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Time Between the First Day of Chemotherapy and the Last Day of Chest Radiation Is the Most Important Predictor of Survival in Limited-Disease Small-Cell Lung Cancer

From the Departments of Radiotherapy and Pulmonology, University Hospital Maastricht, University Maastricht, Groel en Ontwikkeling; Maastro Clinic, Maastricht, the Netherlands; Department of Human Oncology, University of Wisconsin Medical School, Madison, WI; Respiratory Oncology Unit, Department of Pneumology, University Hospital Leuven; and Leuven Lung Cancer Group, Leuven, Belgium.

Address reprint requests to Dirk De Ruysscher, MD, PhD, University Hospital Maastricht, Department of Radiotherapy, Dr Tanslaan 12, 6229 ET Maastricht, the Netherlands; e-mail: dirk.deruysscher{at}maastro.nl

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: To identify time factors for combined chemotherapy and radiotherapy predictive for long-term survival of patients with limited-disease small-cell lung cancer (LD-SCLC).

METHODS: A systematic overview identified suitable phase III trials. Using meta-analysis methodology to compare results within trials, the influence of the timing of chest radiation and the start of any treatment until the end of radiotherapy (SER) on local tumor control, survival, and esophagitis was analyzed. For comparison between studies, the equivalent radiation dose in 2-Gy fractions, corrected for the overall treatment time of chest radiotherapy, was analyzed.

RESULTS: The SER was the most important predictor of outcome. There was a significantly higher 5-year survival rate in the shorter SER arms (relative risk [RR] = 0.62; 95% CI, 0.49 to 0.80; P = .0003), which was more than 20% when the SER was less than 30 days (upper bound of 95% CI, 90 days). A low SER was associated with a higher incidence of severe esophagitis (RR = 0.55; 95% CI, 0.42 to 073; P < .0001). Each week of extension of the SER beyond that of the study arm with the shortest SER resulted in an overall absolute decrease in the 5-year survival rate of 1.83% ± 0.18% (95% CI).

CONCLUSION: A low time between the first day of chemotherapy and the last day of chest radiotherapy is associated with improved survival in LD-SCLC patients. The novel parameter SER, which takes into account accelerated proliferation of tumor clonogens during both radiotherapy and chemotherapy, may facilitate a more rational design of combined-modality treatment in rapidly proliferating tumors.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Patients with small-cell lung cancer (SCLC) account for approximately 20% of all lung cancer patients, with only one third of the patients presenting with limited disease (LD).^1,2 Without treatment, tumor progression in patients with SCLC is rapid, with a median survival time of 2 to 4 months. Although chemotherapy and the combination of chemotherapy and chest radiotherapy have improved the prognosis substantially, long-term survival remains poor.^1-7 The optimal combination of chemotherapy and chest radiation remains controversial.^5-7

Accelerated proliferation of tumor clonogens during radiotherapy has been shown to affect the outcome in squamous cell carcinoma of the head and neck both in literature overviews^8,9 and in randomized controlled trials.^10,11 Although the evidence is not as strong for a number of other solid tumors, there are good reasons to believe that accelerated proliferation is a universal response to fractionated radiotherapy.¹² The possibility that cytotoxic chemotherapy also induces accelerated repopulation has attracted less attention.^13,14 However, several studies in murine tumor models show that chemotherapy may induce accelerated repopulation after a delay of 0 to 14 days.^15-18 Clinically, a few studies have shown an increase in cellular proliferation after chemotherapy,^19,20 at least in some patients.²¹ All of these observations suggest that the overall duration of the radiochemotherapy package is the most relevant predictor for outcome, and this has specifically been proposed for LD-SCLC as a result of the natural history of this disease.^7,14

We propose to use the time from the start of any treatment to the end of chest irradiation (SER) as a quantitative measure reflecting proliferation of cells in the primary tumor. This is based on the following two assumptions: the first cytotoxic insult (whether it is from chemotherapy or radiotherapy) will trigger accelerated tumor repopulation; and, bulky disease must be controlled by the end of radiotherapy, or the treatment will fail in nearly all patients. In this study, we tested the prognostic value of the SER in an analysis of outcome data from six randomized controlled trials of various combinations of chemotherapy and radiotherapy in patients with LD-SCLC.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Identification of Studies
The data were based on a recent systematic review and meta-analysis from our group in the Cochrane Database of Systematic Reviews.²² Briefly, eligible studies were randomized controlled clinical trials that were fully published in journals or identified from other sources (abstracts and proceedings of relevant scientific meetings and contacts with investigators) and for which full details were available from investigators. Patients of any age had to have histologically or cytologically proven LD-SCLC and a performance status of 0 to 2. We used the following definition of LD: cancer confined to one hemithorax including contralateral mediastinal and hilar lymph nodes as well as ipsilateral and/or bilateral supraclavicular involvement, but excluding malignant pleural effusion.

A search for studies was undertaken in the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL, 2003, Issue 4), MEDLINE (1966 to present), EMBASE (1974 to present), and CINAHL (1982 to present). Furthermore, the Cochrane Lung Cancer Groups Specialized Register was searched. Searches were performed without language restrictions. Reference lists from identified studies were scrutinized for references to any additional studies. The electronic searches for clinical trials were complemented with manual searches of the following oncology journals: International Journal of Radiation, Oncology, Biology and Physics (1985 to present); Radiotherapy and Oncology (1985 to present); Journal of Clinical Oncology (1985 to present); Clinical Oncology (1999 to present); Lung Cancer (1985 to present); and Thorax (1985 to present). Abstracts from the principal oncology conferences from 1985 and onwards, with a minimum follow-up of 3 years, were hand searched. Colleagues, collaborators, and other experts in the field were asked to identify missing and unreported trials.

Parameters
A priori, we identified the following parameters to be analyzed for their influence on local tumor control, survival, esophagitis, and pneumonitis: the total radiotherapy dose, the overall treatment time of chest radiotherapy, the day of start of radiotherapy as an indicator of early versus late radiation, the SER (as defined earlier), concurrent versus sequential radiotherapy and chemotherapy, and the equivalent radiation dose in 2-Gy fractions corrected for the overall treatment time of chest radiotherapy (EQD_2,T).

Because individual patient data were not available, we calculated the SER from the published data of each original article. In case the start of radiotherapy was not required at a specific day, we took the mean between the permitted time limits in the study protocol. This was the case in the trial of Turrisi et al,²³ in which the start of chest radiotherapy was allowed during the first cycle of chemotherapy (ie, between days 1 and 20). Thus, the start of chest radiotherapy was assumed to be day 10 for this study.

For local tumor control comparisons, we omitted the trial of Takada et al²⁴ because only data on the first site of recurrence were available, whereas, in all other studies, cumulative local tumor control rates were provided. A quantitative estimate of a 1-week increase in SER was obtained from the overall odds ratio between the two arms of a specific trial. The change in the log odds ratio per week was assumed to be constant when calculating this quantity.

As a measure of the intensity of chest radiotherapy, we used the equivalent dose in 2-Gy fractions with correction for overall treatment time, EQD_2,T, which was calculated in two steps.²⁵ First, an adjustment for dose per fraction was made:

where D is the total radiation dose, d is the dose per fraction, and /ß = 10 Gy.

To take into account proliferation of tumor cells, we used the following formula:

where T_K is the kick-in time of accelerated repopulation, which was assumed in our case to be 30 days. The function MAX(T – T_K,0) will have the value of T – T_K if this difference is positive and the value of zero in all other cases. The parameter D_prolif is the dose recovered per day. This parameter is not well estimated for SCLC, but we assumed that the dose lost per day was at least that estimated for squamous cell carcinoma of the head and neck, and therefore, we assumed D_prolif = 0.7 Gy per day.²⁵ Possible incomplete repair between multiple fractions per day was not considered because there are no reliable data for SCLC.

Chemotherapy
The following two types of chemotherapy were used in the studies: platinum based or anthracycline based. In only one trial, a nonplatinum-based chemotherapy regimen was administered concurrently with chest irradiation.^26,27 In all other studies, platinum-etoposide was administered during chest radiotherapy.^23,24,28-32

Statistics
A weighted estimate of the typical treatment effect across studies was computed for the 5-year survival data and the SER. The relative risk (RR) was used as the effect measure. Possible censoring of survival data could not be taken into account because not enough information could be derived from the published data to calculate this. ² heterogeneity tests were used to test for statistical heterogeneity among trials. Because we anticipated that the trial results would be heterogeneous, all analyses were performed using a random-effects model. Two-tailed P < .05 was considered to be significant. Dose-response relationships were analyzed using logistic regression. All statistical analyses were performed with RevMan (Review Manager Computer Program, version 4.2 for Windows, The Cochrane Collaboration, Oxford, United Kingdom) and STATA version 8.0 for Windows (STATA Corp, College Station, TX).

	RESULTS

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Identification of Phase III Trials
Eight phase III trials with the same chemotherapy regimen in each arm, comparing two different radiation schedules and reporting long-term survival data, were identified.^23,24,26-32 Because, in two major trials,^23,28 the difference in survival between radiation schedules only became apparent after 2 years or more, we only analyzed 5-year survival data from these phase III studies. Five-year survival data are also likely not meaningfully influenced by the use of second-line chemotherapy, whereas 2-year data may be. The trial of Bonner et al³² was omitted because the time factors in both arms of the trial were the same and because patients were only included when they had a remission after induction chemotherapy. Therefore, comparison with the other studies, in which all patients were included up front, was not possible. The European Organisation for Research and Treatment of Cancer trial by Gregor et al³⁰ was not included because no 5-year survival data were available.

One trial used doxorubicin-based chemotherapy concomitantly with chest radiotherapy.^26,27 This type of chemotherapy is currently not used because of its lower efficacy³³ and higher toxicity³⁴ compared with platinum-based chemotherapy. The trial of Work et al²⁹ was omitted because no concurrent chemotherapy and chest radiation was used, which is, at present, considered to be the standard therapy. Therefore, we only analyzed the four trials in which platinum combined with etoposide was administered during chest radiotherapy^23,24,28,31 and for which 5-year survival data were available. In total, the four studies comprised 1,056 patients. Table 1 lists the main features of the included trials.

Only two trials used radiopneumonitis as an end point.^28,31 In the study by Turrisi et al,²³ radiopneumonitis was not specifically mentioned; only pulmonary effects were mentioned, which may include other types of lung injury. Therefore, the meta-analysis technique could not be applied for radiopneumonitis.

The total radiation dose, which was expressed as nominal doses or as EQD₂, differed only slightly between the studies, and no trials used different total radiation doses between the study arms. Therefore, this parameter was not investigated as a variable in the comparisons within trials.

Because the overall treatment time of thoracic radiotherapy was identical in all study arms, except in one trial,²³ this variable could not be investigated using meta-analysis techniques. The timing of radiotherapy was different in three studies.^24,28,31 Thus, meta-analysis techniques could be used. Only one trial²⁴ compared concurrent and sequential chemotherapy and radiotherapy, and therefore, the potential importance of the sequencing of chemotherapy and radiotherapy could not be tested using meta-analysis techniques.

Analysis
Comparisons within trials. Comparisons were calculated using meta-analysis techniques. The two parameters of SER and the timing of chest radiotherapy were predictive for the 5-year survival, with SER being the strongest predictor. The 5-year survival was highest in the shorter SER arms (RR = 0.62; 95% CI, 0.49 to 0.80; P = .0003) or when chest radiotherapy was delivered early after the start of chemotherapy compared with late (RR = 0.63; 95% CI, 0.45 to 0.88; P = .007; Figs 1A and 1B).

View larger version (17K): [in this window] [in a new window]   Fig 1. (A) The survival at 5 years as a function of the start of any treatment and the end of radiotherapy (SER). The relative risk (RR) for the 5-year survival is significantly in favor of the study arms with the lowest SER (P = .0003). (B) The survival at 5 years as a function of the timing of the chest radiotherapy. The RR for the 5-year survival is significantly in favor of the study arms with early radiotherapy (P = .007).

View larger version (15K): [in this window] [in a new window]   Fig 2. (A) Local tumor control at 5 years as a function of the start of any treatment and the end of radiotherapy (SER). The relative risk (RR) for the local tumor control is not significantly different between study arms with a low or a high SER (P = .07). (B) Local tumor control at 5 years as a function of the timing of chest radiotherapy. The RR for the local tumor control is not significantly different between study arms with early or late chest radiotherapy (P = .39).

View larger version (16K): [in this window] [in a new window]   Fig 3. (A) Severe esophagitis as a function of the start of any treatment and the end of radiotherapy (SER). The relative risk (RR) is significantly different between study arms with a low SER and a high SER (P < .0001), with a low SER associated with a higher incidence of severe esophagitis. (B) Severe esophagitis as a function of the timing of chest radiotherapy. The RR is significantly different between study arms with early or late radiation (P = .03), with early radiation associated with a higher incidence of severe esophagitis.

View larger version (13K): [in this window] [in a new window]   Fig 4. Relative risk (RR) of the 5-year survival per week of extension of the time from the start of any treatment and the end of radiotherapy (SER; comparison within trials: arm 2 – arm 1).

View larger version (9K): [in this window] [in a new window]   Fig 5. The survival at 5 years as a function of the time from the start of any treatment and the end of radiotherapy (SER). Each dot represents a single trial ± SE.

View larger version (9K): [in this window] [in a new window]   Fig 6. Local tumor control as a function of the equivalence dose at 2 Gy corrected for the overall treatment time of chest radiotherapy (EQD2,T). Each dot represents a single trial ± SE (P = .76).

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

We decided to include only trials in which platinum-based chemotherapy was delivered concurrently with chest radiotherapy because this is, at present, the standard treatment.^{23,24,28,29,31} Only 5-year survival data were considered because the difference in survival between radiation schedules only became apparent after 2 years or more in two major trials.^23,28 Moreover, this also avoided possible interference with second-line chemotherapy. Trials in which there was no difference in time factors between the arms were omitted. Prophylactic cranial irradiation was administered to at least a group of patients in all studies, and therefore, it was not possible to stratify for this parameter in the analysis. We used SER as a quantitative measure reflecting proliferation of cells in the primary tumor.

To avoid the biases of comparing results between trials, we first analyzed the results within studies. Both the SER and the timing of chest radiotherapy correlated significantly with the long-term survival, with the latter finding being in agreement with two recent meta-analyses.^22,35 Although early chest radiation was correlated with a short SER in all^24,28,29,31 but one study,²³ the SER, a parameter that takes into account time factors of both radiotherapy and chemotherapy, correlated more strongly with the long-term survival than the timing of radiation. From a biologic point of view, the SER is a logical approach to investigate the integration of radiotherapy and drugs because it considers not only whether a drug was administered concurrently or early during radiation, but also the time interactions when agents are delivered intermittently at days when no radiotherapy is administered or even when drugs are administered before the start of radiotherapy. This may be increasingly important when targeted agents are used.³⁶

To quantify the effect of a change in SER on the 5-year survival, we estimated that each week of extension of the SER beyond that of the study arm with the shortest SER resulted in an absolute decrease of the 5-year survival of 1.83%, corresponding to an overall RR per week of 0.96 (95% CI, 0.94 to 0.98; P < .0001). There are two caveats here. First, these estimates are strongly influenced by a single trial, that of Turrisi et al.²³ Second, treatment was continued in the long SER arm during the period when SER was estimated. Thus, the effect of an increased SER may depend on the exact temporal distribution of further therapy as well as, of course, on its effectiveness. The simple interpretation of the SER estimate requires that the therapeutic effects of cycles of chemotherapy and fractions of radiotherapy are nonoverlapping and independent.

The highly significant relationship between the SER and the 5-year survival supports the occurrence of accelerated proliferation of tumor clonogens during chemotherapy and radiotherapy. As a consequence, the best survival of patients with fast-proliferating tumors may be achieved when two or three full-dose cycles of chemotherapy and chest radiotherapy are delivered before accelerated tumor-cell proliferation starts, whether triggered by chemotherapy or by chest radiation. Of course, this has to be balanced with acute adverse effects, which also occur more frequently in schedules with a short SER. Indeed, a short SER or the early delivery of chest radiotherapy were associated with a higher incidence of severe esophagitis. This is in line with previous findings that indicate that intensifying chemotherapy and radiotherapy regimen increases the cytotoxic effects on rapidly proliferating cells, including the mucosa.^11,12 Because too few studies used pneumonitis as an end point, no meta-analysis could be performed for this adverse effect.

No significant relationship between the SER, the timing of chest radiotherapy, or the EQD_2,T and the local tumor control was found. This may be explained by the inadequate assessment of local tumor control.⁷

When comparing the results between trials, which is obviously fraught with errors, we found that a 5-year survival rate of more than 20% could be achieved when the SER was less than 30 days, with an upper bound of the 95% CI of 90 days. In the absence of randomized trials that were specifically designed to investigate the influence of different SER values on survival, the exact value of the optimal SER remains uncertain. Our results are in line with an earlier trial,³⁷ in which nonplatinum chemotherapy was administered, that concluded that the optimal treatment of patients with LD-SCLC was concurrent chemotherapy and chest radiation administered in 3 to 4 weeks.

We conclude that the present results introduce the SER as a novel parameter that could make rational design of trials combining chemotherapy and radiotherapy more feasible. However, confirmation of the value of the SER should be performed in prospective studies or by a meta-analysis with individual patient data from previous phase III trials.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

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Conception and design: Dirk De Ruysscher Financial support: Philippe Lambin Administrative support: Dirk De Ruysscher, Madelon Pijls-Johannesma, Søren M. Bentzen, Johan Vansteenkiste, Philippe Lambin Provision of study materials or patients: Dirk De Ruysscher, Madelon Pijls-Johannesma, Søren M.Bentzen, André Minken, Rinus Wanders, Ludy Lutgens, Monique Hochstenbag, Liesbeth Boersma, Bradly Wouters, Guido Lammering, Johan Vansteenkiste, Philippe Lambin Collection and assembly of data: Dirk De Ruysscher, Madelon Pijls-Johannesma, Søren M. Bentzen, Johan Vansteenkiste, Philippe Lambin Data analysis and interpretation: Dirk De Ruysscher, Madelon Pijls-Johannesma, Søren M. Bentzen, Johan Vansteenkiste, Philippe Lambin Manuscript writing: Dirk De Ruysscher, Søren M. Bentzen, André Minken, Rinus Wanders, Ludy Lutgens, Monique Hochstenbag, Liesbeth Boersma, Bradly Wouters, Guido Lammering, Johan Vansteenkiste, Philippe Lambin Final approval of manuscript: Dirk De Ruysscher, Madelon Pijls-Johannesma, Søren M. Bentzen, André Minken, Rinus Wanders, Ludy Lutgens, Monique Hochstenbag, Liesbeth Boersma, Bradly Wouters, Guido Lammering, Johan Vansteenkiste, Philippe Lambin

 

	NOTES

 
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
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Submitted June 6, 2005; accepted November 9, 2005.

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