1. Comparative Effectiveness and Safety of Radiotherapy Treatments for Head and Neck Cancer Prepared for: Agency for Healthcare Research and Quality (AHRQ) www.ahrq.gov

2. Head and Neck Cancer: Anatomy

3.  Head and neck cancer accounts for approximately 3 to 5 percent of cancers in the United States.  The estimated new cases of head and neck cancer in the U.S. have increased from 47,560 in 2008 to 49,260 in 2010.  The estimated deaths from head and neck cancer in the U.S. have increased from 11,260 in 2008 to 11,450 in 2010. Health Impact of Head and Neck Cancer in the United States National Comprehensive Cancer Network Web site. Available at: http://www.nccn.org/professionals/ physician_gls/f_guidelines.asp; American Cancer Society. Cancer Facts and Figures 2010. Available at: http://www.cancer.org/acs/groups/content/@nho/documents/document/acspc-024113.pdf.

4.  Most types of head and neck cancer arise from a noninvasive precursor in the surface squamous epithelium that progresses to become squamous cell carcinoma.  Approximately 40 percent of head and neck cancers are early stage, and the remaining 60 percent are locally advanced.  Metastatic disease is uncommon at the time of diagnosis. Classification and Staging of Head and Neck Cancer National Comprehensive Cancer Network Web site. Available at: http://www.nccn.org/professionals/ physician_gls/f_guidelines.asp; Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/ index.cfm/search-for-guides-reviews-and-reports/?pageaction= displayproduct&productID=447.

5. Classification and Staging of Head and Neck Cancer (Continued) Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/ ?pageaction=displayproduct&productID=447.

6.  Tobacco and alcohol abuse  Viral infection (e.g., human papillomavirus, Epstein-Barr virus)  Occupational exposures  Nutritional deficiencies  Poor oral health  Behavioral factors  Family history Risk Factors for Head and Neck Cancer Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/ ?pageaction=displayproduct&productID=447.

7.  Treatment of head and neck cancer is complex and usually involves a multidisciplinary team.  The type of treatment used is dictated by the site and extent of the disease.  Nearly all patients with locally advanced disease receive radiation, and many of those also get chemotherapy as part of initial curative treatment.  Patients are subject to early and late treatment-related toxicities, which can profoundly affect their quality of life. Clinical Management of Head and Neck Cancer Forastiere AA. J Surg Oncol 2008;97:701-7; National Comprehensive Cancer Network Web site. Available at: http://www.nccn.org/professionals/ physician_gls/f_guidelines.asp; Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/ ?pageaction=displayproduct&productID=447.

8.  The main goals of improvements in advancing treatment delivery technology have been to maximize disease control and minimize toxicity.  One of the principle technologies used to accomplish this to date has been conformal therapy.  Conformal Therapy  An attempt to deliver radiation to the tumor target while not delivering radiation to nontumor targets (normal tissues). Radiation Delivery Technology Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.Gov/index.cfm/search-for-guides-reviews-and-reports/ ?pageaction=displayproduct&productID=447.

9.  Delivery Methods  Two-dimensional radiation therapy  Three-dimensional conformal radiation therapy  Intensity-modulated radiation therapy  Proton beam therapy External-Beam Radiation Therapy for Head and Neck Cancer Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.Gov/index.cfm/search-for-guides-reviews-and-reports/ ?pageaction=displayproduct&productID=447.

10.  Forward Planning  This type of planning is used in 2DRT and 3DCRT.  Planner designs the beams and then calculates dose given by beam.  Inverse Planning  This type of planning is used in IMRT.  Planner sets goal for dose first (defines goals of dose to tumor and normal tissue); computer algorithms then calculate beam intensity and dose from each beam, based on those goals. Treatment Planning Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/ ? pageaction=displayproduct&productID=447. IMRT = intensity-modulated radiation therapy; 2DRT = two-dimensional radiation therapy; 3DCRT = three-dimensional conformal radiation therapy

11.  2DRT consists of radiation fields designed on 2D fluoroscopic simulation images; typically consists of one to four beams.  3DCRT employs computed tomography simulation, which allows more precise tumor definition.  3DCRT allows the use of a greater number of beams than typically used in 2DRT.  3DCRT allows more accurate dose calculation by accounting for axial anatomy and complex tissue contours. Two-Dimensional Radiation Therapy and Three-Dimensional Conformal Radiation Therapy RT = radiation therapy; 2D = two-dimensional; 3D = three-dimensional; CRT = conformal RT Burri MK, et al. CA Cancer J Clin 2005;55:117-34; Lee NY, Terezakis SA. J Surg Oncol 2008;97:691;-6; Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/ ?pageaction=displayproduct&productID=447.

12.  Intensity-modulated radiation therapy has been implemented over the last decade.  Further refines dose delivery by allowing the modulation of beam intensity within each treatment field and by permitting inverse treatment planning. Intensity-Modulated Radiation Therapy Ballivy O, et al. Clin Transl Oncol 2008;10:407-14; Burri MK, et al. CA Cancer J Clin 2005;55:117-34; Mendenhall WM, et al. J Clin Oncol 2006;24:2618-23; Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/ ?pageaction= displayproduct&productID=447.

13. Potential Advantages and Disadvantages of IMRT When Compared With 2DRT and 3DCRT IMRT = intensity-modulated radiation therapy; 2DRT = two-dimensional radiation therapy; 3DCRT = three-dimensional conformal radiation therapy Ballivy O, et al. Clin Transl Oncol 2008;10:407-14; Burri MK, et al. CA Cancer J Clin 2005;55:117-34; Mendenhall WM, et al. J Clin Oncol 2006;24:2618-23; Samson DJ et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction= displayproduct&productID=447.

14.  A different type of radiation, as opposed to the standard type that uses photons.  At present, it typically uses 1 to 3 beams.  Proton beams can essentially stop at a target, as opposed to photons that continue to travel through tissue.  Proton beam therapy can be planned using 3D images; the technology for using inverse planning with proton beam therapy is just coming into use. Proton Beam Therapy Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and- reports/?pageaction=displayproduct&productID=447.

15.  The topic of the comparative effectiveness review (CER) was nominated in a public process.  Input from experts and stakeholders was used to refine the topic and to develop the clinical questions that the CER would address.  The clinical questions were made available for public comment on the Effective Health Care (EHC) Program Web site and then finalized.  The systematic literature review was conducted using approved AHRQ methods and with input from a technical expert panel.  The draft CER was made available for public comment on the EHC Program Web site and underwent a rigorous peer-review process to improve the final product.  The final CER was published on the EHC Web site. The Comparative Effectiveness Review Development Process Guyatt GH, et al. BMJ 2008;336:924-6; Owens DK, et al. J Clin Epidemiol 2010;63:513-23; Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/ index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=447.

16.  The strength of the overall body of evidence was rated using a system adapted from the method of the GRADE Working Group. The modified system uses four domains—risk of bias, consistency, directness, and precision—for assessment.  The strength of evidence pertaining to each key question was classified into three broad categories or grades: Rating the Strength of Evidence From the CER: A Modification of the GRADE Methodology Guyatt GH, et al. BMJ 2008;336:924-6; Owens DK, et al. J Clin Epidemiol 2010;63:513-23; Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/ index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=447.

17.  2DRT: any treatment plan in which only two-dimensional projection radiographs are used to delineate radiation beams and target volumes.  3DCRT: any treatment plan in which computerized tomography-based treatment planning is used to delineate radiation beams and target volumes in three dimensions.  IMRT: any treatment plan in which intensity-modulated radiation beams and computerized inverse treatment planning is used.  Proton beam therapy: any treatment plan in which proton beam radiation is used. Interventions of Interest Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare. ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=447. IMRT = intensity-modulated radiation therapy; 2DRT = two-dimensional radiation therapy; 3DCRT = three-dimensional conformal radiation therapy

18. Comparative Effectiveness Review: Outcomes of Interest  Primary Outcomes*: Health  Radiation-induced toxicities  Adverse events, both acute and chronic normal tissue toxicity  Effect on quality of life  Clinical effectiveness  Local and locoregional control  Disease-free & overall survival  Secondary Outcomes*: Intermediate  Salivary flow  Probability of completing treatment according to protocol Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and- reports/?pageaction=displayproduct&productID=447. *The specific primary and secondary outcomes selected here were those for which more than five comparative studies provided data and clinical expert consensus indicated their importance.

19.  What is the comparative effectiveness of IMRT, 3DCRT, 2DRT, and proton beam therapy regarding tumor control and patient survival?  What is the comparative effectiveness of IMRT, 3DCRT, 2DRT, and proton beam therapy regarding adverse events and quality of life?  Are there differences in the comparative effectiveness of IMRT, 3DCRT, 2DRT, and proton beam therapy for specific patient and tumor characteristics?  Is there variation in comparative effectiveness of IMRT, 3DCRT, 2DRT, and proton beam therapy because of differences in user experience, target volume delineation, or dosimetric parameters? Key Clinical Questions Addressed by the Comparative Effectiveness Review of Radiotherapy for Head and Neck Cancer Lawrence TS, et al. In: Cancer. principles and practice of oncology. 8th ed, Vol 1. 2008. p. 307-36; National Comprehensive Cancer Network Web site. Available at: http://www.nccn.org/professionals/ physician_gls/f_guidelines.asp; Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides- reviews-and-reports/?pageaction=displayproduct&productID=447. IMRT = intensity-modulated radiation therapy; 2DRT = two-dimensional radiation therapy; 3DCRT = three-dimensional conformal radiation therapy

20.  IMRT vs. 3DCRT  IMRT vs. 2DRT  3DCRT vs. 2DRT  Proton beam therapy vs. 2DRT, 3DCRT, and IMRT Planned Comparisons Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and- reports/?pageaction=displayproduct&productID=447. IMRT = intensity-modulated radiation therapy; 2DRT = two-dimensional radiation therapy; 3DCRT = three-dimensional conformal radiation therapy

21.  Small body of randomized, controlled trials.  Larger body of observational, nonrandomized studies that have high potential for bias of results (e.g., single institution case series).  Clinical diversity of observational studies, with respect to patient characteristics and treatment setting, created uncertainty about significance of confounding. Overview of Available Literature AHRQ. Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews. Available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf; Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq. gov/index.cfm/search-for-guides-reviews-and-reports/ ?pageaction=displayproduct&productID=447.

22.  Tumor Control or Survival: There is insufficient evidence to determine whether 2DRT, 3DCRT, or IMRT confers any advantages when compared with each other.  Level of evidence: insufficient  Adverse Effects: IMRT is associated with a lower incidence of late xerostomia, when compared with 3DCRT or 2DRT.  Level of evidence: moderate  Adverse Effects: For adverse events other than xerostomia, there is insufficient evidence to permit conclusions about the comparative effects of 2DRT, 3DCRT, or IMRT.  Level of evidence: insufficient Clinical Bottom Line: Comparative Evidence for 2DRT, 3DCRT, and IMRT Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and- reports/?pageaction=displayproduct&productID=447. IMRT = intensity-modulated radiation therapy; 2DRT = two-dimensional radiation therapy; 3DCRT = three-dimensional conformal radiation therapy

23.  Quality of Life: Patients who received IMRT had improved quality of life in domains related to late xerostomia when compared with those who received 3DCRT or 2DRT.  Level of evidence: moderate  Quality of Life: There is insufficient evidence to determine the comparative effects of IMRT, 3DCRT, and 2DRT on other quality of life indicators.  Level of evidence: insufficient  Experience of Treatment Team: The data is insufficient to determine whether the experience of the clinical team confers an advantage, as no comparative studies addressed this issue.  Level of evidence: insufficient Clinical Bottom Line: Comparative Evidence for 2DRT, 3DCRT, and IMRT Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/ ?pageaction=displayproduct&productID=447. IMRT = intensity-modulated radiation therapy; 2DRT = two-dimensional radiation therapy; 3DCRT = three-dimensional conformal radiation therapy

24.  No comparative studies addressed the domains of tumor control, survival, adverse effects, quality of life, or experience of the treatment team.  The data, therefore, are insufficient to permit conclusions about proton beam therapy when compared with the other modalities.  Level of evidence: insufficient Clinical Bottom Line: Comparative Evidence for Proton Beam vs. 2DRT, 3DCRT, and IMRT Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and- reports/?pageaction=displayproduct&productID=447.

25. Comparative Effectiveness Regarding Improved Tumor Control or Survival Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/ ?pageaction=displayproduct&productID=447. IMRT = intensity-modulated radiation therapy; 2DRT = two-dimensional radiation therapy; 3DCRT = three-dimensional conformal radiation therapy

26.  The review considered 38 comparative studies.  Of these, four were randomized, controlled trials (RCT).  One RCT could not be clearly rated because a manuscript was unavailable.  One RCT was rated fair.  Two RCTs were rated poor because they lacked intention-to-treat analysis.  The remaining 34 studies were observational, with significant flaws such as: lacking comparable groups at baseline; making comparisons of radiotherapy technologies at different points in time (i.e., the study arms were not contemporaneous); and including poorly performed multivariable analyses. Evidence on the Comparative Effectiveness Regarding Quality of Life and Adverse Events Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/ ?pageaction=displayproduct&productID=447.

27.  Based on 14 comparative studies of IMRT vs. 3DCRT.  One was an unpublished, randomized, controlled trial that was assessed a quality rating of good.  Thirteen were observational studies, of which all were assessed poor quality ratings. Evidence on the Comparative Effectiveness Regarding Quality of Life and Adverse Events: IMRT vs. 3DCRT Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/ ?pageaction=displayproduct&productID=447. IMRT = intensity-modulated radiation therapy; 3DCRT = three-dimensional conformal radiation therapy

28. Studies Regarding Quality of Life and Adverse Events: IMRT vs. 3DCRT NS = not significant; NR = not reported Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/ ?pageaction=displayproduct&productID=447.

29.  IMRT results in less late xerostomia and better quality of life as it relates to xerostomia, when compared with 3DCRT.  Level of Evidence: Moderate Conclusions on the Comparative Effectiveness Regarding Quality of Life and Adverse Events: IMRT vs. 3DCRT Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/ ?pageaction=displayproduct&productID=447. IMRT = intensity-modulated radiation therapy; 3DCRT = three-dimensional conformal radiation therapy

30.  Twenty-two comparative studies addressing IMRT and 2DRT: 2 randomized controlled trials (RCTs) and 20 observational studies, of which 5 were prospective designs.  Nine studies reported on late xerostomia; 5 studies reported on acute xerostomia; quality of life was reported in 1 RCT and 2 observational studies.  Studies not well designed to control for bias and confounding.  All studies, with the exception of one RCT (which was considered to be of fair quality), were of poor quality. Evidence on the Comparative Effectiveness Regarding Quality of Life and Adverse Events: IMRT vs. 2DRT Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/ ?pageaction=displayproduct&productID=447. IMRT = intensity-modulated radiation therapy; 2DRT = two-dimensional radiation therapy

31. Studies Regarding Late Xerostomia: IMRT vs. 2DRT Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=447. IMRT = intensity-modulated radiation therapy; 2DRT = two-dimensional radiation therapy; RT = radiation therapy

32.  The body of evidence suggests less late xerostomia and better quality of life, as it relates to xerostomia, with IMRT.  Level of evidence: Moderate  Eight of nine studies reporting on late xerostomia were statistically significant in favor of IMRT over 2DRT (range of difference, 43 – 62%).  Quality of life measurements generally favored IMRT over 2DRT, although not all domains measured were statistically significant.  The magnitude of difference reported in the studies is uncertain due to poor quality. Conclusions on the Comparative Effectiveness Regarding Quality of Life and Adverse Events: IMRT vs. 2DRT Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq. gov/index.cfm/search-for-guides-reviews-and-reports/ ?pageaction=displayproduct&productID=447. IMRT = intensity-modulated radiation therapy; 2DRT = two-dimensional radiation therapy

33.  Twelve comparative studies addressed 3DCRT and 2DRT: 1 RCT and 11 observational, of which 2 were prospective observational studies.  Studies were of poor quality, were not well designed for control of bias and confounding, and had other weaknesses.  Conclusion: The available literature is of insufficient quantity and quality to ascertain whether there are differences in quality of life or adverse events between 3DCRT and 2DRT. Evidence on the Comparative Effectiveness Regarding Quality of Life and Adverse Events: 3DCRT vs. 2DRT Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/ ?pageaction=displayproduct&productID=447. 2DRT = two-dimensional radiation therapy; 3DCRT = three-dimensional conformal radiation therapy

34.  Level of evidence is insufficient to determine whether:  Specific patient characteristics influence the comparative effectiveness of IMRT, 3DCRT, 2DRT, or proton beam therapy for patients with head and neck cancers.  User experience, target volume delineation, or dosimetric parameters influence the comparative effectiveness of IMRT, 3DCRT, 2DRT or proton beam therapy for patients with head and neck cancers. Other Issues Considered Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/ ?pageaction=displayproduct&productID=447. IMRT = intensity-modulated radiation therapy; 2DRT = two-dimensional radiation therapy; 3DCRT = three-dimensional conformal radiation therapy

35.  Whether critical normal structures are present in the field to be irradiated (e.g., salivary glands, the pituitary gland, optic nerve) and potential resulting adverse events.  The potential benefits and the acute and late harms of the proposed radiation treatment for the individual patient—given the type, location, and stage of his or her cancer.  The potential long-term adverse effects of radiation on quality of life—given the patient’s individual lifestyle and values.  The level of skill and experience of the cancer treatment team in planning and delivering various forms of radiation therapy. What To Discuss With Your Patients About Radiotherapy Treatments for Head and Neck Cancer Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/ ?pageaction=displayproduct&productID=447.

36.  High-quality studies are needed to determine the comparative effectiveness of IMRT, 3DCRT, 2DRT, and proton beam radiation therapy:  In achieving tumor control and improving patient survival.  In reducing adverse events and improving quality of life indicators.  In understanding how outcomes are affected by the characteristics of the tumor, the patient, and the physician/radiotherapy team (e.g., experience), or by radiation treatment planning (e.g., target volume delineation, dosimetric parameters). Gaps in Knowledge: Radiotherapy Treatments for Head and Neck Cancer Samson DJ, et al. AHRQ Comparative Effectiveness Review No. 20. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/ ?pageaction=displayproduct&productID=447. IMRT = intensity-modulated radiation therapy; 2DRT = two-dimensional radiation therapy; 3DCRT = three-dimensional conformal radiation therapy