Patient Selection for Radiotherapy

Performance Status

Performance status, a measure of general well-being and activities of daily life, is one of the most important factors associated with outcome for patients with cancer. Various systems are used to evaluate performance status. The most generally used measures are the Karnofsky score and the Zubrod score (also known as the World Health Organization or ECOG score). The Karnofsky score, named after David A. Karnofsky, ranges from 100 to 0, with 100 indicating “perfect” health and 0 indicating death. The Zubrod score, named after C. Gordon Zubrod, ranges from 0 to 5, with 0 denoting “perfect” health and 5 denoting death. Translation between the Zubrod and Karnofsky scales was validated in a large sample of patients with lung cancer. A Zubrod score of 0 or 1 corresponds with a Karnofsky score of 80–100, a Zubrod score of 2 corresponds with a Karnofsky score of 60–70, and a Zubrod score of 3 or 4 corresponds with a Karnofsky score of 10–50.

In general, a poor performance status is not a contraindication to radiotherapy. However, the value of definitive radiotherapy for a patient with a poor performance status may be limited, as survival times are often shorter for these patients. The benefit of radiotherapy in terms of survival time should be weighed against the risk of treatment toxicity and the time needed to complete the definitive course of treatment. Similar to chemotherapy, radiotherapy may offer notable benefit to selected patients with a poor performance status. Radiotherapy is therefore recommended for this population. The regimen of radiotherapy and its combination with other therapy should be individualized for each patient to achieve a maximum therapeutic effect. Meanwhile, palliative radiotherapy often can be used to improve the quality of life for patients with poor performance status and, therefore, should be recommended for those with advanced disease in whom the tumor is causing clinical symptoms or syndromes. For example, a patient with an ECOG score of 3 or 4 as a result of superior venous cava syndrome, obstructive lung disease, or chest pain may have substantial improvement in quality of life after a short course of palliative radiotherapy. Patient selection for radiotherapy should thus be individualized on the basis of a balanced consideration of both the potential benefits and the potential side effects of such treatment.

Lung Function

Patients with lung cancer often present with poor baseline lung function because of the presence of a tumor or a chronic lung condition. Although it is clear that a patient who has poor lung function caused by a local tumor would benefit from radiotherapy, the impaired baseline lung condition from noncancer reasons can often make high-dose radiotherapy challenging. Traditionally, definitive radiotherapy has been considered to be contraindicated for patients with poor lung function. For example, some Radiation Therapy Oncology Group (RTOG) studies, such as RTOG 9311, have excluded patients with a forced expiratory volume in 1 second (FEV ₁ ) of less than 0.85 L or 0.75 L from treatment with high-dose radiation. Other studies, such as RTOG 0617 and RTOG 1106, allow such treatment only for patients with an FEV ₁ of 1.3 L or more. However, baseline lung function has not consistently been shown to be a risk factor for radiation-induced lung toxicity after conventionally fractionated three-dimensional conformal radiotherapy or hypofractionated stereotactic ablative radiotherapy (SABR). Moreover, the results of pulmonary function tests often are not changed remarkably after modern conformal radiotherapy. Modern dose-escalation studies such as that from the University of Michigan did not limit lung function for very high-dose radiation. In a study of 47 patients, the incidence of lung toxicity had no significant correlation with the results of pulmonary function tests after concurrent chemotherapy and radiotherapy. In a study of 438 patients, FEV ₁ along with other patient-related factors seemed to be more important than dosimetric factors for predicting radiation pneumonitis. In a study of 260 patients, the addition of FEV ₁ and age to the mean lung dose (MLD) slightly improved the predictability of clinically important radiation-induced lung toxicity. Similar to the SABR series, the study showed that patients with higher baseline lung function tests had significantly more clinical lung toxicity.

In summary, pulmonary function should be considered on an individual basis by balancing the improvement in lung function related to tumor shrinkage with the reduction in lung function related to radiotherapy. In the modern era, poor pulmonary function should not be considered a contraindication to definitive radiotherapy.

Comorbidities

Serious comorbidities are very common in patients with lung cancer and can severely affect outcomes. Long-term tobacco consumption is associated with chronic obstructive pulmonary disease (COPD), ischemic heart disease, cerebrovascular disease, and peripheral vascular disease. Furthermore, other tobacco-related cancers, including head and neck cancers, may be diagnosed before, after, or synchronously with lung cancer, thereby complicating the management of the lung cancer, the other cancer, or both. Luchtenborg et al. studied 3152 patients with nonsmall cell lung cancer (NSCLC) who had surgical resection and reported that serious comorbidity caused a decrement in survival equivalent to a single increment in stage grouping. Comorbidities also reduce the tolerability of chemotherapy to patients with NSCLC. High-dose radiotherapy is poorly tolerated by patients with limited cardiorespiratory reserve due to heart or interstitial lung disease, who are at risk of severe dyspnea or even death if they have insufficient reserve to tolerate impaired organ function after treatment. Smith et al. reported that for patients with NSCLC who were managed with curative-intent radiotherapy, a worse score on the Charlson Comorbidity Index correlated with inferior overall survival but not cause-specific survival. Paradoxically, the scarred lungs of patients with severe COPD may be less likely to be affected by severe radiation pneumonitis after SABR. SABR should not be withheld from patients solely because of COPD.

Although the risks of curative radiotherapy can be difficult to estimate for individual patients, it is usually possible to make a reasonable estimate of the consequences related to loss of a substantial proportion of residual lung or heart function. Apart from general comorbidities such as heart disease, several specific conditions may exacerbate the toxicity of radiotherapy.

Autoimmune disorders such as systemic lupus erythematosus and scleroderma have been associated with enhanced intrinsic radiosensitivity of normal tissues and, therefore, a higher risk of serious toxicity resulting from radiotherapy.

Age and Frailty

Age and frailty are obviously two separate entities: the former is expressed as an objective, trivial number, and the latter is derived from the Latin word fragilis , which means “fragile” (i.e., weak). Frailty clearly increases with age, but a young individual can be frail as well. In most geriatric literature, frailty has been defined as either a threshold beyond which the functional reserve of a person is critically reduced and the tolerance of stress is negligible or as a progressive reduction of functional reserve due to a progressive accumulation of deficits. Thus functional reserve should be measured objectively and used as a prognostic indicator of the survival of the patient and/or the tolerance of the treatment.

Many authors have shown that the older population is a very heterogeneous group in terms of physical, biologic, emotional, and cognitive functions. Nevertheless, increased age is associated with comorbidities as well as higher rates of hospitalization and chemotherapy-related toxicity, shifting the overall risk-to-benefit ratio. Older patients and patients with important comorbidities are underrepresented in clinical trials. Because of the lack of data as well as the fear of iatrogenic complications, older patients generally receive less aggressive treatment, which may result in suboptimal survival rates. In selected patients, it has been shown that intensive, state-of-the art therapy benefits older patients. Remarkably, the 5-year survival rate is 15% to 20% with radiotherapy alone for patients with stage III disease who are older than 75 years, have good performance status, and have thorough staging. Defeatism thus is definitively not appropriate. Moreover, oncologic assessment methods specifically designed for older patients have been developed. The clinical implementation of these methods will lead to more rational and appropriate care of older patients with cancer. These methods probably are also useful for younger, frail patients. These developments should move the field forward.