Objectives

In May 2010, the Agency for Healthcare Research and Quality (AHRQ) published the results of Comparative Effectiveness Review (CER) No. 20, “Comparative Effectiveness and Safety of Radiotherapy Treatments for Head and Neck Cancer,” prepared by the Blue Cross and Blue Shield Association Evidence-based Practice Center (EPC).¹ CER No. 20 examined evidence on clinical outcomes achieved with two-dimensional radiotherapy (2DRT), three-dimensional conformal RT (3DCRT), intensity-modulated RT (IMRT), and proton-beam RT (PBT). The main finding of CER No. 20 was that late xerostomia was reduced and quality of life (QOL) domains related to xerostomia were improved in patients treated with IMRT compared with those who underwent 3DCRT or 2DRT. Evidence was insufficient to draw conclusions on overall survival or tumor control; adverse events other than late xerostomia (e.g., mucositis, dysphagia, skin toxicities, or osteoradionecrosis of the jaw); whether patient and tumor characteristics affected relative outcomes; or whether physician experience and treatment characteristics affected relative clinical outcomes such as survival or treatment-associated adverse events.

In 2012, AHRQ published a surveillance report that used methods developed by the RAND and Ottawa EPCs to prioritize an update of AHRQ CER No. 20 in 2013.² In preparing this update, we examined the applicability of opposed beam 2DRT and brachytherapy (BT) in modern radiation oncology practice. Our conclusion, based on the current literature and input from our Technical Expert Panel (TEP) members, was that 2DRT is no longer in routine use in the United States for definitive treatment of head and neck cancer, thus we excluded it from the update.

Brachytherapy is an invasive technique that was the first form of RT in clinical use, dating back to 1901. Historically, it has been used extensively in many tumor types, including head and neck cancer. The primary advantage of BT over traditional opposed external beam 2DRT has been its capability to conform a high, localized radiation dose to the implanted tumor, limiting exposure to noninvolved tissues. However, as conformal external beam RT methods (e.g., 3DCRT and IMRT) have become more prevalent in the past 2 decades, this advantage has been mitigated.

Brachytherapy can be used in select head and neck cancer cases as a means of dose escalation in conjunction with external beam irradiation.^3,4 However, this practice has become uncommon because sufficient dose escalation can usually be achieved in these cases with a noninvasive approach (i.e., conformal RT). Brachytherapy alone is very rarely employed, except with small (T1) tumors of the nasal vestibule, lip, or oral cavity.^5–9 These presentations of head and neck cancers are relatively uncommon (1 percent to perhaps 5 percent of all cases), and RT is typically not first-line treatment in many cases. Therefore, because BT alone for primary management of head and neck malignancies has limited applicability in modern radiation oncology practice, we did not seek evidence of it for this current CER; we focused instead on RT modalities that are used as the sole RT intervention for a given presentation of head and neck cancer.

For this update, we reviewed and assessed new evidence on the comparative effectiveness of 3DCRT, IMRT, and PBT. We also systematically reviewed and assessed evidence on stereotactic body RT (SBRT), a newer RT modality that was not widely available when we prepared CER No. 20. This update used the same Key Questions as in CER No. 20 and, for the most part, the same methods and search strategies, modified to address the changes in the list of interventions. We organized clinical evidence according to treatment regimen, abstracted only from comparative studies (randomized or nonrandomized) of the conformal RT methods used in treatment for any head and neck cancer.

Overview of Multimodal Clinical Management of Head and Neck Cancer

Most patients with SCCHN present with locally advanced but curable disease; only a small percentage of these patients have demonstrable distant metastases. Treatment decisions are primarily determined by the size, location, and grade of the primary tumor; the extent of nodal involvement; and the estimated functional impact of therapy. Patient characteristics may include substantial comorbidities and poor performance status that would be considered in devising a comprehensive treatment plan.¹¹

Aggressive multimodality treatments with curative intent may include surgery, RT, and chemotherapy. Radiotherapy is a mainstay of treatment, offered to nearly 75 percent of all head and neck cancer patients with either curative or palliative intent. Radiotherapy may be used alone or as a part of multimodality approach, often with significant long-term side effects. In planning this CER, we sought to account for multimodal treatment strategies by organizing evidence according to treatments used in comparative studies of the RT modalities. Toxicities associated with RT represent important clinical outcomes that can substantially reduce QOL and the ability of cancer patients to tolerate and complete the entire planned course of treatment.

The main challenge in RT for any type of cancer is to attain the highest probability of tumor control or cure with the least amount of morbidity and toxicity. However, improved outcomes with aggressive RT regimes come at the cost of increased treatment toxicity, mainly due to the close proximity of critical organs and the often large irradiation fields necessary to effect local tumor control in head and neck cancer patients. For example, xerostomia is the most prevalent toxicity of RT to the head and neck and is a major cause of reduced QOL. In addition to patient perception of mouth dryness, it leads to impaired speech and swallow function, all of which also contribute to decreased QOL. Other prominent, RT-associated toxicities include salivary gland dysfunction, accelerated dental caries, and osteoradionecrosis.

Although RT-associated toxicities are highly problematic in any patient with head and neck cancer, such adverse events may assume greater importance in patients identified with HPV-positive compared with those with HPV-negative disease.¹³ Patients with HPV-positive oropharynx cancer not only appear to have a different clinical phenotype from HPV-negative cancers, but they also have had better outcomes in multiple large studies, even when correcting for other known prognostic factors.¹⁴ This trend has led investigators to research deintensification of treatment for patients with HPV-related head and neck cancers to limit toxicities, and alternatively intensification of treatment to improve tumor control in those with a significant HPV-negative cancer with a smoking history.^11,13 However, it is important to note that current practice guidelines, such as the National Comprehensive Cancer Network (NCCN), do not recommend treatment differences based on HPV status (with perhaps the exception of HPV+ unknown primary cancers). In preparing this update, we sought to identify, where possible, HPV-positive patients as separate entities from HPV-negative patients.

RT in Head and Neck Cancer

Summary

The optimal means of delivering external beam ionizing radiation in sufficient doses to cure a patient with SCCHN requires a fine balance between treatment effectiveness and associated toxicity. In CER No. 20, the compiled evidence demonstrated an advantage for IMRT over 3DCRT and 2DRT in reducing late xerostomia and improving measures of xerostomia-related QOL. Evidence was insufficient to demonstrate any relative difference between modalities in measures such as overall survival or tumor control. Since CER No. 20 was published, a newer conformal technology—SBRT—has come into practice, whereas 2DRT has fallen out of use in the U.S. A surveillance study prepared in 2012 by the Ottawa and RAND EPCs suggested rationale to update CER No. 20, based on signals of new evidence that would change several conclusions of that report. Taken together, the emergence of new technology and evidence suggesting potential differences in some comparative outcomes prompted AHRQ to prioritize this update of CER No. 20.

Key Questions

The proposed Key Questions for CER No. 20, entitled “Comparative Effectiveness and Safety of Radiotherapy Treatments for Head and Neck Cancer,” were posted for public comment for 4 weeks during its development. At that time, changes to the Key Questions and the PICOTS were made based on comments received and discussion with the TEP for the report. In the surveillance assessment used to determine the priority to update the 2010 report, the language of the Key Questions was modified slightly, but unchanged in meaning.

The Key Questions we used for this update follow below. In addition to 3DCRT, IMRT, and PBT, we included SBRT, which was not part of CER No. 20. Based on input from TEP discussions and a review of the literature, we excluded 2DRT from further consideration and did not include brachytherapy for reasons listed previously in the report. In response to TEP input, we also revised the language of Key Question 4 to expand the list of potential variables to consider.

Key Question 1.

What is the comparative effectiveness of 3DCRT, IMRT, SBRT, and PBT regarding adverse events and QOL?

Key Question 2.

What is the comparative effectiveness of 3DCRT, IMRT, SBRT, and PBT regarding tumor control and patient survival?

Key Question 3.

Are there differences in the comparative effectiveness of 3DCRT, IMRT, SBRT, and PBT for specific patient and tumor characteristics?

Key Question 4.

Is there variation in the comparative effectiveness of 3DCRT, IMRT, SBRT, and PBT because of differences in user experience, treatment planning, treatment delivery, and target volume delineation?

PICOTS

Analytic Framework

Figure 1 provides an analytic framework illustrating the population, RT modalities to be compared, outcomes, and adverse effects that guided our literature search and synthesis. It links the RT modalities of interest directly with final health outcomes (e.g., overall survival) and adverse events (e.g., xerostomia) as well as indirectly with final outcomes via intermediate outcomes (e.g., local control, disease-free survival).

Figure 1

Analytic framework for comparative effectiveness of RT for head and neck cancer. Figure 1 depicts the Key Questions (KQs) within the context of the PICOTS described in the previous section. In general, the figure illustrates how 3DCRT, IMRT, SBRT, or (more...)

Organization of This Report

In the following sections of this CER update, we outline the methods used in its preparation, including literature search strategies, methods used to select studies for inclusion, data elements and their abstraction, tabulation of results, assessment of study quality and risk of bias, and how we evaluated the SOE. In the Results section, we provide an overview of the literature search results and study inclusion and exclusion. We then present evidence for each Key Question, using bulleted key points and a summary of the results and tabulature of such. The Discussion section contains our assessment of the SOE as related to the conclusions of CER No. 20. Finally, we discuss the applicability of the evidence to clinical decisionmaking and gaps in the evidence base in the Discussion section. The report concludes with an overall summary that ties it together to the CER No. 20 findings.