Practical Radiation Oncology (2015) xx, xxx–xxx
www.practicalradonc.org
Original Report
Pulmonary function and cardiac stress test after multimodality treatment of esophageal cancer Gabriella Alexandersson von Döbeln MD a,⁎, Magnus Nilsson MD, PhD b , Gunnar Adell MD, PhD c , Gjermund Johnsen MD d , Ingunn Hatlevoll MD e , Jon Tsai MD PhD b , Lars Lundell MD, PhD b , Mikael Lund MD b , Pehr Lind MD PhD a, f a
Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden c Department of Oncology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden d Department of Gastrointestinal Surgery, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway e Department of Oncology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway f Centre of Clinical Research Sörmland, Uppsala University, Uppsala, Sweden b
Received 17 June 2015; revised 16 October 2015; accepted 26 October 2015
Abstract Purpose: Curative treatment of esophageal cancer is accompanied by frequent and sometimes severe side effects. However, prospectively collected data on side effects are scarce. The aim of this study was to evaluate if pulmonary function and exercise capacity were affected in the acute setting after neoadjuvant treatment and if there were long-lasting effects after neoadjuvant treatment and surgery. We also aimed to investigate whether the addition of radiation therapy to chemotherapy would aggravate side effects. Methods and materials: A cohort of 97 patients enrolled in the randomized NeoRes trial was used for the present analysis. The patients had been randomized to receive 3 cycles of cisplatin and fluorouracil with or without concurrent radiation therapy to 40 Gy. A cardiac stress test on a stationary bicycle and a spirometry were performed before and after neoadjuvant treatment and 1 to 2 years later after surgery provided that the cancer had not recurred. Results: We found impairment in pulmonary function measured as vital capacity and forced expiratory volume in 1 second and a decrease in exercise capacity after neoadjuvant treatment and 1 to 2 years later after surgery. We did not detect any differences between patients treated with chemoradiation therapy and those treated with chemotherapy alone. Conclusions: Multimodality treatment of esophageal cancer caused short-term and lasting impairments in pulmonary function and exercise capacity. The reductions were not aggravated by the addition of radiation therapy to neoadjuvant chemotherapy. © 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Poster presented at Frontiers in Cancer Research and Therapy in Stockholm, Sweden, March 6-7, 2014. Sources of support: This study was supported by grants from the Swedish Cancer Society (Cancerfonden) and the Cancer Research Foundations of Radiumhemmet. Research nurse Berit Sunde is acknowledged for collecting data. Conflicts of interest: G. A. v.D. and M.N. have received grants from the Swedish Cancer Society and from the Cancer Research Foundations of Radiumhemmet, which are independent nonprofit organizations. None of the other authors declare any conflict of interest. ⁎ Corresponding author. Department of Oncology, Karolinska University Hospital, 171 76 Stockholm, Sweden. E-mail address:
[email protected] (G.A. von Döbeln). http://dx.doi.org/10.1016/j.prro.2015.10.015 1879-8500/© 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
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Introduction Neoadjuvant chemotherapy with or without concurrent radiation therapy followed by surgery is a widely accepted treatment for resectable esophageal cancer because the addition of neoadjuvant treatment improves overall survival compared with surgery alone. 1 However, treatment may cause side effects that can be serious. Acute side effects from neoadjuvant treatment include pneumonitis, pericarditis, and dysrhythmias. Long-term side effects from multimodality treatment include pulmonary fibrosis, cardiomyopathy, and coronary artery disease. However, side effects have thus far been scarcely reported. 2 Two randomized studies comparing neoadjuvant chemotherapy with neoadjuvant chemoradiation therapy have previously been published. 3,4 Late toxicity was not reported in either of the studies, and acute toxicity was reported in only 1 of the reports. 3 Within the Scandinavian Esophageal and Gastric Cancer group, a randomized clinical trial, NeoRes, 5 has been conducted including patients with resectable esophageal cancer. The primary objective was to evaluate if the histopathological tumor response was improved by the addition of radiation therapy to neoadjuvant chemotherapy. A cohort of these patients was included in the present report, in which we aimed to investigate if pulmonary function and exercise capacity were affected soon after neoadjuvant treatment and 1 to 2 years after surgery. A possible aggravation of side effects by addition of radiation therapy to chemotherapy was also investigated.
Methods and materials
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and Norway. The registration number in the Clinical Trials Database is NCT01362127. All participating patients provided written informed consent. No commercial support was given to this study.
Treatment Chemotherapy Three cycles of cisplatin, 100 mg/m 2 day 1 and fluorouracil 750 mg/m 2/24 hours, days 1 through 5 were given. Each cycle lasted 21 days. In case of hearing impairment, tinnitus, or deterioration of renal function, cisplatin was replaced by carboplatin, area under the curve 5 (patients with squamous cell carcinoma) or oxaliplatin 130 mg/m 2 (patients with adenocarcinoma). Radiation therapy Concomitant with chemotherapy 40 Gy was given (2 Gy once daily in 20 fractions, 5 days per week) with a photon beam linear accelerator. A 3-dimensional dose planning system was used. For tumors located mainly above the carina, the caudal border of the clinical target volume (CTV) was 5 cm below the tumor and the supraclavicular nodes defined the upper border. For tumors located mainly below the carina, the cranial border of the CTV was 5 cm cranial of the tumor and the lower border was defined by the celiac lymph nodes. In the lateral, anterior, and posterior directions, the CTV should embrace the gross tumor volume and paraesophageal area with a margin of 1 cm, but also respecting anatomical barriers such as pleura, pericardium, and bone. The planning target volume was according to local routines. The dose to the lungs exceeding 20 Gy was kept as low as possible and should not exceed one-third of the lung volume. The volume of the heart that received ≥ 30 Gy was kept to a minimum.
Eligibility criteria Pulmonary function and cardiac stress tests All 101 patients enrolled into the NeoRes trial in Stockholm and Trondheim were included in the present report, except 4 patients who were not monitored according to the NeoRes protocol. All had a histologically proven adenocarcinoma or squamous cell carcinoma of the esophagus or esophagogastric junction with the clinical stages T1N1 or T2-3N0-1 and M0-M1a according to the American Joint Committee on Cancer tumor-nodesmetastasis staging system 6th edition. Patients with cancers requiring laryngectomy were not included because the preferred treatment was definitive chemoradiation therapy. Because of cardio- and nephrotoxic side effects from treatment, patients had to be aged ≤ 75 years, have an Eastern Cooperative Oncology Group performance status of 0 to 1, be free from uncontrolled cardiac disease without a myocardial infarction within 12 months, and have no complications from diabetes. All had hematological and renal function within normal limits. The study was approved by the Research Ethics Committees in Sweden
According to the NeoRes protocol, patients performed a spirometry and a cardiac stress test before and after oncological treatment. The investigations after oncological treatment were in most cases carried out 1 to 2 weeks before surgery (which was scheduled 4-6 weeks after neoadjuvant treatment). According to local routines in Stockholm, a spirometry and a cardiac stress test were done 1 to 2 years later, provided the cancer had not recurred. The timespan for the follow-up investigations was wide because of patients’ requests and surgical complications. Cardiac stress tests were performed on a stationary bicycle. Maximum exercise capacity, peak heart rate, peak blood pressure, significant changes on the STsegment, and significant arrhythmias were recorded. A significant change on the ST segment was defined as an elevation or depression of more than 1 mm. Significant arrhythmias were defined as atrial fibrillation or frequent
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Esophageal cancer and side effects
3
101 included in the NeoRes trial were randomized in Stockholm or Trondheim
4 not included due to administrative reasons
53 had been assigned to chemotherapy
44 had been assigned to chemoradiation therapy
Spirometry: 41 performed it 12 did not due to administrative reasons Cardiac stress test: 36 performed it. 17 did not due to administrative reasons
36 received chemotherapy according to protocol 15 did not: - 1 dead - 14 side effects 2 lack information
Spirometry: 40 performed it 11 did not: - 9 administrative - 1 progressive disease - 1 dead 2 data could not be found
Baseline investigations
Treatment
Presurgical investigations
Spirometry: 31 performed it 13 did not due to administrative reasons Cardiac stress test: 37 performed it. 7 did not due to administrative reasons
27 received chemotherapy according to protocol 17 did not: - 1 patients request - 11 side effects - 4 administrative - 1 dead
Spirometry: 26 performed it 17 did not - 15 administrative - 1 progressive disease - 1 dead 1 data could not be found
Cardiac stress test 26 performed it 27 did not: - 15 administrative - 1 progressive disease - 1 dead
Cardiac stress test: 21 performed it 23 did not - 21 administrative - 1 progressive disease - 1 dead
Spirometry: 8 performed it 45 did not: - 19 dead - 17 administrative - 9 progressive disease
Spirometry: 10 performed it 34 did not: - 15 dead - 11 administrative - 7 progressive disease - 1 declined to participate
Investigations 1-2 years later
Cardiac stress test: 6 performed it 47 did not: - 19 dead - 18 administrative - 9 progressive disease - 1 declined to participate
38 received radiation therapy according to protocol 6 did not : - 3 patients request - 1 side effect - 1 dead - 1 administrative
Cardiac stress test: 9 performed it 35 did not: - 15 dead - 10 administrative - 7 progressive disease - 3 declined to participate
Figure 1
Flow chart for the current study.
ventricular extra beats. Maximum exercise capacity was achieved when the patient reached the subjective maximum exertion level, experienced chest pain, or had changes in the electrocardiogram indicating ischemia, had severe arrhythmias, or a pathologic blood pressure. In Trondheim, the resistance started at 50 W and was increased by 25 W every 2 minutes. In Stockholm, the resistance was determined individually based on the expected exercise capacity.
Pulmonary function tests were performed with spirometries and carried out under standardized conditions in several different units. The best results of at least 2 consecutive investigations were recorded. Forced expiratory volume in 1 second (FEV1) and vital capacity (VC) were measured and the ratio FEV1/VC (FEV%) was calculated. In 23 investigations completed after oncological treatment, VC was substituted by forced VC. Because there was a span between baseline investigations and
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follow-up, age-adjusted values according to Hedenstrom et al 6,7 are also reported.
Statistical analyses Parameters measured after oncological treatment and 1 to 2 years later were compared with baseline parameters by using Wilcoxon signed-rank test. For these 3 time points, changes over time were analyzed with Friedman 2-way analysis of variance by ranks test and Wilcoxon signed-rank test. Mann Whitney U tests were used for detecting the differences between the treatment groups (chemoradiation therapy vs chemotherapy). The possible correlations between parameters were investigated by using Spearman rank correlation test. A P value b .05 was considered statistically significant.
Results The flow chart is detailed in Fig 1. The patients’ characteristics are detailed in Table 1, demonstrating a good balance between the 2 treatment groups.
Spirometry From baseline until after the oncological treatment, FEV1 and VC decreased slightly. The reduction from baseline until 1 to 2 years later was more pronounced, and median values decreased with 7.4% (FEV1) and 14% (VC). We did not find any corresponding changes in FEV% (for details, see Tables 2 and 3). Eight patients completed a pulmonary function test at all 3 occasions. A gradual deterioration in VC could be demonstrated, but not in FEV1. We did not find any differences between those treated with chemoradiation therapy and those given chemotherapy alone (Fig 2).
Cardiac stress test Maximum exercise capacity and blood pressure decreased from baseline until after oncological treatment, and median values were reduced by 17% (maximum exercise capacity) and 13% (maximum blood pressure), respectively. When baseline observations were compared with those 1 to 2 years later, median values were decreased by 16% (maximum exercise capacity) and 15% (maximum blood pressure), respectively (Tables 2 and 3). Twelve patients completed all 3 stress tests, and we could not detect any changes from the investigations after oncological treatment until 1 to 2 years later. When the maximum exercise capacity was adjusted for hemoglobin levels (by dividing the maximum exercise capacity by the current hemoglobin value), we were unable
Practical Radiation Oncology: Month 2015 Table 1 Demographic and disease-specific characteristics of patients enrolled in the study Total Patients assigned to receive chemotherapy (n = 53)
Patients assigned to receive chemoradiation therapy (n = 44)
Median age (y) 63 64 Sex Male 82 45 (85%) 37 (84%) Female 15 8 (15%) 7 (16%) Eastern Cooperative Oncology Group Performance Status 0 88 47 (89%) 41 (93%) 1 8 5 (9%) 3 (7%) Unknown 1 1 (2%) Stage II 30 16 (30%) 14 (32%) III 66 36 (68%) 30 (68%) IVa 1 1 (2%) Tumor location Proximal 1 1 (2%) Mid 19 10 (19%) 9 (20%) Distal 60 34 (64%) 26 (59%) Cardia type II 17 9 (17%) 8 (18%) Smoking Never 13 5 (9%) 8 (18%) smoked 25 15 (28%) 10 (23%) Stopped smoking more than 1 y ago Smoker 44 26 (49%) 18 (41%) Unknown 15 7 (13%) 8 (18%) Diabetes mellitus Yes 18 9 (17%) 9 (20%) No 74 41 (77%) 33 (75%) Unknown 5 3 (6%) 2 (5%) Cardiovascular disease Yes 34 20 (38%) 14 (32%) No 59 30 (57%) 29 (66%) Unknown 4 3 (6%) 1 (3%) Data are number of patients unless otherwise indicated.
to detect any reduction in exercise capacity from before until after neoadjuvant treatment. However, there was a reduction from baseline investigations until 1 to 2 years later, where the median value was reduced with 18%. We could not demonstrate any changes in the occurrence of significant arrhythmias or elevation/depression of the ST segment at follow-up investigations compared with baseline. We did not detect any differences between those who received chemoradiation therapy and those given chemotherapy alone (Fig 2).
Radiation therapy Dosimetry data for patients who received 40 Gy are listed in Table 4. Because of a change of radiation therapy planning systems, information was not captured on doses
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Results from cardiac stress tests and spirometries, before and after neoadjuvant treatment
VC (L) FEV1 (L) FEV% Maximum exercise capacity (W) Hb (g/L) Maximum exercise capacity/Hb (W/g/L) Maximum heart rate (/min) Maximum blood pressure (mm Hg)
Before treatment median (interquartile range)
After neoadjuvant treatment median (interquartile range)
P value (Wilcoxon signed-rank test)
n
4.2 (3.5-4.8) 2.9 a (2.6-3.5) 73 (68-78) 150 (125-175) 139 (129-149) 1.09 (0.93-1.33) 152 (142-164) 200 (170-210)
4.0 (3.0-4.8) 2.9 a (2.3-3.4) 73 (67-79) 125 (103-153) 118 (108-129) 1.10 (0.93-1.33) 149 (139-164) 175 (150-200)
.001 b .001 .609 b .001 b .001 .697 .158 b .001
55
65
64 59
FEV%, FEV1/VC; FEV1, forced expiratory volume in 1 s; Hb, hemoglobin; n, number; VC, vital capacity. a Median values are the same implicating that the reduction in pulmonary function is small.
to the heart in 7 patients and doses to the lungs in 9 patients treated in Stockholm. We did not find any correlation between doses to the heart and changes in exercise capacity, either from baseline until after neoadjuvant treatment or from baseline until 1 to 2 years later. Likewise, we saw no correlation between the doses to the lungs and the changes in FEV1 or VC.
Discussion In the present study, exercise capacity and pulmonary function were reduced after neoadjuvant treatment for esophageal cancer, and the deterioration remained years after the ensuing surgical resection. No differences were revealed between patients treated with chemoradiation therapy and those treated with chemotherapy alone. Our findings of reduced exercise capacity after neoadjuvant treatment are supported by data from Liedman and coworkers, 8 who evaluated 26 patients and found similar acute effects on exercise capacity. On the contrary, Tatematsu and coworkers 9 could not prove a decrease in exercise capacity following neoadjuvant treatment when evaluating 27
Table 3
patients. The conflicting results could well be explained by the less intense treatment given in the latter study. To our knowledge, long-term effects on exercise capacity after multimodality treatment has not previously been studied. There are various explanations behind the decline in exercise capacity. First, it could be caused by a reduction in hemoglobin levels. In our study, hemoglobin levels decreased after neoadjuvant treatment, and, interestingly, after adjustment for hemoglobin levels, we were unable to confirm the reduction in exercise capacity when assessed after neoadjuvant treatment. However, 1 to 2 years later, hemoglobin levels were back to pretreatment values and could not explain the decrease in exercise capacity. Second, fatigue is a well-known symptom that may persist for years in patients treated for cancer. 10 Fatigue may prevent patients from physical activity, leading to impaired physical performances. Third, the large surgical trauma, in most cases including abdominal as well as thoracic surgery, is a possible contributor to the long-term reduction in exercise capacity, even though not previously demonstrated. Fourth, fluorouracil, cisplatin, and radiation therapy are all known to exert cardiotoxic effects, 11,12 and we have previously reported that the neoadjuvant treatment in the NeoRes trial seemed to have an acute
Results from cardiac stress tests and spirometries, before the neoadjuvant treatment and 1 to 2 y later
VC (L) VC (% of reference value) FEV1 (L) FEV1 (% of reference value) FEV% Maximum exercise capacity (W) Maximum exercise capacity/Hb (W/g/L) Hb (g/L) Maximum heart rate (/min) Maximum blood pressure (mm Hg)
Before treatment median (interquartile range)
After 1 to 2 y median (interquartile range)
P value (Wilcoxon signed-rank test)
n
3.7 (3.3-4.8) 96 (75-103) 2.7 (1.9-3.0) 89 (64-95) 71 (55-74) 128 (115-170) 0.97 (0.88-1.14) 138 (132-149) 153 (142-166) 200 (170-220)
3.2 (2.6-4.2) 74 (65-85) 2.49 (2.0-2.7) 69 (57-87) 70 (60-87) 107 (80-125) 0.80 (0.64-0.92) 134 (128-139) 142 (129-157) 170 (150-180)
.005 .004 .013 .007 .120 .001 .017 .065 .002 .012
11
15
% of reference value, percent of reference values adjusted by age, height, and length; FEV%, FEV1/VC; FEV1, forced expiratory volume in 1 s; Hb, hemoglobin; VC, vital capacity.
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Figure 2
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Maximum exercise capacity and vital capacity in patients receiving CRT or CT alone.
negative effect on left ventricular function. 13 However, because cardiotoxicity from chemotherapy and radiation therapy might develop much later, it would be of interest to have a longer follow-up time to further evaluate cardiac side effects. Another important result of the present study was the deterioration in pulmonary function as measured by a decline in VC. FEV1 was also reduced, but this may be explained by the reduction in VC because the relation between VC and FEV 1 (FEV%) remained unchanged. The acute effects were small, and not necessarily clinically relevant. The long-lasting effects were more pronounced and cannot be explained by aging. There are few previous reports on pulmonary function after oncological treatment for esophageal cancer. In 1 study, 19 patients were investigated after curative or palliative treatment, whereupon a reduction of pulmonary function was found directly after chemoradiation therapy. 14 When applying a less aggressive chemoradiation therapy regimen, any change in
Table 4
Dosimetry data for those who received 40 Gy
Overall treatment time (days) V20 lung (%) Mean lung dose (Gy) V10 heart (%) V30 heart (%)
Median
Interquartile range
n
29 11.3 8.8 80.0 41.4
26-30 8.1-16.2 6.5-11.8 63.5-86.6 21.2-71.7
38 29 29 31 31
V10 heart, volume of the heart receiving 10 Gy or more; V20 lung, volume of the lung receiving 20 Gy or more; V30 heart, volume of the heart receiving 30 Gy or more.
pulmonary function could not be seen, 15 suggesting that toxicity is dose-dependent. Late effects on pulmonary function after multimodality treatment for esophageal cancer have, to our knowledge, not previously been reported. However, our findings are consistent with other studies where surgery alone for esophageal cancer 16,17 and chemoradiation therapy for breast cancer or lymphoma have been shown to decrease pulmonary function. 18,19 The extent of the long-term effect on pulmonary function after surgery varies between different studies, and it has not been documented that surgery would maintain such effects longer than a year. Our study is not designed to separate the effects of oncological treatment and surgery, and we cannot differentiate the long-term effects on pulmonary function of surgery from that exerted by neoadjuvant therapy. There are multiple possible explanations to the observed decrease in pulmonary function. First, the lungs are incidentally irradiated, and irradiation is a well-known cause of pulmonary toxicity. 20 Second, chemotherapy is known to affect muscular strength, 21 which in turn may affect the ability to take deep breaths and thereby impair VC and FEV1. Third, it has previously been shown that surgery affects pulmonary capacity, partly explained by thoracotomy. 16 To further enhance the complexity, there may by a covariation between pulmonary function and exercise capacity. 22 A possible confounder in our study is that forced VC was sometimes used as a substitute for VC. These parameters are most often equivalent, but in moderately or heavily obstructed patients, the forced VC tends to be lower than the VC. 23 Interestingly, we did not detect any differences in the cardiac stress test and in pulmonary function between patients treated with neoadjuvant chemoradiation therapy
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and those treated with chemotherapy alone. This is in accordance with the observations by Burmeister and coworkers, 3 who failed to reveal differences in acute toxicity grade ≥ 3 when comparing neoadjuvant chemoradiation therapy and chemotherapy in patients with esophageal cancer. There is, however, a risk for a type II error because we completed a full investigational program only in a limited number of patients. The small number of patients in the long-term follow-up is a limitation of the study. To study long-term side effects of treatment on a larger group of patients, a much larger cohort of patients would be required because of the dismal prognosis of esophageal cancer. Previous studies have demonstrated that supervised physical training can improve patients’ exercise capacity and oxygen uptake after treatment for cancer; 24,25 an interesting research area would be to define and further develop strategies for the rehabilitation of patients treated for esophageal cancer. Moreover, because prevention is a preferred strategy, pretreatment optimization should be explored. In conclusion, multimodality treatment of esophageal cancer causes short-term and long-lasting impairments in pulmonary function and exercise capacity. These reductions were not aggravated by adding radiation therapy to neoadjuvant chemotherapy.
References 1. Sjoquist KM, Burmeister BH, Smithers BM, Zalcberg JR, Simes RJ, Barbour A, et al. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: An updated meta-analysis. Lancet Oncol. 2011;12:681-692. 2. Monjazeb AM, Blackstock AW. The impact of multimodality therapy of distal esophageal and gastroesophageal junction adenocarcinomas on treatment-related toxicity and complications. Semin Radiat Oncol. 2013;23:60-73. 3. Burmeister BH, Thomas JM, Burmeister EA, Walpole ET, Harvey JA, Thomson DB, et al. Is concurrent radiation therapy required in patients receiving preoperative chemotherapy for adenocarcinoma of the oesophagus? A randomised phase II trial. Eur J Cancer. 2011;47:354-360. 4. Stahl M, Walz MK, Stuschke M, Lehmann N, Meyer HJ, Riera-Knorrenschild J, et al. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol. 2009;27:851-856. 5. Klevebro F, Johnsen G, Johnson E, Viste A, Myrnäs T, Szabo E, et al. Morbidity and mortality after surgery for cancer of the oesophagus and gastro-oesophageal junction: A randomized clinical trial of neoadjuvant chemotherapy vs. neoadjuvant chemoradiation. Eur J Surg Oncol. 2015;41:920-926. 6. Hedenstrom H, Malmberg P, Agarwal K. Reference values for lung function tests in females. Regression equations with smoking variables. Bull Eur Physiopathol Respir. 1985;21:551-557. 7. Hedenstrom H, Malmberg P, Fridriksson HV. Reference values for lung function tests in men: Regression equations with smoking variables. Ups J Med Sci. 1986;91:299-310.
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8. Liedman B, Johnsson E, Merke C, Ruth M, Lundell L. Preoperative adjuvant radiochemotherapy may increase the risk in patients undergoing thoracoabdominal esophageal resections. Dig Surg. 2001;18:169-175. 9. Tatematsu N, Ezoe Y, Tanaka E, Muto M, Sakai Y, Tsuboyama T. Impact of neoadjuvant chemotherapy on physical fitness, physical activity, and health-related quality of life of patients with resectable esophageal cancer. Am J Clin Oncol. 2013;36:53-56. 10. Ahlberg K, Ekman T, Gaston-Johansson F, Mock V. Assessment and management of cancer-related fatigue in adults. Lancet. 2003;362:640-650. 11. Senkus E, Jassem J. Cardiovascular effects of systemic cancer treatment. Cancer Treat Rev. 2011;37:300-311. 12. Darby SC, Cutter DJ, Boerma M, Constine LS, Fajardo LF, Kodama K, et al. Radiation-related heart disease: Current knowledge and future prospects. Int J Radiat Oncol Biol Phys. 2010;76:656-665. 13. Lund M, Alexandersson von Dobeln G, Nilsson M, et al. Effects on heart function of neoadjuvant chemotherapy and chemoradiotherapy in patients with cancer in the esophagus or gastroesophageal junction–A prospective cohort pilot study within a randomized clinical trial. Radiat Oncol. 2015;10:16. 14. Gergel TJ, Leichman L, Nava HR, Blumenson LE, Loewen GM, Gibbs JE, et al. Effect of concurrent radiation therapy and chemotherapy on pulmonary function in patients with esophageal cancer: Dose-volume histogram analysis. Cancer J. 2002;8: 451-460. 15. Riedel M, Stein HJ, Mounyam L, Zimmermann F, Fink U, Siewert JR. Influence of simultaneous neoadjuvant radiotherapy and chemotherapy on bronchoscopic findings and lung function in patients with locally advanced proximal esophageal cancer. Am J Respir Crit Care Med. 2000;162:1741-1746. 16. Fagevik Olsen M, Larsson M, Hammerlid E, Lundell L. Physical function and quality of life after thoracoabdominal oesophageal resection. Results of a follow-up study. Dig Surg. 2005;22:63-68. 17. Ikeguchi M, Maeta M, Kaibara N. Respiratory function after esophagectomy for patients with esophageal cancer. Hepatogastroenterology. 2002;49:1284-1286. 18. Theuws JC, Muller SH, Seppenwoolde Y, Kwa SL, Boersma LJ, Hart GA, et al. Effect of radiotherapy and chemotherapy on pulmonary function after treatment for breast cancer and lymphoma: A follow-up study. J Clin Oncol. 1999;17:3091-3100. 19. Spyropoulou D, Leotsinidis M, Tsiamita M, Spiropoulos K, Kardamakis D. Pulmonary function testing in women with breast cancer treated with radiotherapy and chemotherapy. In Vivo. 2009;23:867-871. 20. Abid SH, Malhotra V, Perry MC. Radiation-induced and chemotherapy-induced pulmonary injury. Curr Opin Oncol. 2001;13:242-248. 21. Christensen JF, Jones LW, Andersen JL, Daugaard G, Rorth M, Hojman P. Muscle dysfunction in cancer patients. Ann Oncol. 2014;25:947-958. 22. Win T, Groves AM, Ritchie AJ, Wells FC, Cafferty F, Laroche CM. The effect of lung resection on pulmonary function and exercise capacity in lung cancer patients. Respir Care. 2007;52:720-726. 23. Chhabra SK. Forced vital capacity, slow vital capacity, or inspiratory vital capacity: Which is the best measure of vital capacity? J Asthma. 1998;35:361-365. 24. Dimeo FC, Thomas F, Raabe-Menssen C, Propper F, Mathias M. Effect of aerobic exercise and relaxation training on fatigue and physical performance of cancer patients after surgery. A randomised controlled trial. Support Care Cancer. 2004;12:774-779. 25. Courneya KS, Mackey JR, Bell GJ, Jones LW, Field CJ, Fairey AS. Randomized controlled trial of exercise training in postmenopausal breast cancer survivors: Cardiopulmonary and quality of life outcomes. J Clin Oncol. 2003;21:1660-1668.