Multidisciplinary Management of Locally Advanced SCCHN: Optimizing Treatment Outcomes

The management of locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) is highly complex. Data from recent clinical trials have altered the treatment landscape by refining the use of existing therapies, such as radiation therapy and chemotherapy, and providing new treatment options, such as cetuximab. Selecting the most appropriate treatment for an individual patient requires a multidisciplinary approach and careful assessment of the relative advantages and disadvantages of each treatment approach. Surgery is highly effective but can have debilitating long-term consequences. Chemoradiation and altered fractionation radiation therapy are more effective than conventional radiation therapy, but also more toxic; as a consequence of toxicity, suboptimal delivery of radiation may diminish, in practice, the efficacy observed in clinical trials of these strategies. Cetuximab plus radiation therapy is more effective than radiation alone and does not substantially increase radiation-related toxicity, or affect the delivery of planned radiotherapy. However, whether cetuximab plus radiation therapy is similar in efficacy to chemoradiation is unknown at this time. Ideally, multidisciplinary teams weigh all these factors when making individual treatment decisions. Data from current trials will help further optimize multimodality treatment for LA-SCCHN. The Oncologist 2008;13:000–000 INTRODUCTION The management of patients with head and neck cancer is complex, and treatment of squamous cell carcinoma of the head and neck (SCCHN) varies according to clinical characteristics and the expertise of the medical team. Comorbidity is frequent in SCCHN patients and can preclude aggressive therapy [1–4]. Moreover, SCCHN and its treatment may negatively affect basic physiological functions, senses, speech, and physical appearance [5]. As a result, the optimal management must often account for clinical and psychosocial factors beyond disease eradication. Approximately 60% of SCCHN patients present with locally advanced (LA) disease [5]. The majority of these patients will require multimodality treatment. Standard treatment in this setting includes surgery, radiation therapy (RT), chemotherapy (CT), and biological or targeted Correspondence: K. Kian Ang, M.D., Ph.D., Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 0097, Houston, Texas 77030, USA. Telephone: 713-563-2323; Fax: 713-563-2331; e-mail: [email protected] Received September 4, 2007; accepted for publication June 27, 2008; first published online in THE ONCOLOGIST Express on August 13, 2008. ©AlphaMed Press 1083-7159/2008/$30.00/0 doi: 10.1634/theoncologist.2007-0157 The Oncologist Head and Neck Cancers The Oncologist 2008;13:000–000 www.TheOncologist.com Published Ahead of Print on August 13, 2008 as 10.1634/theoncologist.2007-0157. by gest on July 1, 2017 http://thologist.alpham edpss.org/ D ow nladed from agents. Data from recent clinical trials have led to the refinement of current therapies and new treatment options. Given the inherent complexity of SCCHN and wide range of treatment combinations available, a multidisciplinary approach is essential. This article reviews the recent data that have shaped the current approach to treatment for LA-SCCHN and addresses some of the practical challenges of implementing multimodality treatment. CURRENT TREATMENT MODALITIES IN SCCHN Surgery Surgery continues to play an important role in managing resectable tumors of the larynx, hypopharynx, and oropharynx, despite the emergence of organ-preserving strategies as part of the standard of care, often regardless of resectability [5]. Larynx-preserving strategies may allow for natural speech conservation without compromising survival compared with total laryngectomy [6–8]. This opportunity for long-term survival with organ preservation has shifted the role of surgery toward managing the neck nodes (e.g., planned neck dissection) and disease recurrence. Technologic advances, however, now allow for nonradical surgical approaches with acceptable function recovery, such as laser-based procedures or transoral robotic surgery, and may offer an alternative to aggressive organ-sparing approaches (see below). Even for operable patients, surgery is often accompanied by other treatment modalities. Multidisciplinary assessments are thus crucial to postoperative/adjuvant planning, which may include RT, a strategy shown to improve locoregional control (LRC) and recommended for patients with a moderate recurrence risk (i.e., multiple positive nodes or perineural, lymphatic, or vascular invasion) [5]. RT Conventional RT typically consists of 2 Gy/day given in a single fraction 5 days/week for 7 weeks. Altered fractionation (AF) schedules have been developed in an effort to improve outcomes following RT without substantial worsening of the late toxicity profile. Accelerated fractionation reduces the total treatment time to hinder tumor cell repopulation between doses and improve LRC. Hyperfractionation involves daily administration of two reduced-dose fractions (1.1–1.2 Gy), which allows increasing the total dose by up to 15% without increasing the risk for late toxicity. In a meta-analysis of 15 clinical trials comparing AF with conventional RT in patients with SCCHN [9], AF was associated with longer overall survival (OS), longer cancerrelated survival, and better LRC (Table 1). The OS improvement was attributed mainly to better local control. AF had no apparent effect on the development of distant metastases. Overall, the survival benefit was greater with hyperfractionated RT than with accelerated fractionation (p .02), and in younger than in older patients (p .007). However, some accelerated fractionation regimens were shown to yield LRC improvements similar to those seen with hyperfractionation [9, 10]. The tolerability of AF was difficult to assess in the meta-analysis because of the variability in toxicity assessment and reporting, particularly late radiation effects. Intensity-modulated RT (IMRT), which conforms closely to the tumor volume, avoids or minimizes exposure to unaffected tissue [11–15]. The feasibility of this approach was demonstrated in a study in 15 patients with SCCHN. When compared with standard irradiation plans generated retrospectively for each patient, IMRT led to a higher minimum dose delivered to the targeted tumor (95.2% versus 91% of the prescribed dose; p .02) and a lower maximal radiation dose to normal tissue (p .001) [11]. Available data also suggest that IMRT is as effective as conventional RT or accelerated concomitant-boost RT, and can reduce some late toxicity [12, 14]. The locoregional progression-free and OS rates were similar in 112 patients with stage III/IV oropharyngeal cancer, 71 treated with accelerated concomitant boost RT and 41 treated with IMRT [14]. There was a substantial difference, however, in the Table 1. Absolute benefit at 5 years of AFRT compared with conventional RT: results of a meta-analysis of 15 clinical trials [9] Outcome Hyperfractionation, % Accelerated fractionation without TDR, % Accelerated fractionation with TDR, % All 3 groups, % (p-value) Survival 8.0 2.0 1.7 3.4 ( .003) Cancer-related survival 7.8 3.5 2.3 4.3 (.0002) Locoregional control 9.4 7.3 2.3 6.4 ( .0001) Abbreviations: AFRT, altered fractionation radiotherapy; RT, radiotherapy; TDR, total dose reduction. 2 Optimizing Treatment Outcomes in Head and Neck Cancer Published Ahead of Print on August 13, 2008 as 10.1634/theoncologist.2007-0157. by gest on July 1, 2017 http://thologist.alpham edpss.org/ D ow nladed from rates of acute and late toxicities, with lower rates of skin toxicity, 10% versus 20%, mucositis, 66% versus 72%, and grade 2 xerostomia, 12% versus 67%, associated with the use of IMRT. The 2-year rate of dependence on gastric (percutaneous endoscopic gastrostomy [PEG]) feeding tubes was also significantly lower with IMRT (4% versus 21%; p .02). At M.D. Anderson Cancer Center, we found that IMRT was effective in a retrospective review of 51 patients with small primary oropharyngeal carcinoma [13]. A substantial proportion of patients treated with IMRT still required a gastric tube (40%), although, consistent with previous observations, feeding tube use was brief: only 10% still required the tube 6 months after treatment, all patients were tube-free after 1 year, and only three patients had chronic difficulty swallowing. Based on our results, we now use IMRT to treat most patients with small and even advanced oropharyngeal tumors. IMRT has been increasingly adopted for SCCHN treatment, but involves a learning curve for the practitioner, and standardization (in terms of target definition and dose specification) still needs to be resolved [5, 14]. CT In parallel to the development of AF schedules, numerous trials have evaluated adding CT to locoregional treatment for patients with LA-SCCHN. In a meta-analysis of 87 trials of CT plus locoregional treatment, CT was found to improve survival, with an absolute benefit of 5% at 5 years (Table 2) [16, 17]. The improvement was particularly noteworthy when CT was given concomitantly with RT: 8% at 5 years. Platinum-based CT was more effective than non– platinum-based regimens (p .01). More recent trials of platinum-based CT generally support these findings [8, 18– 22]. As with AFRT, chemoradiotherapy (CRT) was associated with more toxicity than RT alone, and had no apparent effect on the rate of distant metastasis. The potential advantage of CRT, however, may be outweighed by the impact of treatment-derived complications in certain patients that may contribute to non– cancer-related deaths [23]. This may be particularly evident as these patients are followed up in the long term [23], or in the subpopulation of elderly patients, who seem to consistently derive less benefit from concurrent CRT regimens [24]. CRT postsurgery has also been the object of two recent phase III studies: the Radiation Therapy Oncology Group (RTOG)-9501 trial and the European Organization for Research and Treatment of Cancer (EORTC)-22931 trial [25, 26]. Both studies randomized patients with high-risk surgical-pathologic features after surgery to RT or RT plus cisplatin (100 mg/m every 3 weeks for three cycles). In the RTOG-9501 trial [25], CRT resulted in a significantly lower risk for locoregional recurrence compared with RT alone (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.41–0.91; p .01), but did not lead to a longer OS. In the EORTC-22931 trial [26], both progression-free survival (HR, 0.75; 95% CI, 0.56–0.99; p .04) and OS (HR, 0.70; 95% CI, 0.52– 0.95; p .02) were significantly longer with CRT. Notably, neither trial found a significant effect on distant metastases. Postoperative CRT was also more toxic than RT alone (grade 3 adverse events in the CRT arm: RTOG, 77% versus 34%, p .001; EORTC, 41% versus 21%, p .001), an observation that triggered a pooled analysis to identify those patients most likely to benefit from intensive postoperative CRT [27]. Based on the only two risk factors found to be significantly associated with benefit from CRT across both trials, CRT following surgery is now recommended for patients at high risk for recurrence, as defined by the presence of extracapsular extension and/or positive surgical margins [5, 27]. Given the demonstrated benefit of adding CT to RT, concomitant CRT is the standard of care for unresectable LA-SCCHN patients who are medically fit to receive CT, and for organ preservation in patients with resectable disease. Postoperative CRT is also an option for patients at high risk for recurrence. As management trends move forward, the addition of CT to RT regimens beyond conventional fractionation will probably become more relevant. As discussed above, AFRT may lead to superior efficacy over conventional schedules, and CT may enhance the efficacy of AFRT as it does with conventional regimens [22, 28–33]. However, the exacerbation of toxicities associated with such regimens could become a concerning issue, and, to date, it may be considered an area in need of optimization [22, 31]. As improvements in LRC have altered patterns of treatment failure and placed greater emphasis on control of disTable 2. Meta-analysis: survival outcomes when adding CT to RT [17]