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II) non-small-cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy alone
Lung Cancer 40 (2003) 317 /323 www.elsevier.com/locate/lungcan
Impact of treatment interruptions due to toxicity on outcome of patients with early stage (I/II) non-small-cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy alone Branislav Jeremic a,*, Yuta Shibamoto b, Biljana Milicic a, Aleksandar Dagovic a, Nebojsa Nikolic a, Jasna Aleksandrovic a, Ljubisa Acimovic a, Slobodan Milisavljevic a b
a University Hospital, Kragujevac, Yugoslavia Department of Radiology, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan
Received 10 October 2002; received in revised form 23 January 2003; accepted 27 January 2003
Abstract We investigated the effect of treatment interruptions due to high-grade ( E/3) toxicity on outcome of patients with early stage (I/II) non-small-cell lung cancer treated with hyperfractionated radiation therapy (Hfx RT). Of 116 patients treated with total tumour doses of 69.6 Gy, 1.2 Gy b.i.d. fractionation, 44 patients refused surgery while 72 patients were medically inoperable due to existing co-morbid states. Patients who were medically inoperable had worse KPS (P /0.0059) and more pronounced weight loss (P/ 0.0005). Among them, 12 patients experienced high-grade toxicity and 11 of them with either acute (n/6) or ‘consequential’ late (n /5) high-grade toxicity requested interruption in the Hfx RT course (range, 12 /25 days; median, 17 days). Superior survival (OS) was observed in patients who refused surgery when compared to those who were medically inoperable (P/0.0041), as well as superior local recurrence-free survival (LRFS) (P /0.011), but not different distant metastasis-free survival (P/0.14). Causespecific survival (CSS) also favoured patients who refused surgery (P /0.004). Multivariate analysis showed independent influence of the reason for not undergoing surgery on OS (P /0.035), but not on LRFS (P/0.084) or CSS (P/0.068). Patients who refused surgery did not experience high-grade toxicity (0/44), whereas 11 of 72 patients with medical inoperability and co-morbid states experienced high-grade toxicity and had treatment interruptions to manage toxicity (P/0.0064). Patients without treatment interruptions had significantly better OS (P/0.00000), LRFS (P /0.00000) and CSS (P/0.00000) than those with treatment interruptions. When corrected for treatment interruptions, the reason for not undergoing surgery independently influenced OS (P/ 0.040), but not LRFS (P/0.092) or CSS (P/0.068). In contrast to this, treatment interruption was independent prognosticator of all three endpoints used (P/0.00031, P /0.0075 and P /0.00033, respectively). When 11 patients with treatment interruptions were excluded, the reason for not undergoing surgery still affected OS (P/0.037) and CSS (P/0.039) but not LRFS (P/0.11). Multivariate analyses using OS, CSS and LRFS showed that the reason for not undergoing surgery affected OS (P /0.0436), but neither CSS (P/0.083) nor LRFS (P/0.080). # 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Early stage; Non-small-cell lung cancer; Hyperfractionation; Treatment interruption; Toxicity
1. Introduction Standard treatment approach for patients with early stage non-small-cell lung cancer (NSCLC) is surgery [1 /
* Corresponding author. Present address: Department of Radiotherapy, Klinikum rechts der Isar, Technical University Munich, Ismaninger Strasse 22, D-81675 Munich, Germany. Tel.: / 49-89-4140-4512; fax: /49-89-4140-4882. E-mail address: [email protected] (B. Jeremic).
3]. Due to medical inoperability or patient refusal, however, radiation therapy (RT) is frequently used in these cases [4 /8]. With high-dose, conventionally fractionated (CF) or hyperfractionated (Hfx) RT 5-years survival rates of up to 30% were achieved [4 /10]. Analysis of patterns of failure clearly showed predominance of local failure. Importance of local tumour control, in general, has been frequently stressed in the last two decades [11 /14]. Local failure is not only a frequent cause of death, but can also lead to increase in
0169-5002/03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0169-5002(03)00078-3
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the distant metastasis rate, another frequent cause of death in patients with tumours not controlled locally. It is, therefore, that patients with early stage NSCLC may represent a suitable group for investigation of various reasons for local failure, proliferation of tumour clonogens during RT being one of these. This proliferation may accelerate days to weeks after first treatments result in marked tumour cell loss. Indeed, a number of studies in head and neck (H&N) cancer clearly showed detrimental effect of accelerated tumour clonogen repopulation occurring with treatment prolongation [15 /17], including high-dose Hfx RT regimens [18]. Last decade also brought initial evidence that this may as well happen in NSCLC, with basically two reasons for unplanned treatment prolongation: treatment-related (acute) toxicity necessitating treatment break to manage existing toxicity, and treatment machine breaks or prolonged holidays. Cox et al. [19] were first to report on significantly inferior outcome of patients with locally advanced NSCLC treated with Hfx doses of E/69.6 Gy using 1.2 Gy b.i.d. fractionation who experienced treatment prolongation. While Koukourakis et al. [20] and Chen et al. [21] confirmed this observation, Willers et al. [22] were unable to do so. In all of these studies, a proportion of patients with early stage NSCLC, sometimes treated with Hfx RT, were included in the analysis. However, no report provided clear data or separate analysis on the impact of treatment interruptions in patients with early (I and II) stage NSCLC treated with Hfx RT. Having continuous interest in altered fractionated regimens, given with or without concurrent chemotherapy (CHT) in lung cancer, the aim of this report is to investigate the impact of treatment interruptions due to toxicity in patients with early stage NSCLC treated with high-dose Hfx RT.
2.2. Therapy Hfx RT regimen was introduced in both clinical stage I and II NSCLC with total tumour doses of 69.6 Gy in 58 fractions in 29 treatment days (b.i.d. fractionation) over 6 weeks. Two daily fractions of 1.2 Gy were used with an interfraction interval of 4.5 /6 h. All fields were treated daily. The target volume for stage I patients included the primary tumour and ipsilateral hilum with a 2-cm margin up to 50.4 Gy followed by the treatment of primary tumour only up to 69.6 Gy. For Stage II patients the target volume included the primary tumour and ipsilateral hilum with a 2-cm margin and the ipsilateral mediastinum from the suprasternal notch to a level 6 cm below the carina (upper or middle lobe lesions) or to the diaphragm (lower lobe lesions), followed by the treatment of primary tumour and ipsilateral hilum up to 69.6 Gy. Doses were specified at middepth at the central axis for parallel-opposed fields and at the intersection of central axes for other techniques. The follow-up procedures included laboratory and clinical tests including chest X-rays, and thoracic and upper abdominal CT scanning, accompanied with other tests, if needed. The schedule for follow-up examination included examination at the end treatment, every month for 6 months after the completion of treatment, every 2 months for 2 years thereafter, and every 4/6 months thereafter. The radiation-induced effects on normal tissue were assessed as either acute or late phenomena, according to the RTOG/European Organization for the Research and treatment of Cancer (EORTC) criteria [23].
2.3. Statistical analysis 2. Material and methods
2.1. Patient population Between 1988 and 1993, a total of 116 patients with NSCLC at early stages (I and II) according to the International Staging System [1] were treated with Hfx RT alone [9,10]. In all cases patients were, although technically operable, deemed unsuitable for surgery due to their concomitant medical problems (cardiovascular or pulmonary diseases) (n/72) or because they refused surgery (n /44). No patient underwent surgery and no patient received any form of adjuvant (chemo- or immuno-) therapy. All patients underwent pretreatment staging including thoracic CT scanning. No patient underwent mediastinoscopy.
Differences between pairs of groups in characteristics and incidence of toxicity were evaluated by g2-test. Survival (OS) and relapse-free survival rates were calculated from the date of start of Hfx RT by the Kaplan /Meier method, and differences between pairs of groups in survival curves were analysed by the log-rank test. In calculating local recurrence-free survival (LRFS), distant metastasis-free survival or causespecific survival (CSS) rates, patients who developed either type of failure were considered at risk for the other endpoint and censored at the time of last evaluation. The interaction of potential prognostic factors and their effect on OS, LRFS or CSS was analysed using the Cox proportional hazards model. All these statistical analyses were carried out by using the computer program HALWIN (Gendaisuugakusha, Kyoto, Japan).
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3. Results The median survival time (MST) and 5-year survival rate for all 116 patients are 29 months and 28%, respectively. Since in this study higher percentage of patients refusing surgery than in other contemporary studies [4 /8] in early NSCLC was encountered, we then evaluated the difference between patients refusing surgery and those deemed inoperable due to concurrent cardiopulmonary disease. Regarding various pretreatment clinical prognostic factors there were no difference between patients who refused surgery and those with medical inoperability, except that patients with medical inoperability had significantly worse KPS (P/0.0059) and more pronounced weight loss (P /0.0005) (Table 1). A significantly higher MST and 5-year survival was observed for patients refusing surgery than in those who were medically inoperable (MST, 38 vs. 22 months; 5year survival, 45% vs. 18%, P /0.0041). There was also a significantly better median time to local recurrence and 5-year LRFS (not achieved vs. 28 months and 60 vs. 41%, respectively; P /0.011). There was no difference in distant metastasis control (P /0.14). Since no information or rational explanation currently exist to support difference in either OS and LRFS we observed, we tried to exclude possible effect of co-morbid states in medically inoperable patients using a CSS as an endpoint which still favoured patients who refused surgery (median time, 38 vs. 22 months; 5-year CSS, 48 vs. 28%; P /0.004). A multivariate analysis using a number of possible pretreatment clinical prognostic factors corrected for the reason for not undergoing surgery showed that reason for not undergoing surgery was an important predictor of survival (P /0.035), but was insignificant when LRFS (P /0.084) or CSS (P /0.068) were used as endpoints (Table 2). Patients who refused surgery did not experience high-grade toxicity (0/44), whereas 12 or 72 patients with medical inoperability and co-morbid states experienced it, 11 of the latter group (11/72) requested treatment interruptions (P/0.0064) (range, 12/25 days; median, 17 days) in the course of Table 1 Patient characteristics Variable
Sex Age (years) KPS Weight loss Location T stage N stage
M/F B/60/E/60 70 /80/90 /100 / Center/periphery 1/2 0/1
Table 2 Multivariate analyses investigating effect of various pretreatment factors including the reason for not undergoing surgery (all patients, n/116) Variable
Sex Age KPS Weight loss Location T stage N stage Reason for not undergoing surgery
P
31/13 15/29 7/37 43/1 25/19
55/17 28/44 29/43 52/20 34/38
0.48 0.60 0.0059 0.0005 0.32
25/19 24/20
31/41 43/29
0.15 0.58
KPS, Karnofsky performance status.
OS
LRFS CSS
P
P
P
0.68 0.93 B/0.00001 0.0004 0.044 0.047 0.43 0.035
0.49 0.86 0.0010 0.068 0.21 0.012 0.28 0.084
0.85 0.82 B/0.00001 0.0006 0.12 0.021 0.31 0.068
OS, overall survival; LRFS, local recurrence-free survival; CSS, cause-specific survival; KPS, Karnofsky performance status.
Hfx RT to manage either acute high-grade (n /6) or ‘consequential’ late (n /5) toxicity. There were 3 bronchopulmonary grade 3 acute toxicity and 3 oesophageal grade 3 acute toxicity. All late toxicity was ‘consequential’, being 2 bronchopulmonary grade 3, 3 oesophageal grade 3, and one osseous grade 3 late toxicity. To identify factors that may have influenced treatment outcome, the impact of treatment interruptions caused by high-grade (E/3) toxicity was first taken into account in all patients. Patients with treatment interruptions caused by high-grade toxicity had significantly poorer OS (MST, 30 vs. 5 months; 5-year survival, 31 vs. 0%; P /0.00000) and CSS (5-year, 39 vs. 0%, P / 0.00000) as well as poorer LRFS (5-year, 54 vs. 0%, P /0.00000) than those without treatment interruptions, confirmed by multivariate analyses using the same three endpoints (OS, P /0.00031; CSS, P / 0.00033; LRFS, P /0.00748) (Table 3). When these 11 patients with treatment interruptions were excluded Table 3 Multivariate analyses investigating effect of various pretreatment factors including the reason for not undergoing surgery and treatment interruptions (all patients, n/116) Variable
Refusal Medical inoperability
319
OS
LRFS
CSS
P
P
P
0.41 0.92 0.00079 0.94 0.21 0.081 0.32 0.092 0.0075
0.40 0.98 B/0.00000 0.053 0.059 0.022 0.098 0.068 0.00033
Sex 0.31 Age 0.94 KPS B/0.00001 Weight loss 0.040 Location 0.021 T stage 0.043 N stage 0.17 Reason for not undergoing surgery 0.040 Treatment interruption 0.00031
OS, overall survival; LRFS, local recurrence-free survival; CSS, cause-specific survival; KPS, Karnofsky performance status.
320
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Fig. 1. Overall survival according to the reason for not undergoing surgery; patients (n/11) with treatment interruptions excluded: patient refusal ( */ */) and medical inoperability (-----).
Fig. 3. LRFS according to the reason for not undergoing surgery; patients with treatment interruptions (n/11) excluded: patient refusal ( */ */) and medical inoperability (-----).
from further analyses, the reason for not undergoing surgery still affected OS (MST, 38 vs. 27 months; 5-year survival: 45 vs. 21%; P /0.037) (Fig. 1) and CSS (5-year CSS, 48 vs. 33%; P /0.039) (Fig. 2), but not LRFS (not achieved vs. 32 months; 5-year LRFS, 60 vs. 48%; P / 0.11) (Fig. 3). When, however, multivariate analyses using the three endpoints were done, the reason for not undergoing surgery still affected OS (P /0.0436), but not either CSS or LRFS (P /0.083 and P /0.080, respectively) (Table 4).
Table 4 Multivariate analyses investigating effect of various pretreatment factors including the reason for not undergoing surgery and excluding patients with treatment interruptions (n /105)
4. Discussion Anticipating deleterious impact of accelerated repopulation during the course of RT, it has been tried to overcome by correcting the total dose that which
Fig. 2. CSS according to the reason for not undergoing surgery; patients with treatment interruptions (n/11) excluded: patient refusal (- - - - -); medical inoperability (-----); all patients ( */ */).
Variable
Sex Age KPS Weight loss Location T stage N stage Reason for not undergoing surgery
OS
LRFS
CSS
P
P
P
0.57 0.78 B/0.0001 0.024 0.056 0.023 0.57 0.043
0.37 0.80 0.0015 0.7002 0.11 0.0067 0.33 0.080
0.78 0.65 B/0.0001 0.0311 0.15 0.0092 0.46 0.082
OS, overall survival; LRFS, local recurrence-free survival; CSS, cause-specific survival; KPS, Karnofsky performance status.
patients should receive. In RT for head and neck cancer, it was calculated that the daily dose required circumventing the decrease in tumour control probability with treatment prolongation ranges 0.6 /1.0 Gy [15,24,25]. Also, Fowler and Lindstrom [17] used 12 data sets to calculate the loss of local control (LC) with prolongation of RT time, being 14% per week (range, 3 /25%). Unfortunately, such calculation was not attempted for Hfx RT regimens. Another possibility to address the issue of accelerated repopulation of tumour clonogens during (standard) RT course is accelerated treatment. Currently, there are only two prospective randomised studies that investigated this issue. While Ball et al. [26] did not found an impact of accelerated treatment, with or without concurrent carboplatin in patients with early stage NSCLC, results from CHART [27,28] showed the estimated reduction in
B. Jeremic et al. / Lung Cancer 40 (2003) 317 /323
the relative risk of death of 25% in 169 stage I/II A patients. Evidence for deleterious effect of treatment prolongation in NSCLC slowly emerged in the nineties of the last century. Cox et al. [19] reported on 1244 patients with unresectable NSCLC treated on three randomised RTOG studies, 907 of who experienced treatment interruptions. Of the latter, 614 were treated with Hfx RT. Survivals for Hfx RT patients with any interruptions were significantly shorter than those without interruptions. Multivariate analyses showed that effect of interruption was entirely in patients treated with 69.6 Gy or higher. Minority of patients enrolled into this study (RTOG 8311) were early stage, inoperable NSCLC. No separate analysis was provided for patients with stage I/II NSCLC. One of intriguing finding of the study of Cox et al. [19] was that there were fewer delays with CF and what seemed to be no difference when these patients were compared with their CF counterparts experiencing interruptions. Furthermore, results with the lower two Hfx arms did not differ when interruptions were taken into account. Whether total dose or dose-intensity plays more dominant role, it is still unknown. While the study of Cox et al. [19] and the current one focuses on treatment interruptions, other studies focused on the influence of overall treatment time (OTT) on treatment outcome. Koukourakis et al. [20] evaluated the impact of OTT on disease-free survival and LC after RT in NSCLC. Since a number of time/dose/fractionation regimens were used, authors performed RT dose homogenisation with calculation of the normalized total dose without (NTD) and with time correction (NTD-T) for a/b /10 Gy. Their analysis showed that any analysis based on RT dose could be imprecise without time factor taken into account. When NTD-T was used, for cases without mediastinal involvement, the daily dose lost because of treatment prolongation beyond 20 days after the beginning of RT was estimated to 0.2 Gy/day, but when all cases were pooled together, it was 0.45 Gy/ day. It indicated that the daily loss may be much higher in bulky disease, but nevertheless not underestimated in early NSCLC. Chen et al. [21] also evaluated the impact of OTT on outcomes in RT of 256 patients with stages I/III B NSCLC. Biologically effective dose (BED) was used to standardize RT effects. Patients treated with prolonged OTT (/45 days) had significantly poorer local progression-free survival than those with OTT 0/45 days. In order to include influence of OTT on RT effects, they also used BED-T formula, which took into account time factor (i.e. proliferation during RT). When local progression was correlated with BED only, no difference was found in local progression-free survival among various subgroups treated with different BED. However, when BED-T was used local progression-free
321
survival improved as BED-T increased, showing that OTT might have influenced RT effects. In this study, 3year local progression-free survivals decreased by 9% per week with prolongation of OTT. In multivariate analysis, OTT was shown to be an independent prognosticator for local progression-free survival as well as overall survival. No separate analysis was done on patients early stage treated with Hfx RT. Contrasting these studies is the study of Willers et al. [22] on 229 patients with stage I /III NSCLC treated with CF total dose of 70 Gy through a split-course technique. Ninety-six patients were stage I/II NSCLC. OTTs were divided into 7/11 weeks, 12 weeks and /12 weeks (total range, 7 /24 weeks; median 12 weeks). Forty-three patients who initially started curative RT were excluded from the second course and data analysis because of various reasons. Treatment duration was not found to be a significant prognosticator of survival in both univariate and multivariate analyses. This held true when patients with stage I/II were analysed separately. The three OTT groups had 2- and 5- year survival figures of 29 and 6% vs. 26 and 10% vs. 31 and 15%, respectively. Authors speculated about accelerated repopulation not occurring in a large number of patients, although exclusion of patients during treatment breaks in statistical analysis may have contributed to the favourable prognosis of patients receiving full RT dose over extended periods of time. During this study, we have observed high-grade toxicity occurring only in patients who were medically inoperable and not in those who refused surgery. It led to treatment interruptions which ranged 12 /25 days (median, 17 days) needed to manage the toxicity. Ten percent of all our patients (n /116) with early stage NSCLC treated with Hfx RT dose of 69.6 Gy using 1.2 Gy b.i.d. fractionation experienced considerable treatment interruptions, but this percentage goes up to 15 when only medically inoperable patients (n /72) are concerned. Treatment interruptions we observed must be considered as substantial since 10 out of 11 interruptions were for E/14 days. If we apply categories used by Cox et al. [19], than 90% of interruptions in our study would be described as ‘major deviation-unacceptable’. One of the interesting findings of this study is that patients who refused surgery had the best outcome, almost identical to surgical counterparts when latter are staged clinically. It appears that these patients are the ones whose outcome should be compared with their surgical counterparts, because they would have been subjected to surgery and are not deemed medically inoperable. In this patient population, using OS may be more meaningful than in elderly and/or medically inoperable patients in whom other endpoints such as DSS or CSS must be used in order to correct for events other than cancer-related.
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This study also emphasizes the need to better prevent and treat RT-induced toxicity, particularly acute, since it may directly influence treatment outcome. Principal concern represents normal lung and oesophagus, affection of which is almost always the cause of treatment interruptions. In our study this may have been caused by elective nodal irradiation. In stage I this meant inclusion of ipsilateral hilum while in stage II it meant inclusion of ipsilateral mediastinum. Both approaches definitely lead to more inclusion of both uninvolved lung and longer segments of oesophagus, leading to more toxicity. To further extend this issue, some studies showed promising results with using more limited RT fields in early stage NSCLC [29 /31]. By omitting elective nodal RT it would be reasonable to expect a decrease in toxicity. More ‘localized’ fields would allow for dose escalation (biologically or technologically) in this disease, attempt that is now under investigation in a number of centres around the world. Another imperative is to better understand the nature of toxicity and to identify the factors, both pre-treatment and treatment, because it may eventually lead to the decrease in toxicity. Implementation of novel substances that can ameliorate the symptoms is another necessary approach that may bring certain degree of improvement in prevention/treatment of these toxicities. It seems that during the interruption periods significant tumour clonogen repopulation occurred, manifested in significantly inferior LRFS, CSS and OS in these patients. Multivariate analysis confirmed importance of treatment interruptions using these endpoints. As additional evidence, patient refusal, which was shown to be significant predictor of treatment outcome when all (n/116) patients were considered became insignificant when patients (n/11) with treatment interruptions were excluded from further analysis. Although patients who refuse surgery are the most favourable subset of all patients with early stage NSCLC treated with RT alone, there should be no rational biological explanation for them to have better LRFS than either of other, more unfavourable, patient subgroups. Patients who refuse surgery may be good candidates for investigating newer approaches such as RT dose escalation, limitation of RT fields or use of CHT concurrently with RT. Those who present with concurrent medical diseases must be carefully investigated prior to RT, because common prognostic factors for both treatment outcome and treatment interruptions are factors such as tissue catabolism, asthenia, and severe chronic obstructive lung disease. Their treatment planning must be vigorously performed as not to leave any doubt whether curative intent may lead to higher toxicity, treatment interruptions and unfavourable outcome. Both subgroups are, however, suitable for investigation of newer agents/techniques that may protect normal tissues from RT.
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Impact of treatment interruptions due to toxicity on outcome of patients with early stage (I/II) non-small-cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy alone Branislav Jeremic a,*, Yuta Shibamoto b, Biljana Milicic a, Aleksandar Dagovic a, Nebojsa Nikolic a, Jasna Aleksandrovic a, Ljubisa Acimovic a, Slobodan Milisavljevic a b
a University Hospital, Kragujevac, Yugoslavia Department of Radiology, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan
Received 10 October 2002; received in revised form 23 January 2003; accepted 27 January 2003
Abstract We investigated the effect of treatment interruptions due to high-grade ( E/3) toxicity on outcome of patients with early stage (I/II) non-small-cell lung cancer treated with hyperfractionated radiation therapy (Hfx RT). Of 116 patients treated with total tumour doses of 69.6 Gy, 1.2 Gy b.i.d. fractionation, 44 patients refused surgery while 72 patients were medically inoperable due to existing co-morbid states. Patients who were medically inoperable had worse KPS (P /0.0059) and more pronounced weight loss (P/ 0.0005). Among them, 12 patients experienced high-grade toxicity and 11 of them with either acute (n/6) or ‘consequential’ late (n /5) high-grade toxicity requested interruption in the Hfx RT course (range, 12 /25 days; median, 17 days). Superior survival (OS) was observed in patients who refused surgery when compared to those who were medically inoperable (P/0.0041), as well as superior local recurrence-free survival (LRFS) (P /0.011), but not different distant metastasis-free survival (P/0.14). Causespecific survival (CSS) also favoured patients who refused surgery (P /0.004). Multivariate analysis showed independent influence of the reason for not undergoing surgery on OS (P /0.035), but not on LRFS (P/0.084) or CSS (P/0.068). Patients who refused surgery did not experience high-grade toxicity (0/44), whereas 11 of 72 patients with medical inoperability and co-morbid states experienced high-grade toxicity and had treatment interruptions to manage toxicity (P/0.0064). Patients without treatment interruptions had significantly better OS (P/0.00000), LRFS (P /0.00000) and CSS (P/0.00000) than those with treatment interruptions. When corrected for treatment interruptions, the reason for not undergoing surgery independently influenced OS (P/ 0.040), but not LRFS (P/0.092) or CSS (P/0.068). In contrast to this, treatment interruption was independent prognosticator of all three endpoints used (P/0.00031, P /0.0075 and P /0.00033, respectively). When 11 patients with treatment interruptions were excluded, the reason for not undergoing surgery still affected OS (P/0.037) and CSS (P/0.039) but not LRFS (P/0.11). Multivariate analyses using OS, CSS and LRFS showed that the reason for not undergoing surgery affected OS (P /0.0436), but neither CSS (P/0.083) nor LRFS (P/0.080). # 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Early stage; Non-small-cell lung cancer; Hyperfractionation; Treatment interruption; Toxicity
1. Introduction Standard treatment approach for patients with early stage non-small-cell lung cancer (NSCLC) is surgery [1 /
* Corresponding author. Present address: Department of Radiotherapy, Klinikum rechts der Isar, Technical University Munich, Ismaninger Strasse 22, D-81675 Munich, Germany. Tel.: / 49-89-4140-4512; fax: /49-89-4140-4882. E-mail address: [email protected] (B. Jeremic).
3]. Due to medical inoperability or patient refusal, however, radiation therapy (RT) is frequently used in these cases [4 /8]. With high-dose, conventionally fractionated (CF) or hyperfractionated (Hfx) RT 5-years survival rates of up to 30% were achieved [4 /10]. Analysis of patterns of failure clearly showed predominance of local failure. Importance of local tumour control, in general, has been frequently stressed in the last two decades [11 /14]. Local failure is not only a frequent cause of death, but can also lead to increase in
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the distant metastasis rate, another frequent cause of death in patients with tumours not controlled locally. It is, therefore, that patients with early stage NSCLC may represent a suitable group for investigation of various reasons for local failure, proliferation of tumour clonogens during RT being one of these. This proliferation may accelerate days to weeks after first treatments result in marked tumour cell loss. Indeed, a number of studies in head and neck (H&N) cancer clearly showed detrimental effect of accelerated tumour clonogen repopulation occurring with treatment prolongation [15 /17], including high-dose Hfx RT regimens [18]. Last decade also brought initial evidence that this may as well happen in NSCLC, with basically two reasons for unplanned treatment prolongation: treatment-related (acute) toxicity necessitating treatment break to manage existing toxicity, and treatment machine breaks or prolonged holidays. Cox et al. [19] were first to report on significantly inferior outcome of patients with locally advanced NSCLC treated with Hfx doses of E/69.6 Gy using 1.2 Gy b.i.d. fractionation who experienced treatment prolongation. While Koukourakis et al. [20] and Chen et al. [21] confirmed this observation, Willers et al. [22] were unable to do so. In all of these studies, a proportion of patients with early stage NSCLC, sometimes treated with Hfx RT, were included in the analysis. However, no report provided clear data or separate analysis on the impact of treatment interruptions in patients with early (I and II) stage NSCLC treated with Hfx RT. Having continuous interest in altered fractionated regimens, given with or without concurrent chemotherapy (CHT) in lung cancer, the aim of this report is to investigate the impact of treatment interruptions due to toxicity in patients with early stage NSCLC treated with high-dose Hfx RT.
2.2. Therapy Hfx RT regimen was introduced in both clinical stage I and II NSCLC with total tumour doses of 69.6 Gy in 58 fractions in 29 treatment days (b.i.d. fractionation) over 6 weeks. Two daily fractions of 1.2 Gy were used with an interfraction interval of 4.5 /6 h. All fields were treated daily. The target volume for stage I patients included the primary tumour and ipsilateral hilum with a 2-cm margin up to 50.4 Gy followed by the treatment of primary tumour only up to 69.6 Gy. For Stage II patients the target volume included the primary tumour and ipsilateral hilum with a 2-cm margin and the ipsilateral mediastinum from the suprasternal notch to a level 6 cm below the carina (upper or middle lobe lesions) or to the diaphragm (lower lobe lesions), followed by the treatment of primary tumour and ipsilateral hilum up to 69.6 Gy. Doses were specified at middepth at the central axis for parallel-opposed fields and at the intersection of central axes for other techniques. The follow-up procedures included laboratory and clinical tests including chest X-rays, and thoracic and upper abdominal CT scanning, accompanied with other tests, if needed. The schedule for follow-up examination included examination at the end treatment, every month for 6 months after the completion of treatment, every 2 months for 2 years thereafter, and every 4/6 months thereafter. The radiation-induced effects on normal tissue were assessed as either acute or late phenomena, according to the RTOG/European Organization for the Research and treatment of Cancer (EORTC) criteria [23].
2.3. Statistical analysis 2. Material and methods
2.1. Patient population Between 1988 and 1993, a total of 116 patients with NSCLC at early stages (I and II) according to the International Staging System [1] were treated with Hfx RT alone [9,10]. In all cases patients were, although technically operable, deemed unsuitable for surgery due to their concomitant medical problems (cardiovascular or pulmonary diseases) (n/72) or because they refused surgery (n /44). No patient underwent surgery and no patient received any form of adjuvant (chemo- or immuno-) therapy. All patients underwent pretreatment staging including thoracic CT scanning. No patient underwent mediastinoscopy.
Differences between pairs of groups in characteristics and incidence of toxicity were evaluated by g2-test. Survival (OS) and relapse-free survival rates were calculated from the date of start of Hfx RT by the Kaplan /Meier method, and differences between pairs of groups in survival curves were analysed by the log-rank test. In calculating local recurrence-free survival (LRFS), distant metastasis-free survival or causespecific survival (CSS) rates, patients who developed either type of failure were considered at risk for the other endpoint and censored at the time of last evaluation. The interaction of potential prognostic factors and their effect on OS, LRFS or CSS was analysed using the Cox proportional hazards model. All these statistical analyses were carried out by using the computer program HALWIN (Gendaisuugakusha, Kyoto, Japan).
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3. Results The median survival time (MST) and 5-year survival rate for all 116 patients are 29 months and 28%, respectively. Since in this study higher percentage of patients refusing surgery than in other contemporary studies [4 /8] in early NSCLC was encountered, we then evaluated the difference between patients refusing surgery and those deemed inoperable due to concurrent cardiopulmonary disease. Regarding various pretreatment clinical prognostic factors there were no difference between patients who refused surgery and those with medical inoperability, except that patients with medical inoperability had significantly worse KPS (P/0.0059) and more pronounced weight loss (P /0.0005) (Table 1). A significantly higher MST and 5-year survival was observed for patients refusing surgery than in those who were medically inoperable (MST, 38 vs. 22 months; 5year survival, 45% vs. 18%, P /0.0041). There was also a significantly better median time to local recurrence and 5-year LRFS (not achieved vs. 28 months and 60 vs. 41%, respectively; P /0.011). There was no difference in distant metastasis control (P /0.14). Since no information or rational explanation currently exist to support difference in either OS and LRFS we observed, we tried to exclude possible effect of co-morbid states in medically inoperable patients using a CSS as an endpoint which still favoured patients who refused surgery (median time, 38 vs. 22 months; 5-year CSS, 48 vs. 28%; P /0.004). A multivariate analysis using a number of possible pretreatment clinical prognostic factors corrected for the reason for not undergoing surgery showed that reason for not undergoing surgery was an important predictor of survival (P /0.035), but was insignificant when LRFS (P /0.084) or CSS (P /0.068) were used as endpoints (Table 2). Patients who refused surgery did not experience high-grade toxicity (0/44), whereas 12 or 72 patients with medical inoperability and co-morbid states experienced it, 11 of the latter group (11/72) requested treatment interruptions (P/0.0064) (range, 12/25 days; median, 17 days) in the course of Table 1 Patient characteristics Variable
Sex Age (years) KPS Weight loss Location T stage N stage
M/F B/60/E/60 70 /80/90 /100 / Center/periphery 1/2 0/1
Table 2 Multivariate analyses investigating effect of various pretreatment factors including the reason for not undergoing surgery (all patients, n/116) Variable
Sex Age KPS Weight loss Location T stage N stage Reason for not undergoing surgery
P
31/13 15/29 7/37 43/1 25/19
55/17 28/44 29/43 52/20 34/38
0.48 0.60 0.0059 0.0005 0.32
25/19 24/20
31/41 43/29
0.15 0.58
KPS, Karnofsky performance status.
OS
LRFS CSS
P
P
P
0.68 0.93 B/0.00001 0.0004 0.044 0.047 0.43 0.035
0.49 0.86 0.0010 0.068 0.21 0.012 0.28 0.084
0.85 0.82 B/0.00001 0.0006 0.12 0.021 0.31 0.068
OS, overall survival; LRFS, local recurrence-free survival; CSS, cause-specific survival; KPS, Karnofsky performance status.
Hfx RT to manage either acute high-grade (n /6) or ‘consequential’ late (n /5) toxicity. There were 3 bronchopulmonary grade 3 acute toxicity and 3 oesophageal grade 3 acute toxicity. All late toxicity was ‘consequential’, being 2 bronchopulmonary grade 3, 3 oesophageal grade 3, and one osseous grade 3 late toxicity. To identify factors that may have influenced treatment outcome, the impact of treatment interruptions caused by high-grade (E/3) toxicity was first taken into account in all patients. Patients with treatment interruptions caused by high-grade toxicity had significantly poorer OS (MST, 30 vs. 5 months; 5-year survival, 31 vs. 0%; P /0.00000) and CSS (5-year, 39 vs. 0%, P / 0.00000) as well as poorer LRFS (5-year, 54 vs. 0%, P /0.00000) than those without treatment interruptions, confirmed by multivariate analyses using the same three endpoints (OS, P /0.00031; CSS, P / 0.00033; LRFS, P /0.00748) (Table 3). When these 11 patients with treatment interruptions were excluded Table 3 Multivariate analyses investigating effect of various pretreatment factors including the reason for not undergoing surgery and treatment interruptions (all patients, n/116) Variable
Refusal Medical inoperability
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OS
LRFS
CSS
P
P
P
0.41 0.92 0.00079 0.94 0.21 0.081 0.32 0.092 0.0075
0.40 0.98 B/0.00000 0.053 0.059 0.022 0.098 0.068 0.00033
Sex 0.31 Age 0.94 KPS B/0.00001 Weight loss 0.040 Location 0.021 T stage 0.043 N stage 0.17 Reason for not undergoing surgery 0.040 Treatment interruption 0.00031
OS, overall survival; LRFS, local recurrence-free survival; CSS, cause-specific survival; KPS, Karnofsky performance status.
320
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Fig. 1. Overall survival according to the reason for not undergoing surgery; patients (n/11) with treatment interruptions excluded: patient refusal ( */ */) and medical inoperability (-----).
Fig. 3. LRFS according to the reason for not undergoing surgery; patients with treatment interruptions (n/11) excluded: patient refusal ( */ */) and medical inoperability (-----).
from further analyses, the reason for not undergoing surgery still affected OS (MST, 38 vs. 27 months; 5-year survival: 45 vs. 21%; P /0.037) (Fig. 1) and CSS (5-year CSS, 48 vs. 33%; P /0.039) (Fig. 2), but not LRFS (not achieved vs. 32 months; 5-year LRFS, 60 vs. 48%; P / 0.11) (Fig. 3). When, however, multivariate analyses using the three endpoints were done, the reason for not undergoing surgery still affected OS (P /0.0436), but not either CSS or LRFS (P /0.083 and P /0.080, respectively) (Table 4).
Table 4 Multivariate analyses investigating effect of various pretreatment factors including the reason for not undergoing surgery and excluding patients with treatment interruptions (n /105)
4. Discussion Anticipating deleterious impact of accelerated repopulation during the course of RT, it has been tried to overcome by correcting the total dose that which
Fig. 2. CSS according to the reason for not undergoing surgery; patients with treatment interruptions (n/11) excluded: patient refusal (- - - - -); medical inoperability (-----); all patients ( */ */).
Variable
Sex Age KPS Weight loss Location T stage N stage Reason for not undergoing surgery
OS
LRFS
CSS
P
P
P
0.57 0.78 B/0.0001 0.024 0.056 0.023 0.57 0.043
0.37 0.80 0.0015 0.7002 0.11 0.0067 0.33 0.080
0.78 0.65 B/0.0001 0.0311 0.15 0.0092 0.46 0.082
OS, overall survival; LRFS, local recurrence-free survival; CSS, cause-specific survival; KPS, Karnofsky performance status.
patients should receive. In RT for head and neck cancer, it was calculated that the daily dose required circumventing the decrease in tumour control probability with treatment prolongation ranges 0.6 /1.0 Gy [15,24,25]. Also, Fowler and Lindstrom [17] used 12 data sets to calculate the loss of local control (LC) with prolongation of RT time, being 14% per week (range, 3 /25%). Unfortunately, such calculation was not attempted for Hfx RT regimens. Another possibility to address the issue of accelerated repopulation of tumour clonogens during (standard) RT course is accelerated treatment. Currently, there are only two prospective randomised studies that investigated this issue. While Ball et al. [26] did not found an impact of accelerated treatment, with or without concurrent carboplatin in patients with early stage NSCLC, results from CHART [27,28] showed the estimated reduction in
B. Jeremic et al. / Lung Cancer 40 (2003) 317 /323
the relative risk of death of 25% in 169 stage I/II A patients. Evidence for deleterious effect of treatment prolongation in NSCLC slowly emerged in the nineties of the last century. Cox et al. [19] reported on 1244 patients with unresectable NSCLC treated on three randomised RTOG studies, 907 of who experienced treatment interruptions. Of the latter, 614 were treated with Hfx RT. Survivals for Hfx RT patients with any interruptions were significantly shorter than those without interruptions. Multivariate analyses showed that effect of interruption was entirely in patients treated with 69.6 Gy or higher. Minority of patients enrolled into this study (RTOG 8311) were early stage, inoperable NSCLC. No separate analysis was provided for patients with stage I/II NSCLC. One of intriguing finding of the study of Cox et al. [19] was that there were fewer delays with CF and what seemed to be no difference when these patients were compared with their CF counterparts experiencing interruptions. Furthermore, results with the lower two Hfx arms did not differ when interruptions were taken into account. Whether total dose or dose-intensity plays more dominant role, it is still unknown. While the study of Cox et al. [19] and the current one focuses on treatment interruptions, other studies focused on the influence of overall treatment time (OTT) on treatment outcome. Koukourakis et al. [20] evaluated the impact of OTT on disease-free survival and LC after RT in NSCLC. Since a number of time/dose/fractionation regimens were used, authors performed RT dose homogenisation with calculation of the normalized total dose without (NTD) and with time correction (NTD-T) for a/b /10 Gy. Their analysis showed that any analysis based on RT dose could be imprecise without time factor taken into account. When NTD-T was used, for cases without mediastinal involvement, the daily dose lost because of treatment prolongation beyond 20 days after the beginning of RT was estimated to 0.2 Gy/day, but when all cases were pooled together, it was 0.45 Gy/ day. It indicated that the daily loss may be much higher in bulky disease, but nevertheless not underestimated in early NSCLC. Chen et al. [21] also evaluated the impact of OTT on outcomes in RT of 256 patients with stages I/III B NSCLC. Biologically effective dose (BED) was used to standardize RT effects. Patients treated with prolonged OTT (/45 days) had significantly poorer local progression-free survival than those with OTT 0/45 days. In order to include influence of OTT on RT effects, they also used BED-T formula, which took into account time factor (i.e. proliferation during RT). When local progression was correlated with BED only, no difference was found in local progression-free survival among various subgroups treated with different BED. However, when BED-T was used local progression-free
321
survival improved as BED-T increased, showing that OTT might have influenced RT effects. In this study, 3year local progression-free survivals decreased by 9% per week with prolongation of OTT. In multivariate analysis, OTT was shown to be an independent prognosticator for local progression-free survival as well as overall survival. No separate analysis was done on patients early stage treated with Hfx RT. Contrasting these studies is the study of Willers et al. [22] on 229 patients with stage I /III NSCLC treated with CF total dose of 70 Gy through a split-course technique. Ninety-six patients were stage I/II NSCLC. OTTs were divided into 7/11 weeks, 12 weeks and /12 weeks (total range, 7 /24 weeks; median 12 weeks). Forty-three patients who initially started curative RT were excluded from the second course and data analysis because of various reasons. Treatment duration was not found to be a significant prognosticator of survival in both univariate and multivariate analyses. This held true when patients with stage I/II were analysed separately. The three OTT groups had 2- and 5- year survival figures of 29 and 6% vs. 26 and 10% vs. 31 and 15%, respectively. Authors speculated about accelerated repopulation not occurring in a large number of patients, although exclusion of patients during treatment breaks in statistical analysis may have contributed to the favourable prognosis of patients receiving full RT dose over extended periods of time. During this study, we have observed high-grade toxicity occurring only in patients who were medically inoperable and not in those who refused surgery. It led to treatment interruptions which ranged 12 /25 days (median, 17 days) needed to manage the toxicity. Ten percent of all our patients (n /116) with early stage NSCLC treated with Hfx RT dose of 69.6 Gy using 1.2 Gy b.i.d. fractionation experienced considerable treatment interruptions, but this percentage goes up to 15 when only medically inoperable patients (n /72) are concerned. Treatment interruptions we observed must be considered as substantial since 10 out of 11 interruptions were for E/14 days. If we apply categories used by Cox et al. [19], than 90% of interruptions in our study would be described as ‘major deviation-unacceptable’. One of the interesting findings of this study is that patients who refused surgery had the best outcome, almost identical to surgical counterparts when latter are staged clinically. It appears that these patients are the ones whose outcome should be compared with their surgical counterparts, because they would have been subjected to surgery and are not deemed medically inoperable. In this patient population, using OS may be more meaningful than in elderly and/or medically inoperable patients in whom other endpoints such as DSS or CSS must be used in order to correct for events other than cancer-related.
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This study also emphasizes the need to better prevent and treat RT-induced toxicity, particularly acute, since it may directly influence treatment outcome. Principal concern represents normal lung and oesophagus, affection of which is almost always the cause of treatment interruptions. In our study this may have been caused by elective nodal irradiation. In stage I this meant inclusion of ipsilateral hilum while in stage II it meant inclusion of ipsilateral mediastinum. Both approaches definitely lead to more inclusion of both uninvolved lung and longer segments of oesophagus, leading to more toxicity. To further extend this issue, some studies showed promising results with using more limited RT fields in early stage NSCLC [29 /31]. By omitting elective nodal RT it would be reasonable to expect a decrease in toxicity. More ‘localized’ fields would allow for dose escalation (biologically or technologically) in this disease, attempt that is now under investigation in a number of centres around the world. Another imperative is to better understand the nature of toxicity and to identify the factors, both pre-treatment and treatment, because it may eventually lead to the decrease in toxicity. Implementation of novel substances that can ameliorate the symptoms is another necessary approach that may bring certain degree of improvement in prevention/treatment of these toxicities. It seems that during the interruption periods significant tumour clonogen repopulation occurred, manifested in significantly inferior LRFS, CSS and OS in these patients. Multivariate analysis confirmed importance of treatment interruptions using these endpoints. As additional evidence, patient refusal, which was shown to be significant predictor of treatment outcome when all (n/116) patients were considered became insignificant when patients (n/11) with treatment interruptions were excluded from further analysis. Although patients who refuse surgery are the most favourable subset of all patients with early stage NSCLC treated with RT alone, there should be no rational biological explanation for them to have better LRFS than either of other, more unfavourable, patient subgroups. Patients who refuse surgery may be good candidates for investigating newer approaches such as RT dose escalation, limitation of RT fields or use of CHT concurrently with RT. Those who present with concurrent medical diseases must be carefully investigated prior to RT, because common prognostic factors for both treatment outcome and treatment interruptions are factors such as tissue catabolism, asthenia, and severe chronic obstructive lung disease. Their treatment planning must be vigorously performed as not to leave any doubt whether curative intent may lead to higher toxicity, treatment interruptions and unfavourable outcome. Both subgroups are, however, suitable for investigation of newer agents/techniques that may protect normal tissues from RT.
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