Japanese Journal of Clinical Oncology Advance Access published online on February 11, 2008
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hym159
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© The Author (2008). Published by Oxford University Press. All rights reserved
High-dose Thoracic Radiation Therapy at 3.0 Gy/Fraction in Inoperable Stage I/II Non-small Cell Lung Cancer
1 Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
2 Department of Radiation Oncology, Dankook University College of Medicine, Cheonan, South Korea
For reprints and all correspondence: Yong Chan Ahn, Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Gangnam-gu, Seoul 135-710, South Korea. E-mail: yber55{at}nate.com, ahnyc{at}skku.edu
Received May 27, 2007; accepted November 4, 2007
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Objective: High-dose thoracic radiation therapy (HDTRT) alone has been an alternative to surgery in stage I/II non-small cell lung cancer patients with medical co-morbidities and/or poor performance status. Here, we report on the outcome and safety of HDTRT at 3.0 Gy per fraction for reduced treatment duration.
Methods: HDTRT alone at 3.0 Gy per fraction was given to 35 patients (22 at stage I and 13 at stage II). The median age was 73 years old and 14 patients had ECOG performance above 2. The median radiation dose to the primary lesion was 60 (54–66) Gy over 27 (23–38) days, and the dose to the mediastinum was individualized.
Results: After the median follow-up of 24 (3–72) months, local in-field progression developed in 11 patients (31.4%) and distant metastases in 14 (40.0%). The median survival period and the 3- and 5-year overall survival (OS) rates for all patients were 24.0 (95% CI: 13.57–34.43) months, 31.4 and 11.2%. Intercurrent deaths were observed in 11 patients. Treatment-related acute and subacute morbidities were observed in 20 patients (57.1%); however, there was neither treatment interruption nor long-term morbidity.
Conclusions: On the basis of the above observations, we achieved treatment outcomes comparable with those of conventional protracted fractionation schedules at considerably shorter duration and lower cost by HDTRT at 3.0 Gy per fraction.
Key Words: non-small cell lung cancer • radiation therapy
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Lung cancer is the most common cancer worldwide which accounts for nearly 13% of all new cancer diagnoses (1). Unfortunately, only
20% of non-small cell lung cancer (NSCLC) patients have limited disease stage at diagnosis (2–4). The standard treatment for stage I/II NSCLC has been surgical resection, and 5 year overall survival (OS) rates by surgery range from 53 to 82% for stage I and from 29 to 51% for stage II (5–7). Not all the patients with surgically resectable stage I/II disease, however, are fit for surgery because of various reasons including medical co-morbidities, and this proportion has not been well studied. In the report by McGarry et al., 66% (85/128) of early stage lung cancer patients receiving no treatment were with medical co-morbidities. Although this represents only a small sample from a single institution, it suggests that the proportion of medically inoperable patients with early stage NSCLC be substantial. Moreover, a large number of these medically inoperable patients who received neither surgery nor radiation therapy showed very poor outcome, where more than half died of lung cancer (8). Radiation therapy alone for early stage NSCLC has been a potentially curative treatment option for these patients, but the reported 5-year OS rates range from 0 to 42%, which are much poorer than the surgical results (9). The fractionation schedule of definitive radiation therapy for medically inoperable NSCLC varies among countries and institutes. The so-called ‘conventional fractionation schedule’ most commonly employ the fractional dose of 1.8 or 2.0 Gy to deliver up to 60–66 Gy over 6–7 weeks. Previously, we reported the results of the stage III NSCLC patients who were treated with radiotherapy using 3.0 Gy fractions size to reduce the treatment duration and cost. They were treated with radiotherapy alone due to poor general or medical conditions. The treatment results were comparable with those of other conventional schedules and the risks of complications were also comparable (10).
After confirming the safety of radiotherapy using 3.0 Gy fraction size, the authors have employed 3.0 Gy per fraction for high-dose thoracic radiation therapy (HDTRT) for medically inoperable stage I/II NSCLC patients to reduce the overall treatment duration and to improve treatment results. It was based on the results reported by Koukourakis et al. According to their analyses, 2-year local progression free probability was influenced by overall treatment time and daily dose lost because of treatment time beyond 20 days after beginning of radiotherapy was estimated to 0.27 Gy/day for stage I/II NSCLC (11).
In this report, we present our experience by retrospective review and compare our results with those using different fractionation schedules.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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From January 1996 till February 2001, 35 stage I/II NSCLC patients were the subjects of this study, all of who received HDTRT alone at Samsung Medical Center by 3.0 Gy per fraction. Histopathologic confirmation of NSCLC was made in all patients by bronchoscopy or percuteneous needle aspiration procedures. The clinical stages were assigned according to the AJCC/UICC staging system adopted in 1997/2002 after thorough history taking and physical examination, simple X-rays and CT scans of the chest, bone scan, pulmonary function tests and routine blood tests (CBC, blood chemistry). Brain MRI was done in two patients with clinical CNS symptoms, which turned out to be unrelated to NSCLC.
Radiation therapy was given using 6, 10 or 15 MV photon beams from linear accelerators, and the radiation volume included the primary tumor and the involved lymph node with a 1–2 cm margin. The decision for elective mediastinal irradiation was individually determined, and the patients with either centrally located large tumor (T2) or positive hilar lymph nodes (N1) were candidates for elective mediastinal irradiation. During the earlier study period, most patients were given AP/PA fields initially, which were followed by off-spinal cord oblique fields using a computerized CT plan, whereas three-dimensional conformal radiation therapy technique (3D CRT) was routinely applied during the later study period (3D CRT alone in 6 patients, 3D CRT combined with 2D radiotherapy in 10 patients). The spinal cord dose was kept at or below 36 Gy in all patients. The radiation dose was prescribed at the isocenter without heterogeneity correction for AP/PA fields (at 100% level) and with heterogeneity correction for computerized CT plans (usually at 97–103% level depending on the local anatomy and the beam quality). The intended total radiation dose to the gross lesion was 60 Gy over 4 weeks at daily 3.0 Gy fractions unless the esophagus was in contact with target volume.
The first follow-up evaluation was scheduled in 1 month of HDTRT completion with chest CT scan, and then every 3–4 months thereafter. Work-ups for possible recurrence or metastasis were performed whenever clinically indicated. The treatment responses were evaluated using the UICC criteria, and the local tumor progression was defined as radiological, bronchoscopic or pathologic evidence of tumor growth within the previously irradiated area. Signs and symptoms of radiation toxicity were assessed using the RTOG/EORTC grading system.
All time intervals were quoted from the first day of radiation therapy. Survival rates were calculated using the Kaplan–Meyer method, and p values between groups were determined using the log-rank test. Multivariate analysis using the Cox's proportional hazard model was performed to assess the relationships between survival and local tumor progression and the possible prognostic variables.
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RESULTS |
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The median patients' age was 73 (55–84) years and the majority was male (91.4%, 32/35). Twenty-one patients (60.0%) had an ECOG performance score of 0–1, 12 patients (34.3%) a score of 2 and 2 (5.7%) a score of 3. Significant weight loss defined as >5% within 6 months was observed in nine patients (25.7%). The most common histopathologic type was squamous cell carcinoma (65.7%, 23/35), followed by adenocarcinoma (22.9%, 8/35). Twenty-two patients (62.9%) had stage I disease and 13 (37.1%) had stage II (Table 1).
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All patients received radiation therapy as an alternative to surgery due to medical co-morbidities: poor pulmonary function in 17 (48.6%); history of malignancy other than NSCLC (synchronous or metachronous) in 7 (20.0%); diabetes mellitus in 5 (14.3%); hypertension in 4 (11.4%); ischemic heart disease in 3 (8.6%); asthma in 2 (5.7%); refusal of surgery in 1 (2.9%); old age in 1 (2.9%). Vast majority (33/35; 94.3%) were with more than one reason. In addition to seven patients who presented with history of synchronous or metachronous cancer at the time of current diagnosis, two additional patients later developed second cancer during the follow-up.
The median radiation dose to the primary lesion was 60 (54–66) Gy over a median duration of 27 (23–38) days. The elective irradiation to the mediastinal lymphatics was applied to 22 patients (62.9%) (Table 2).
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The median follow-up period was 24 (3–72) months. At the time of the last follow-up, 8 (22.9%) patients were alive and 27 (77.1%) patients had died. The median survival period was 24.0 (95% CI: 13.57–34.43) months and the 3- and 5-year OS rates for all patients were 31.4 and 11.2%. The median survival periods for stages I/II were 32.0/15.0 months, and the 3- and 5-year OS rates were 45.5/7.7 and 30.3/0%, respectively (Fig. 1). The median progression-free survival (PFS) period for all patients was 14.0 (95% CI: 4.73–23.27) months and the 3- and 5-year PFS rates were 31.4 and 18.0% (Fig. 2). Among the 27 patients who succumbed, 11 deaths were not related to NSCLC. The median cause-specific survival (CSS) period for all patients was 45 (95% CI: 27.13–62.87) months, and the 3- and 5-year CSS rates were 50.0 and 20.9%. The median CSS periods and the 3- and 5-year CSS rates for stage I/II were 45.0/18.0 months, 59.6/41.6 and 47.7/0%, respectively (Fig. 3). At the time of the last follow-up, local recurrence was observed in 11 patients (31.4%): distant metastasis alone developed in eight (22.9%); local recurrence component in three (8.6%). The 3- and 5-year local control (LC) rates for all patients were 60.7 and 52.0%. The 3- and 5-year LC rates for stage I/II were 69.6/43.1 and 69.6/0%, respectively (Fig. 4). The lung was the most common distant failure site affected in eight patients (72.7%). At the last follow-up, additional three patients showed distant metastasis following local failure, and two had local failure following distant metastasis (Table 3). All treatment failures except two occurred within 36 months. The median durations to local failure and distant metastasis were 14 (3–41) months and 8 (2–52) months.
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By univariate analysis, stage I and omission of elective mediastinal irradiation were identified as significant prognostic factors that favorably affected OS, PFS and LC, whereas squamous cell carcinoma histologic type was for LC. By multivariate analysis, stage I was identified as a significant prognostic factor that favorably affected PFS, whereas squamous cell carcinoma histologic type and a good immediate post-radiation response were for LC (Table 4).
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Treatment-related acute and subacute morbidities occurred in 20 patients (57.1%); however, no severe complication requiring treatment interruption occurred. Radiation esophagitis was the most common occurring in 17 patients (48.6%) and symptomatic radiation pneumonitis needing steroid medication occurred in 5 (14.3%), but neither was of grade 3 or higher. There was no incidence of long-term symptomatic pulmonary fibrosis that required prolonged management (Table 5).
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Compared with other conventional fractionation schedules, the overall treatment duration and the cost of this fractionation schedule were
60% of the conventional schedule. However, treatment results, especially in case of stage I, were comparable to those of conventional fractionation schedules and no increase in complications was observed. |
DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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In stage I/II NSCLC, despite progress in diagnosis and therapeutic strategies, long-term survival and LC rates by radiation therapy alone are lower than surgery series. Five-year OS rate is only 0–42%, and LC rate is 30
94% when treated with radiation therapy alone, which are poorer than surgical series results (29–72% and over 80%) (9). Inclusion of higher stages in radiation therapy alone series, by stage migration phenomenon, might have caused the less favorable outcomes when compared with the surgical series (5–7). Less thorough (usually clinical, not surgical) staging work-ups in most of the radiation therapy alone series might have led to insufficient radiation dose and inaccurate radiation therapy targeting (12). In this study, considering the short durations to distant metastasis (2–52 months; median 8 months), rather poor outcomes might naturally be ascribable to less thorough work-up to detect systemic metastases, which might have resulted in down-staging of the patients. Moreover, inclusion of nine patients with multiple cancer history, either synchronous or metachronous, might have further increased the risk of metastasis: four among nine multiple cancer patients developed distant metastases as their initial treatment failures. The long-term LC rates at 5 years, in our study, were higher than 52.0% for all patients and 69.6% for stage I, which were favorably comparable with those achieved by other rather conventional radiation therapy schedules. Most local recurrences, however, developed within 3 years of radiation therapy with the median time to local failure of 14.0 (3–41) months, and the patients with larger primary tumors tended to develop more and earlier local failures: 7 among 11 local failures were with tumors larger than 5 cm; 4 among 5 local failures which occurred within the first year of radiation therapy were with tumors larger than 5 cm. On the basis of these observations, total radiation dose employed in this study at 3.0 Gy per fraction appeared insufficient to achieve adequate LC especially for larger tumors, and further dose escalation study may be warranted.
3D CRT has gained wide acceptance as a more effective tool to achieve optimal tumor coverage without increasing the dose to the critical normal structures. Lagerwaard et al. (13) reported the results of high-dose 3D CRT (median dose was 66 Gy at 2 Gy per fraction) for stage I NSCLC, which showed the possibility of dose–LC relationship even though their overall and CSSs were rather disappointing. Willner et al. (14) clearly found improved LC and survival by radiation doses higher than 70 Gy compared with lower doses, and Martel et al. (15) estimated that the doses of higher than 84 Gy by conventional fractionation were needed to achieve a 50% LC in NSCLC. Thirion et al. (16), after assessing the feasibility and efficacy of 3D-CRT (72 Gy at 3.0 Gy per fraction) in stages I–III NSCLC, reported that this schedule was effective with acceptable acute and long-term radiation-induced morbidities, and postulated that the fraction size could be further increased in proportion to the increased therapeutic ratio, which resulted from the use of 3D-CRT technique and the omission of elective nodal irradiation. However, the dose escalation and/or the increase in fraction size might be limited due to the uncontrolled breathing and the motility of lung tumors (17). Thus, many efforts have been made to improve tumor targeting, including respiratory movement suppression, tumor tracking and respiratory gating.
Recently, hypofractionated stereotactic radiation therapy (SRT) has been used and found to improve treatment results, especially for patients with medically inoperable stage I NSCLC. Uematsu et al. (18) reported 94% LC, 66% OS and 88% CSS at 3 years using respiratory gating and CT-guided frameless SRT. Hiraoka et al. (19) reported one local recurrence during a follow-up of 6–71 months for NSCLC with tumors smaller than 4 cm treated with 48 Gy in four fractions over a 2-week period, and concluded that this modality was expected to become a standard treatment for inoperable patients and an alternative to lobectomy for operable patients (19). McGarry et al. (20) also suggested that stereotactic body radiation therapy in medically inoperable stage I lung cancer seemed to be safe and effective. The results by a multi-institutional prospective trial currently on-going in Japan and the USA (RTOG 0236) are awaited (20).
A few altered fractionation strategies have been tried in early stage NSCLC and reached at different conclusions: no impact on outcomes was achieved through accelerated fractionation with or without concurrent carboplatin (21); whereas reduced relative death risk by 25% was shown through CHART (continuous hyperfractionated accelerated radiation therapy) (22,23). More studies may be needed for more conclusive information.
In medically inoperable stage I or II NSCLC patients, only some proportion of the patients are eligible for hypofractionated SRT. The patients who had large tumors are usually not adequate for hypofractionated SRT due to poorer dose distributions and the higher proportions of hypoxic tumor cells, which needs reoxygenation process in order to secure adequate responses to ionizing radiation compared to small tumors (24). Twenty-four out of the 35 enrolled patients in our study had tumors not <4 cm and 10 out of those 35 patients had tumors larger than 5 cm [median; 4.5 (1–11) cm]. Not only the tumor size, but also N1 nodal involvement was also detected in 8 patients. So the strict comparison of the treatment results of this study with the results of other hypofractionated SRT is not possible and the relatively poor results of this study are no wonder.
On the basis of the experiences of the authors and others, definitive HDTRT of 3.0 Gy per fraction was found to be safe and effective at shorter treatment duration. This 3.0 Gy schedule can be used in early stage NSCLC, regardless of the tumor size or nodal status. Areas of further refinements to achieve better results would include anatomic staging accuracy, optimal radiation therapy volume determination and 3D technique, control of respiratory movement and delivery of higher tumor dose by higher dose per fraction.
Conflict of interest statement None declared.
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