Intensity-Modulated Radiation Therapy
Intensity-modulated radiation therapy (IMRT) is becoming routinely adapted by the radiation oncologist in order to treat the target volume(s) with nonuniform amounts of radiation in a given beam. Multiple coplanar beam angles—typically five to nine beam angles—are used. The planning involved with IMRT is labor-intensive for the physician to draw target volumes and normal structures and also for the physicist to generate a plan. However, IMRT creates very tight target volume coverage with rapid radiation dose falloff, allowing for critical normal tissues such as the spinal cord and parotid glands to be spared, and has been routinely adopted by radiation oncologists due to improved salivary function compared to that seen with two- or three-dimensional radiation planning.[24]
Most centers do not employ altered-fractionation schedules of radiation when using IMRT treatment planning, due to the added expense of time and labor required for IMRT. However, the simultaneous integrated boost (SIB) strategy, wherein multiple targets are treated simultaneously with different prescribed doses, has commonly been used with IMRT. For example, the primary tumor and gross nodal disease may be treated to 66 Gy in 30 fractions (2.2 Gy/fraction), while at the same time, high-risk areas receive 60 Gy (2 Gy/fraction) and low-risk areas receive 54 Gy (1.8 Gy/fraction). Due to the higher dose per fraction, however, this scheme may produce increased late morbidity.
Alternatively, the gross disease may be treated with standard doses of 1.8 to 2 Gy per fraction, while subclinical disease is treated with a lower-than-standard daily dose. When this approach is employed, particularly in patients with advanced disease, concurrent chemotherapy should be administered. It should be noted that the highest doses per fraction, such as those described by Butler et al,[25]should not be delivered with concurrent chemotherapy, given the risk of severe acute mucositis.
The use of SIB has not been compared with traditional altered-fractionation radiation in a randomized study and, therefore, whether IMRT with a SIB offers the same benefit as the aforementioned altered-fractionation schemes is, at present, unknown.
The Chemotherapy Variable in Combined-Modality Therapy
While the advances in radiation therapy described above have been evolving, there have also been numerous clinical trials incorporating chemotherapy in patients with locoregionally advanced or unresectable head and neck cancer. Through the 1980s, surgery and radiation were the mainstays of treatment. These approaches resulted in relatively poor outcomes, with 5-year survival rates of 10% to 40%.[26] In an effort to improve this dismal outcome, investigators became increasingly interested in the incorporation of chemotherapy.
Induction Chemotherapy
The initial focus was on the addition of induction (neoadjuvant) chemotherapy. Numerous randomized trials were published in the 1980s and 1990s. Although high response rates were noted and a decrease in distant metastases was often observed, most trials failed to consistently demonstrate a significant benefit for locoregional control or overall survival.[27-28] In contrast to the predominant observations, two trials did yield positive results.
In 1994, Paccagnella et al published a phase III trial involving 237 patients with stage III or IV nonmetastatic resectable and unresectable SCCHN randomized into two groups.[29] One group received induction chemotherapy (cisplatin and fluorouracil(Drug information on fluorouracil) [5-FU]) followed by locoregional treatment, which included either resection and RT for resectable patients or RT alone for unresectable disease. The second group received locoregional treatment alone. The primary endpoint was overall survival. The results were analyzed separately for patients with resectable and unresectable disease. For the unresectable patients, induction chemotherapy resulted in an overall survival benefit at 3 years of 24% compared to 10% (P = .04). This was maintained with 10-year follow-up at 16% compared to 6% (P = .04). No survival advantage was seen for the resectable patients.
In 2000, Domenge et al published the results of a phase III trial in patients with resectable and unresectable, stage III or IV, nonmetastatic oropharyngeal carcinoma randomized to receive either cisplatin(Drug information on cisplatin) plus 5-FU followed by locoregional treatment (resection with RT or RT alone), or locoregional treatment alone.[30] The investigators found a significant overall survival benefit of induction chemotherapy, which resulted in a median survival of 5.1 vs 3.3 years in the group receiving locoregional treatment alone (P = .03). No difference in locoregional control rate was noted.
Also important at this time were the results from the MACH-NC meta-analysis, published by Pignon et al in 2000,[23] which did not demonstrate an overall survival benefit with induction chemotherapy. The MACH-NC meta-analysis showed a benefit in trials of a platinum agent plus 5-FU (P = .05), and is described in greater detail in the next section. Based on the bulk of available data at that time, induction chemotherapy did not become widely accepted as standard practice in the management of this group of patients. Nevertheless, two trials reported during this time did demonstrate a benefit with induction chemotherapy in the context of organ preservation in patients with advanced squamous cell cancers of the larynx and hypopharynx.[31,32]
Concurrent Chemoradiotherapy
Historically, what followed was the concept of concurrent chemoradiotherapy. This strategy appeared attractive based on the potential radiosensitizing properties of selected chemotherapeutic agents with an expectation of improving locoregional control.
Beginning in the 1990s, several published trials that will be discussed later reported improved outcomes using chemoradiotherapy compared to radiation alone. Chemoradiotherapy gained a wider acceptance with the publication of the pivotal MACH-NC.[23] This meta-analysis of data from 63 published and unpublished trials, evaluated 10,741 patients with resectable and unresectable cancer of the oropharynx, oral cavity, larynx, and hypopharynx. The study compared induction, concurrent, and adjuvant chemotherapy to locoregional therapy alone. The chemotherapy differed greatly.
Overall survival was the primary endpoint. The study revealed that chemotherapy delivered neoadjuvantly, concurrently, or adjuvantly carried an absolute survival benefit of 4% at 5 years (P < .0001). Concurrent chemotherapy was found to produce the greatest benefit, with an absolute overall survival benefit of 8% at 5 years (27% vs 35%, P < .0001). In contrast, induction chemotherapy was found to have a statistically insignificant overall survival benefit of 2% at 5 years . No significant benefit was observed with the addition of adjuvant chemotherapy.
An update of the MACH-NC meta-analysis reported in 2004 by Bourhis et al included an additional 24 trials (and increased the total number of patients to 16,000).[33] This subsequent analysis confirmed the 5% overall survival benefit for patients receiving chemotherapy and an 8% absolute overall survival benefit with chemoradiotherapy, with a 19% reduction in the risk of death (hazard ratio = 0.81, P < .001).[33]
Randomized Trials of Multiagent Chemotherapy Agents in Concurrent Chemoradiation and RT Alone in Locoregionally Advanced Squamous Cell Cancer of the Head and Neck• Single-Agent vs Combination Chemotherapy—The benefit of chemoradiotherapy has also been established by several published randomized trials. These trials have used a variety of chemotherapeutic agents as well as varying radiation techniques. Several agents have been investigated in the setting of concurrent chemoradiation including bleomycin(Drug information on bleomycin), mitomycin(Drug information on mitomycin), methotrexate(Drug information on methotrexate), 5-FU, and cisplatin. Table 2 lists selected randomized trials that have studied single-agent regimens vs RT alone. These trials have demonstrated improvements in locoregional control and, most often, an improvement in overall survival in the chemotherapy-containing arm.
Several randomized trials incorporating combination chemotherapy regimens given concurrently with radiation also reported improved outcomes compared to RT alone. Table 2 lists some of these trials with varying chemotherapeutic regimens as well as differing radiation schedules. Despite these apparent differences, results have shown a fairly consistent demonstration of benefit in terms of locoregional control and overall survival.
Only one of these trials directly compared two differing chemotherapy regimens. As outlined in Table 2, a phase III Intergroup trial undertaken between 1992 and 1999 randomized 295 patients with unresectable head and neck cancer into three treatment arms.[34] Arm A (the control group) received conventional fractionated RT at 2 Gy/d for a total of 70 Gy. Arm B received identical radiation therapy with concurrent high-dose cisplatin at 100 mg/m2 given on days 1, 22, and 43. Patients in arm C received a split course of single daily fractionated radiation with three cycles of concurrent infusional 5-FU and bolus cisplatin chemotherapy, 30 Gy given with the first cycle and 30 to 40 Gy given with the third cycle. Surgery was encouraged if disease was rendered resectable after the second chemotherapy cycle in arm C patients.
The 3-year projected overall survival for arm A (RT alone) was 23%, compared to 37% (P = .014) for arm B (chemoradiotherapy). No survival benefit was noted in arm C, which incorporated 5-FU and cisplatin. It should be noted that the spilt-course radiation schedule used in arm C is not considered an optimal schedule and makes any direct comparison difficult.
Taking into account all of these results, concurrent chemoradiotherapy became a standard of care in treating patients with locoregionally advanced or unresectable SSCHN. Except for the Intergroup trial, no subsequent randomized trials have directly compared cisplatin in varying dosing schedules or against other combination regimens.
Several phase II trials have also investigated the incorporation of taxane-based regimens given concurrently with radiation. Although these regimens are feasible, no phase III data are available to allow a direct comparison to single-agent cisplatin. Cisplatin administered at 100 mg/m2 on days 1,22, and 43 of radiation therapy is viewed by many as the standard of care in the treatment of this cohort of patients. The addition of chemotherapy to radiation clearly increases both acute and late toxicities of therapy, and this is an important factor in selecting the most appropriate treatment regimen for any given patient. Subsequent trials of this cisplatin schedule in organ preservation,[35] in the postoperative adjuvant setting,[36] and in numerous phase II chemoradiotherapy regimens have further supported the effectiveness of this treatment strategy.
• Targeted Therapy With Cetuximab(Drug information on cetuximab)—The epidermal growth factor receptor (EGFR) is abnormally activated and overexpressed in cancers of epithelial origin, which includes SCCHN.[37-38] Cetuximab (Erbitux), a monoclonal antibody against EGFR has been associated with clinically significant rates of tumor regression in patients with platinum-refractory head and neck cancer.[39-40]
Bonner et al reported the results of a phase III trial that compared radiation therapy alone to concurrent cetuximab and RT.[41]. In this study, 424 patients with locoregionally advanced SCCHN were randomized to receive treatment with either definitive RT or RT plus weekly cetuximab. Cetuximab was administered at an initial dose of 400 mg/m2, followed by 250 mg/m2 weekly for the duration of therapy.
The median duration of locoregional control was improved from 14.9 months in the RT-alone arm to 24.4 months in the cetuximab-plus-RT arm (P = .005). In addition, a benefit in overall survival was seen in the cetuximab-plus-RT arm after a median follow-up of 54 months. The overall survival was 49 months among patients who received the combined therapy and 29.3 months in the RT-alone group (P = .03). There was no difference in the incidence of distant metastases between the two groups. Importantly, with the exception of cetuximab-related acneiform rash and infusion reactions, the incidence of toxic effects did not differ significantly between the two groups.
Although this study clearly revealed a benefit in locoregional control and survival when cetuximab was added to RT, it is unclear how this regimen compares to cisplatin-based chemoradiotherapy. However, in light of no significant added toxicity with cetuximab, it emerges as a valuable therapeutic option in patients with coexisting medical conditions and decreased performance status, for whom the risks of chemotherapy may outweigh its benefits.
RTOG 0522 is an ongoing phase III randomized trial that is further exploring the activity of cetuximab in combination with radiation for locoregionally advanced SCCHN. In this trial, patients are randomized to receive either RT and cisplatin or RT, cisplatin, and cetuximab.[42]
