In locoregionally advanced head and neck squamous cell carcinomas, outcomes using single-modality therapy are usually poor. Although chemotherapy alone is not considered a curative therapy, the addition of chemotherapy to other modalities can lead to improved outcomes. Discussed here is the use of chemotherapy for oropharyngeal and/or oral cavity squamous cell carcinomas in 3 settings: in combination with radiation as definitive therapy, as induction treatment before definitive therapy, and in combination with radiation therapy as adjuvant treatment following surgical resection. The role of the targeted agent cetuximab in combination with radiation therapy for locally advanced disease is also discussed.
Key points
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Patients with squamous cell carcinoma of the head and neck frequently present with locally advanced disease. In this setting, outcomes can be improved by the incorporation of multimodality treatment, often with chemotherapy.
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In locally advanced oropharyngeal squamous cell carcinomas, concurrent chemoradiation with cisplatin is the standard of care and improves outcomes compared with radiation alone.
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In patients with oropharyngeal squamous cell carcinomas, radiation with concurrent cetuximab improves disease-free and overall survival compared with radiation alone and is another treatment option for patients with locally advanced disease.
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The use of induction chemotherapy before definitive radiation has been extensively studied and may improve outcomes in certain groups. Its use, however, remains controversial.
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Following surgical resection, adjuvant concurrent chemoradiation with cisplatin improves outcomes for patients with nodal extracapsular extension or positive margins.
Introduction
In locoregionally advanced head and neck squamous cell carcinomas, outcomes using single-modality therapy are usually poor. Head and neck cancers are chemosensitive malignancies, with response rates as high as 90% described with chemotherapy in treatment-naïve patients. Although chemotherapy alone is not considered a curative therapy, the addition of chemotherapy to other modalities can lead to improved outcomes. Discussed here is the use of chemotherapy for oropharyngeal and/or oral cavity squamous cell carcinomas in 3 settings:
- 1.
In combination with radiation as definitive therapy
- 2.
As induction treatment before definitive therapy
- 3.
In combination with radiation therapy as adjuvant treatment following surgical resection
The authors also discuss the role of the targeted agent cetuximab in combination with radiation therapy for locally advanced disease.
Introduction
In locoregionally advanced head and neck squamous cell carcinomas, outcomes using single-modality therapy are usually poor. Head and neck cancers are chemosensitive malignancies, with response rates as high as 90% described with chemotherapy in treatment-naïve patients. Although chemotherapy alone is not considered a curative therapy, the addition of chemotherapy to other modalities can lead to improved outcomes. Discussed here is the use of chemotherapy for oropharyngeal and/or oral cavity squamous cell carcinomas in 3 settings:
- 1.
In combination with radiation as definitive therapy
- 2.
As induction treatment before definitive therapy
- 3.
In combination with radiation therapy as adjuvant treatment following surgical resection
The authors also discuss the role of the targeted agent cetuximab in combination with radiation therapy for locally advanced disease.
Concurrent chemoradiation therapy
Definitive radiation treatment of patients with unresectable or locoregionally advanced head and neck cancer has been associated with high rates of both locoregional failure and distant recurrence. The addition of chemotherapy to radiation therapy has been studied in an attempt to improve cure rates and functional outcomes as well as survival rates.
Locally Advanced Oropharyngeal Cancer
For patients with locally advanced oropharyngeal cancer, a pivotal randomized phase III trial by the French Groupe Oncologie Radiotherapie Tete et Cou (GORTEC) group was designed to compare radiotherapy alone to radiotherapy and concomitant chemotherapy.
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Both groups received identical radiation therapy with conventional fractionation of 70 Gy in 35 fractions.
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Patients in the chemotherapy arm received a 4-day chemotherapy regimen consisting of carboplatin (70 mg/m 2 /d) and 5-flourouracil (600 mg/m 2 /d) by continuous infusion for the duration of radiotherapy.
Results yielded the following:
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An improvement in both progression-free survival and overall survival at three years for patients receiving combined modality therapy (42% and 51%) versus radiation therapy alone (20% and 31%)
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Improvement in locoregional control rates in the chemoradiation arm (66%) versus radiation therapy alone (42%)
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Similar rates of distant metastases in both arms (11%)
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Higher hematologic toxicities and incidence of grade 3 and 4 mucositis in the chemotherapy arm, leading to a need for a temporary feeding tube more frequently when compared with the radiation therapy alone arm
These results suggest that the addition of chemotherapy concurrently to radiation therapy improves locoregional control, which translates into both an overall and progression-free survival benefit for these patients, at the expense of more acute toxicities. Long-term follow-up of this study confirms the results in favor of the concurrent chemoradiation therapy arm, with an improvement in overall survival primarily secondary to a reduced incidence of locoregional failure.
Resectable or Unresectable Head and Neck Cancer
To better assess the impact of chemotherapy on the treatment of head and neck cancer and overall survival, an updated meta-analysis of 87 randomized trials between 1965 and 2000 was performed.
The Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) pooled data from clinical trials in which patients with resectable or unresectable disease were randomized to receive definitive local therapy (surgery or radiation) or definitive local therapy plus chemotherapy. Trials included patients who had received chemotherapy in the induction, concurrent, or adjuvant setting and had a diagnosis of oral cavity, oropharynx, hypopharynx, or larynx cancer.
Results yielded the following:
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The addition of chemotherapy in any setting had a statistically significant overall absolute survival benefit of 4.5% at 5 years and an even greater benefit of 6.5% at 5 years in the concurrent chemoradiation trials.
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As in the GORTEC trial, the improvement in survival was primarily caused by an impact of concurrent chemotherapy on locoregional control, with an absolute reduction of the cumulative rate of locoregional recurrence of 9.3% in the concurrent group at 5 years.
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Concurrent chemotherapy also reduced the cumulative rate of distant metastases but to a lesser extent (absolute reduction of 2.5% at 5 years). This analysis did not define an optimal concurrent chemotherapy regimen but found a greater benefit of platinum-based chemotherapy. Multidrug regimens including 5-flourouracil had similar benefit when compared with single-agent cisplatin; however, monotherapy with a drug other than cisplatin yielded inferior results.
High-Dose Cisplatin Concurrent with Radiation Therapy
High-dose cisplatin administered at 100 mg/m 2 on days 1, 22, and 43 concurrent with radiation therapy has been associated with an improvement in overall survival and has been considered the preferred regimen for definitive treatment. Because of both acute and late toxicities, it is reserved for patients with a good performance status and limited comorbidities. Alternative schedules and dosing of cisplatin including daily and weekly treatment have demonstrated improvements in both locoregional control and survival but have not been directly compared with high-dose cisplatin. Because of a more tolerable side-effect profile, specifically less nephrotoxicity, ototoxicity, and neurotoxicity, carboplatin has also been investigated as an alternative option, although it has not been directly compared as a single agent against cisplatin. However, when carboplatin is used in combination with another agent, such as 5-flourouracil, there is a survival benefit when compared with radiation therapy alone. Definitive radiation therapy with carboplatin monotherapy is occasionally used for patients with a poor performance status, multiple comorbidities, or a contraindication to cisplatin therapy.
Accelerated Radiation Therapy and Hyperfractionation
The impact of altered radiation schedules with concurrent chemotherapy on overall survival and locoregional control has also been studied. Accelerated radiation, which delivers the same dose as conventional therapy over a shorter period of time, and hyperfractionation, which gives higher doses of radiation therapy via multiple small fractions, were developed to help improve locoregional control rates. For patients receiving radiation therapy alone, studies have shown hyperfractionation to have an 8% absolute benefit in the 5-year overall survival. When combined with chemotherapy, the value of these techniques remains unclear. In a comparison of conventional radiation with 3 cycles of standard high-dose cisplatin to accelerated boost radiation with 2 cycles of high-dose cisplatin, there was no statistically significant difference in overall survival, locoregional failure, progression-free survival, or development of distant metastases between the 2 chemoradiation schedules.
Radiation with concurrent cetuximab
The use of targeted therapies for the treatment of head and neck cancer has been of high interest because of, potentially, a more favorable side-effect profile than platinum-based therapies. Cetuximab is a monoclonal antibody against the epidermal growth factor receptor (EGFR) and is the only targeted agent currently approved for the management of locally advanced and/or recurrent and metastatic head and neck squamous cell carcinomas. Preclinically, EGFR-targeted agents have been demonstrated to reduce cancer cell proliferation, increase apoptosis, inhibit invasiveness and metastatic potential, and augment sensitivity to chemotherapy and radiation therapy.
In a multinational study, weekly cetuximab in combination with radiation therapy was compared with radiation therapy alone.
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Eligibility criteria included previously untreated stage III or IV nonmetastatic cancer of the oropharynx, larynx, or hypopharynx and a Karnofsky performance score of at least 60.
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Three radiotherapy schedules were allowed and chosen by the investigators before patient registration (70.0 Gy in once-daily fractions, 72.0–76.8 Gy in twice-daily fractions, or 72.0 Gy in once-daily fractions with a concomitant twice-daily boost in the last 2.4 weeks of treatment).
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In the experimental arm, cetuximab was added to the elected radiotherapy treatment, given at a loading dose of 400 mg/m 2 (starting 1 week before radiation) followed by a weekly 250 mg/m 2 maintenance dose for the duration of radiotherapy.
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Patients were stratified according to performance status, nodal involvement, tumor stage, and radiation-fractionation regimen.
Results yielded the following:
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The 3-year rates of locoregional control (the study’s primary endpoint) were significantly higher for the cetuximab-radiotherapy arm as compared with the radiotherapy alone arm (47% vs 34%, respectively, P <.01).
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Median progression-free survival was 17.1 months versus 12.4 months for the experimental and control arms, respectively ( P = .006).
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The 3-year overall survival was 55% among patients treated with the combined modality versus 45% among those given radiation only ( P = .03).
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Response rates were significantly higher for the experimental group as compared with control patients (74% vs 64%, respectively, P = .02).
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The cumulative rates of distant metastases were similar between the two groups. Grade 3 to 5 mucositis and dermatitis occurred in 56% and 23% of the experimental group versus 52% and 18% of the control group.
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Other toxicities were similar between the arms, except for acneiform rash (17% in the cetuximab arm vs 1% in the radiation alone arm, P <.001) and infusion-related side effects (3% for cetuximab).
Taken together, this study demonstrates that cetuximab increases survival and locoregional control rates without significant additional toxicity.
Long-Term Follow-up
On long-term follow-up, the survival benefits of cetuximab added to radiation therapy remained (overall survival of 46% and 36% at 5 years for the experimental and control arms, respectively). Subgroup analysis demonstrated more pronounced improvement in survival by the addition of cetuximab in the following cohorts: patients with oropharyngeal cancers (compared with larynx or hypopharynx), T1 to T3 primary tumor (vs T4), N1 to N3 nodal status (vs N0), treatment in the United States, use of concomitant boost radiotherapy, Karnofsky performance status of 90 to 100, male gender, and younger age (<65 years). These results should be interpreted with caution, given the low number of patients in each group and the exploratory nature of the analysis.
Although this study showed a benefit of concurrent cetuximab versus radiation alone, there has been no head-to-head comparison with concurrent cisplatin with radiation therapy, the standard of care, and it is unknown which patients would derive greater benefits from one approach versus the other.
In a follow-up to the trial of Bonner and colleagues described above, The Radiation Therapy Oncology Group (RTOG) study 0522 randomized patients to cisplatin chemoradiation therapy with or without cetuximab. The combination with cetuximab did not improve progression-free or overall survival and increased adverse events when compared with cisplatin and radiation, and this strategy should not be used.
Unfortunately, despite extensive efforts, no predictive biomarkers of the efficacy of cetuximab have been identified to date. The demographics of the patients who had improved survival in the study by Bonner and colleagues suggest that patients with human papillomavirus (HPV)-positive oropharyngeal tumors could be appropriate candidates for this therapy because they typically present at a younger age, with a low T primary tumor and more advanced nodal stage. Nonetheless, exploratory analysis of a recent trial in the recurrent/metastatic setting evaluating chemotherapy ± panitumumab (another anti-EGFR antibody) demonstrated a survival benefit of the targeted agent in the HPV-negative group only. It is unknown whether these results hold true in the setting of locally advanced disease, using cetuximab combined with radiation therapy. Currently, the RTOG1016 study is evaluating cetuximab and radiation therapy versus cisplatin and radiation therapy in locally advanced, HPV-positive oropharyngeal squamous cell carcinomas using a noninferiority phase III trial design ( NCT01302834 ).
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