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January - March 2010: 
Volume 23, Issue 1

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Pneumon 2010, 23(1):91-102
ERS/ESTS clinical guidelines on the fitness of patients for radical treatment of lung cancer (surgery and chemo-radiotherapy)
Abstract
SUMMARY. Collaboration of a multidisciplinary team of experts on the functional evaluation of patients with lung cancer was facilitated by the European Respiratory Society (ERS) and the European Society of Thoracic Surgery (ESTS), in order to draw up recommendations and provide clinicians with clear, up-to-date guidelines on their fitness for surgery and chemo-radiotherapy. The subject was divided into various different topics, each of which was then assigned to at least two experts. The authors searched the literature according to their own strategies, with no central literature Review and compiled draft reports on each topic, which were then reviewed, discussed and voted on by the entire expert panel. The evidence supporting each recommendation was summarized, and graded as described by the Scottish Intercollegiate Guidelines Network Grading Review Group. Clinical practice guidelines were generated and finalized in a functional algorithm for risk stratification of the lung resection candidates, with emphasis on the cardiological evaluation, forced expiratory volume in 1 s (FEV1), systematic carbon monoxide lung diffusion capacity (DLCO) and exercise testing. In contrast to lung resection, for which the scientific evidence is more robust, it was not possible to recommend any specific test, cut-off value, or algorithm for chemo-radiotherapy, due to the lack of data. It is highly recommended that patients with lung cancer should be managed in specialized units by experienced multidisciplinary teams. Pneumon 2010, 23(1):91-102.
Full text

INTRODUCTION

Despite refinement of medical treatment, lung resection remains the only curative treatment for lung cancer. However, since only 20-25% of patients with lung cancer have operable lesions, and because of the widespread use of neoadjuvant chemotherapy, most patients are treated with chemo- and/or radiotherapy.

The remit of the task force was reassessment of the functional evaluation of patients before surgery for lung cancer, assessment of the acute and long-term risks related to chemoradiotherapy which should be taken into account when elaborating treatment strategy, and formulation of recommendations for patients who are not eligible for surgery.

The guidelines should provide the physician with a basis for evaluation of the benefit/risk ratio related to each therapeutic option offered to the patient.

METHODS

The task force was composed of 14 participants, identified on the basis of their expertise in the area of lung cancer. The subject was divided into several different topics, which were each assigned to at least two experts who searched the relevant literature, made draft reports and solicited comments in advance of the meetings [2008 European Respiratory Society (ERS) and the European Society of Thoracic Surgery (ESTS) congresses] at which the recommendations were reviewed, discussed and voted upon. The recommendations were graded as described by the Scottish Intercollegiate Guidelines Network Grading Review Group (SIGN) (table 1).



CARDIOLOGICAL EVALUATION BEFORE LUNG RESECTION FOR LUNG CANCER


The cardiological evaluation should be based on a well-validated index providing estimates of patient risks, but more detailed evaluation should be based on the characteristics of the individual patient. Detailed evaluation for coronary heart disease is generally not recommended for patients with an acceptable exercise tolerance, such as the ability to walk up two flights of stairs without stopping. Aggressive cardiac interventions should be instituted prior to surgery in patients who would need them irrespective of the surgery, but interventions specifically for surgery are of limited benefit1. Furthermore, recovery after coronary bypass surgery may take several months, and the need for aggressive anti-platelet therapy presents a major challenge in the perioperative context2.

Beta-blockers reduce perioperative myocardial infarction significantly, but the commonly used beta-blocker regimens increase the risk of stroke, presumably due to bradycardia and hypotension, and can increase overall mortality3,4. In patients with very advanced coronary disease, in whom the risks of myocardial infarction are especially high, the cardioprotective benefits of short-acting beta-blockers, whose potential deleterious effects are easier to reverse, may outweigh their bradycardic and hypotensive effects5. Alternative adrenergic modulation, such as administration of clonidine and related drugs6, may be useful, but larger randomized trials will be required to evaluate the effectiveness of a2-adrenergic agonists and statins.

Recommendations for cardiological evaluation before lung resection are given in table 2 and are summarized in an algorithm (figure 1). Patients who are at low cardiological risk or who have optimized cardiological treatment may proceed with the pulmonary evaluation.



PULMONARY EVALUATION BEFORE LUNG RESECTION FOR LUNG CANCER

The predicted post-operative forced expiratory volume in 1 s (ppo)-FEV1 is pivotal in choosing further tests or excluding patients from operation without further tests7. Many case series have shown that the peri-operative risk increases substantially when ppo-FEV1 is <40% predicted, with reported mortality rates in the range of 16-50%8. Nakahara and coworkers found a mortality rate as high as 60% when ppo-FEV1 was <30% predicted9. More recently, Brunelli et al10, showed that ppo-FEV1 was not a reliable predictor of complications in patients with pre-operative FEV1 >70% predicted, and also that in patients with a ppo-FEV1 <40% predicted, the mortality rate was only 4.8%. These findings have been partly explained by the so-called “lung volume reduction effect” that can reduce the functional loss in patients with moderate or severe chronic obstructive pulmonary disease (COPD)11,12.

Immediate post-operative estimation of pulmonary function

Although ppo-FEV1 is fairly accurate in predicting the definitive residual value of FEV1 3-6 months after surgery, it substantially overestimates the actual FEV1 observed in the initial post-operative days, when most complications occur13.

Varela et al13 showed also that on post-operative day 1 after lobectomy the actual FEV1 was 30% lower than predicted, and as a result was a better predictor of complications than ppo-FEV114,15. According to these findings, an attempt should be made to predict FEV1 early after lobectomy and pneumonectomy.

Recommendation: The ppo-FEV1 should not be used alone to select patients with lung cancer for lung resection, particularly patients with moderate to severe COPD. It tends to underestimate the functional loss in the initial 1-3 postoperative days and does not appear to be a reliable predictor of complications in patients with COPD. A ppo-FEV1 value of 30% predicted is suggested to be a high risk threshold for this parameter when included in algorithm 2.

Use of DLCO before surgical resection for lung cancer

Early reports demonstrated that the carbon monoxide lung diffusion capacity (DLCO) decreases after lung resection, and that DLCO <40% predicted is associated with a high risk of postoperative mortality. Based on data collected by the panel experts, the limit should be lowered to 30% predicted16,12. DLCO is very important test even in patients with a normal FEV1 (>80%) or normal FEV1/FVC ratio (>70%)16.

Recommendation:
DLCO should be measured and evaluated in combination with FEV1 in algorithm 2 (Level of evidence 2++, grade of recommendation B).

It is suggested that the limit of 40% predicted for the DLCO is high and should be decreased to 30% predicted because of the advancements in preoperative and perioperative technology and surgical technique.

Split function studies


Ventilation scintigraphy and perfusion scintigraphy both provide good prediction of post-operative lung function, but only one of the two is needed as there is no additional benefit in performing both. (Level of evidence 2+).

Teams concerned with research in preoperative evaluation before lung cancer surgery should be encouraged to use quantitative CT, MRI or SPECT. (Level of evidence 2+).



Exercise tests: systematic or selective?

The aim of exercise testing is to stress the overall cardiopulmonary/systemic oxygen delivery systems and estimate the physiological reserve that may be available after surgery. During exercise, the lung experiences increases in ventilation, oxygen uptake, carbon dioxide output and blood flow similar to those observed during the post-operative period after lung resection.

A recently published meta-analysis showed that the exercise capacity, expressed as VO2, peak is lower in patients who develop post-operative cardiorespiratory complications after lung resection17.

Several authors have found a good correlation between a low VO2 peak (% of predicted) and poor post-operative outcome18,19. It is generally reported that a value <50-60% predicted increases the surgical mortality risk. Surgical treatment was contraindicated for patients with a VO2 peak <40% or 2 peak 19,20.

Recommendation: Exercise tests are indicated for all patients undergoing surgery for lung cancer with FEV1 or DLCO <80% of normal values. (Level of evidence 2++, grade of recommendation B).



Low-technology exercise


Distance walked in 6-12 min has been shown to be highly reliable in estimating VO2 peak in healthy subjects, patients with COPD and transplant candidates, but non-unequivocal findings have been published regarding its association with post-operative outcome after lung resection21-23.

Several papers have reported the effectiveness of the stair climbing test in predicting major cardiopulmonary complications after lung resection. Patients climbing 22 m (<1% mortality rate); even in patients with pro-FEV1 and/or pro DLCO <40% predicted, the mortality rate in those climbing >22 m was zero24.

It has been reported that oxygen desaturation <90% during standardized incremental cycle ergometry was not a significant predictor of post-operative cardiopulmonary morbidity25. It was recently found, however, that a desaturation of >4% was significantly associated with post-operative complications, even after adjusting for other factors with regression analysis26.

Recommendation: The stair climbing test (height of ascent >22 m) should be used as a first-line functional screening test to select patients who can safely undergo operation or to identify those who need more sophisticated exercise testing. (Level of evidence 2++, grade of recommendation C).

The role of cardiopulmonary exercise testing (CPET)

In CPET, maximal or symptom-limited exercise is performed, usually on a bicycle or treadmill. CPET is performed in a controlled environment with continuous monitoring of various parameters; VO2 peak is the single most important parameter as a direct measure of exercise capacity. CPET not only allows assessment of overall cardiopulmonary reserves but, in the case of limitation of exercise capacity, it also enables elucidation of the reason for this, such as pulmonary, cardiovascular or musculoskeletal limitations.

There is currently wide consensus that values of VO2 peak of >20 mL/kg/min qualify the patient for lung resection procedures up to pneumonectomy, whereas values 75% and <40% predicted. CPET should be performed according to the published ATS guidelines27.

Recommendation: CPET is performed in controlled environment, and is reproducible and safe. VO2 peak measured during an incremental exercise on treadmill or cycle should be regarded as the most important parameter to consider as a measure of exercise capacity and it is highly predictive of post-operative complications. (Level of evidence 2++, grade of recommendation B).

The following basic cut-off values for VO2 peak should be considered: >75% predicted or >20 mL/kg/min qualifies for pneumonectomy; <35% or <10ml/kg/min indicates high risk for any resection. The evidence is not sufficient to recommend separate cut-off values for lobectomy.

Wang et al found, in 57 patients, that the increase in DLCO from rest to 70% of maximal workload was the best pre-operative predictor of post-operative complications, followed by VO2 peak measurement28.

PATIENT CARE MANAGEMENT

The role of rehabilitation before and after lung resection surgery


Pulmonary rehabilitation is effective in respiratory patients with disability.

Chest physiotherapy was found to be more effective than incentive spirometry in reducing the rate of pulmonary atelectasis after lobectomy. Pre-operative inspiratory muscle training may decrease the prevalence of late complications after cardiac surgery29,30.

Comprehensive pulmonary rehabilitation was shown to improve VO2 rate before surgery in patients wit COPD who had low VO2 (15mL/kg/min), reducing late complications and not influencing operability and prognosis31. Pre-operative training programmes have led to a reduction of the length of hospital stay and complications in patients with COPD operated on for lung cancer32.

Recommendation: For smokers, smoking cessation of sufficient duration (2-4 weeks) before surgery should be recommended, since it may decrease post-operative complications. (Level of evidence 2+, grade of recommendation B).

Early pre- and post-operative rehabilitation should be recommended, since it may produce functional benefits in patients with resectable lung cancer. (Level of evidence 2+, grade of recommendation C).

Although lacking accuracy for assigning specific risk for individual patients, models incorporating functional characteristics, comorbidity factors, and surgical variables are valid and useful tools for predicting relative operative death or major cardiopulmonary complications in groups of patients.

Do we need to send all patients with thoracotomy to the intensive care unit (ICU)?

Systematic admission to the ICU after thoracotomy should not be recommended. (Level of evidence 2++, grade of recommendation C).

Patients undergoing complex pulmonary resection, those with marginal cardiopulmonary reserve and those with moderate to high risk (i.e., patients with coronary disease, EF <40%, arrhythmia, symptomatic cerebrovascular disease, FEV1 <50% predicted, central or obstructive sleep apnoea, VO2 max <15ml/kg/min, liver dysfunction, pneumonectomy or bilobectomy) should be admitted to a high dependency unit (HDU). (Level of evidence 2++, grade of recommendation B).

Residual function and quality of life (QoL) after radical treatment


Many studies have shown that after lobectomy there is a disproportionate functional early loss. FEV1, DLCO and VO2 peak may reach values as high as 90-95% of preoperative values, 3-6 months after operation33-36. In general, exercise tolerance displays more complete recovery compared to airflow and gas exchange capacities, presumably due to other compensatory mechanisms related to the cardiovascular system and the peripheral oxygen extraction capacity.

Several studies have shown that lung resection is associated with a transient worsening of QoL one month following the operation, but with most of the scales returning to pre-operative values after 3-6 months. An exception to this trend is represented by patients undergoing pneumonectomy, who display a persistent deterioration of physiological and mental QoL37,38. With the exception of DLCO, the objective measures of cardiorespiratory function do not appear to correlate well with QoL which mainly depends on the patients’ symptoms such as dyspnea and post-thoracotomy pain33,39,40.

Surprisingly, elderly patients and those considered at increased surgical risk showed no difference in the post-operative physiological and mental QoL status from those of lower risk counterparts38.

Recommendation:
Specific QoL instruments should always be used for QoL evaluation. Perception of symptoms has been reported to be more important for QoL, implying the need for monitoring respiratory symptoms and pain after thoracotomy or chemotherapy. (Level of evidence 2+).

SURGICAL TECHNIQUES IN LUNG CANCER


Combined cancer surgery and lung volume reduction surgery (LVRS)


A subgroup of patients with upper lobe emphysema appeared to be the ideal candidates for lung volume reduction surgery (LVRS) with significant improvement in exercise capacity and survival despite their severe pre-operative pulmonary function defect (PFTs). After anatomical lobectomy, patients with normal or mildly diseased lungs have the greatest post-operative decrease in FEV1, whereas those with poor baseline function present minimal change or even improvement in post-operative FEV1.

Accurate estimation of post-operative pulmonary function should take into account the effect of deflating the over-expanded thorax and reinflating perfused lung areas. Quantitative imaging techniques (ventilation and perfusion scintigraphy) may provide useful information about these effects45.

Recommendation
: Consideration of fitness for surgery should acknowledge the effects of lobar LVRS in patients with severe COPD and early lung cancer stages: resecting a hyperinflated and poorly perfused tumour-containing lobe can outweigh any loss of function or the risks of major adverse events. (Level of evidence 2++, grade of recommendation B).

Surgical techniques charcterized by minor degrees of intervention (segmentectomy and wedge resection)


Comparison of effectiveness (regarding the likelihood of recurrence) between wedge resection and lobectomy showed 38/122 recurrence for wedge resection and 23/125 for lobectomy46, but other studies show equivalent survival47. In patients with lung cancer who have low reserves, it appears that segmentectomy offers similar survival to lobectomy with less stress on respiratory function48. Comparison of the outcome of wedge resection and segmentectomy shows that in tumours of 2-3 cm in diameter segmentectomy is associated with less recurrences49, while for tumours smaller than 2 cm it appears that wedge resection offers similar survival to segmentectomy50.

Recommendation

A) Segmentectomy can be carried out:

  • In patients with stage 1A cancer (2-3 cm tumour) with margins of resection of >1cm (Level of evidence 2, grade of recommendation D)
  • In patients with stage 1 cancer with poor functional capacity (Level of evidence 2, grade of recommendation D)
  • In patients who have undergone a prior lobectomy (Level of evidence 2, grade of recommendation D)


B) Wedge resection can be carried out:

  • In patients with stage 1A cancer (1-2 cm tumour) (Level of evidence 2, grade of recommendation D) 
  • For a small (<2cm) peripheral adenocarcinoma with an air-containing image (ground glass opacity) on HRCT. (Level of evidence 2, grade of recommendation D)

CHEMO-RADIOTHERAPY IN LUNG CANCER


Neoadjuvant chemotherapy for lung cancer may have several advantages, including: 1) more efficacious distribution of the chemotherapeutic agent prior to surgical manipulation; 2) in vivo testing of the chemotherapeutic agent; 3) follow-up not hindered by the residual effects of chemo- or radiotherapy administered after surgery.

The evidence from randomized phase III trials indicates improved resectability after chemotherapy and suggests a marginal survival advantage for lobectomy51.

Significantly overall morbidity and mortality rates have been reported for pneumonectomy after chemotherapy, and in particular, for right pneumonectomy52,53.

Induction of chemo-radiotherapy may, however, be a prelude to significant morbidity and mortality, although recent evidence from institutional studies shows increased safety in adding radiotherapy to chemotherapy induction regimens54,55. A prospective randomised trial powered on post-operative morbidity and mortality is needed to compare chemotherapy versus chemo-radiotherapy followed by surgery.

Radiotherapy of the lung may cause radiation pneumonitis in 5-15% of patients with lung cancer56. Several chemotherapeutic agents are known sensitizers to radiotherapy, including, among others, doxorubicin, taxanes, mitomycine, vinorelbine, gemcitabine and platinum derivatives57.

Recommendation:
After induction chemotherapy and/or radiotherapy, a new functional evaluation (particularly of DLCO) before surgery is recommended. (Level of evidence 2+, grade of recommendation C).

Statements


The addition of induction chemotherapy to surgical resection of a degree less than pneumonectomy does not significantly increase morbidity and mortality. (Level of evidence 1).

The addition of radiotherapy to neoadjuvant chemotherapy followed by pneumonectomy increases mortality. (Level of evidence 1).

The effects of radiotherapy on pulmonary function

It is generally assumed that patients with preexisting pulmonary disease, particularly COPD, are at increased risk of radiation morbidity58.

In reports based not exclusively on patients with lung cancer, low arterial oxygen tension value (<80mmHg) and low DLCO have been associated with increased lung toxicity and morbidity59,60. A model including pre-radiation lung volumes and DLCO could not segregate patients at high risk from those at low risk for radiation pneumonitis.

The effects of chemotherapy on pulmonary function

Safe lower limits of respiratory function (FEV1 or DLCO) for radical chemotherapy have not been defined as they have for surgery. (Level of evidence 2++).

The patient at prohibitive surgical risk: alternatives to surgery

1) Among 2000 patients with medically inoperable lung cancer stage I and IIA treated with radiation alone, survival was 13-19% at 5 years. Radiation alone for medically inoperable NSCLC must be regarded as the best established alternative treatment to surgery. (Level of evidence 1, grade of recommendation B).

2) The use of CHART (continuous, hyperfractionated, accelerated radiotherapy) must be preffered to conventional radiotherapy as it improves 2 year survival. (Level of evidence 1, grade of recommendation B)61.

Recommendations

1) For medically inoperable NSCLC, radiation alone must be regarded as the best established alternative treatment to surgery. (Level of evidence 1, grade of recommendation B).
2) The use of continuous, hyperfractionated, accelerated radiotherapy (CHART) must be preferred to conventional radiotherapy, as it achieves better local control rates and survival. (Level of evidence 1, grade of recommendation B).

WHO SHOULD TREAT THORACIC PATIENTS AND WHERE SHOULD THEY BE TREATED?

According to the ACCP guidelines (accepted by ESTS and the EORTC Radiotherapy Group), qualified thoracic surgeons achieved better results than nonspecialized surgeons in terms of perioperative mortality and resection rates.

The management of patients with lung cancer must be undertaken by a multidisciplinary team (ideally a thoracic surgeon specializing in lung cancer, a medical oncologist and a pulmonologist). (Level of evidence 2++, grade of recommendation B).

The surgical treatment of lung cancer patients must be performed in specialized centres by qualified thoracic surgeons, since specialization has been shown to have a positive impact on resectability, postoperative mortality and long-term survival. (Level of evidence 2++, grade of recommendation B).

Lung cancer surgery should be performed in centres with an adequate volume of cases (minimum surgical volume of 20-25 major lung resections per year); lobectomy or pneumonectomy, should be advised). (Level of evidence 2++, grade of recommendation C).

Radiotherapy should be applied by radiotherapists in centres that routinely treat patients by this combined modality.

ALGORITHM FOR THE ASSESSMENT OF RISK BEFORE LUNG RESECTION

The panel of experts agreed to emphasise the role and importance role of exercise tests in the preoperative assessment of candidates for lung resection. As cycle-ergometry may be not readily available in some centres, a low-technology exercise test, such as the stair climbing test, has been proposed as a possible surrogate and as a first-line screening ergometric step in the algorithm, with the strong recommendation, however, that if the performance on the stair climbing test is poor, patients need to be referred for formal CPET.

Owing to the advances in surgical techniques and the ongoing improvement in post-operative care, the limits of functional operability are constantly being lowered. The algorithm emphasizes the importance of a preliminary cardiological assessment. Those patients at low cardiological risk or with optimized cardiological treatment may proceed with pulmonary evaluation. Complete spirometry and DLCO assessment is recommended for all patients. All those patients with either FEV1 or DLCO or both <80% predicted should undergo an ergometric assessment. Ideally, a format CPET with VO2 peak measurement should be performed. A low-technology exercise test, preferentially stair climbing, may be used as a screening test. Those patients showing suboptimal performance (<22m) on tests for stair climbing should have a formal CPET.

A limitation of such an algorithm, which is centred on ergometric evaluation, may be that a certain proportion of lung resection candidates may be unable to perform any type of reliable exercise test due to concomitant incapacitating comorbidities. Such patients have been shown to have an increased risk of death after major lung resection and, after a careful selection based on the available cardiac and pulmonary parameters, they should be regarded as high-risk patients and monitored in an advanced care management setting.

Most of the evidence in these guidelines is of level 2, and most of the recommendations are graded at B or C levels. This is mainly due to the nature of the subject, which makes the design of randomized trials difficult and impractical.

Age alone [elderly (>70 yrs) or very elderly (>80 yrs) should not be used as selection criteria for surgery. The increased risk for radical treatment observed in elderly patients is probably a function of their underlying comorbidities. In contrast to suitability for lung resection, for which the scientific evidence is more robust, the panel was unable to recommend any specific test, cut-off value, or algorithm for chemo-radiotherapy, owing to lack of relevant data.

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