Results of the Dutch National Study of the Palliative Effect of Irradiation Using Two Different Treatment Schemes for Non–Small-Cell Lung Ca
http://www.100md.com
《临床肿瘤学》
the Department of Radiotherapy, RADIAN, Arnhems Radiotherapeutic Institute, Arnhem
MAASTRO clinic Maastricht/Heerlen
Department of Clinical Oncology, and Department of medical decision making, Leiden University Medical Center, Leiden
Radiotherapeutic Institute Stedendriehoek en Omstreken, Deventer, the Netherlands
ABSTRACT
PURPOSE: A national multicenter randomized study compared the efficacy of 2 x 8 Gy versus our standard 10 x 3 Gy in patients with inoperable stage IIIA/B (with an Eastern Cooperative Oncology Group score of 3 to 4 and/or substantial weight loss) and stage IV non–small-cell lung cancer.
PATIENTS AND METHODS: Between January 1999 and June 2002, 297 patients were eligible and randomized to receive either 10 x 3 Gy or 2 x 8 Gy by external-beam irradiation. The primary end point was a patient-assessed score of treatment effect on seven thoracic symptoms using an adapted Rotterdam Symptom Checklist. Study sample size was determined based on an average total symptom score difference of more than one point over the initial 39 weeks post-treatment. The time course of symptom scores were also evaluated, and other secondary end points were toxicity and survival.
RESULTS: Both treatment arms were equally effective, as the average total symptom score over the initial 39 weeks did not differ. However, the pattern in time of these scores differed significantly (P < .001). Palliation in the 10 x 3-Gy arm was more prolonged (until week 22) with less worsening symptoms than in 2 x 8-Gy. Survival in the 10 x 3-Gy arm was significantly (P = .03) better than in the 2 x 8-Gy arm with 1-year survival of 19.6% (95%CI, 14.1% to 27.3%) v 10.9% (95%CI, 6.9% to 17.3%).
CONCLUSION: The 10 x 3-Gy radiotherapy schedule is preferred over the 2 x 8-Gy schedule for palliative treatment, as it improves survival and results in a longer duration of the palliative response.
INTRODUCTION
The treatment of non–small-cell lung cancer (NSCLC) is still a challenge for the oncologist. In the past decade, combined-modality treatment in stage III disease and chemotherapy for stage IV disease improved the survival and quality of life in NSCLC patients.1 Unfortunately, many patients are unfit to undergo these intensive treatments.2 Patients who undergo palliative chemotherapy may eventually require treatment for locoregional complaints.
Symptoms such as hemoptysis, chest pain, dysphagia, and dyspnea in NSCLC can all be effectively palliated using different radiation treatment schemes.3 The effectiveness of these palliative schemes varies for each symptom, but is most effective for hemoptysis and chest pain in patients with Eastern Cooperative Oncology Group (ECOG) score of 2 to 3.4 The optimal dose for palliation remains controversial.5 In the first Medical Research Council (MRC) trial reported in 1991, no differences in palliative effect or in survival were seen between 13 x 3 Gy and 2 x 8.5 Gy.6 In a second MRC study (1992)7 for poor prognostic patients only, no differences in palliation or survival were seen between 10 Gy single dose and 2 x 8.5 Gy. However, in a study by Bezjak et al8 a difference in survival between 20 Gy in five fractions and a 10-Gy single dose was demonstrated in favor of the multifractionation treatment. In a subgroup-analysis, however, this survival advantage was not seen in patients with an ECOG score 2. Later data suggested a survival advantage of 13 x 3 Gy over 2 x 8.5 Gy in patients with good performance status.9 For patients in a poor general condition it still has to be proven whether 2 x 8.5 Gy is equally effective as 10 x 3 Gy.
Due to the contradictory literature, radiation oncologists in the Netherlands were unable to reach a consensus on the palliative schedule for patients with poor-prognosis NSCLC. The present study was designed for patients with stage IV NSCLC (ECOG 0 to 1) in whom chemotherapy options were exhausted. Patients with ECOG 2, stage IV disease were also eligible, as chemotherapy for this group of patients was not general practice at the start of this study.10 We focused on patients with poor general condition and/or significant weight loss with stage III or stage IV NSCLC, comparing 10 x 3 Gy with 2 x 8 Gy. Because of the results of the MRC studies mentioned here, we expected both treatment arms to have an equal outcome for palliation as for survival.6
PATIENTS AND METHODS
Patient Population
Patient characteristics are presented in Table 1. The diagnosis NSCLC had to be cytologically or histologically confirmed. Tumor stage was IIIA to IV in combination with performance status of 3 to 4 and/or a weight loss of more than 5% in 3 months or greater than 10% in 6 months before diagnosis. Patients with stage IV, ECOG stage 0 to 2 disease could also be included if, in the opinion of the treating pulmonologist, no further chemotherapeutic options were left after prior chemotherapy, or a substantial weight loss and/or comorbidity prevented the use of chemotherapy. Patients had to have a minimum patient-assessed total symptom score of 8, indicating at least some burden on at least one of the complaints caused by the tumor itself (Fig 1). Furthermore, the patient should be physically and mentally fit enough to participate in this study. Patients having superior vena cava syndrome (SVCS) at presentation, prior radiotherapy to the chest, and/or other malignant diseases in the past or concurrent chemotherapy were excluded.
Study End Points and Data Collection
Primary end point of this study were palliation of thoracic symptoms measured over 26 questionnaires (39 weeks) after random assignment. Secondary end points were toxicity and survival. Patients were also asked to provide information about quality of life and costs. These data will be published separately in a cost-utility analysis.
Thoracic symptoms were measured using a total symptom score that measured the extent to which patients were bothered by seven tumor-related symptoms (Fig 1). Existing validated questionnaires were considered either too burdensome11 or not specific enough for our patient population.11,12 Based on symptoms previously observed in irradiated patients with NSCLC,13 we instead adapted the Rotterdam Symptom Checklist.11 We maintained the symptoms lack of appetite and dyspnea, and added chest pain, coughing, hemoptysis, and hoarseness. In a different format, patients also reported their level of dysphagia.14 Using four-point Likert scales for each symptom, the total symptom score could range from 7 (not bothered at all on any symptom) to 28 (bothered very much on all symptoms). Palliation was defined as an average total score below the baseline score.
In addition, information about acute toxicity such as nausea, vomiting, and radiation esophagitis–induced dysphagia was collected, using the National Cancer Institute of Canada Clinical Trials Group Expanded Common Toxicity Criteria.15
The data collection schedule for follow-up is presented in Table 2. All symptoms were entirely patient-based scored. A maximum of 33 sets of questionnaires would be sent in case follow-up could be completed. On average, 17.4 sets (53%) per patient were received because a substantial number of patients did not survive long enough or stay fit enough to fill in all the questionnaires over 52 weeks. Of the 4,369 questionnaires sent by the data manager to the individual patient, 4,306 were returned.
The first questionnaire was completed before random assignment, the last questionnaire in the 52nd week after random assignment.
Follow-up after 52 weeks was continued by the data manager, who made three monthly inquiries to establish the survival.
Statistical Analysis
The study was designed as an equivalence study. We assumed as null hypothesis that the response score of the 2 x 8 Gy would be at least 10% lower compared with our standard 10 x 3 Gy. We expected a response rate of 65% with the standard treatment. We compared the average total symptom score for all present symptoms during 39 weeks. With this design, 134 patients per treatment arm were needed to obtain, at a 5% significance level, a power of .90 of correctly concluding equivalent effectiveness. Expecting an ineligibility and withdrawal of patients of 10%, a total of 300 patients were needed.
A response was defined as a reduction in the total symptom score by more than one point compared with baseline. Progression was defined as an increase in the total symptom score by more than one point if re-treatment was given or in case that the patient did not return the questionnaire. A difference in palliative effect between the two schedules was defined as a difference of at least one point in the average total symptom score for at least one of the symptoms. Data are presented over the initial 39 weeks, as too few patients remained alive to allow for meaningful analysis.
A secondary analysis was performed in which average total symptom score was corrected for the initial total symptom score at the start of the treatment and time of follow-up during this period. The latter was performed as initially higher total symptom score could result in a higher chance of a declining total symptom score and would suggest a better outcome. Also, differences in the course of the total symptom score between each treatment arm over the first 39 weeks were analyzed using the random effects model using the natural splines function in S-PLUS 6.2 Professional Edition.16
The overall survival with both treatments was described using the Kaplan-Meier survival curves.17 The log-rank test was used to compare overall survival between both treatments.
Fisher's exact test was used to compare the rates of toxicity between both groups. All reported P values are two-sided, and significance level was set at .05.
All data were evaluated according to the intention-to-treat principle.
Radiation Treatment
Patients were randomized, without stratification, either to the multiple fractionation scheme of 10 x 3 Gy, four to five times per week, or the hypofractionated scheme of 2 x 8 Gy, given on day 1 and day 8. Irradiation was given using two opposing anterior-posterior fields with 6- to 18-MV photon beams. The treatment portals encompassed the tumor, with a margin of 1 1/2-2 cm including adjacent pathological lymph nodes. No limitations were set for the target volume. Dose calculation was not corrected for tissue inhomogeneities.
Comedication, including corticosteroids and analgetics and supplemental oxygen were allowed and documented.
Ethical Issues
The study fulfilled all criteria as prescribed by the Dutch Law on Medical Research. Approval of the protocol by the Central Medical Committee of Ethics was obtained and each participating radiotherapy center had also a separate approval by their local medical committee of ethics. Random assignment took place after receiving informed consent of the patient.
RESULTS
the January 1, 1999, to May 31, 2002, 303 patients from 13 radiotherapy centers were randomized. Six patients were not eligible because of stage III disease with WHO performance scores 0 to 1 and no weight loss. Of the 297 patients who were eligible, 148 patients received 10 x 3 Gy and 149 patients received 2 x 8 Gy. All patients' survival and toxicity data were available and were analyzed.
Baseline patient characteristics were well balanced between the two groups (Table 1). No major differences were seen between the two treatment groups for age, histology, stage, and prior chemotherapy. Requirements for comedications and supplemental oxygen were well balanced between the two treatment arms. Most patients had a poor general condition, as 213 patients (71.7%) had substantial weight loss at randomization. Also, 190 patients (63.9%) presented with an ECOG score of 2 or more. Only a slight, but statistically not significant (P = .145) imbalance in ECOG 2 and 3 in favor of the 10 x 3-Gy arm was recorded.
Most patients suffered from dyspnea (87%) and cough (84%), followed by lack of appetite (61%), chest pain (48%), hemoptysis (38%), hoarseness (31%), and dysphagia (10%). Distribution and intensity of symptoms were well balanced across both treatments groups (Table 3).
The difference in the start of the treatment after random assignment between 10 x 3 Gy and 2 x 8 Gy was less than 2 days. After random assignment, 35 patients did not receive the prescribed treatment scheme. In the 2 x 8-Gy arm, 14 patients did not finish their treatment. In the 10 x 3-Gy arm 18 patients received less than 10 fractions of 3.0 Gy, one patient had one additional fraction of 3.0 Gy, and two patients received 16 Gy in two fractions.
The overall results show that both treatments were equally effective, as they differ by less than one point in average total symptom score. Symptom scores for both arms did not differ at start of the treatment, being 12.71 (95% CI, 10.28 to 15.14) and 12.87 (95% CI, 10.35 to 15.39) for the 10 x 3-Gy and 2 x 8-Gy arms, respectively (Fig 2). The average total symptom score over the initial 39 weeks was 12.71 (95% CI, 12.28 to 13.12) in the 10 x 3-Gy arm and 13.07 (95% CI, 12.66 to 13.49) 2 x 8 Gy arm, with a difference of 0.37 (95% CI, –0.22 to 0.96; P = .22).
Corrected for initial total symptom score and for time of follow-up, the difference remained less than 1 point, with respectively 0.26 (95% CI, –0.23 to 0.75; P = .299) and 0.24 (95% CI, –0.30 to 0.78; P = .388).
Analysis of each symptom showed some tendencies in response patterns during treatment (Fig 3). For cough (P = .84) and dyspnea (P = .84) no significant differences were seen. For the other symptoms, numbers were too small to compare these differences for each separate symptom and particularly for the changes in intensity per symptom between both treatment arms. All symptoms, except hemoptysis, initially intensified as the number of the patients suffering from that particular symptom rose and/or the severity of the symptom increased as a result of acute toxicity. The incidence of dysphagia initially rose to 30% to 40% of the patients and was finally hardly palliated. All other symptoms were eventually palliated in comparison with the pretreatment situation.
An overview of the evolution of total symptom score pattern for both treatment arms over the initial 39 weeks is presented in Figure 2. In both arms, total symptom scores initially rose as a result of treatment-related side effects. This rise seems to be earlier and more intense in the 2 x 8-Gy arm, reaching significance in week 1 to 2. Palliation was reached in week 5 in the 2 x 8-Gy arm and in week 7 in the 10 x 3-Gy arm, as the average total symptom score was below the initial score. The palliative effect was longer in the 10 x 3-Gy arm, persisting until week 22, and was also less progressive in intensity than in the 2 x 8-Gy arm. This difference over time was significant (P < .001).
No differences in severe (grade 3 to 5) toxicity between both arms influenced the different pattern of palliation. Five patients experienced severe acute toxicity of dyspnea, malaise, and/or nausea, four of whom were treated in the 10 x 3-Gy arm, and one, in the 2 x 8-Gy arm. No patient developed a myelopathy in our study. No significant differences in the usage and kind of comedication existed between both treatment arms to explain the observed differences.
Reirradiation took place in eight patients (5%) in the 10 x 3-Gy arm. One of these patients was even reirradiated twice. In the 2 x 8-Gy arm, nine patients (6%) were re-treated with irradiation.
A subsequent treatment with chemotherapy after randomization was not registered. In a retrospective subgroup analysis of a sample of 105 patients equally assigned to both treatment arms, four patients retrieved re-treatment with chemotherapy. These four patients were all previously treated according the 10 x 3-Gy arm.
Somewhat unexpectedly, the survival analysis revealed a significantly better survival in the 10 x 3-Gy arm (P < .03; Fig 4). The 1-year survival was 19.6% (95% CI, 14.1% to 27.3%) in the 10 x 3-Gy arm (26 of 148 patients) and only 10.9% (95% CI, 6.9% to 17.3%) in the 2 x 8-Gy arm (15 of 149 patients). Even after 3 years, the survival rate in the 10 x 3-Gy arm was 5.6% (95% CI, 2.8 to 11.3; four of 148) v 1.6% (95% CI, 0.4 to 6.1; two of 149) in the 2 x 8-Gy arm. This difference in survival existed from week 15 and further and varied between 4% and 11%.
DISCUSSION
Our study comparing 10 x 3-Gy with 2 x 8-Gy palliative irradiation in NSCLC revealed a superiority of the former over the hypofractionation scheme. Thoracic symptom scores for both schemes were similar over the initial 39 weeks. However, the palliative effect differed significantly over time between treatment arms. In the 10 x 3-Gy arm, the onset of the palliative effect occurred later and persisted longer. Furthermore, the 1-year survival was better in patients treated using the 10 x 3-Gy arm.
We observed a reduction of symptoms in line with several other randomized studies, which found no differences in palliative effect using different fractionation schemes.6-8,18-20 Only one report thus far has shown a better palliative effect with 45 Gy in 18 fractions over 3.5 weeks compared with 31.2 Gy in four fractions over 4 weeks.21
Our total symptom score gives no information on symptom relief per symptom, but is an indicator of the overall palliative effect. Symptom relief will vary depending the type, number, and intensity of the complaints.4,22,23 An equal distribution for prognostic factors over both treatment arms is also important. Although in our study no stratification for all these factors was performed, all items were well balanced over both treatment arms.
Bezjak et al8 proposed to restrict measurements of palliation only to the index symptom, because response of individual symptoms will be less than that of the index symptom. These larger changes in an individual patient will therefore not be seen at the group level when the average change was reported. As a result, analyzing the index symptom may be more sensitive to change at the expense of providing inadequate information about the overall palliative effect.
Stephens et al22 proposed that palliation should not only measure reduction of complaints, but also stabilization and occurrence of new complaints due to tumor and/or treatment. Furthermore the duration of palliation should be stated. All these aspects are included in our scoring system of the palliative effect.
We observed a significantly different pattern in palliation over a period of 39 weeks between the two treatment arms. The method for assessing palliation appears crucial. Hopwood et al24 showed that differences in missing information between studies can lead to incorrect conclusions, which may be a consequence of differing patterns of change in symptoms during treatment. The differences in the pattern of symptom reduction between both our treatment arms can support this finding. Measuring once or only a few times, or weekly as in our study, will produce differences in outcome. Therefore, comparing studies is difficult, as frequency and duration of measurements vary substantially.5
Combining the sum of the palliative effect by symptom reduction and the symptoms induced by the treatment in our total symptom score can be responsible for visualizing these different effects in time and results in a more precise view on the overall effect of these particular treatments.
Our results are consistent with those of Macbeth et al,9 who also observed that hypofractionation resulted in a quicker reduction of complaints, whereas hyperfractionation resulted in a longer duration of palliation.
Our data gave insufficient support to the assumption that the difference in pattern we found could occur because of differences in the radiobiological equivalent dose (BED).25,26 The 10 x 3-Gy arm was less toxic, and a steep and significant rise in total symptom scores was seen in the first weeks post-treatment after 2 x 8 Gy.
The relation between tumor control and radiation dose with these palliative treatment schedules is uncertain. Notably, in this poor prognostic group, local tumor growth could be the major cause of complaints and possibly local tumor progression, and also the major cause of death. As follow-up in our study was based only on questionnaires, no data about objective tumor response were available. An earlier MRC study6 found no differences in radiological responses, using radiation doses comparable with those used in our study. Even with higher doses, data about tumor control are conflicting. Sundstrm et al20 presented no relation between tumor dose and local control on chest x-ray, whereas Nestle et al19 and Reinfuss et al27 found a tendency of better control with higher radiation doses.
The observation of a survival gain in the 10 x 3-Gy arm in our study was the most surprising finding, and it must be interpreted with caution, as differences in survival were not detected in most other comparable studies,4,6,7,18-20 and especially not in patients with poor general condition.6,8 The difference in survival seen in patients treated with a multiple fractionation scheme was only seen in those having a good performance score.8,9,27 In a subgroup analysis, we also found that the advantage in survival in the 10 x 3-Gy arm over the 2 x 8-Gy arm was statistically significant in patients with ECOG 0 to 1, but not in patients with ECOG 2 to 4. All patients with ECOG 0 to 1 had stage IV disease. Although there was a tendency, no significant difference in survival was seen in subgroup analysis between both treatment arms for stage IV. The fact that most patients had also a substantial weight loss could be responsible for this finding. The definition of a poor-prognosis patient population remains to be elucidated.
a statistical point of view, chance could be another explanation for finding a difference in survival between both treatment arms, although the level of significance that was detected is considered sufficient.28 Stephens29 has critically reviewed the risks of obtaining false-positive results with sample sizes, and this factor cannot be fully excluded. As such, conformation of a survival advantage for the 10 x 3 Gy scheme will be necessary as it appears to be significant, and clinically relevant.
Despite the prolongation in symptom relief and better survival, hardly any re-treatment, including chemotherapy, was observed. This can be a result of our selection, as patients were at referral no (longer) candidates for chemotherapy. Secondly, the performance state will not automatically improve, despite a symptom response. And finally, only recently indications for an ECOG score of 2 are formulated.10
In patients with short expected survival 2 x 8 Gy can be the treatment of choice as most acute symptoms induced by toxicity can be treated or prevented with steroids and/or analgetics.30 However, based on the criteria of this study, we could not define this particular group of patients. Therefore, although the overall palliative effect is equal to that of 2 x 8 Gy, we still recommend 10 x 3 Gy because of a longer duration of the palliative response and a significant benefit in survival.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We thank following colleagues for participating in this study: A.L.J. Uitterhoeve (AMC, Amsterdam), J. Bussink (RADIAN, UMC St Radboud, Nijmegen), A.H.D. van de Leest (AZG, Groningen), C. Nil (MCH, The Hague), M.J.C. van der Sangen (Catharina Hospital, Eindhoven), E.H.J.M. Rutten (MCA, Alkmaar), M.F.H. Dielwart (ZRTI, Vlissingen), P. van der Maden (Sophia Hospital/Isala, Zwolle), J. Pomp (RDGG, Delft).
NOTES
Supported by the Dutch Health Care Insurance Board (College voor Zorgverzekeringen) as CKVO (Clinical Trial Review Committee) study OG98/009.
Presented orally at the 10th World Conference on Lung Cancer, Vancouver, Canada, August 10-14, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Nestle U, Nieder C, Walter K, et al: A palliative accelerated irradiation regimen for advanced non-small cell lung cancer vs. conventionally fractionated 60 Gy: Results of a randomized equivalence study. Int J Rad Onc Biol Phys 48:95-103, 2000
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MAASTRO clinic Maastricht/Heerlen
Department of Clinical Oncology, and Department of medical decision making, Leiden University Medical Center, Leiden
Radiotherapeutic Institute Stedendriehoek en Omstreken, Deventer, the Netherlands
ABSTRACT
PURPOSE: A national multicenter randomized study compared the efficacy of 2 x 8 Gy versus our standard 10 x 3 Gy in patients with inoperable stage IIIA/B (with an Eastern Cooperative Oncology Group score of 3 to 4 and/or substantial weight loss) and stage IV non–small-cell lung cancer.
PATIENTS AND METHODS: Between January 1999 and June 2002, 297 patients were eligible and randomized to receive either 10 x 3 Gy or 2 x 8 Gy by external-beam irradiation. The primary end point was a patient-assessed score of treatment effect on seven thoracic symptoms using an adapted Rotterdam Symptom Checklist. Study sample size was determined based on an average total symptom score difference of more than one point over the initial 39 weeks post-treatment. The time course of symptom scores were also evaluated, and other secondary end points were toxicity and survival.
RESULTS: Both treatment arms were equally effective, as the average total symptom score over the initial 39 weeks did not differ. However, the pattern in time of these scores differed significantly (P < .001). Palliation in the 10 x 3-Gy arm was more prolonged (until week 22) with less worsening symptoms than in 2 x 8-Gy. Survival in the 10 x 3-Gy arm was significantly (P = .03) better than in the 2 x 8-Gy arm with 1-year survival of 19.6% (95%CI, 14.1% to 27.3%) v 10.9% (95%CI, 6.9% to 17.3%).
CONCLUSION: The 10 x 3-Gy radiotherapy schedule is preferred over the 2 x 8-Gy schedule for palliative treatment, as it improves survival and results in a longer duration of the palliative response.
INTRODUCTION
The treatment of non–small-cell lung cancer (NSCLC) is still a challenge for the oncologist. In the past decade, combined-modality treatment in stage III disease and chemotherapy for stage IV disease improved the survival and quality of life in NSCLC patients.1 Unfortunately, many patients are unfit to undergo these intensive treatments.2 Patients who undergo palliative chemotherapy may eventually require treatment for locoregional complaints.
Symptoms such as hemoptysis, chest pain, dysphagia, and dyspnea in NSCLC can all be effectively palliated using different radiation treatment schemes.3 The effectiveness of these palliative schemes varies for each symptom, but is most effective for hemoptysis and chest pain in patients with Eastern Cooperative Oncology Group (ECOG) score of 2 to 3.4 The optimal dose for palliation remains controversial.5 In the first Medical Research Council (MRC) trial reported in 1991, no differences in palliative effect or in survival were seen between 13 x 3 Gy and 2 x 8.5 Gy.6 In a second MRC study (1992)7 for poor prognostic patients only, no differences in palliation or survival were seen between 10 Gy single dose and 2 x 8.5 Gy. However, in a study by Bezjak et al8 a difference in survival between 20 Gy in five fractions and a 10-Gy single dose was demonstrated in favor of the multifractionation treatment. In a subgroup-analysis, however, this survival advantage was not seen in patients with an ECOG score 2. Later data suggested a survival advantage of 13 x 3 Gy over 2 x 8.5 Gy in patients with good performance status.9 For patients in a poor general condition it still has to be proven whether 2 x 8.5 Gy is equally effective as 10 x 3 Gy.
Due to the contradictory literature, radiation oncologists in the Netherlands were unable to reach a consensus on the palliative schedule for patients with poor-prognosis NSCLC. The present study was designed for patients with stage IV NSCLC (ECOG 0 to 1) in whom chemotherapy options were exhausted. Patients with ECOG 2, stage IV disease were also eligible, as chemotherapy for this group of patients was not general practice at the start of this study.10 We focused on patients with poor general condition and/or significant weight loss with stage III or stage IV NSCLC, comparing 10 x 3 Gy with 2 x 8 Gy. Because of the results of the MRC studies mentioned here, we expected both treatment arms to have an equal outcome for palliation as for survival.6
PATIENTS AND METHODS
Patient Population
Patient characteristics are presented in Table 1. The diagnosis NSCLC had to be cytologically or histologically confirmed. Tumor stage was IIIA to IV in combination with performance status of 3 to 4 and/or a weight loss of more than 5% in 3 months or greater than 10% in 6 months before diagnosis. Patients with stage IV, ECOG stage 0 to 2 disease could also be included if, in the opinion of the treating pulmonologist, no further chemotherapeutic options were left after prior chemotherapy, or a substantial weight loss and/or comorbidity prevented the use of chemotherapy. Patients had to have a minimum patient-assessed total symptom score of 8, indicating at least some burden on at least one of the complaints caused by the tumor itself (Fig 1). Furthermore, the patient should be physically and mentally fit enough to participate in this study. Patients having superior vena cava syndrome (SVCS) at presentation, prior radiotherapy to the chest, and/or other malignant diseases in the past or concurrent chemotherapy were excluded.
Study End Points and Data Collection
Primary end point of this study were palliation of thoracic symptoms measured over 26 questionnaires (39 weeks) after random assignment. Secondary end points were toxicity and survival. Patients were also asked to provide information about quality of life and costs. These data will be published separately in a cost-utility analysis.
Thoracic symptoms were measured using a total symptom score that measured the extent to which patients were bothered by seven tumor-related symptoms (Fig 1). Existing validated questionnaires were considered either too burdensome11 or not specific enough for our patient population.11,12 Based on symptoms previously observed in irradiated patients with NSCLC,13 we instead adapted the Rotterdam Symptom Checklist.11 We maintained the symptoms lack of appetite and dyspnea, and added chest pain, coughing, hemoptysis, and hoarseness. In a different format, patients also reported their level of dysphagia.14 Using four-point Likert scales for each symptom, the total symptom score could range from 7 (not bothered at all on any symptom) to 28 (bothered very much on all symptoms). Palliation was defined as an average total score below the baseline score.
In addition, information about acute toxicity such as nausea, vomiting, and radiation esophagitis–induced dysphagia was collected, using the National Cancer Institute of Canada Clinical Trials Group Expanded Common Toxicity Criteria.15
The data collection schedule for follow-up is presented in Table 2. All symptoms were entirely patient-based scored. A maximum of 33 sets of questionnaires would be sent in case follow-up could be completed. On average, 17.4 sets (53%) per patient were received because a substantial number of patients did not survive long enough or stay fit enough to fill in all the questionnaires over 52 weeks. Of the 4,369 questionnaires sent by the data manager to the individual patient, 4,306 were returned.
The first questionnaire was completed before random assignment, the last questionnaire in the 52nd week after random assignment.
Follow-up after 52 weeks was continued by the data manager, who made three monthly inquiries to establish the survival.
Statistical Analysis
The study was designed as an equivalence study. We assumed as null hypothesis that the response score of the 2 x 8 Gy would be at least 10% lower compared with our standard 10 x 3 Gy. We expected a response rate of 65% with the standard treatment. We compared the average total symptom score for all present symptoms during 39 weeks. With this design, 134 patients per treatment arm were needed to obtain, at a 5% significance level, a power of .90 of correctly concluding equivalent effectiveness. Expecting an ineligibility and withdrawal of patients of 10%, a total of 300 patients were needed.
A response was defined as a reduction in the total symptom score by more than one point compared with baseline. Progression was defined as an increase in the total symptom score by more than one point if re-treatment was given or in case that the patient did not return the questionnaire. A difference in palliative effect between the two schedules was defined as a difference of at least one point in the average total symptom score for at least one of the symptoms. Data are presented over the initial 39 weeks, as too few patients remained alive to allow for meaningful analysis.
A secondary analysis was performed in which average total symptom score was corrected for the initial total symptom score at the start of the treatment and time of follow-up during this period. The latter was performed as initially higher total symptom score could result in a higher chance of a declining total symptom score and would suggest a better outcome. Also, differences in the course of the total symptom score between each treatment arm over the first 39 weeks were analyzed using the random effects model using the natural splines function in S-PLUS 6.2 Professional Edition.16
The overall survival with both treatments was described using the Kaplan-Meier survival curves.17 The log-rank test was used to compare overall survival between both treatments.
Fisher's exact test was used to compare the rates of toxicity between both groups. All reported P values are two-sided, and significance level was set at .05.
All data were evaluated according to the intention-to-treat principle.
Radiation Treatment
Patients were randomized, without stratification, either to the multiple fractionation scheme of 10 x 3 Gy, four to five times per week, or the hypofractionated scheme of 2 x 8 Gy, given on day 1 and day 8. Irradiation was given using two opposing anterior-posterior fields with 6- to 18-MV photon beams. The treatment portals encompassed the tumor, with a margin of 1 1/2-2 cm including adjacent pathological lymph nodes. No limitations were set for the target volume. Dose calculation was not corrected for tissue inhomogeneities.
Comedication, including corticosteroids and analgetics and supplemental oxygen were allowed and documented.
Ethical Issues
The study fulfilled all criteria as prescribed by the Dutch Law on Medical Research. Approval of the protocol by the Central Medical Committee of Ethics was obtained and each participating radiotherapy center had also a separate approval by their local medical committee of ethics. Random assignment took place after receiving informed consent of the patient.
RESULTS
the January 1, 1999, to May 31, 2002, 303 patients from 13 radiotherapy centers were randomized. Six patients were not eligible because of stage III disease with WHO performance scores 0 to 1 and no weight loss. Of the 297 patients who were eligible, 148 patients received 10 x 3 Gy and 149 patients received 2 x 8 Gy. All patients' survival and toxicity data were available and were analyzed.
Baseline patient characteristics were well balanced between the two groups (Table 1). No major differences were seen between the two treatment groups for age, histology, stage, and prior chemotherapy. Requirements for comedications and supplemental oxygen were well balanced between the two treatment arms. Most patients had a poor general condition, as 213 patients (71.7%) had substantial weight loss at randomization. Also, 190 patients (63.9%) presented with an ECOG score of 2 or more. Only a slight, but statistically not significant (P = .145) imbalance in ECOG 2 and 3 in favor of the 10 x 3-Gy arm was recorded.
Most patients suffered from dyspnea (87%) and cough (84%), followed by lack of appetite (61%), chest pain (48%), hemoptysis (38%), hoarseness (31%), and dysphagia (10%). Distribution and intensity of symptoms were well balanced across both treatments groups (Table 3).
The difference in the start of the treatment after random assignment between 10 x 3 Gy and 2 x 8 Gy was less than 2 days. After random assignment, 35 patients did not receive the prescribed treatment scheme. In the 2 x 8-Gy arm, 14 patients did not finish their treatment. In the 10 x 3-Gy arm 18 patients received less than 10 fractions of 3.0 Gy, one patient had one additional fraction of 3.0 Gy, and two patients received 16 Gy in two fractions.
The overall results show that both treatments were equally effective, as they differ by less than one point in average total symptom score. Symptom scores for both arms did not differ at start of the treatment, being 12.71 (95% CI, 10.28 to 15.14) and 12.87 (95% CI, 10.35 to 15.39) for the 10 x 3-Gy and 2 x 8-Gy arms, respectively (Fig 2). The average total symptom score over the initial 39 weeks was 12.71 (95% CI, 12.28 to 13.12) in the 10 x 3-Gy arm and 13.07 (95% CI, 12.66 to 13.49) 2 x 8 Gy arm, with a difference of 0.37 (95% CI, –0.22 to 0.96; P = .22).
Corrected for initial total symptom score and for time of follow-up, the difference remained less than 1 point, with respectively 0.26 (95% CI, –0.23 to 0.75; P = .299) and 0.24 (95% CI, –0.30 to 0.78; P = .388).
Analysis of each symptom showed some tendencies in response patterns during treatment (Fig 3). For cough (P = .84) and dyspnea (P = .84) no significant differences were seen. For the other symptoms, numbers were too small to compare these differences for each separate symptom and particularly for the changes in intensity per symptom between both treatment arms. All symptoms, except hemoptysis, initially intensified as the number of the patients suffering from that particular symptom rose and/or the severity of the symptom increased as a result of acute toxicity. The incidence of dysphagia initially rose to 30% to 40% of the patients and was finally hardly palliated. All other symptoms were eventually palliated in comparison with the pretreatment situation.
An overview of the evolution of total symptom score pattern for both treatment arms over the initial 39 weeks is presented in Figure 2. In both arms, total symptom scores initially rose as a result of treatment-related side effects. This rise seems to be earlier and more intense in the 2 x 8-Gy arm, reaching significance in week 1 to 2. Palliation was reached in week 5 in the 2 x 8-Gy arm and in week 7 in the 10 x 3-Gy arm, as the average total symptom score was below the initial score. The palliative effect was longer in the 10 x 3-Gy arm, persisting until week 22, and was also less progressive in intensity than in the 2 x 8-Gy arm. This difference over time was significant (P < .001).
No differences in severe (grade 3 to 5) toxicity between both arms influenced the different pattern of palliation. Five patients experienced severe acute toxicity of dyspnea, malaise, and/or nausea, four of whom were treated in the 10 x 3-Gy arm, and one, in the 2 x 8-Gy arm. No patient developed a myelopathy in our study. No significant differences in the usage and kind of comedication existed between both treatment arms to explain the observed differences.
Reirradiation took place in eight patients (5%) in the 10 x 3-Gy arm. One of these patients was even reirradiated twice. In the 2 x 8-Gy arm, nine patients (6%) were re-treated with irradiation.
A subsequent treatment with chemotherapy after randomization was not registered. In a retrospective subgroup analysis of a sample of 105 patients equally assigned to both treatment arms, four patients retrieved re-treatment with chemotherapy. These four patients were all previously treated according the 10 x 3-Gy arm.
Somewhat unexpectedly, the survival analysis revealed a significantly better survival in the 10 x 3-Gy arm (P < .03; Fig 4). The 1-year survival was 19.6% (95% CI, 14.1% to 27.3%) in the 10 x 3-Gy arm (26 of 148 patients) and only 10.9% (95% CI, 6.9% to 17.3%) in the 2 x 8-Gy arm (15 of 149 patients). Even after 3 years, the survival rate in the 10 x 3-Gy arm was 5.6% (95% CI, 2.8 to 11.3; four of 148) v 1.6% (95% CI, 0.4 to 6.1; two of 149) in the 2 x 8-Gy arm. This difference in survival existed from week 15 and further and varied between 4% and 11%.
DISCUSSION
Our study comparing 10 x 3-Gy with 2 x 8-Gy palliative irradiation in NSCLC revealed a superiority of the former over the hypofractionation scheme. Thoracic symptom scores for both schemes were similar over the initial 39 weeks. However, the palliative effect differed significantly over time between treatment arms. In the 10 x 3-Gy arm, the onset of the palliative effect occurred later and persisted longer. Furthermore, the 1-year survival was better in patients treated using the 10 x 3-Gy arm.
We observed a reduction of symptoms in line with several other randomized studies, which found no differences in palliative effect using different fractionation schemes.6-8,18-20 Only one report thus far has shown a better palliative effect with 45 Gy in 18 fractions over 3.5 weeks compared with 31.2 Gy in four fractions over 4 weeks.21
Our total symptom score gives no information on symptom relief per symptom, but is an indicator of the overall palliative effect. Symptom relief will vary depending the type, number, and intensity of the complaints.4,22,23 An equal distribution for prognostic factors over both treatment arms is also important. Although in our study no stratification for all these factors was performed, all items were well balanced over both treatment arms.
Bezjak et al8 proposed to restrict measurements of palliation only to the index symptom, because response of individual symptoms will be less than that of the index symptom. These larger changes in an individual patient will therefore not be seen at the group level when the average change was reported. As a result, analyzing the index symptom may be more sensitive to change at the expense of providing inadequate information about the overall palliative effect.
Stephens et al22 proposed that palliation should not only measure reduction of complaints, but also stabilization and occurrence of new complaints due to tumor and/or treatment. Furthermore the duration of palliation should be stated. All these aspects are included in our scoring system of the palliative effect.
We observed a significantly different pattern in palliation over a period of 39 weeks between the two treatment arms. The method for assessing palliation appears crucial. Hopwood et al24 showed that differences in missing information between studies can lead to incorrect conclusions, which may be a consequence of differing patterns of change in symptoms during treatment. The differences in the pattern of symptom reduction between both our treatment arms can support this finding. Measuring once or only a few times, or weekly as in our study, will produce differences in outcome. Therefore, comparing studies is difficult, as frequency and duration of measurements vary substantially.5
Combining the sum of the palliative effect by symptom reduction and the symptoms induced by the treatment in our total symptom score can be responsible for visualizing these different effects in time and results in a more precise view on the overall effect of these particular treatments.
Our results are consistent with those of Macbeth et al,9 who also observed that hypofractionation resulted in a quicker reduction of complaints, whereas hyperfractionation resulted in a longer duration of palliation.
Our data gave insufficient support to the assumption that the difference in pattern we found could occur because of differences in the radiobiological equivalent dose (BED).25,26 The 10 x 3-Gy arm was less toxic, and a steep and significant rise in total symptom scores was seen in the first weeks post-treatment after 2 x 8 Gy.
The relation between tumor control and radiation dose with these palliative treatment schedules is uncertain. Notably, in this poor prognostic group, local tumor growth could be the major cause of complaints and possibly local tumor progression, and also the major cause of death. As follow-up in our study was based only on questionnaires, no data about objective tumor response were available. An earlier MRC study6 found no differences in radiological responses, using radiation doses comparable with those used in our study. Even with higher doses, data about tumor control are conflicting. Sundstrm et al20 presented no relation between tumor dose and local control on chest x-ray, whereas Nestle et al19 and Reinfuss et al27 found a tendency of better control with higher radiation doses.
The observation of a survival gain in the 10 x 3-Gy arm in our study was the most surprising finding, and it must be interpreted with caution, as differences in survival were not detected in most other comparable studies,4,6,7,18-20 and especially not in patients with poor general condition.6,8 The difference in survival seen in patients treated with a multiple fractionation scheme was only seen in those having a good performance score.8,9,27 In a subgroup analysis, we also found that the advantage in survival in the 10 x 3-Gy arm over the 2 x 8-Gy arm was statistically significant in patients with ECOG 0 to 1, but not in patients with ECOG 2 to 4. All patients with ECOG 0 to 1 had stage IV disease. Although there was a tendency, no significant difference in survival was seen in subgroup analysis between both treatment arms for stage IV. The fact that most patients had also a substantial weight loss could be responsible for this finding. The definition of a poor-prognosis patient population remains to be elucidated.
a statistical point of view, chance could be another explanation for finding a difference in survival between both treatment arms, although the level of significance that was detected is considered sufficient.28 Stephens29 has critically reviewed the risks of obtaining false-positive results with sample sizes, and this factor cannot be fully excluded. As such, conformation of a survival advantage for the 10 x 3 Gy scheme will be necessary as it appears to be significant, and clinically relevant.
Despite the prolongation in symptom relief and better survival, hardly any re-treatment, including chemotherapy, was observed. This can be a result of our selection, as patients were at referral no (longer) candidates for chemotherapy. Secondly, the performance state will not automatically improve, despite a symptom response. And finally, only recently indications for an ECOG score of 2 are formulated.10
In patients with short expected survival 2 x 8 Gy can be the treatment of choice as most acute symptoms induced by toxicity can be treated or prevented with steroids and/or analgetics.30 However, based on the criteria of this study, we could not define this particular group of patients. Therefore, although the overall palliative effect is equal to that of 2 x 8 Gy, we still recommend 10 x 3 Gy because of a longer duration of the palliative response and a significant benefit in survival.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We thank following colleagues for participating in this study: A.L.J. Uitterhoeve (AMC, Amsterdam), J. Bussink (RADIAN, UMC St Radboud, Nijmegen), A.H.D. van de Leest (AZG, Groningen), C. Nil (MCH, The Hague), M.J.C. van der Sangen (Catharina Hospital, Eindhoven), E.H.J.M. Rutten (MCA, Alkmaar), M.F.H. Dielwart (ZRTI, Vlissingen), P. van der Maden (Sophia Hospital/Isala, Zwolle), J. Pomp (RDGG, Delft).
NOTES
Supported by the Dutch Health Care Insurance Board (College voor Zorgverzekeringen) as CKVO (Clinical Trial Review Committee) study OG98/009.
Presented orally at the 10th World Conference on Lung Cancer, Vancouver, Canada, August 10-14, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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