common, but there is increasing evidence that metastases and distant metastases can occur. On initial presentation, 10% of cases will show metastases, but that figure can triple to 30% upon subsequent evaluation.

"What are the primary challenges in this patient population?" asked Athanassios "Ethan" Argiris, MD, a professor of medicine and medical director of the aerodigestive cancers program at the University of Pittsburgh. First, almost all patients with recurrent disease have already received radiotherapy, which can lead to chronic toxicities from prior therapy and functional impairment. It's not simply a matter of re-treating, Dr. Argiris pointed out. Issues that need to be addressed are:

Athanassios 'Ethan' Argiris, MD

• The time interval between therapies
• The resectability of the tumor
• The patient's overall condition and comorbidities
• The potential for curative treatment

"We should individualize care, and a multimodality approach is needed," Dr. Argiris said. "Salvage may play a role, and the best example of that is salvage laryngectomy. Re-irradiation may play a role in the form of intensity-modulated radiotherapy (IMRT) or stereotactic radiosurgery. There's certainly a role for systemic therapy, including traditional chemotherapy and novel agents, mainly EGFR inhibitors, and one can combine those modalities."

At the 2010 ASTRO Multidisciplinary Head and Neck Cancer Symposium in Chandler, Ariz., Dr. Argiris moderated a session on the therapeutic challenges of recurrent squamous cell carcinoma of the head and neck (SCCHN). A trio of experts offered the pros and cons of three treatment modalities: systemic therapy, re-irradiation with or without systemic therapy, and surgery.

Pros and Cons of Systemic Therapy

Systemic therapy
Presented by DR. JAN VERMORKEN
DR. JAN VERMORKEN
Outcome of patients with recurrent metastatic squamous cell carcinoma of the head and neck remains unchanged over the last 30 years despite improvement in cytotoxic therapies.
Combination therapy leads to more toxicity than single-agent therapy. However, treatment with taxanes seems to result in lower toxicity, compared with methotrexate.
Addition of cetuximab to standard platinum-based chemotherapy improves OS and PFS vs platinum-based chemotherapy alone without adversely affecting quality of life. Cetuximab also has shown promise as second-line therapy.

Conventional agents for recurrent metastatic disease include methotrexate, cisplatin, fluorouracil (5-FU), vinblastine, and doxorubicin. Used as single agents, conventional chemotherapy induces a response rate of around 25% based on data culled from multiple studies, said Jan Vermorken, MD, PhD, professor of oncology and head of the medical oncology department at University Hospital Antwerp in Belgium. Newer agents include gemcitabine (Gemzar), vinorelbine (Navelbine), irinotecan (Camptosar), paclitaxel, and docetaxel (Taxotere).

Unfortunately, neither conventional nor new agents have done much to boost overall survival (OS) rates. In Europe, methotrexate has been the standard of care for recurrent metastatic disease, but global randomized trials that have compared single-agent methotrexate with single-agent cisplatin have not shown a difference in OS, Dr. Vermorken said (Eur J Cancer 40:2071-2076, 2004; Ann Oncol 10:693-700, 1999; Cancer 52:206-210, 1983; Cancer Treat Rep 69:577-581, 1985).

This lack of impact on OS also holds true for studies that have compared methotrexate with taxanes. In the European trial that Dr. Vermorken was involved in, weekly methotrexate was compared with two schedules of paclitaxel. The response rate varied from 11% to 23%, but there was still no impact on OS.

"Going a little bit into the details of this study, patients were treated for first-line recurrent metastatic disease, and methotrexate [was used] in the way that we think of as standard: 40 mg/m2 per week, which could be escalated up to 60 mg/m2 per week. Paclitaxel was given by three-hour infusion or by 24-hour infusion, but at the same dose, 175 mg/m2, which is rather high for 24-hour infusion," he said (Ann Oncol 10:693-700, 1999).

But what the trial clearly demonstrated was the value of paclitaxel in the recurrent metastatic disease setting because of a lower toxicity rate with the three-hour infusion. Specifically, stomatitis was seen less frequently with the taxanes than with methotrexate, Dr. Vermorken said.

In terms of managing toxicity, physicians must decide whether to use single-agent therapy or combination therapy. The trend in cancer care is to rely on increasingly aggressive treatment and that's especially true when dealing with recurrent metastatic disease. Studies that have evaluated a combination of cisplatin and 5-FU have noted that toxicity was moderate and that patients with a good performance status (≥ 70%) responded well to treatment (Cancer Treat Rep 70:461-464, 1986; Cancer 53:1819-1824, 1984).

A phase III trial of the EORTC Head and Neck Cancer Cooperative Group compared cisplatin, methotrexate, bleomycin, and vincristine (CABO) with cisplatin and 5-FU in combination vs single-agent cisplatin. According to the results, both hematologic and nonhematologic toxicities were worse in the combination chemotherapy arms. However, both combination treatments were superior to the single agent with regards to time-to-progression. In addition, there was no overall difference in progression-free survival (PFS) or OS among the three arms. Other trials have come up with similar results (Ann Oncol 5:521-526, 1994; J Clin Oncol 10:1245-1251, 1992 and 23:3562-3567, 2005).

"It's quite obvious if you look at toxicity, whether you're using the CABO regimen or the [cisplatin/5-FU] regimen, there's clearly more toxicity observed and reported than when you give the single agent," Dr. Vermorken advised. "So if you have a patient that is in good condition and is symptomatic, it may be preferable to use combination chemotherapy. But you have to balance that with the toxicity that will be enhanced if you give combination chemotherapy. You should realize that ultimately the outcome in terms of survival is not much different."

Finally, Dr. Vermorken, highlighted some of the targets for next-generation therapy, such as the epidermal growth factor receptor (EGFR). Nearly all patients with SCCHN express EGFR, and overexpression is correlated with late-stage disease, resistance to chemotherapy and radiation, and poor outcomes, he said.

There are currently a number of EGFR-targeting agents under investigation in head and neck cancer, including the monoclonal antibodies cetuximab (Erbitux) and panitumumab (Vectibix) as well as the tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) (Targ Oncol 2:73-88, 2007).

In the completed EXTREME trial, patients in the control arm were treated with cisplatin/5-FU or carboplatin/5-FU. In the experimental arm, the same regimen was combined with cetuximab. Dr. Vermorken and colleagues concluded that cetuximab plus platinum/5-FU chemotherapy improved OS when given as first-line treatment. The most common grade 3 or 4 adverse events in both arms were neutropenia and anemia; a small number of patients receiving cetuximab had grade 3-4 infusion-related reactions (N Engl J Med 359:1116-1127, 2008).

"There was no crossover in this trial, and I think that that is very important for the outcome," Dr. Vermorken said. "Patients had a maximum of six cycles of chemotherapy, and if they responded or had stabilization of disease, they continued with the monoclonal antibody until disease progression or toxicity, whatever came first. And again there was no crossover, so the patients in the control arm did not receive the monoclonal antibody."

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