Improving Consistency and Quality of Care for Older Adults With Cancer: The Challenges of Developing Consensus Guidelines for Radiation Therapy

Abstract

The demographics of cancer patients are changing. For decades, epidemiologists and clinicians have predicted rising numbers of older patients with cancer (1Smith B.D. Smith G.L. Hurria A. et al.Future of cancer incidence in the United States: Burdens upon an aging, changing nation.J Clin Oncol. 2009; 27: 2758-2765Crossref PubMed Scopus (1313) Google Scholar, 2Yancik R. Cancer burden in the aged: An epidemiologic and demographic overview.Cancer. 1997; 80: 1273-1283Crossref PubMed Scopus (533) Google Scholar). Although aging is a heterogeneous process, older patients often present with challenges that can significantly affect their ability to tolerate antineoplastic therapy. Older age is associated with higher rates of comorbidities, polypharmacy, organ dysfunction, and immune cell senescence (3Vestal R.E. Aging and pharmacology.Cancer. 1997; 80: 1302-1310Crossref PubMed Scopus (175) Google Scholar). Many of these changes with aging are silent until the patients are introduced to stressors (eg, surgery, chemotherapy, or radiation therapy) that unmask the aging process and manifest as an increased risk of toxicity or functional decline. Unfortunately, although older adults now make up the majority of patients in our clinic, they make up the minority of patients enrolled in clinical trials (4Hutchins L.F. Unger J.M. Crowley J.J. et al.Underrepresentation of patients 65 years of age or older in cancer-treatment trials.N Engl J Med. 1999; 341: 2061-2067Crossref PubMed Scopus (1851) Google Scholar). Thus, clinicians often have less evidence to help guide treatment of older patients. For some older patients, the standard treatment that was defined based on studies performed in younger healthier individuals may be appropriate. Yet, for others, a standard treatment may be too toxic, offer little benefit, or cause decreases in quality of life that patients are unwilling to accept. Given the paucity of data, treatment patterns can vary, and individual physicians may find it difficult to determine best practices for their older patients. Consensus guidelines are particularly important to improve the quality and consistency of care delivery in areas where practice patterns vary in this way. Prior research has shown that the guidelines most frequently used by practicing oncologists are those developed by the National Comprehensive Cancer Network (NCCN) (5Jagsi R. Huang G. Griffith K. et al.Attitudes toward and use of cancer management guidelines in a national sample of medical oncologists and surgeons.J Natl Compr Canc Netw. 2014; 12: 204-212Crossref PubMed Scopus (14) Google Scholar). NCCN engages representatives from its member sites to participate in evidence- and consensus-based guideline creation that has been, for the most part, site specific. However, NCCN has also developed overarching consensus guidelines specifically focused on the management of older adults with cancer (Older Adult Oncology Guidelines), in which disease- and modality-specific considerations are addressed (6National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Older Adult Oncology (Version 1.2016). National Comprehensive Cancer Network, Fort Washington, PA2016Google Scholar). This past year, the guideline committee made a concerted effort to update, on the basis of available evidence, the radiation therapy–related disease-specific recommendations. The purpose of this article is to discuss the process, potential benefits, and limitations of updating the radiation therapy–specific recommendations in this context. As the former chair and the two radiation oncologists on the committee, we present our experience here in the hopes that the lessons we have learned may help to improve future radiation therapy–based research and guidelines for older adults with cancer. Although the recommendations within the NCCN guidelines are often made based on the best available high-level data, when such data do not exist, recommendations are made based on consensus opinions of panel members. This approach has led to some criticism, and other organizations, including the American Society of Clinical Oncology (ASCO) and American Society for Radiation Oncology, have considered Institute of Medicine guidance to create guidelines on specific topics that follows a somewhat different approach. Although such guidelines may be less vulnerable to the influence of panel members or expert consensus, they tend to be narrower in scope as they often do not adequately address areas where gaps in evidence exist. Hence, they may also be more limited in the numbers of patients to which they apply. To date, NCCN is unique in attempting to address a specific set of treatment recommendations in older adults with cancer. The Older Adult Oncology Guidelines (formerly the Senior Adult Oncology Guidelines) were originally created in 2004. The guidelines highlight the latest literature supporting the specific workup, geriatric assessment, treatment, and survivorship issues facing older adults with multiple different cancer types. As guideline writing is an iterative process that constantly needs updating, this year's update included a concerted effort to report the available evidence for radiation treatments in older adults. To achieve this goal, a request was sent to each radiation oncologist on the NCCN panels to review the previous site-specific comments and recommendations and to recommend updates based on available literature. On the basis of the responses to this request, as well as a thorough review of available literature, new statements on radiation therapy for older adults were added to the guidelines for bladder cancer, breast cancer, central nervous system cancers, both non–small cell and small cell lung cancers, hepatobiliary cancers, and prostate cancer. Of note, head and neck cancer statements were updated as part of recommendations just prior to this radiation therapy–specific review, and thus no changes to the current head and neck cancer recommendations were considered to be necessary after literature review. These recommendations are summarized in Table 1. Further details on these updated statements were published in the November 2016 edition of the Journal of the National Comprehensive Cancer Network (JNCCN) (39VanderWalde N. Jagsi R. Dotan E. et al.NCCN guidelines insights: Older adult oncology, version 2.2016.J Natl Compr Canc Netw. 2016; 14: 1357-1370Crossref PubMed Scopus (63) Google Scholar). However, what became quickly obvious to the persons involved in updating these guidelines were the large knowledge gaps that exist for treatment decisions in older patients, particularly with respect to radiation treatment.Table 1Summary of RT-related older adult oncology guideline discussionDisease siteSummarySourcesBladder cancer•Age alone should not be the criterion for treatment decisions.•Older patients appear to have similar response rates and a good late toxicity profile with selective bladder preservation.Mak et al 7Mak R.H. Hunt D. Shipley W.U. et al.Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: A pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233.J Clin Oncol. 2014; 32: 3801-3809Crossref PubMed Scopus (262) Google Scholar, Efstathiou et al 8Efstathiou J.A. Bae K. Shipley W.U. et al.Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06.J Clin Oncol. 2009; 27: 4055-4061Crossref PubMed Scopus (162) Google ScholarBreast cancer•Data on omission of RT for patients aged ≥70 y were again reviewed. Omission of RT was considered appropriate for those who met the criteria for the CALGB 9343 study.•Of note, the Prime II study results were also considered. The panel believed the data need further maturation before recommending omission of RT in patients aged ≥65 y.Hughes et al 9Hughes K.S. Schnaper L.A. Berry D. et al.Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer.N Engl J Med. 2004; 351: 971-977Crossref PubMed Scopus (851) Google Scholar, Hughes et al 10Hughes K.S. Schnaper L.A. Bellon J.R. et al.Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: Long-term follow-up of CALGB 9343.J Clin Oncol. 2013; 31: 2382-2387Crossref PubMed Scopus (778) Google Scholar, Kunkler et al 11Kunkler I.H. Williams L.J. Jack W.J. et al.Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): A randomised controlled trial.Lancet Oncol. 2015; 16: 266-273Abstract Full Text Full Text PDF PubMed Scopus (571) Google ScholarCentral nervous system cancerGlioblastoma•Data on single-modality therapy and hypofractionation for older frail patients were reviewed, and recommendations were updated and discussed.•Data on multimodality therapy including hypofractionation were reviewed, and recommendations were updated and discussed.Keime-Guibert et al 12Keime-Guibert F. Chinot O. Taillandier L. et al.Radiotherapy for glioblastoma in the elderly.N Engl J Med. 2007; 356: 1527-1535Crossref PubMed Scopus (646) Google Scholar, Roa et al 13Roa W. Brasher P.M. Bauman G. et al.Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: A prospective randomized clinical trial.J Clin Oncol. 2004; 22: 1583-1588Crossref PubMed Scopus (655) Google Scholar, Wick et al 14Wick W. Platten M. Meisner C. et al.Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: The NOA-08 randomised, phase 3 trial.Lancet Oncol. 2012; 13: 707-715Abstract Full Text Full Text PDF PubMed Scopus (811) Google Scholar, Malmstrom et al 15Malmstrom A. Gronberg B. Marosi C. et al.Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: The Nordic randomised, phase 3 trial.Lancet Oncol. 2012; 13: 916-926Abstract Full Text Full Text PDF PubMed Scopus (875) Google Scholar, Stupp et al 16Stupp R. Hegi M. Mason W. et al.Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial.Lancet Oncol. 2009; 10: 459-466Abstract Full Text Full Text PDF PubMed Scopus (5510) Google Scholar, Scott et al 17Scott J. Suh J. Elson P. et al.Aggressive treatment is appropriate for glioblastoma multiforme patients 70 years old or older: A retrospective review of 206 cases.Neuro Oncol. 2011; 13: 428-436Crossref PubMed Scopus (75) Google Scholar, Behm et al 18Behm T. Horowski A. Schneider S. et al.Concomitant and adjuvant temozolomide of newly diagnosed glioblastoma in elderly patients.Clin Neurol Neurosurg. 2013; 115: 2142-2146Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, Minniti et al 19Minniti G. Scaringi C. Lanzetta G. et al.Standard (60 Gy) or short-course (40 Gy) irradiation plus concomitant and adjuvant temozolomide for elderly patients with glioblastoma: A propensity-matched analysis.Int J Radiat Oncol Biol Phys. 2015; 91: 109-115Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, Minniti et al 20Minniti G. Lanzetta G. Scaringi C. et al.Phase II study of short-course radiotherapy plus concomitant and adjuvant temozolomide in elderly patients with glioblastoma.Int J Radiat Oncol Biol Phys. 2012; 83: 93-99Abstract Full Text Full Text PDF PubMed Scopus (96) Google ScholarHead and neck cancerRT alone•Data on toxicity differences between older and younger patients were reviewed and discussed.Combined modality therapy•There is a lack of evidence to support use of chemoradiation therapy in patients aged ≥70 y.•There is a lack of evidence to support use of cetuximab RT in patients aged ≥64 y.•There is possible increased late toxicity in older patients.Pignon et al 21Pignon T. Horiot J.C. Van den Bogaert W. et al.No age limit for radical radiotherapy in head and neck tumours.Eur J Cancer. 1996; 32A: 2075-2081Abstract Full Text PDF PubMed Scopus (134) Google Scholar, Pignon et al 22Pignon J.P. le Maitre A. Maillard E. et al.Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients.Radiother Oncol. 2009; 92: 4-14Abstract Full Text Full Text PDF PubMed Scopus (2186) Google Scholar, Bonner et al 23Bonner J.A. Harari P.M. Giralt J. et al.Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival.Lancet Oncol. 2010; 11: 21-28Abstract Full Text Full Text PDF PubMed Scopus (1570) Google Scholar, Machtay et al 24Machtay M. Moughan J. Trotti A. et al.Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: An RTOG analysis.J Clin Oncol. 2008; 26: 3582-3589Crossref PubMed Scopus (1034) Google Scholar, Maggiore et al 25Maggiore R.J. Curran E.K. Witt M.E. et al.Survival and selected outcomes of older adults with locally advanced head/neck cancer treated with chemoradiation therapy.J Geriatr Oncol. 2013; 4: 327-333Abstract Full Text Full Text PDF PubMed Scopus (26) Google ScholarHepatobiliary cancer•Data on SBRT were reviewed and added to recommendations.Bujold et al 26Bujold A. Massey C.A. Kim J.J. et al.Sequential phase I and II trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma.J Clin Oncol. 2013; 31: 1631-1639Crossref PubMed Scopus (532) Google ScholarNon–small cell lung cancer•SABR and SBRT recommendations were added.•Data on SBRT outcomes in elderly patients were reviewed and discussed.Palma et al 27Palma D. Visser O. Lagerwaard F.J. et al.Treatment of stage I NSCLC in elderly patients: A population-based matched-pair comparison of stereotactic radiotherapy versus surgery.Radiother Oncol. 2011; 101: 240-244Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, Chang et al 28Chang J.Y. Senan S. Paul M.A. et al.Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: A pooled analysis of two randomised trials.Lancet Oncol. 2015; 16: 630-637Abstract Full Text Full Text PDF PubMed Scopus (1042) Google Scholar, Samuels et al 29Samuels M.A. Kandula S. Koru-Sengul T. et al.Stereotactic body radiotherapy in patients with stage I non-small-cell lung cancer aged 75 years and older: Retrospective results from a multicenter consortium.Clin Lung Cancer. 2013; 14: 446-451Abstract Full Text Full Text PDF PubMed Scopus (27) Google ScholarSmall cell lung cancerChemoradiation therapy•Data on efficacy and toxicity in older patients were reviewed, showing similar efficacy and possible increased rate of toxicity among older patients.PCI•Data on safety and efficacy in older patients were reviewed, and recommendations were updated. PCI is not recommended in older patients with poor performance status or baseline neurocognitive deficits.Yuen et al 30Yuen A.R. Zou G. Turrisi A.T. et al.Similar outcome of elderly patients in intergroup trial 0096: Cisplatin, etoposide, and thoracic radiotherapy administered once or twice daily in limited stage small cell lung carcinoma.Cancer. 2000; 89: 1953-1960Crossref PubMed Scopus (119) Google Scholar, Schild et al 31Schild S.E. Stella P.J. Brooks B.J. et al.Results of combined-modality therapy for limited-stage small cell lung carcinoma in the elderly.Cancer. 2005; 103: 2349-2354Crossref PubMed Scopus (68) Google Scholar, Rule et al 32Rule W.G. Foster N.R. Meyers J.P. et al.Prophylactic cranial irradiation in elderly patients with small cell lung cancer: Findings from a North Central Cancer Treatment Group pooled analysis.J Geriatr Oncol. 2015; 6: 119-126Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, Wolfson et al 33Wolfson A.H. Bae K. Komaki R. et al.Primary analysis of a phase II randomized trial Radiation Therapy Oncology Group (RTOG) 0212: Impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with limited-disease small-cell lung cancer.Int J Radiat Oncol Biol Phys. 2011; 81: 77-84Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, Le Pechoux et al 34Le Pechoux C. Laplanche A. Faivre-Finn C. et al.Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01).Ann Oncol. 2011; 22: 1154-1163Crossref PubMed Scopus (150) Google ScholarProstate cancerRT + ADT•Data on efficacy and toxicity of ADT with RT were reviewed and discussed. Among older patients with significant comorbidities, it is recommended to consider a shorter course of ADT over a longer course in patients with high-risk disease.Piccirillo et al 35Piccirillo J.F. Vlahiotis A. Barrett L.B. et al.The changing prevalence of comorbidity across the age spectrum.Crit Rev Oncol Hematol. 2008; 67: 124-132Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar, Thompson et al 36Thompson I.M. Ankerst D.P. Chi C. et al.Assessing prostate cancer risk: Results from the Prostate Cancer Prevention Trial.J Natl Cancer Inst. 2006; 98: 529-534Crossref PubMed Scopus (754) Google Scholar, D'Amico et al 37D'Amico A.V. Chen M.-H. Renshaw A.A. et al.Androgen suppression and radiation vs radiation alone for prostate cancer: A randomized trial.JAMA. 2008; 299: 289-295Crossref PubMed Scopus (579) Google Scholar, D'Amico et al 38D'Amico A.V. Renshaw A.A. Loffredo B. et al.Duration of testosterone suppression and the risk of death from prostate cancer in men treated using radiation and 6 months of hormone therapy.Cancer. 2007; 110: 1723-1728Crossref PubMed Scopus (28) Google ScholarAbbreviations: ADT = androgen deprivation therapy; CALGB = Cancer and Leukemia Group B; PCI = prophylactic cranial irradiation; RT = radiation therapy; SABR = stereotactic ablative radiation therapy; SBRT = stereotactic body radiation therapy. Open table in a new tab Abbreviations: ADT = androgen deprivation therapy; CALGB = Cancer and Leukemia Group B; PCI = prophylactic cranial irradiation; RT = radiation therapy; SABR = stereotactic ablative radiation therapy; SBRT = stereotactic body radiation therapy. To strengthen the evidence base for future iterations of the guidelines, to best serve our patients, the radiation oncology community must vigorously pursue additional research in a number of areas. First, although geriatric assessments can be used to predict which patients may tolerate anticancer treatments, including chemotherapy and surgery (40Hurria A. Mohile S. Gajra A. et al.Validation of a prediction tool for chemotherapy toxicity in older adults with cancer.J Clin Oncol. 2016; 34: 2366-2371Crossref PubMed Scopus (367) Google Scholar, 41Audisio R.A. Pope D. Ramesh H.S. et al.Shall we operate? Preoperative assessment in elderly cancer patients (PACE) can help. A SIOG surgical task force prospective study.Crit Rev Oncol Hematol. 2008; 65: 156-163Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar), there is less literature in the context of radiation therapy. Both surgery (which requires anesthesia) and chemotherapy require some amount of systemic tolerance, whereas radiation therapy, with its localized effects, has toxicities that are highly dependent on the area of the body being treated. Older adult trials attempting to identify associations between baseline function and radiation therapy tolerance are few in nature. Geriatric assessment for older patients with cancer has not been routinely performed in most radiation oncology clinics or clinical trials; however, there is a critical need for additional rigorous research to identify the patterns and correlates of radiation therapy–related toxicity in older adults, for each disease site. This is particularly important because the localized nature of radiation therapy may actually lead many older patients deemed poor candidates for other modalities toward our clinics. Indeed, previous studies have suggested that physicians may be more inclined to approach older patients for radiation therapy–related clinical trials than for trials of other modalities (42Chamberlain R.M. Winter K.A. Vijayakumar S. et al.Sociodemographic analysis of patients in radiation therapy oncology group clinical trials.Int J Radiat Oncol Biol Phys. 1998; 40: 9-15Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 43Movsas B. Moughan J. Owen J. et al.Who enrolls onto clinical oncology trials? A radiation Patterns Of Care Study analysis.Int J Radiat Oncol Biol Phys. 2007; 68: 1145-1150Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). Therefore, radiation oncologists have a tremendous opportunity to contribute to research that benefits older adults with cancer, especially given that the daily nature of most radiation therapy regimens allows for repeated, thorough interaction with older patients and provides the opportunity for collection of function, toxicity, and quality of life throughout their treatments. As a field, radiation oncology must generate better evidence not only regarding tolerability but more generally regarding the efficacy, toxicity, and relative value of the wide variety of radiation therapy options now available for the poorly studied growing population of older patients with cancer, who may differ significantly from those younger patients typically included in clinical trials. In a recent statement, ASCO recommended multiple ways to improve the evidence base for older adults with cancer (44Hurria A. Levit L.A. Dale W. et al.Improving the evidence base for treating older adults with cancer: American Society of Clinical Oncology statement.J Clin Oncol. 2015; 33: 3826-3833Crossref PubMed Scopus (281) Google Scholar). For persons designing clinical trials, careful consideration should be placed on the inclusion and exclusion criteria so as not to unnecessarily exclude older adults. Additional variables other than just age and performance status (functional status, nutritional status, comorbid conditions, falls, and so on) should be collected and reported at baseline and at routine follow-up time points. Validated patient-reported measures such as the geriatric assessment for oncologists developed by the Cancer and Leukemia Group B (now called the Alliance) and Cancer and Aging Research Group (40Hurria A. Mohile S. Gajra A. et al.Validation of a prediction tool for chemotherapy toxicity in older adults with cancer.J Clin Oncol. 2016; 34: 2366-2371Crossref PubMed Scopus (367) Google Scholar, 45Hurria A. Cirrincione C.T. Muss H.B. et al.Implementing a geriatric assessment in cooperative group clinical cancer trials: CALGB 360401.J Clin Oncol. 2011; 29: 1290-1296Crossref PubMed Scopus (260) Google Scholar), as well as the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), could be considered for inclusion in trial design (46Dueck A.C. Mendoza T.R. Mitchell S.A. et al.Validity and reliability of the US National Cancer Institute's patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).JAMA Oncol. 2015; 1: 1051-1059Crossref PubMed Scopus (445) Google Scholar). Outcomes important to many older adults including quality of life, independence, and caregiver burden should be designed into studies. Unique trial designs, including trials specific to older adults or extended trials (in which the winning arm of a randomized study is reopened to older patient accrual if not enough older patients were included in the initial run), should be considered and emphasized. Entities funding or publishing research in our field must also consider the importance of comparative effectiveness research performed through secondary analyses of clinical trials or through national databases to study a treatment in a population that represents the age and health-risk distribution of the population with the disease (44Hurria A. Levit L.A. Dale W. et al.Improving the evidence base for treating older adults with cancer: American Society of Clinical Oncology statement.J Clin Oncol. 2015; 33: 3826-3833Crossref PubMed Scopus (281) Google Scholar). Journals should encourage their authors to report the distribution of age, comorbidities, functional status, and quality-of-life outcomes. Clinicians should consider the importance of obtaining these data in older patients and encourage their patients to participate in clinical research. Finally, societies such as ASCO and the American Society for Radiation Oncology should incorporate explicit discussion of special considerations in older adults in their guidelines. By implementing some of the aforementioned and other recommendations, it is our hope that we will begin to move forward in filling in the knowledge gaps that became so evident to us as we sought to develop guidelines to improve the quality and consistency of care for older adults receiving radiation therapy. Given the nature of radiation therapy treatments and their delivery, we have a unique opportunity to vastly improve the evidence base of the ever-increasing population of older patients with cancer. As a field, we can choose to accept the changing demographics of cancer care or we can continue to study our treatments in a minority of our patients without knowing if they will benefit the patients we treat the most. The choice is ours. The authors acknowledge the hard work of the staff at the National Comprehensive Cancer Network, including Mary Anne Bergmann. They also acknowledge the effort put in by the entire committee on the guidelines for older adult oncology, including the new chair of the committee, Efrat Dotan.