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Local Control and Survival Following Concomitant Chemoradiotherapy in Inoperable Stage I Non-Small-Cell Lung Cancer
Int. J. Radiation Oncology Biol. Phys., Vol. 74, No. 5, pp. 1371–1375, 2009 Crown Copyright Ó 2009 Published by Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/09/$–see front matter
doi:10.1016/j.ijrobp.2008.10.067
CLINICAL INVESTIGATION
Lung
LOCAL CONTROL AND SURVIVAL FOLLOWING CONCOMITANT CHEMORADIOTHERAPY IN INOPERABLE STAGE I NON-SMALL-CELL LUNG CANCER MARIE-PIERRE CAMPEAU, M.D.,* ALAN HERSCHTAL, B.SC.(HONS),y GREG WHEELER, M.B.B.S, F.R.A.N.Z.C.R.,* MICHAEL MAC MANUS, M.D., F.R.C.R.,* ANDREW WIRTH, M.B.B.S., F.R.A.C.P., F.R.A.N.Z.C.R.,* MICHAEL MICHAEL, B.SC(HONS), M.B.B.S.(HONS), F.R.A.C.P.,z ANNETTE HOGG, PH.D.,x ELIZABETH DRUMMOND, M.SC.,x AND DAVID BALL, M.B.B.S., M.D., F.R.A.N.Z.C.R.* Departments of *Radiation Oncology, y Centre for Biostatistics and Clinical Trials, z Haematology and Medical Oncology, and x Metabolic Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia Purpose: Concomitant chemoradiotherapy (CRT) increases survival rates compared with radical radiotherapy alone (RT) in Stage III non-small-cell lung cancer (NSCLC), as a result of improved local control. The effect of CRT on local control in Stage I NSCLC is less well documented. We retrospectively reviewed local control and survival following CRT or RT for inoperable Stage I NSCLC patients. Methods and materials: Eligible patients had histologically/cytologically proved inoperable Stage I NSCLC and had undergone complete staging investigations including an F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scan. Radiotherapy was planned as (1) 60 Gy in 30 fractions over 6 weeks with or without concomitant chemotherapy or (2) 50–55 Gy in 20 fractions without chemotherapy. Results: Between 2000 and 2005, 73 patients met the eligibility criteria and were treated as follows: CRT (60 Gy)— 39; RT (60 Gy)—23; RT (50–55 Gy)—11. The median follow-up time for all patients was 18 months (range, 1–81 months). Survival analysis was based on intent to treat. Local progression-free survival (PFS) at 2 years was 66% with CRT and 55% with RT. The 2-year distant PFS was 60% following CRT and 63% after RT. The 2-year PFS rates were 57% and 50%, respectively. The 2-year survival rate for patients treated with CRT was 57% and 33% in patients receiving RT. Conclusions: Despite the use of CRTand routine staging with FDG-PET, both local and distant recurrences remain important causes of treatment failure in patients with inoperable stage I NSCLC. Crown Copyright Ó 2009 Published by Elsevier Inc. Medically inoperable, Early-stage, Lung cancer, Three-dimensional conformal radiation therapy, Chemoradiation.
INTRODUCTION Surgery is usually considered the treatment of choice for early stage non-small-cell lung cancer (NSCLC). For medically inoperable patients or those who decline surgery, radical radiotherapy (RT) is generally accepted as the standard of care. Results with radiotherapy alone in Stage I and II NSCLC are disappointing with local failure rates varying between 6% to 70% and 2-year overall survival rates between 33% to 72% (1). To improve these outcomes, different strategies have been explored such as the combined use of chemotherapy and radiotherapy. In Stage III NSCLC, the addition of chemotherapy to radiation therapy increases survival rates compared with RT alone, as a result of improved local control (2, 3).
Limited data suggest that concomitant chemoradiotherapy (CRT) might improve survival in Stage I NSCLC. A metaanalysis from the Non-small Cell Lung Cancer Collaborative Group reported a 13% reduction in the risk of death in patients receiving sequential chemotherapy and radiotherapy compared to RT alone (4). This benefit was present regardless of disease stage. A subgroup analysis of an Australian Phase III trial of radiation with or without chemotherapy in inoperable NSCLC has shown an advantage of combined treatment compared to radiation alone for Stage I and II disease (5, 6). On the basis of this experience, we adopted CRT as the standard of care for patients with medically inoperable Stage
Reprint requests to: Marie-Pierre Campeau M.D., Radiation Oncology Department, CHUM—Notre-Dame Hospital, 1560 Sherbrooke East, Montreal, Quebec, Canada H2L 4M1. Tel: (514)-890-8254; E-mail: [email protected]. qc.ca
The abstract for this article was selected for poster viewing at the Chicago Multidisciplinary Symposium in Thoracic Oncology. Conflict of interest: none. Received Aug 30, 2008, and in revised form Oct 15, 2008. Accepted for publication Oct 16, 2008. 1371
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I NSCLC provided that the patient is judged fit for chemotherapy. The aim of this study was to review retrospectively disease control and survival in patients with Stage I NSCLC patients who were treated with CRT or RT between 2000 and 2005. METHODS AND MATERIALS Patients planned to be treated with radical radiotherapy for NSCLC between January 2000 and December 2005 were identified in the Peter MacCallum Cancer Centre (Peter Mac) radiotherapy database. This review was restricted to those patients with Union Internationale Contre le Cancer (UICC) clinical Stage I histologically or cytologically proven NSCLC who were treated with or without concomitant chemotherapy. All patients had a complete clinical examination, a computed tomography (CT) of the chest and upper abdomen, and an F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scan. Exclusion criteria consisted of previous diagnosis of lung cancer, prior treatment for NSCLC, surgery forming part of the initial treatment, and evidence of recurrence from a previous cancer. Patients were deemed unsuitable for surgery only after review by a multidisciplinary team consisting of thoracic physicians, thoracic surgeons, and radiation and medical oncologists. The study protocol was approved by the Peter Mac ethics committee. The following demographic data, known and potential prognostic factors (7) were collected: age, sex, clinical UICC stage, performance status estimated according to the Eastern Cooperative Oncology Group (ECOG) scale, percentage of weight loss over the 3 months preceding diagnosis, forced expiratory volume in 1 second (FEV1), hemoglobin and albumin at diagnosis, previous cancer, tumor histology, and the simplified comorbidity score (SCS). The SCS is a clinical score taking into account the following comorbidities: tobacco consumption, clinical comorbidities (diabetes mellitus, renal insufficiency, respiratory, neoplastic, and cardiovascular comorbidities) and alcoholism (8). Seventy-three patients were found to meet the eligibility criteria. Patients’ baseline characteristics are shown in Table 1. There was a predominance of male and Stage IB patients in both the CRT and the RT groups. Seventeen patients had a prior history of cancer, head and neck cancer being the most common primary site, followed by bladder cancer and prostate cancer.
Radiotherapy Radiotherapy was delivered with $ 6 MV photons using a threedimensional conformal radiation therapy (3DCRT) technique for all patients. Planning was performed using corrections for tissue inhomogeneities. No elective nodal irradiation was performed. The RT regimen used was a function of whether concomitant chemotherapy was administered with RT and can be described as follows: 1-CRT group: Thirty-nine patients were treated with CRT. RT consisted of 60 Gy in 30 fractions over 6 weeks. 2-RT group: Thirty-four patients were treated with RT. RT consisted of 60 Gy in 30 fractions over 6 weeks in 23 of patients. Eleven patients, due to resource constraints, were treated with a hypofractionated regimen consisting of 50–55 Gy in 20 fractions over 4 weeks. The hypofractionated regimen was used only in cases in which the mediastinum and spinal cord were not included in the treatment volume. Four patients did not complete the RT as planned (CRT: n = 1, RT: n = 3). They were included in the analysis. The reason for not
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Table 1. Baseline patient characteristics
Sex F M Age Median Range Stage 1A 1B ECOG 0 1 2 3 NA Weight loss Nil < 10% > 10% NA FEV1 Median Range SCS <9 >9 NA Prior malignancy No Yes Histology Squamous Adenocarcinoma Large cell NSCLC NOS
CRT n = 39 (%)
RT n = 34 (%)
13 (33) 26 (67)
14 (41) 20 (59)
71 58–85
81 54–88
15 (38) 24 (62)
10 (29) 24 (71)
11 (28) 18 (46) 2 (5) 0 (0) 8 (21)
3 (9) 6 (18) 9 (26) 2 (6) 14 (41)
29 (74) 5 (13) 2 (5) 3 (8)
18 (53) 6 (18) 6 (18) 4 (12)
1.41 0.67–3.91
1.66 0.51–2.69
18 (46) 21 (54) 0
12 (35) 21 (62) 1 (3)
31 (79) 8 (21)
25 (74) 9 (26)
20 (51) 10 (26) 6 (15) 3 (8)
12 (35) 13 (38) 2 (6) 7 (21)
Abbreviations: CRT = concomitant chemoradiotherapy; ECOG = Eastern Cooperative Oncology Group; FEV1 = forced expiratory volume in one 1 second; NOS = not otherwise specified; NSCLC = non-small-cell lung cancer; RT = radical radiotherapy alone; SCS = simplified comorbidity score. completing the planned RT course was treatment-related toxicity for the 4 patients.
Chemotherapy Patients in the CRT group were treated with concomitant chemotherapy. Chemotherapy consisted of a single-agent carboplatin given weekly (area under the curve [AUC] 2) or at Week 1 and Week 6 (AUC 6 fractionated over 5 days for each of these weeks) in 26 patients. Nine patients were treated with a cisplatinum-based doublet: weekly carboplatin (AUC 2) and paclitaxel (45 mg/m2) or weekly carboplatin (AUC 2) and docetaxel (20 mg/m2). The chemotherapy regimen was not known in four patients. Chemotherapy was delivered within 2–4 hours before the RT fraction. Chemotherapy was delivered both at Peter Mac and at affiliated centers, and information on the number of cycles received by every patient was not available.
Follow-up Patients were generally seen every 3 months after completion of treatment for the first 2 years. The interval was usually increased to
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Table 2. Two-year outcomes by treatment group
Local PFS 2 Distant PFS 2 PFS 2 OS 2
CRT (95% CI)
RT (95% CI)
66% (49%–81%) 60% (41%–76%) 57% (39%–73%) 57% (41%–72%)
55% (28%–79%) 63% (41%–80%) 50% (28%–72%) 33% (18%–51%)
Abbreviations: CI = confidence interval; CRT = concomitant chemoradiotherapy; OS = overall survival; PFS = progression-free survival; RT = radical radiotherapy alone.
every 6 months provided there was no evidence of recurrence. Chest X-ray or CT scan of the chest and upper abdomen were performed before each visit in most cases. An F-18 FDG PET scan was performed in case of equivocal CT scan results. The median follow-up time for all patients was 18 months (range, 1–81 months), and 28 months for patients still alive at the study closeout date.
Statistical methods The primary endpoint of this study was to assess overall survival (OS). Secondary endpoints were local progression-free survival (PFS), distant PFS, and PFS. OS was measured from treatment starting date to the date of death, regardless of the cause of death. Local progression was defined as per the RECIST guidelines (9): at least a 20% increase in the longest diameter of target lesion, taking as the reference the smallest of the longest diameters recorded since the treatment started. For the purpose of this study, distant progression was defined as any recurrence outside the radiotherapy treatment volume. Local PFS was measured from the treatment starting date to the date of local progression or cancer related death. Local PFS was not censored by distant progression. Distant PFS was measured from the treatment starting date to the date of distant metastasis or cancer-related death. Distant PFS was not censored by local progression. PFS was measured from the treatment starting date to either any progression or cancer-related death. Those three endpoints were censored by non-cancer-related death, and the follow-up for each patient was until the date of the last medical assessment of that patient. Deaths were the only events documented following the last medical assessment. The study closeout date was December 31, 2007. The survival endpoints were calculated using the Kaplan-Meier product limit method. Data analysis was performed using the S-Plus 2000 software.
RESULTS Results with respect to the four endpoints are presented by treatment group in Table 2. The 2-year OS rate for patients treated with CRT was 57% (95% confidence interval [CI], 41%–72%) and 33% (95% CI, 18%–51%) in patients receiving RT (Fig. 1). The local PFS at 2 years was 66% (95% CI, 49%–81%) with CRT and 55% (95% CI, 28%–79%) with RT (Fig. 2). One patient in the RT group underwent salvage surgery following local progression. This patient developed both distant progression (5 months) and local progression (10 months) following the salvage lobectomy. All other patients were managed with palliative intent following local progression.
Fig. 1. Overall survival by treatment group. CRT = concomitant chemoradiotherapy; RT = radical radiotherapy alone.
The 2-year distant PFS was 60% (95% CI, 41%–76%) following CRT and 63% (41%–80%) after RT. The 2-year PFS rates were 57% (95% CI, 39%–73%) and 50% (28%–72%), respectively. Seventeen patients had relapsed by the time of last medical assessment in the CRT group, and of those, local progression alone was the first site of relapse in 5 patients. In the RT group, 11 relapses were documented. Local progression alone was the first site of relapse in 5 patients (4 patients received a total dose of 60 Gy, and one patient received 52.25 Gy in 19 fractions). None of the 73 patients relapsed locally following distant progression and 5 (CRT: n = 5, RT: n = 0) had a simultaneous diagnosis of local and distant progression. The pattern of site of first relapse for both groups is represented in Table 3. Patients with a prior malignancy had a worse distant PFS rate than those without (p = 0.03). There was also a tendency for inferior local PFS (p = 0.2), PFS (p = 0.05) and OS (p = 0.2) rates in patients with a prior malignancy. Effect of treatment modality As a part of this study, a Cox regression model was built to test the effect of treatment modality (CRT vs. RT) on each of the four survival endpoints. The following prognostic factors were controlled for: ECOG performance status, weight loss, SCS, tumor histology, sex, hemoglobin, and albumin. In all four endpoints, none of the prognostic factors was statistically significant and were thus removed from the model. Furthermore, there was no statistically significant effect of treatment modality on any of the four survival endpoints. DISCUSSION This study provides useful benchmark information on survival and disease control in patients with inoperable Stage I NSCLC who were staged and treated using contemporary techniques. Despite the use of FDG-PET staging and concomitant chemotherapy, both local and distant progression were important causes of treatment failure. An effect on survival or local control of the addition of chemotherapy to RT
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Table 3. Site of first relapse by treatment group
Number of relapses Local Distant Local + Distant
Fig. 2. Local progression-free survival by treatment group. CRT = concomitant chemoradiotherapy; RT = radical radiotherapy alone.
could not be demonstrated. This was expected given the limited number of events in each group and the magnitude of the expected relative contribution, if any, of chemotherapy. In locally advanced NSCLC, the addition of concomitant CT to RT has shown to improve the 2-year locoregional PFS rate by 16% (2) and the 3-year OS rate by 12% (10). Compared with previous studies on conventional RT for early-stage NSCLC, our series is unique in that all patients have been staged with an F-18 FDG-PET scan and treated with 3DCRT. In addition, all patients in our series had a cytologically or histologically confirmed diagnosis, a weakness of previous series in which up to 43% of patients did not have histological diagnosis (11). The addition of PET scan to the conventional staging has been shown to upstage nearly half of patients with Stage I NSCLC (12). MacManus et al. (13) reported that 7.5% of patients with Stage I disease are found to have unsuspected distant metastases with the addition of a PET scan to the conventional staging. Fang et al. (14) assessed the role of 3DCRT in Stage I NSCLC patients treated with RT. They reported on a series of 200 patients with Stage I NSCLC treated with RT. Patients treated with 3DCRT had higher OS and locoregional control rates compared with those treated with two-dimensional radiotherapy. Similar to results from previous series, the OS at 2 years in both groups were poor. The major reason for inoperability is comorbidity, and therefore many patients were at risk of competing causes of death other than cancer. This is reflected by the high proportion of patients (58%) with a SCS greater than 9. Colinet et al. (8) reported that a SCS > 9 was an independent prognostic factor of poor outcome in NSCLC patients. In our study, the SCS was not found to be predictor of poor survival. This result should be interpreted in the context of a relatively small sample size and retrospective documentation of the SCS. It is worth noting that more than 50% of the patient in our series did not have evidence of recurrence at 2 years. This certainly justifies a radical treatment approach in this high-risk population not eligible for a surgical approach.
CRT n = 39 (%)
RT n = 34 (%)
17 (44) 5 (13) 7 (18) 5 (13)
11 (32) 5 (15) 6 (18) 0 (0)
The local PFS at 2 years of 66% in the CRT group and 55% in the RT group compare well to published literature on conventional RT for Stage I NSCLC. Lagerwaard et al. (11) reported a local PFS rate of 43% at 3 years in 113 Stage I NSCLC patients treated with 3DCRT. A higher local control rate at 2 years of 77% in patients treated with 3DCRT was reported in the previously mentioned series by Fang et al. (14). Compared with our series, their study included a higher proportion of Stage IA patients, and a higher radiation dose was used (median dose, 66 Gy). Those factors might have contributed to the high local control rate. Qiao et al. (15) have reviewed 18 studies on Stage I NSCLC treated by RT alone. They found a high variability in the frequency of local recurrence among the studies, ranging from 6.4% to 70% with a median local recurrence rate of 40%. A similar range of local failure was reported in a Cochrane review on radical radiotherapy in early-stage NSCLC (1). This high variability in treatment outcomes indicates that caution must be used when comparing series because local control definitions vary among studies, as do methods of follow-up investigations. In our series, patients were usually followed-up with regular CT scans of the chest, in contrast to previous studies in which chest X-ray was often used as the follow-up modality. Moreover, in our cohort, the cumulative incidence of local progression was documented, regardless of progression elsewhere. Analyzing the local PFS rate by this technique equals or underestimates the local PFS rate as opposed to analyzing it with censorship by distant progression. In our study, none of the patients relapsed locally following distant progression; therefore, analyzing the local progression with censorship by distant metastasis would have resulted in an equivalent local PFS estimate. Given the aforementioned factors, the local PFS of 66% at 2 years in patients treated with CRT is encouraging compared with the previous published local control rates with RT. A similar 2-year local PFS of 69% was reported by Jeremic et al. (16) in their Phase II study assessing the role of hyperfactionated radiotherapy and concurrent chemotherapy. Recently, high local control rates in the order of 80%–95% at 2 years have been reported with stereotactic radiotherapy (SRT) for inoperable Stage I NSCLC (17). Data on longterm toxicity are, however, not as well documented as they are for conventional RT, and this treatment technique is not available in all treatment centers. Furthermore, not all the Stage I patients are eligible for SRT; patients with larger tumors, for example, are not candidates for this technique. Caution must be used in patients with central tumor location because high toxicity rate have been reported with the use
Chemoradiotherapy in Stage I NSCLC d M.-P. CAMPEAU et al.
of a high dose per fraction (18). More fractionated SRT schemes may be associated with acceptable toxicity for centrally located tumor, although longer follow-up is necessary (19). It is therefore important to investigate alternative treatment strategies to improve the local control rates obtained with conventional RT alone. The main limitation of this study is the lack of data on acute and long-term toxicity. Concerns about tolerance of concomitant treatment have been raised in inoperable earlystage patients. In our study, most of the patients receiving CRT were treated with single-agent carboplatin, which is
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better tolerated than a cisplatinum-based doublet. It is worth noting that only one patient undergoing CRT did not complete the planned RT course, which might be considered as a surrogate measure for acute treatment toxicity. In conclusion, results of this single-institution retrospective study show that both local progression and distant progression remain important causes of treatment failure in patients with inoperable Stage I NSCLC despite the use of concomitant chemotherapy and PET staging in all cases. The outcomes presented here provide a benchmark by which future treatment strategies for Stage I NSCLC can be judged.
REFERENCES 1. Rowell NP, Williams CJ. Radical radiotherapy for Stage I/II non-small cell lung cancer in patients not sufficiently fit for or declining surgery (medically inoperable). Cochrane Database Syst Rev 2001:CD002935. 2. Rowell NP, O’Rourke NP. Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev 2004: CD002140. 3. Auperin A, Rolland E, Curran W, et al. Concomitant radio-chemotherapy (RT-CT) versus sequential RT-CT in locally advanced non-small cell lung cancer: A meta-analysis using individual patient data from randomised clinical trials [abstract]. J Thorac Oncol 2007;2(Suppl. 4):S310. 4. 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. 5. Ball D, Bishop J, Smith J, et al. A randomised Phase III study of accelerated or standard fraction radiotherapy with or without concurrent carboplatin in inoperable non-small cell lung cancer: Final report of an Australian multi-centre trial. Radiother Oncol 1999;52:129–136. 6. Ball DL, Peters LJ, Smith J. Reasons for the slow implementations of CHART for patients with non-small cell lung cancer in clinical practice. Radiother Oncol 2001;58:89–90. 7. Gospodarowicz MM, Henson DE, Hutter RVP, et al. Lung cancer. In: Brundage D and Mackillop W, editors. Prognostic factors in cancer. 2nd ed. New York: Wiley-Liss; 2001. p. 351–369. 8. Colinet B, Jacot W, Bertrand D, et al. A new simplified comorbidity score as a prognostic factor in non-small-cell lung cancer patients: Description and comparison with the Charlson’s index. Br J Cancer 2005;93:1098–1105. 9. Husband JE, Schwartz LH, Spencer J, et al. Evaluation of the response to treatment of solid tumours—a consensus statement of the International Cancer Imaging Society. Br J Cancer 2004; 90:2256–2260. 10. Rolland E, Le Chevalier T, Auperin A, et al. Sequential radiochemotherapy (RT-CT) versus radiotherapy alone (RT) and concomitant RT-CT versus RT alone in locally advanced
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non-small cell lung cancer (NSCLC): Two meta-analyses using individual patient data (IPD) from randomised clinical trials (RCTs) [abstract]. J Thorac Oncol 2007;2(Suppl. 4): S309–S310. Lagerwaard FJ, Senan S, van Meerbeeck JP, Graveland WJ. Has 3-D conformal radiotherapy (3D CRT) improved the local tumour control for Stage I non-small cell lung cancer? Radiother Oncol 2002;63:151–157. Hicks RJ, Kalff V, MacManus MP, et al. (18)F-FDG PET provides high-impact and powerful prognostic stratification in staging newly diagnosed non-small cell lung cancer. J Nucl Med 2001;42:1596–1604. MacManus MP, Hicks RJ, Matthews JP, et al. High rate of detection of unsuspected distant metastases by pet in apparent stage III non-small-cell lung cancer: implications for radical radiation therapy. Int J Radiat Oncol Biol Phys 2001;50:287–293. Fang LC, Komaki R, Allen P, et al. Comparison of outcomes for patients with medically inoperable Stage I non-small-cell lung cancer treated with two-dimensional vs. three-dimensional radiotherapy. Int J Radiat Oncol Biol Phys 2006;66:108–116. Qiao X, Tullgren O, Lax I, et al. The role of radiotherapy in treatment of stage I non-small cell lung cancer. Lung Cancer 2003;41:1–11. Jeremic B, Milicic B, Acimovic L, Milisavljevic S. Concurrent hyperfractionated radiotherapy and low-dose daily carboplatin and paclitaxel in patients with stage III non-small-cell lung cancer: Long-term results of a phase II study. J Clin Oncol 2005;23: 1144–1151. Ball D. Stereotactic radiotherapy for nonsmall cell lung cancer. Curr Opin Pulm Med 2008;14:297–302. Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity when treating central tumors in a Phase II study of stereotactic body radiation therapy for medically inoperable earlystage lung cancer. J Clin Oncol 2006;24:4833–4839. Lagerwaard FJ, Haasbeek CJ, Smit EF, et al. Outcomes of risk-adapted fractionated stereotactic radiotherapy for Stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2008;70:685–692.
doi:10.1016/j.ijrobp.2008.10.067
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LOCAL CONTROL AND SURVIVAL FOLLOWING CONCOMITANT CHEMORADIOTHERAPY IN INOPERABLE STAGE I NON-SMALL-CELL LUNG CANCER MARIE-PIERRE CAMPEAU, M.D.,* ALAN HERSCHTAL, B.SC.(HONS),y GREG WHEELER, M.B.B.S, F.R.A.N.Z.C.R.,* MICHAEL MAC MANUS, M.D., F.R.C.R.,* ANDREW WIRTH, M.B.B.S., F.R.A.C.P., F.R.A.N.Z.C.R.,* MICHAEL MICHAEL, B.SC(HONS), M.B.B.S.(HONS), F.R.A.C.P.,z ANNETTE HOGG, PH.D.,x ELIZABETH DRUMMOND, M.SC.,x AND DAVID BALL, M.B.B.S., M.D., F.R.A.N.Z.C.R.* Departments of *Radiation Oncology, y Centre for Biostatistics and Clinical Trials, z Haematology and Medical Oncology, and x Metabolic Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia Purpose: Concomitant chemoradiotherapy (CRT) increases survival rates compared with radical radiotherapy alone (RT) in Stage III non-small-cell lung cancer (NSCLC), as a result of improved local control. The effect of CRT on local control in Stage I NSCLC is less well documented. We retrospectively reviewed local control and survival following CRT or RT for inoperable Stage I NSCLC patients. Methods and materials: Eligible patients had histologically/cytologically proved inoperable Stage I NSCLC and had undergone complete staging investigations including an F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scan. Radiotherapy was planned as (1) 60 Gy in 30 fractions over 6 weeks with or without concomitant chemotherapy or (2) 50–55 Gy in 20 fractions without chemotherapy. Results: Between 2000 and 2005, 73 patients met the eligibility criteria and were treated as follows: CRT (60 Gy)— 39; RT (60 Gy)—23; RT (50–55 Gy)—11. The median follow-up time for all patients was 18 months (range, 1–81 months). Survival analysis was based on intent to treat. Local progression-free survival (PFS) at 2 years was 66% with CRT and 55% with RT. The 2-year distant PFS was 60% following CRT and 63% after RT. The 2-year PFS rates were 57% and 50%, respectively. The 2-year survival rate for patients treated with CRT was 57% and 33% in patients receiving RT. Conclusions: Despite the use of CRTand routine staging with FDG-PET, both local and distant recurrences remain important causes of treatment failure in patients with inoperable stage I NSCLC. Crown Copyright Ó 2009 Published by Elsevier Inc. Medically inoperable, Early-stage, Lung cancer, Three-dimensional conformal radiation therapy, Chemoradiation.
INTRODUCTION Surgery is usually considered the treatment of choice for early stage non-small-cell lung cancer (NSCLC). For medically inoperable patients or those who decline surgery, radical radiotherapy (RT) is generally accepted as the standard of care. Results with radiotherapy alone in Stage I and II NSCLC are disappointing with local failure rates varying between 6% to 70% and 2-year overall survival rates between 33% to 72% (1). To improve these outcomes, different strategies have been explored such as the combined use of chemotherapy and radiotherapy. In Stage III NSCLC, the addition of chemotherapy to radiation therapy increases survival rates compared with RT alone, as a result of improved local control (2, 3).
Limited data suggest that concomitant chemoradiotherapy (CRT) might improve survival in Stage I NSCLC. A metaanalysis from the Non-small Cell Lung Cancer Collaborative Group reported a 13% reduction in the risk of death in patients receiving sequential chemotherapy and radiotherapy compared to RT alone (4). This benefit was present regardless of disease stage. A subgroup analysis of an Australian Phase III trial of radiation with or without chemotherapy in inoperable NSCLC has shown an advantage of combined treatment compared to radiation alone for Stage I and II disease (5, 6). On the basis of this experience, we adopted CRT as the standard of care for patients with medically inoperable Stage
Reprint requests to: Marie-Pierre Campeau M.D., Radiation Oncology Department, CHUM—Notre-Dame Hospital, 1560 Sherbrooke East, Montreal, Quebec, Canada H2L 4M1. Tel: (514)-890-8254; E-mail: [email protected]. qc.ca
The abstract for this article was selected for poster viewing at the Chicago Multidisciplinary Symposium in Thoracic Oncology. Conflict of interest: none. Received Aug 30, 2008, and in revised form Oct 15, 2008. Accepted for publication Oct 16, 2008. 1371
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I NSCLC provided that the patient is judged fit for chemotherapy. The aim of this study was to review retrospectively disease control and survival in patients with Stage I NSCLC patients who were treated with CRT or RT between 2000 and 2005. METHODS AND MATERIALS Patients planned to be treated with radical radiotherapy for NSCLC between January 2000 and December 2005 were identified in the Peter MacCallum Cancer Centre (Peter Mac) radiotherapy database. This review was restricted to those patients with Union Internationale Contre le Cancer (UICC) clinical Stage I histologically or cytologically proven NSCLC who were treated with or without concomitant chemotherapy. All patients had a complete clinical examination, a computed tomography (CT) of the chest and upper abdomen, and an F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scan. Exclusion criteria consisted of previous diagnosis of lung cancer, prior treatment for NSCLC, surgery forming part of the initial treatment, and evidence of recurrence from a previous cancer. Patients were deemed unsuitable for surgery only after review by a multidisciplinary team consisting of thoracic physicians, thoracic surgeons, and radiation and medical oncologists. The study protocol was approved by the Peter Mac ethics committee. The following demographic data, known and potential prognostic factors (7) were collected: age, sex, clinical UICC stage, performance status estimated according to the Eastern Cooperative Oncology Group (ECOG) scale, percentage of weight loss over the 3 months preceding diagnosis, forced expiratory volume in 1 second (FEV1), hemoglobin and albumin at diagnosis, previous cancer, tumor histology, and the simplified comorbidity score (SCS). The SCS is a clinical score taking into account the following comorbidities: tobacco consumption, clinical comorbidities (diabetes mellitus, renal insufficiency, respiratory, neoplastic, and cardiovascular comorbidities) and alcoholism (8). Seventy-three patients were found to meet the eligibility criteria. Patients’ baseline characteristics are shown in Table 1. There was a predominance of male and Stage IB patients in both the CRT and the RT groups. Seventeen patients had a prior history of cancer, head and neck cancer being the most common primary site, followed by bladder cancer and prostate cancer.
Radiotherapy Radiotherapy was delivered with $ 6 MV photons using a threedimensional conformal radiation therapy (3DCRT) technique for all patients. Planning was performed using corrections for tissue inhomogeneities. No elective nodal irradiation was performed. The RT regimen used was a function of whether concomitant chemotherapy was administered with RT and can be described as follows: 1-CRT group: Thirty-nine patients were treated with CRT. RT consisted of 60 Gy in 30 fractions over 6 weeks. 2-RT group: Thirty-four patients were treated with RT. RT consisted of 60 Gy in 30 fractions over 6 weeks in 23 of patients. Eleven patients, due to resource constraints, were treated with a hypofractionated regimen consisting of 50–55 Gy in 20 fractions over 4 weeks. The hypofractionated regimen was used only in cases in which the mediastinum and spinal cord were not included in the treatment volume. Four patients did not complete the RT as planned (CRT: n = 1, RT: n = 3). They were included in the analysis. The reason for not
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Table 1. Baseline patient characteristics
Sex F M Age Median Range Stage 1A 1B ECOG 0 1 2 3 NA Weight loss Nil < 10% > 10% NA FEV1 Median Range SCS <9 >9 NA Prior malignancy No Yes Histology Squamous Adenocarcinoma Large cell NSCLC NOS
CRT n = 39 (%)
RT n = 34 (%)
13 (33) 26 (67)
14 (41) 20 (59)
71 58–85
81 54–88
15 (38) 24 (62)
10 (29) 24 (71)
11 (28) 18 (46) 2 (5) 0 (0) 8 (21)
3 (9) 6 (18) 9 (26) 2 (6) 14 (41)
29 (74) 5 (13) 2 (5) 3 (8)
18 (53) 6 (18) 6 (18) 4 (12)
1.41 0.67–3.91
1.66 0.51–2.69
18 (46) 21 (54) 0
12 (35) 21 (62) 1 (3)
31 (79) 8 (21)
25 (74) 9 (26)
20 (51) 10 (26) 6 (15) 3 (8)
12 (35) 13 (38) 2 (6) 7 (21)
Abbreviations: CRT = concomitant chemoradiotherapy; ECOG = Eastern Cooperative Oncology Group; FEV1 = forced expiratory volume in one 1 second; NOS = not otherwise specified; NSCLC = non-small-cell lung cancer; RT = radical radiotherapy alone; SCS = simplified comorbidity score. completing the planned RT course was treatment-related toxicity for the 4 patients.
Chemotherapy Patients in the CRT group were treated with concomitant chemotherapy. Chemotherapy consisted of a single-agent carboplatin given weekly (area under the curve [AUC] 2) or at Week 1 and Week 6 (AUC 6 fractionated over 5 days for each of these weeks) in 26 patients. Nine patients were treated with a cisplatinum-based doublet: weekly carboplatin (AUC 2) and paclitaxel (45 mg/m2) or weekly carboplatin (AUC 2) and docetaxel (20 mg/m2). The chemotherapy regimen was not known in four patients. Chemotherapy was delivered within 2–4 hours before the RT fraction. Chemotherapy was delivered both at Peter Mac and at affiliated centers, and information on the number of cycles received by every patient was not available.
Follow-up Patients were generally seen every 3 months after completion of treatment for the first 2 years. The interval was usually increased to
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Table 2. Two-year outcomes by treatment group
Local PFS 2 Distant PFS 2 PFS 2 OS 2
CRT (95% CI)
RT (95% CI)
66% (49%–81%) 60% (41%–76%) 57% (39%–73%) 57% (41%–72%)
55% (28%–79%) 63% (41%–80%) 50% (28%–72%) 33% (18%–51%)
Abbreviations: CI = confidence interval; CRT = concomitant chemoradiotherapy; OS = overall survival; PFS = progression-free survival; RT = radical radiotherapy alone.
every 6 months provided there was no evidence of recurrence. Chest X-ray or CT scan of the chest and upper abdomen were performed before each visit in most cases. An F-18 FDG PET scan was performed in case of equivocal CT scan results. The median follow-up time for all patients was 18 months (range, 1–81 months), and 28 months for patients still alive at the study closeout date.
Statistical methods The primary endpoint of this study was to assess overall survival (OS). Secondary endpoints were local progression-free survival (PFS), distant PFS, and PFS. OS was measured from treatment starting date to the date of death, regardless of the cause of death. Local progression was defined as per the RECIST guidelines (9): at least a 20% increase in the longest diameter of target lesion, taking as the reference the smallest of the longest diameters recorded since the treatment started. For the purpose of this study, distant progression was defined as any recurrence outside the radiotherapy treatment volume. Local PFS was measured from the treatment starting date to the date of local progression or cancer related death. Local PFS was not censored by distant progression. Distant PFS was measured from the treatment starting date to the date of distant metastasis or cancer-related death. Distant PFS was not censored by local progression. PFS was measured from the treatment starting date to either any progression or cancer-related death. Those three endpoints were censored by non-cancer-related death, and the follow-up for each patient was until the date of the last medical assessment of that patient. Deaths were the only events documented following the last medical assessment. The study closeout date was December 31, 2007. The survival endpoints were calculated using the Kaplan-Meier product limit method. Data analysis was performed using the S-Plus 2000 software.
RESULTS Results with respect to the four endpoints are presented by treatment group in Table 2. The 2-year OS rate for patients treated with CRT was 57% (95% confidence interval [CI], 41%–72%) and 33% (95% CI, 18%–51%) in patients receiving RT (Fig. 1). The local PFS at 2 years was 66% (95% CI, 49%–81%) with CRT and 55% (95% CI, 28%–79%) with RT (Fig. 2). One patient in the RT group underwent salvage surgery following local progression. This patient developed both distant progression (5 months) and local progression (10 months) following the salvage lobectomy. All other patients were managed with palliative intent following local progression.
Fig. 1. Overall survival by treatment group. CRT = concomitant chemoradiotherapy; RT = radical radiotherapy alone.
The 2-year distant PFS was 60% (95% CI, 41%–76%) following CRT and 63% (41%–80%) after RT. The 2-year PFS rates were 57% (95% CI, 39%–73%) and 50% (28%–72%), respectively. Seventeen patients had relapsed by the time of last medical assessment in the CRT group, and of those, local progression alone was the first site of relapse in 5 patients. In the RT group, 11 relapses were documented. Local progression alone was the first site of relapse in 5 patients (4 patients received a total dose of 60 Gy, and one patient received 52.25 Gy in 19 fractions). None of the 73 patients relapsed locally following distant progression and 5 (CRT: n = 5, RT: n = 0) had a simultaneous diagnosis of local and distant progression. The pattern of site of first relapse for both groups is represented in Table 3. Patients with a prior malignancy had a worse distant PFS rate than those without (p = 0.03). There was also a tendency for inferior local PFS (p = 0.2), PFS (p = 0.05) and OS (p = 0.2) rates in patients with a prior malignancy. Effect of treatment modality As a part of this study, a Cox regression model was built to test the effect of treatment modality (CRT vs. RT) on each of the four survival endpoints. The following prognostic factors were controlled for: ECOG performance status, weight loss, SCS, tumor histology, sex, hemoglobin, and albumin. In all four endpoints, none of the prognostic factors was statistically significant and were thus removed from the model. Furthermore, there was no statistically significant effect of treatment modality on any of the four survival endpoints. DISCUSSION This study provides useful benchmark information on survival and disease control in patients with inoperable Stage I NSCLC who were staged and treated using contemporary techniques. Despite the use of FDG-PET staging and concomitant chemotherapy, both local and distant progression were important causes of treatment failure. An effect on survival or local control of the addition of chemotherapy to RT
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Table 3. Site of first relapse by treatment group
Number of relapses Local Distant Local + Distant
Fig. 2. Local progression-free survival by treatment group. CRT = concomitant chemoradiotherapy; RT = radical radiotherapy alone.
could not be demonstrated. This was expected given the limited number of events in each group and the magnitude of the expected relative contribution, if any, of chemotherapy. In locally advanced NSCLC, the addition of concomitant CT to RT has shown to improve the 2-year locoregional PFS rate by 16% (2) and the 3-year OS rate by 12% (10). Compared with previous studies on conventional RT for early-stage NSCLC, our series is unique in that all patients have been staged with an F-18 FDG-PET scan and treated with 3DCRT. In addition, all patients in our series had a cytologically or histologically confirmed diagnosis, a weakness of previous series in which up to 43% of patients did not have histological diagnosis (11). The addition of PET scan to the conventional staging has been shown to upstage nearly half of patients with Stage I NSCLC (12). MacManus et al. (13) reported that 7.5% of patients with Stage I disease are found to have unsuspected distant metastases with the addition of a PET scan to the conventional staging. Fang et al. (14) assessed the role of 3DCRT in Stage I NSCLC patients treated with RT. They reported on a series of 200 patients with Stage I NSCLC treated with RT. Patients treated with 3DCRT had higher OS and locoregional control rates compared with those treated with two-dimensional radiotherapy. Similar to results from previous series, the OS at 2 years in both groups were poor. The major reason for inoperability is comorbidity, and therefore many patients were at risk of competing causes of death other than cancer. This is reflected by the high proportion of patients (58%) with a SCS greater than 9. Colinet et al. (8) reported that a SCS > 9 was an independent prognostic factor of poor outcome in NSCLC patients. In our study, the SCS was not found to be predictor of poor survival. This result should be interpreted in the context of a relatively small sample size and retrospective documentation of the SCS. It is worth noting that more than 50% of the patient in our series did not have evidence of recurrence at 2 years. This certainly justifies a radical treatment approach in this high-risk population not eligible for a surgical approach.
CRT n = 39 (%)
RT n = 34 (%)
17 (44) 5 (13) 7 (18) 5 (13)
11 (32) 5 (15) 6 (18) 0 (0)
The local PFS at 2 years of 66% in the CRT group and 55% in the RT group compare well to published literature on conventional RT for Stage I NSCLC. Lagerwaard et al. (11) reported a local PFS rate of 43% at 3 years in 113 Stage I NSCLC patients treated with 3DCRT. A higher local control rate at 2 years of 77% in patients treated with 3DCRT was reported in the previously mentioned series by Fang et al. (14). Compared with our series, their study included a higher proportion of Stage IA patients, and a higher radiation dose was used (median dose, 66 Gy). Those factors might have contributed to the high local control rate. Qiao et al. (15) have reviewed 18 studies on Stage I NSCLC treated by RT alone. They found a high variability in the frequency of local recurrence among the studies, ranging from 6.4% to 70% with a median local recurrence rate of 40%. A similar range of local failure was reported in a Cochrane review on radical radiotherapy in early-stage NSCLC (1). This high variability in treatment outcomes indicates that caution must be used when comparing series because local control definitions vary among studies, as do methods of follow-up investigations. In our series, patients were usually followed-up with regular CT scans of the chest, in contrast to previous studies in which chest X-ray was often used as the follow-up modality. Moreover, in our cohort, the cumulative incidence of local progression was documented, regardless of progression elsewhere. Analyzing the local PFS rate by this technique equals or underestimates the local PFS rate as opposed to analyzing it with censorship by distant progression. In our study, none of the patients relapsed locally following distant progression; therefore, analyzing the local progression with censorship by distant metastasis would have resulted in an equivalent local PFS estimate. Given the aforementioned factors, the local PFS of 66% at 2 years in patients treated with CRT is encouraging compared with the previous published local control rates with RT. A similar 2-year local PFS of 69% was reported by Jeremic et al. (16) in their Phase II study assessing the role of hyperfactionated radiotherapy and concurrent chemotherapy. Recently, high local control rates in the order of 80%–95% at 2 years have been reported with stereotactic radiotherapy (SRT) for inoperable Stage I NSCLC (17). Data on longterm toxicity are, however, not as well documented as they are for conventional RT, and this treatment technique is not available in all treatment centers. Furthermore, not all the Stage I patients are eligible for SRT; patients with larger tumors, for example, are not candidates for this technique. Caution must be used in patients with central tumor location because high toxicity rate have been reported with the use
Chemoradiotherapy in Stage I NSCLC d M.-P. CAMPEAU et al.
of a high dose per fraction (18). More fractionated SRT schemes may be associated with acceptable toxicity for centrally located tumor, although longer follow-up is necessary (19). It is therefore important to investigate alternative treatment strategies to improve the local control rates obtained with conventional RT alone. The main limitation of this study is the lack of data on acute and long-term toxicity. Concerns about tolerance of concomitant treatment have been raised in inoperable earlystage patients. In our study, most of the patients receiving CRT were treated with single-agent carboplatin, which is
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better tolerated than a cisplatinum-based doublet. It is worth noting that only one patient undergoing CRT did not complete the planned RT course, which might be considered as a surrogate measure for acute treatment toxicity. In conclusion, results of this single-institution retrospective study show that both local progression and distant progression remain important causes of treatment failure in patients with inoperable Stage I NSCLC despite the use of concomitant chemotherapy and PET staging in all cases. The outcomes presented here provide a benchmark by which future treatment strategies for Stage I NSCLC can be judged.
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