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Journal of Clinical Oncology, Vol 26, No 24 (August 20), 2008: pp. 3920-3922 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.17.3674
Just Enough Palliation: Radiation Dose and Outcome in Patients With Non–Small-Cell Lung CancerDivision of Radiation Oncology, Thoracic Oncology Program, Penn State Hershey Cancer Institute, Hershey, PA Lung cancer is a common disease, increasing in worldwide incidence, for which current strategies of prevention, detection, and therapy remain unsatisfactory. In the United States, 161,840 deaths from lung cancer are estimated to occur in 2008.1 Recurrence is common even among patients with apparently localized disease amenable to definitive local therapies. Most patients present with locally advanced or metastatic disease and are not appropriate candidates for resection. Although death resulting from lung cancer may come predominantly from distant disease, much suffering comes from uncontrolled local disease. Studying palliative therapies for patients with lung cancer is necessary, complex, and difficult. Patients vary in their prior therapy, such as previously untreated stage IIIA or IIIB and not a candidate for curative intent treatment, newly diagnosed stage IV, locally recurrent after surgery, relapsing after a response to initial chemotherapy, and refractory to initial chemotherapy. In addition, they vary in the extent of known disease, including intrathoracic only and intrathoracic and extrathoracic (with or without intracranial disease), and in age and comorbidities.2 The concept of locally advanced "incurable" disease is culturally as well as medically defined. Symptoms that may warrant palliation range from those clearly caused by intrathoracic tumor (such as airway and vascular obstruction, pain resulting from chest wall invasion, cough, hemoptysis), through those likely resulting from a combination of cancer and underlying benign pulmonary disease (such as dyspnea), to systemic symptoms such as fatigue, anorexia, and malaise that may have only a tenuous relation to the status of intrathoracic disease. The response of these symptoms may be assessed by the patient, the physician, or both. The study design may select any of a variety of primary end points including frequency and duration of symptom palliation, survival, or quality of life. Much of the rise in lung cancer incidence is occurring in parts of the world where the availability of radiation therapy is quite limited.3 It is estimated that in 2020, approximately 70% of the world cancer incidence will occur in countries of moderate or low income, and that these will typically be diagnosed at advanced stage with most patients in need of palliative treatment.4 The proportion of these cancers related to tobacco will also be high, in the range of 10%. Thus, there is an increasing need for better determination of the appropriate dose and fractionation requirements for effective and resource-efficient palliative radiation therapy for patients with incurable non–small-cell lung cancer (NSCLC). In those parts of the world with well-developed and distributed health care systems, we debate the convenience of one or two fractions compared with five or 10 fractions. In other areas, where radiation therapy is available for only a small portion of cancer patients, we may be talking about explicit rationing of care: who gets treated and who does not.5,6 Although palliative radiotherapy is cost effective by North American and European metrics, such arguments hold little weight when the required treatment facilities and the expertise to run them safely and effectively are simply not available.7,8 The study by Fairchild et al9 in this issue of Journal of Clinical Oncology reports the results of a systematic review of 13 trials involving 3,475 patients in which patients receiving palliative radiation therapy for NSCLC were randomly assigned among two or more radiation dose/fractionation schedules. Most of these trials compared very short (one- or two-fraction) with moderately short (five- up to 15- to 20-fraction) schedules. Their results show a modest but statistically significant benefit in improvement of total symptom score (but not individual symptoms) and survival for the higher doses up to doses of 35 Gy.10 One-year survival was 26.5% for patients in high-dose arms compared with 21.7% for patients in low-dose arms (P = .002). Along with these benefits came an increase in physician-assessed dysphagia of modest (5.6%) but significant (P = .01) degree. These results are not too surprising, and I suspect confirm the clinical impressions of many, if not most, radiation oncologists. The authors concluded that short schedules were satisfactory for most patients but that longer schedules and higher doses should be considered for patients of better performance status and realistic potential for longer term survival. This is not the first overview of these randomized trials of palliative fractionation for patients with NSCLC. The Cochrane Collaborative has published an analysis of a similar data set of 13 trials through 2002 and updated in 2006.10,11 Because of considerable heterogeneity in dose regimens, patient characteristics, and the methods of evaluating and reporting outcomes, a formal meta-analysis was not felt to be appropriate and a narrative synthesis and interpretation was made. They found that short and longer palliative schedules had similar response rates. There was no clear evidence for an overall survival difference, but several trials suggested a benefit for longer-course, higher-dose regimens in patients with good performance status (Eastern Cooperative Oncology Group performance status of 0 to 1).12-13 The Fairchild study differs methodologically from the Cochrane analysis in converting the doses in each treatment regimen to Biologically Equivalent Dose10 values and in comparing dose-outcome relations among all the trials despite the clinical heterogeneity of the patients studied. Several limitations detract from the clinical utility of these observations and conclusions. The first is that the studies included in this review did not make formal assessment of quality of life. Symptomatic relief scores are not a substitute for this. The authors note this deficiency, as well as the limitations of much of the patient-reported data on both symptom relief and adverse effects. These deficiencies in the primary data make it difficult to know which dose/fractionation schedule is truly better for patients when symptom relief, treatment toxicity, and inconvenience of more protracted treatment are weighed in the clinical balance. Future studies of palliative therapies must pay greater attention to the use of validated instruments for collecting data on relief of specific symptoms, quality of life, and treatment cost and convenience.14 A second limitation is the lack of data on the use of any chemotherapy in these patients, other than the exclusion of studies using radiotherapy with another modality, such as chemotherapy. The patient populations studied included both those with locally advanced disease who were not felt appropriate for curative-intent and patients with known distant metastatic disease. Many of these patients will receive palliative chemotherapy at some time in their course, generally before or after palliative irradiation, given that most clinicians wish to avoid the additional toxicities of concurrent treatment in this noncurative setting. Although two decades ago there was widespread skepticism as to the benefits of any chemotherapy in providing meaningful palliation and survival prolongation for patients with metastatic lung cancer, there are now clear data that both first- and second-line chemotherapy using either conventional cytotoxics or molecularly targeted agents can both relieve symptoms and prolong survival for suitable patients.15-16 In addition, other local palliative therapies, including tumor ablation by radiofrequency heating or cryotherapy, endobronchial brachytherapy, or endobronchial laser excision with or without stent placement, provide complementary or alternative treatment to radiation therapy for patients with airway obstruction.17-19 The authors of this study may be in the unfortunate position of having accurately summarized a treatment (palliative radiotherapy as single modality) whose era is passing, at least for patients of adequate performance status for whom other therapies are available. If we take, as a broad conclusion, that short and long radiotherapy schedules are about equally good for patients of poor performance status and longer ones of modest benefit for patients of better performance status, are radiation oncologists likely to change practice patterns as a result? Our history is discouraging. Fairchild et al20 have recently published an analysis of prescription patterns at the Rapid Response Radiotherapy Program trying to determine whether or not publication of data on the rough equivalence of short and long regimens made a difference in physician behavior. They found no evidence for such a change. Similar slow alteration of established patterns has been noted in the use of hypofractionated compared with conventionally fractionated radiotherapy for palliation of bone metastases, the use of twice-daily fractionation in small-cell lung cancer, or continuous hyperfractionated accelerated radiation therapy and continuous hyperfractionated accelerated radiation therapy (weekendless) three-times-daily regimens in NSCLC. In each case, level I evidence has failed to bring about major changes in physician behavior. The reluctance of radiation oncologists to change established patterns of practice is not well studied and probably multiply determined, but may include elements of habit, lack of knowledge of recent (ie, post specialty certification) clinical data, or—in some cases—economic advantages of established fractionation regimens. Do patients prefer short schedules? The general assumption made by most clinicians is that factors of convenience, for the patients or their caregivers, would lead to such a preference. Yet there are few published data on what patients actually prefer and why. A survey of patients with bone metastases from a variety of malignancies found that 80% of patients preferred a six-fraction regimen over a single-fraction one, based primarily on a lower anticipated need for re-treatment.21 This trial was conducted in Singapore, where the majority of patients lived within 20 km of the radiotherapy center; results may not be generalizable to other geographic and cultural locales, or for patients with lung cancer being treated for thoracic symptoms. Future comparative studies of fractionation should capture data on patient preferences in a variety of health care settings. The caution of Fairchild et al20 in endorsing a single specific palliative regimen is quite appropriate in view of the heterogeneity of patients and practice environments for patients with incurable NSCLC. Their observation that there does appear to be some increased benefit to higher doses may be most applicable when administering palliative radiotherapy to patients who have shown a good response to chemotherapy and in whom survival of a year or more is a realistic possibility. This article brings attention to the need for more prospective studies of the integration of local radiotherapy and systemic therapies for patients of good performance status and access to advanced care and the optimization of time- and resource-efficient brief palliative therapies for patients living in areas of more limited medical resources.22 It will be critically important to directly assess the perceived clinical benefit by the patients (palliation of symptoms minus toxicities of treatment, convenience and expense of longer rather than shorter courses of treatment) rather than assume that health professionals are good surrogate evaluators of these end points. It will continue to be imperative to base our treatment recommendations, both curative and palliative, on solid evidence.23-25 New clinical trials of both chemotherapy and palliative radiation therapy should better recognize that both of these modalities are likely to be used for many patients; we should seek to facilitate, rather than forbid, such combinations. It is common for trials of new systemic agents to require a waiting period after completion of radiation therapy. A quick review of five such trials currently open in our institution disclosed waiting intervals of 1, 2, 3, 3, and 4 weeks, with no consideration of radiation dose, field size, or normal tissues irradiated. Although waiting several weeks between the completion of a course of radiotherapy and start of chemotherapy may have made sense when radiation consisted of large opposed fields encompassing much of the mediastinum, it is not needed when a single fraction to a small target volume is used to palliate chest wall pain or hemoptysis. Patients should not have to choose between access to investigational therapies and effective radiation therapy to palliate local symptoms. Finally, in an era in which we have an increasingly aging population, the costs of such therapies must be evaluated in the context of other health care priorities. Such concerns should not limit development and application of more effective systemic therapies for patients with NSCLC, but such activities should be pursued in the context of equally aggressive basic and applied research in smoking prevention and cessation, lung cancer prevention, and early detection. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a ‘U’ are those for which no compensation was received; those relationships marked with a ‘C’ were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Henry Wagner Jr, Physicians Education Resources, Quintiles Research Funding: None Expert Testimony: None Other Remuneration: None REFERENCES
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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