Annals of Oncology Advance Access published online on August 20, 2008
Annals of Oncology, doi:10.1093/annonc/mdn559
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Eligibility for concurrent chemotherapy and radiotherapy of locally advanced lung cancer patients: a prospective, population-based study
1 Department of Radiation Oncology (Maastro Clinic), GROW Research Institute, University Medical Center Maastricht
2 Maastricht Cancer Registry, Comprehensive Cancer Centre Limburg (IKL)
3 Department of Pulmonology, University Medical Center Maastricht
4 Maastro Clinic, Maastricht
5 Department of Pulmonology, Atrium Medical Center, Heerlen
6 Department of Lung Diseases, Maasland Hospital, Sittard
7 Department of Lung Diseases, Laurentius Hospital, Roermond
8 Department of Lung Diseases, Sint Jans Gasthuis, Weert, The Netherlands
* Correspondence to: Dr D. K. M. De Ruysscher, Department of Radiation Oncology (Maastro Clinic), University Medical Center Maastricht, GROW Research Institute, Dr Tanslaan 12, 6229 ET Maastricht, The Netherlands. Tel: +31-88-445-57-00; Fax: +31-88-445-57-73; E-mail: dirk.deruysscher{at}maastro.nl
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Abstract |
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Background: Patients with stage III non-small-cell lung cancer (NSCLC) and limited disease small-cell lung cancer are excluded from concurrent chemoradiation mostly on the basis of comorbidity and age. The purpose of this prospective study was to get insight in what proportion of patients with locally advanced lung cancer would be suitable for concurrent chemoradiation.
Patients and methods: From 2002 to 2005, all patients with a pathological diagnosis of lung cancer and with locally advanced disease in the Maastricht Cancer Registry, the Netherlands, comorbidity were prospectively assessed. Patients were regarded as noneligible for concurrent chemoradiation if they had one or more important comorbidity or were 75 years or older.
Results: In all, 711 patients were included, 577 with NSCLC and 134 with SCLC. Overall, 166 patients (23.3%) were 75 years or older. Of the 526 patients <75 years, comorbidities were as follows: 278 (52.9%) 0, 188 (35.7%) 1, and 56 (11.4%) 2 or more. In all, 408/686 (59%) of the whole patient group were considered as ineligible for concurrent chemoradiation.
Conclusions: More than half of patients with stage III lung cancer were theoretically not eligible for concurrent chemoradiation. Less toxic alternatives are needed for these patients.
combined modality treatment, comorbidity, concurrent chemotherapy and radiotherapy, lung cancer, Maastricht Cancer Registry
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Several randomized clinical trials as well as meta-analyses have established that the best survival can be achieved in patients with locally advanced (stage III) non-small-cell lung cancer (NSCLC) and limited disease small-cell lung cancer (LD-SCLC) with concurrent chemoradiation instead of the sequential approach [1–12]. This is reflected in guidelines for standard practice [13–15]. However, due to the higher toxicity of concurrent treatment, this is generally only given to patients with minimal or no comorbidities, a good general condition, and who are relatively young. For example, in the meta-analysis on concurrent versus sequential chemoradiation in NSCLC, the majority of patients was <65 years (only 16% was 70 or older), nearly no patients had a World Health Organization (WHO) performance status (PS) of two, and none had a PS below two [7].
Comorbidity is frequently observed in elderly patients and in smokers, two groups with a high incidence of lung cancer [16–22]. These patients often receive less aggressive treatment [16, 19, 20] and are vastly underrepresented in clinical trials.
The aim of this study was to evaluate what proportion of patients would be suitable for concurrent chemoradiation on the basis of a priori criteria. In order to avoid selection bias as much as possible, we report on a population-based study that prospectively evaluated comorbidities in all patients diagnosed with lung cancer, stage III for NSCLC, and LD-SCLC, from 2002 to 2005 in South and Middle Limburg, The Netherlands.
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patients and methods |
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patient population
All patients diagnosed with lung cancer, both NSCLC and SCLC (according to the WHO classification), were obtained from the Maastricht Cancer Registry (MCR) over the period 2002–2005. Only patients with stage III NSCLC or LD-SCLC were included in this study.
maastricht cancer registry
The MCR is a population-based cancer registry, which was established in 1984 and is a department of the Comprehensive Cancer Centre Limburg (IKL). The MCR covers the region of mid- and southern Limburg, which is situated in the southeast of The Netherlands. On 1 January 2006, the region covered a total of 853 553 inhabitants. The main sources of information are regional hospitals and pathology laboratories from which the MCR receives reports on a weekly basis since 1986. After receiving the notification reports, trained registration clerks collect all relevant data of the patients and tumors from the medical records. Information on topography and morphology was coded according to the International Classification of Diseases for Oncology [23]. Tumor stage was recorded in accordance with the tumour–node–metastasis classification system [24].
Completeness of case ascertainment of the MCR is very high; for lung cancer, this is estimated to be >95% [25].
scoring of comorbidity
Comorbidity of all lung cancer patients was scored using a slightly adapted version of the Charlson comorbidity index (CCI) [26], as depicted in Table 1. The data were extracted from previous admissions, letters from and to other specialists, medical history, and preoperative screening. Comorbidity was defined as disease that was present at the time of diagnosis.
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In this study, only patients with important comorbidities were labeled as having a comorbidity (Table 1). From 25 patients, comorbidity could not be retrieved. Analysis was carried out on the 686 patients with known comorbidity status.
eligibility for concurrent chemoradiation
On the basis of the inclusion criteria of key phase III trials involving concurrent chemoradiation [2–9], current American College of Chest Physicians and National Institute for Health and Clinical Excellence guidelines [13–15], and the ongoing major phase III trial RTOG 0617/NCCTG N0628/CALGB 3060 [27], we chose the worst inclusion parameters in these representative studies. These were age at maximum 74 years, WHO PS at maximum two, weight loss <10% in the last 3 months, Forced expiratory volume (FEV1) at 1 second at least 40% of the age-predicted value, and adequate cardiac, renal and hematological functions. As WHO PS and CCI are closely related [28], we restricted eligibility for concurrent chemoradiation in this series to patients <75 years old or one or more important comorbidities on the CCI. Other inclusion parameters that could influence the selection for high-dose radiation like the size of the radiation field and hence the volume of healthy lung to be irradiated were not taken into account.
statistical analysis
Descriptive statistics were used as indicated in the text. To compute significance between groups, the chi-square test was used. P values <0.05 were considered significant.
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results |
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patient characteristics
From 2002 to 2005, 711 patients had stage III NSCLC or LD-SCLC. Of these 711 patients, 545 (76.7%) were <75 years. Most patients were male (507 of 711 or 71.2%) and 204 (28.8%) female (Tables 2 and 3). The majority of patients suffered from NSCLC (81%); SCLC accounted for 19% of the patients.
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comorbidities
From the 686 patients with known comorbidity status, patients <75 years had significantly less important comorbidities than older patients (47.1% versus 63.1% respectively; P = 0.001) (Figure 1). Of the 526 patients <75 years, comorbidities were as follows: 278 (52.9%) 0, 188 (35.7%) 1, and 56 (11.4%) 2 or more. As expected, lung diseases and cardiovascular disorders represented the overwhelming proportion of comorbidities in both genders (Tables 4 and 5).
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No significant differences in the incidence of comorbidities were observed between NSCLC and SCLC patients (287 of 555, 51.7% versus 62 of 131, 47.3%; P = 0.35) (Tables 2 and 3). In the age group <75 years, males had significantly more comorbidities than females (190 of 362, 52.5% versus 58 of 164, 35.4%, respectively; P = 0.0003) (Tables 2 and 3).
eligibility for concurrent chemoradiation
As depicted in Figures 2 and 3, a decreasing number and proportion of patients were considered as being eligible for concurrent chemoradiation with increasing age. In the age group of 60–69, only 50% of the patients were eligible for concurrent chemoradiotherapy. In the age 70–74 years, less than half were suitable for aggressive therapy. However, already 23.3% of the patients were 75 years or older, excluding them directly for concurrent chemotherapy and radiotherapy. As a result, 408 of 686 (59%) of the whole patient group was considered as ineligible for concurrent chemoradiation.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Concurrent chemoradiation is at present the treatment of choice for patients with locally advanced NSCLC and LD-SCLC [1–15]. However, due to its higher toxicity, this combination is mostly restricted to patients in a good general condition, minimal comorbidity and who are relatively young [7, 13–15]. Although other groups have reported on the incidence of comorbidity, PS and its impact on treatment of lung cancer patients [16–22, 28–30], to the best of our knowledge, no population-based study has investigated which proportion of patients would be eligible for concurrent chemotherapy and radiotherapy.
In this prospective, population-based study, more than half of the patients with stage III NSCLC or LD-SCLC were not eligible for concurrent chemoradiation on the basis of criteria of age and important comorbidities that were present at diagnosis. About one-fourth was 75 years or older, and of the younger group, only 53% had no comorbidity. Comorbidity was as expected composed of lung diseases (mainly chronic obstructive pulmonary disease (COPD) and cardiovascular disorders.
Some potential caveats of this study should be discussed. First, the a priori criterion of one or more significant comorbidity to exclude patients for concurrent chemoradiation may be too wide. A considerable proportion of patients with lung cancer and COPD or cardiovascular diseases may still be eligible for concurrent chemoradiotherapy. Functional criteria like lung function and exercise capacity were unfortunately not available from the datasets. However, solely on the basis of the existence of COPD, patients should not a priori be excluded from potentially curative therapy. Also for cardiovascular disease, the presence of this comorbidity as such should not exclude patients for high-dose chemoradiation. Exercise tolerance, and on indication electrocardiography and cardiac ultrasound, may give more insight on the potential eligibility for aggressive therapy. A simple functional test like the 6-min walking distance may be a pragmatic, but at present unproven, method to get more insight in the functional status of the patient and hence its tolerance for concurrent chemoradiation than comorbidity on itself. Second, the incidence of comorbidities could be overestimated. However, as only selected comorbidities were used, and not the full CCI items, the real incidence of all comorbidity may be higher [18]. Third, although the PS was not determined, we believe that as PS and comorbidity are strongly correlated [28], our results are still valuable. Moreover, it has been shown that comorbidity influences significantly treatment choices, underlining its clinical usefulness [29, 30].
Fourth, we selected patients suitable for concurrent treatment also on the basis of age, being <75 and the presence of at maximum one important comorbidity. Weight loss was not taken into account because it was not scored prospectively. Also the size of the radiation field and the related irradiated lung volume (e.g. the mean lung dose or the volume of the lungs receiving >20 Gy, i.e. the V20) was not considered. This represents eligibility criteria for concurrent chemoradiation that are probably very close to those of important phase III studies and advocated by guidelines [2–15, 27]. We therefore believe that our figures are not only representative for the general population in the MCR region but also reflect realistic inclusion criteria for aggressive treatment. However, with the rising numbers of patients >75 years without significant comorbidities, the exclusion of patients for concurrent chemoradiation should clearly be reconsidered [31].
In spite of that we found that only 41% of the patients with stage III lung cancer would be suitable for concurrent chemoradiation.
This finding has important implications. First, it should be investigated to what extend patients with given comorbidities and/or advanced age are suitable for concurrent chemoradiation. Indeed, the patient population that is in reality included in trials is younger and healthier than the eligibility criteria of studies allow [7]. As a consequence, only sparse data on the outcome of elderly patients and those with comorbidity are available. It may be possible that provided adequate supportive care could be given, they would be suitable for more aggressive but also more efficacious combination treatment. Ultimately, this should be reflected in clinical guidelines. Secondly, the development of less toxic but still curative treatments for individuals that cannot tolerate concurrent therapy should be a priority in view of the large number of patients that fall in this category. Sequential chemotherapy and high-dose radiotherapy may be a somewhat less, but still valuable alternative for patients who are not eligible for concurrent chemotherapy and radiation [2–7]. Personalized radiotherapy [32], the use of charged particle radiation [33], and the combination of radiation with targeted agents [34] are some of the other possibilities.
Received for publication May 15, 2008. Revision received July 11, 2008. Accepted for publication July 14, 2008.
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References |
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|
TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
|---|
1. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ (1995) 311:899–909.
2. Fournel P, Robinet G, Thomas P, et al. Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique–Groupe Français de Pneumo-Cancérologie NPC 95-01 Study. J Clin Oncol (2005) 23:5910–5917.
3. Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol (1999) 17:2692–2699.
4. Curran WJ, Scott CB, Langer CJ, et al. Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemoradiation for patients with unresectable stage III NSCLC: RTOG 94-10. Proc Am Soc Clin Oncol (2003) 22:621a. (Abstr 2499).
5. Zatloukal P, Petruzelka L, Zemanova M, et al. Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Lung Cancer (2004) 46:87–98.[CrossRef][Web of Science][Medline]
6. Rowell NP, O'rourke NP. Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev (2004) (4). CD002140.
7. Auperin A, Rolland E, Curran W Jr, et al. Concomitant radio-chemotherapy (RT-CT) versus sequential RT-CT in locally advanced non-small cell lung cancer (NSCLC): a meta-analysis using individual patient data (IPD) from randomised clinical trials (RCTs). J Thorac Oncol (2007) 2(Suppl 4):S310. (Abstr A1–A05).
8. Turrisi AT, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med (1999) 340:265–271.
9. Takada M, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol (2002) 20:3054–3060.
10. Fried DB, Morris DE, Poole C, et al. Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer. J Clin Oncol (2004) 22:4785–4793.
11. Pijls-Johannesma M, De Ruysscher D, Vansteenkiste J, et al. Timing of chest radiotherapy in patients with limited stage small cell lung cancer: a systematic review and meta-analysis of randomised controlled trials. Cancer Treat Rev (2007) 33:461–473.[CrossRef][Web of Science][Medline]
12. De Ruysscher D, Pijls-Johannesma M, Bentzen SM, et al. Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer. J Clin Oncol (2006) 24:1057–1063.
13. Robinson LA, Ruckdeschel JC, Wagner H Jr, et al, American College of Chest Physicians. Treatment of non-small cell lung cancer-stage IIIA: ACCP evidence-based clinical practice guidelines 2nd edition. Chest (2007) 132:243S–265S.[CrossRef][Web of Science][Medline]
14. Jett JR, Schild SE, Keith RL, et al, American College of Chest Physicians. Treatment of non-small cell lung cancer, stage IIIB: ACCP evidence-based clinical practice guidelines 2nd edition. Chest (2007) 132:266S–276S.[CrossRef][Web of Science][Medline]
15. Mayor S. NICE issues guidance for diagnosis and treatment of lung cancer. BMJ (2005) 330:439.
16. Janssen-Heijnen ML, Schipper RM, Razenberg PP, et al. Prevalence of comorbidity in lung cancer patients and its relationship with treatment: a population-based study. Lung Cancer (1998) 21:105–113.[CrossRef][Web of Science][Medline]
17. van de Schans SA, Janssen-Heijnen ML, Biesma B, et al. COPD in cancer patients: higher prevalence in the elderly, a different treatment strategy in case of primary tumours above the diaphragm, and a worse overall survival in the elderly patient. Eur J Cancer (2007) 43:2194–2202.[CrossRef][Web of Science][Medline]
18. Janssen-Heijnen ML, Lemmens VE, van den Borne BE, et al. Negligible influence of comorbidity on prognosis of patients with small cell lung cancer: a population-based study in the Netherlands. Crit Rev Oncol Hematol (2007) 62:172–178.[CrossRef][Web of Science][Medline]
19. Vulto AJ, Lemmens VE, Louwman MW, et al. The influence of age and comorbidity on receiving radiotherapy as part of primary treatment for cancer in South Netherlands, 1995 to 2002. Cancer (2006) 106:2734–2742.[Medline]
20. Janssen-Heijnen ML, Smulders S, Lemmens VE, et al. Effect of comorbidity on the treatment and prognosis of elderly patients with non-small cell lung cancer. Thorax (2004) 59:602–607.
21. Gridelli C, Langer C, Maione P, et al. Lung cancer in the elderly. J Clin Oncol (2007) 25:1898–1907.
22. Lilenbaum RC, Cashy J, Hensing TA, et al. Prevalence of poor performance status in lung cancer patients: implications for research. J Thorac Oncol (2008) 3:125–129.[CrossRef][Medline]
23. World Health Organization. International Classification of Diseases for Oncology (ICD-O-3) (2000) 3rd edition. Geneva: WHO Press.
24. Sobin LH, Wittekind Ch. International Union Against Cancer (UICC). TNM Classification of Malignant Tumours (2002) 6th edition. New York: Wiley-Liss.
25. Schouten LJ, Hoppener P, van den Brandt PA, et al. Completeness of cancer registration in Limburg, The Netherlands. Int J Epidemiol (1993) 22:369–376.
26. Charlson M, Szatrowski TP, Peterson J, et al. Validation of a combined comorbidity index. J Clin Epidemiol (1994) 47:1245–1251.[CrossRef][Web of Science][Medline]
27. Radiation Therapy Oncology Group. RTOG 0617/NCCTG N0628/CALGB 30609 A randomzed phase III comparison of standard-dose (60 Gy) versus high dose (74 Gy) conformal radiotherapy with concurrent and consolidation carboplatin/paclitaxel in patients with stage IIIA/IIIB non-small cell lung cancer. http://www.rtog.org/members/protocols/0617/0617.pdf. (22 May 2008, date last accessed).
28. Asmis TR, Ding K, Seymour L, et al, National Cancer Institute of Canada Clinical Trials Group. Age and comorbidity as independent prognostic factors in the treatment of non small-cell lung cancer: a review of National Cancer Institute of Canada Clinical Trials Group trials. J Clin Oncol (2008) 26:54–59.
29. Firat S, Pleister A, Byhardt RW, et al. Age is independent of comorbidity influencing patient selection for combined modality therapy for treatment of stage III nonsmall cell lung cancer (NSCLC). Am J Clin Oncol (2006) 29:252–257.[CrossRef][Web of Science][Medline]
30. Read WL, Tierney RM, Page NC, et al. Differential prognostic impact of comorbidity. J Clin Oncol (2004) 22:3099–3103.
31. Owonikoko TK, Ragin CC, Belani CP, et al. Lung cancer in elderly patients: an analysis of the surveillance, epidemiology, and end results database. J Clin Oncol (2007) 25:5570–5577.
32. van Baardwijk A, Bosmans G, Boersma L, et al. Individualized radical radiotherapy of non-small-cell lung cancer based on normal tissue dose constraints: a feasibility study. Int J Radiat Oncol Biol Phys (2008) 71:1103–1110.[Web of Science][Medline]
33. Brada M, Pijls-Johannesma M, De Ruysscher D. Proton therapy in clinical practice: current clinical evidence. J Clin Oncol (2007) 25:965–970.
34. Hanna N, Lilenbaum R, Ansari R, et al. Phase II trial of cetuximab in patients with previously treated non-small-cell lung cancer. J Clin Oncol (2006) 24:5253–5258.
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