Thoracic Oncology Unit, Centre Hospitalier Universitaire de Montpellier, Hôpital Arnaud de Villeneuve, France.
Disclosure: The authors declare no conflicts of interest.
Address for correspondence: Jean Louis Pujol, MD, Thoracic Oncology Unit, Centre Hospitalier Universitaire de Montpellier, Hôpital Arnaud de Villeneuve, 34295 Montpellier Cedex 5, France. E-mail: email@example.com
Patients suffering from non-small cell lung cancer (NSCLC) are frequently affected by a high level of symptom burden.1 Consequently, these patients also have a poor quality of life, insofar as symptom score is one of the five dimensions of quality of life (aside, functional, psychologic, social, and spiritual dimensions2). A high symptom score, by itself might require specific interventions, palliation or supportive therapies to achieve symptoms alleviation. Consequences of a high symptom score could be regarded from two major points of view. (i) some symptoms can indicate a severe patient disability and therefore might modify anticancer treatment program by limiting indication for some important treatment modalities such as surgery. (ii) high symptom score is reducing patient ability to achieve a normal familial and social activity. This interference between symptoms score and social life, referred to as global health status in quality of life scale, has been demonstrated as indicating a poor outcome.3
Among the most frequently observed symptoms in NSCLC, two could be regarded as directly involved in reducing patient daily activity living: dyspnoea and fatigue. Both symptoms have major impact in cardiopulmonary fitness on exercise. Studies that aim at measuring cardiopulmonary fitness in NSCLC might therefore be regarded as a global investigation exploring main host-tumor relationship features that could have major impact in both treatment decision and quality of life.4 Conversely, studies that aim at improving cardiopulmonary fitness on exercise might be considered as interesting approaches at improving quality of life. In this issue of the journal, Kasymjanova et al.5 presented a noninterventional study evaluating exercise capacity in patients with newly diagnosed advanced NSCLC and its relationship with survival. Temel et al.,6 also in this issue report an interventional study performed in an effort at improving functional outcome and symptoms in a similar advanced NSCLC population by mean of a structured exercise program. In this brief editorial we would like to summarize and comment on results of both studies by highlighting three different issues: (1) methodological aspects of the evaluation of cardiopulmonary fitness in oncologic patients; (2) multidimensional aspect of fatigue and dyspnoea in patients receiving treatment for advanced NSCLC; and (3) meaning of the evaluation and intervention on cardiopulmonary fitness for these patients in daily practice.
Briefly, in the study by Kasymjanova et al., patients receiving chemotherapy for a NSCLC have underwent repeated evaluation by exercise tests (by means of the submaximum 6-minute walk test [6MW]): One before chemotherapy (preceded by a training test) and the second after the second cycle of chemotherapy. The main findings are as follows: a poor performance during the prestudy 6MW test (6MW <400 m) at presentation by itself, is an independent unfavorable prognostic factor; patients who did not achieve the complete program (but were only able to perform the prestudy test) were at higher risk of death. Among patients who completed both pre- and posttreatment 6MW tests, patients for whom performance on exercise had decreased, were at higher risk of disease progression when compared with patients with stable performance. The study by Temel et al. has dealt with possible quality of life improvement and symptom alleviation in advanced NSCLC patients who have underwent an exercise program. The authors have constructed a twice-weekly exercise program performed in their medical unit on an out-patient basis. The program has been adapted to the demography and specificities of patients suffering from inoperable NSCLC who underwent chemotherapy, in parallel to the exercise program. A total of 16 training sessions were planned. The feasibility of the program is not demonstrated by itself inasmuch as, only 41% of patients achieved the whole program. Nevertheless, the patients had completed it, experienced a significant reduction in lung cancer symptoms and no deterioration in their 6MW test or muscle strength.
First, we should address the methodology of cardiorespiratory fitness testing. Cardiorespiratory fitness is determinant in patients who are planned for major surgical resection for lung cancer.7 The optimal means to assess cardiorespiratory fitness is an incremental cardiopulmonary exercise test (CPET) to exhaustion or symptom limitation. This test requires complex equipments, rigorous methodology in standardizing and monitoring the maximal exercise test. According to the American Thoracic Society/American College of Chest Physicians recommendations,8 up to 10 different parameters might be analyzed, among them the more useful are respiratory exchange ratio, maximum oxygen consumption at peak, heart rate, and oxygen pulse. All these parameters are critical when the primary goal of the CPET is to determine whether or not a patient with compromised cardiorespiratory fitness, will be able to undergo major pulmonary resection. However, complexity of maximum CPET limits its use in other settings than presurgical work-up, such as evaluation of exercise limitation in patients with otherwise resectable NSCLC. Submaximum testing (without gas-exchange measurement) such as the 6MW test, might be appropriate for patients who are frail or elderly, or with heavy disease burden that compromised the completion of a maximum CPET, such as it is the case in most patients suffering from advanced NSCLC. However, the interpretation might be with caution, as submaximum testing relies on an extrapolation of cardiorespiratory fitness from submaximum work rate. The two main reported results of the 6MW are heart rate and covered distance. This latter important parameter depends on normative data taking into account different patients characteristics including age. In patients affected by cancer who underwent chemotherapy, it is possible that autonomic dysfunctions that modify heart rate are emphasized in comparison with other categories of patients. Nonetheless, 6MW test is inexpensive, safe, and can be reproduced easily.9 In addition, several studies have demonstrated that the distance covered is a robust and strength result that could be regarded as an independent prognostic determinant in various disorders such as chronic heart failure or chronic obstructive pulmonary disease. The study by Kasymjanova et al. similarly demonstrated a relationship between distance covered and survival in advanced NSCLC. We must acknowledge the authors for this important observation. Some limitations of this study would warrant further investigations, however. One can hypothesize that a confirmatory study performed in a larger population would be able to take into account the multidimensional feature of cardiorespiratory unfitness in patients with lung cancer.
Secondly, there are multidimensional aspects of fatigue and dyspnoea. Cardiorespiratory unfitness in NSCLC has been demonstrated to depend on many different factors. Incidence of important comorbid conditions such as coronary artery disease, heart failure, and chronic obstructive pulmonary disease are quite common in this disease. Interaction between disease and comorbidity in cardiorespiratory fitness are important components explaining poor performance on maximum CPET such as the one observed in patients with preexisting compromised respiratory function and suffering from otherwise resectable NSCLC. The pulmonary function impairment frequently observed in patients affected by a more advanced disease (locally advanced or metastatic), might frequently result in poor cardiovascular fitness. Frequency of this deconditioning is higher when compared with that observed in localized NSCLC patients. As simple indicators, 56% of patients with advanced NSCLC present with dyspnoea on exercise and 79% complain from fatigue. The different factors reducing cardiorespiratory fitness in advanced NSCLC can be classified in three different categories: first, those directly related to the disease such as cough, bronchial obstruction, pulmonary volume limitation due to pleural effusion, etc. In addition, lung cancer-induced cytokine productions such as tumor-necrosis-factor-α, might also induce weight loss and muscle weaknesses as a consequence of cachexia. Second, comorbidities, as aforementioned, particularly, those comorbid conditions related to tobacco consumption, mainly chronic obstructive pulmonary disease, may be the major limiting factor limiting exercise. An important proportion of patients with advanced lung cancer have history of several decades of dyspnoea on exercise previous to cancer diagnosis. Third, and perhaps most importantly, there are many treatment-related factors that might interact with the ability for a given patient to complete an exercise test. Among them, one can consider the following: chemotherapy-induced anemia, chemotherapy-induced neuropathy and muscle disease, radiotherapy induced-pneumonitis, chemotherapy agents- or gefitinib-induced interstitial lung disease. In our opinion, these factors that putatively interfere with cardiorespiratory fitness might be taken into account when interpreting a decrease in distance covered by a patient, when two different 6MW tests are performed at the beginning and during a medical treatment for cancer.
The last question deals with the meaning of cardiopulmonary fitness for these patients daily practice. As clearly demonstrated by the noninterventional Kasymjanova’s study, patients with poor performance on exercise are at higher risk of death and disease progression. Although, this observation could not take into account the multidimensional aspect of the lack of cardiorespiratory fitness, the results reported here is an additional clue that patients with poor quality of life at presentation also have a poor prognosis when compared with patients with a good global health status at presentation. The study by Temlet et al. clearly suggested that this is changeable and that an adapted exercise program can improve ability to perform exercise for some patients. Further investigations in this field are warranted in consideration of the true alteration of patient quality of life related to dyspnoea and fatigue.
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