- Email: [email protected]
etoposide chemotherapy in stage III non–small-cell lung cancer: A randomized trial
Int. J. Radiation Oncology Biol. Phys., Vol. 50, No. 1, pp. 19 –25, 2001 Copyright © 2001 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/01/$–see front matter
PII S0360-3016(00)01546-7
CLINICAL INVESTIGATION
Lung
HYPERFRACTIONATED RADIATION THERAPY AND CONCURRENT LOWDOSE, DAILY CARBOPLATIN/ETOPOSIDE WITH OR WITHOUT WEEKEND CARBOPLATIN/ETOPOSIDE CHEMOTHERAPY IN STAGE III NON–SMALLCELL LUNG CANCER: A RANDOMIZED TRIAL BRANISLAV JEREMIC, M.D., PH.D.,* YUTA SHIBAMOTO, M.D., D. M.SC.,† LJUBISA ACIMOVIC, M.D., M.SC.,‡ BILJANA MILICIC, M.D., M.SC.,* SLOBODAN MILISAVLJEVIC, M.D.,‡ NEBOJSA NIKOLIC, M.D.,* ALEKSANDAR DAGOVIC, M.D.,* JASNA ALEKSANDROVIC, M.D.,* AND GORDANA RADOSAVLJEVIC-ASIC, M.D., PH.D.§ Departments of *Oncology and ‡Surgery, University Hospital, Kragujevac, Yugoslavia; †Department of Oncology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan; §Institute for Lung Disease and TB, Belgrade, Yugoslavia Purpose: To investigate whether the addition of weekend chemotherapy consisting of carboplatin/etoposide to hyperfractionated radiation therapy (Hfx RT) and concurrent daily carboplatin/etoposide offers an advantage over the same Hfx RT/daily carboplatin/etoposide. Methods and Materials: A total of 195 patients (Group I, 98; Group II, 97) were treated with either Hfx RT to a total tumor dose of 69.6 Gy via 1.2 Gy b.i.d. fractionation and daily 50 mg each of carboplatin and etoposide during the RT course (Group I) or the same Hfx RT with daily carboplatin/etoposide consisting of 30 mg each of carboplatin and etoposide and with weekend (Saturdays and Sundays) 100 mg each of carboplatin and etoposide during the RT course (Group II). Results: No difference was found regarding median survival time and 5-year survival rates (20 vs. 22 months and 20% vs. 23%; p ⴝ 0.57). Median time to local progression was 20 and 19 months, respectively, while 5-year local progression-free survival rates were 28% and 27%, respectively (p ⴝ 0.66). Also, there was no difference regarding either median time to distant metastasis and 5-year distant metastasis-free survival (21 vs. 25 months and 29% vs. 34%, p ⴝ 0.29). There was no difference in the incidence of various nonhematologic toxicities between the two treatment groups, but patients treated with the weekend CHT had significantly more high-grade (> 3) hematologic toxicity (p ⴝ 0.0046). Late high-grade toxicity was not different between the two treatment groups. Conclusion: The addition of weekend carboplatin/etoposide did not improve results over those obtained with Hfx RT and concurrent low-dose, daily carboplatin/etoposide, but it led to a higher incidence of acute high-grade hematologic toxicity. © 2001 Elsevier Science Inc. Non–small-cell lung cancer, Radiotherapy, Hyperfractionation, Chemotherapy, Carboplatin, Etoposide.
INTRODUCTION Stage III non–small-cell lung cancer (NSCLC) represents one of the major challenges in thoracic oncology. Numerous studies of radiation therapy (RT) alone revealed distant metastasis to be an important pattern of failure (1–3). To improve treatment outcome, a number of strategies addressing this issue evolved in the last two decades. They include various combinations of RT and chemotherapy (CHT) with (4 – 8) or without (9 –14) surgery. The combination of the former two methods mostly concentrates around two approaches, assumed to be of the greatest benefit, namely, induction (neoadjuvant) CHT followed by RT and concur-
rent RT/CHT, although possibilities for alternating RT/CHT clearly exist. Expecting an improvement in survival obtained through an improvement in the distant metastasis control, induction CHT followed by radical, standard fraction RT became increasingly used owing to the results of the Cancer and Leukemia Group B (CALGB) Study 8433 (10) and the French multi-institutional study (9). They showed that induction CHT and standard fraction, radical RT are superior to RT alone. This largely affected the “standards of practice” around the world and led to the recommendations about its wider applicability (15). To further extend this issue, preliminary results of a joint Radiation Therapy On-
Reprint requests to: Dr. Branislav Jeremic, Department of Radiation Oncology, University Hospital, Hoppe-Seyler-Strasse 3, D-72076 Tuebingen, Germany. Tel: ⫹49-7071-298-2165; Fax: ⫹49-7071-295-894; E-mail: [email protected]
This study was supported in part by the Grant-in-Aid for Scientific Research (B) from the Japanese Ministry of Education, Science and Culture (10557087, 11470190, 11877152) Accepted for publication 30 October 2000. 19
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cology Group (RTOG)/Eastern Cooperative Oncology Group (ECOG) study also showed an advantage for the same (as CALGB 8433) induction CHT (two cycles of cisplatin and vinblastine) followed by standard fraction radical RT over not just the same radical RT, but high-dose hyperfractionated (Hfx) RT as well (11). This approach, however, while being successful in addressing the issue of distant metastasis, does not successfully address the issue of the control of the local (intrathoracic) disease, which has been shown to be as low as 17% after 1 year when pathologic evaluation was used (9). The local tumor control, however, is the major focus of the concurrent RT/CHT regimens. Both approaches carry an increase in the toxicity, which appeared somewhat higher in concurrent regimens. Our previous studies in Stage III NSCLC showed that high-dose Hfx RT can be successfully combined with concurrent chemotherapy consisting of carboplatin and etoposide (16, 17). We have identified a regimen consisting of 69.6 Gy via 1.2 Gy b.i.d. fractionation and 50 mg of daily dose of both carboplatin and etoposide as an efficient treatment regimen (median survival time [MST] ⫽ 22 months; 4-year survival ⫽ 23%) with acceptable toxicity (17), much lower than that observed when higher doses of platinating agents alone or with other agents are used (12–14, 16). However, the issue of controlling the distant metastasis may not have been properly addressed by that study design, which led us to opening a Phase II study on the use of somewhat lower daily dose of carboplatin/etoposide (reduced from 50 mg each to 30 mg each of carboplatin and etoposide, both given daily) but with somewhat higher weekend (Saturdays and Sundays) doses of both carboplatin and etoposide (100 mg each), to optimize the treatment of presumed micrometastasis present from the outset (18). Because the early experience with the latter approach was favorable, we underwent a prospective randomized trial in which we compared the high-dose Hfx RT and concurrent low-dose carboplatin/etoposide with the same approach including lower daily doses of carboplatin/etoposide and higher weekend doses of carboplatin/etoposide as applied in our Phase II study (18). METHODS AND MATERIALS Eligibility criteria included age of 18 years or older, histologically or cytologically confirmed, advanced NSCLC classified as Stage IIIA or IIIB by the International System (19), a Karnofsky performance status (KPS) score of at least 50%, and no previous therapy. Patients were excluded if they had postoperative thoracic recurrence or a history of any prior or concurrent cancer (except that of the skin), unless the patient had shown no evidence of disease for more than 5 years. Patients with malignant pleural effusion were also excluded. The pretreatment evaluation included medical history, physical examination, complete blood count, biochemical screening tests, postero-anterior and lateral chest radiographs, and computed tomography (CT) scans of the thorax and upper abdomen as well as abdominal
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ultrasound and bone radionuclide scan. Brain CT scan and pulmonary function tests were strongly recommended and performed when possible. No patient underwent mediastinoscopy for the purpose of staging. The patients were randomly divided into the following groups: Group I, Hfx RT with 1.2 Gy twice daily with a total dose of 69.6 Gy and carboplatin and etoposide, both given as 50 mg daily during the RT course, Mondays to Fridays. In Group II, the same Hfx RT regimen was administered with daily CHT consisting of 30 mg each of carboplatin and etoposide during the RT course (Mondays to Fridays), plus weekend CHT consisting of 100 mg each of carboplatin and etoposide, both given on Saturdays and Sundays during the RT course. The weekly dose for carboplatin and etoposide was 250 mg in Group I, while, in the Group II, it was 350 mg. This study was performed after approval was obtained from the Institutional Ethics Committee. Informed consent was obtained from all patients. The patients were examined at the end of Hfx RT, every month for 6 months after the completion of Hfx RT, every 2 months for 2 years thereafter, and every 4 months thereafter. Complete blood counts, biochemical tests, and chest radiographs were performed at each visit. Pathologic verifications were not performed routinely but were recommended if signs of tumor persistence or recurrence were present. Restaging at the time of any progression was performed by using all procedures outlined above and radiography of the bones, whenever necessary. RT was administered with 6 –10 MV photons using linear accelerators. The primary tumor was encompassed with a minimum 2-cm margin, as was the entire mediastinum from the suprasternal notch to a level 6 cm below the carina (upper and middle lobe lesions) or to the diaphragm (lower lobe lesions); the ipsilateral hilum was encompassed with a 2-cm margin and the contralateral hilum with a 1-cm margin. The ipsilateral supraclavicular fosse was included in the treatment field only when the primary tumor was located in the upper or middle lobe. The initial target volume was treated with a minimum dose of 50.4 Gy through anteroposterior/postero-anterior (AP-PA) fields, after which the RT field was reduced but included all detectable tumors (total dose, 69.6 Gy), using the combination of an anterior, lateral, and/or posterior oblique fields. Doses were specified at middepth at the central axis for parallel-opposed fields or at the intersection of the central axes for other techniques. The maximum dose to the spinal cord was 50.4 Gy. The maximum dose used was 21.6 Gy for the contralateral lung, 45.6 Gy for the entire heart, and 60 Gy for the esophagus. Two daily fractions of 1.2 Gy were administered 5 times a week with an interfraction interval of 4.5– 6 h. An interfraction interval of 4.5–5.0 h or 5.5– 6.0 h was nonrandomly assigned to each patient and under no circumstance was it allowed to change from the shorter to the longer interval and vice versa. Daily CHT was administered as a short i.v. infusion during the intervals between the two daily RT fractions, 3– 4 h after the first one (i.e., 1–2 h before the second one). The weekend CHT was
Hfx RT and concurrent CBDCA/VP 16 in Stage III NSCLC
also administered as short (30 min) i.v. infusion. No dose corrections were made for lung inhomogenities. No dose modification of either RT or CHT was allowed during treatment, but only temporary interruptions in the treatment course due to toxicity were allowed. The criteria for treatment response were as follows: complete response (CR) was defined as the disappearance for at least 4 weeks of all measurable or evaluable disease and the absence of new lesions. For measurable disease, partial response (PR) was defined as a 4-week reduction of more than 50% of the sum of the products of the cross-sectional diameters of all measurable lesions, together with the absence of new lesions. For evaluable lesions, PR was defined as a decrease in tumor size for at least 8 weeks. Stable disease (SD) was defined as a reduction of less than 50% or an increase of less than 25% in the sum of the products of the cross-sectional diameters of all measurable lesions and no clear pattern of either regression or progression of disease for at least 8 weeks. Progression of disease (PD) was defined as an increase of more than 25% in the sum of the products of the cross-sectional diameters of measured lesions, together with increase in evaluable disease or the appearance of new lesions. 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 (20). Statistical tests were based on a two-sided significance level. To allow detection of an increase in the 2-year survival rate from 30% to 50%, with a significance of 0.05 and a power of 80% (21), randomization of 192 patients was planned. With the same significance and power, this number of patients could also allow detection of a 1.6-fold increase in the MST. No interim analysis was planned during the trial and no early stopping rules were used. Differences between pairs of groups in response rate and incidence of toxicity were evaluated by Fisher’s Exact unless otherwise noted. Survival and relapse-free survival rates were calculated from the date of randomization by the Kaplan–Meier method, and differences between pairs of groups in survival curves were analyzed by the log–rank test. In calculating local progression-free and distant metastasis-free survival rates, patients who developed either type of failure were considered at risk for the other endpoint and censored at the time of last evaluation. All these statistical analyses were carried out by one of us (Y.S.), using the computer program HALBAU 4 (Gendaisuugakusha, Kyoto, Japan).
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Table 1. Patients characteristics Group I Group II Total (n ⫽ 98) (n ⫽ 97) (n ⫽ 195)
Characteristic Gender Age (years) KPS
Weight loss Stage
M F median range 50 60 70 80 90 100 ⬎5% ⱕ5% IIIA IIIB
Interfraction interval (h) 4.5 5.0 5.5 6.0
63 35 59 41–69 8 9 11 24 29 17 46 52 51 47
65 32 59 45–69 8 9 9 23 28 20 43 54 52 45
128 67 59 41–69 16 18 20 47 57 37 89 106 103 92
23 30 21 24
24 31 19 23
47 61 40 47
KPS ⫽ Karnofsky performance status.
treatment, and finding of second (concurrent) cancer before the start of treatment. Therefore, a total of 195 patients (Group I, 98; Group II, 97) were fully evaluable for response, survival, and toxicity. All patients completed treatment as planned, and no patient was lost to follow-up. Patient characteristics are given in Table 1. Response to treatment is given in Table 2. There was no difference in either CR or overall (CR ⫹ PR) response rates between the two treatment groups (p ⫽ 0.68). No difference was found regarding overall survival (MST: 20 vs. 22 months; 1-, 2-, 3-, and 5-year survival rates: 80%, 47%, 29%, and 20%, respectively vs. 78%, 49%, 34%, and 23%, respectively; p ⫽ 0.57) (Fig. 1). No difference was seen in local tumor control. The median time to local progression was 20 and 19 months, respectively, while 2- and 5-year local progression-free survival rates were 37% and 28%, respectively vs. 44% and 27%, respectively (p ⫽ 0.66) (Fig. 2). Also, there was no difference regarding distant metastasis control, with the median time to distant metastasis being 21 and 25 months, respectively, and 2- and 5-year distant metastasis-free survival being 45% and 29% vs. 51% and 34%, respectively (p ⫽ 0 .29) (Fig. 3). Table 2. Response to treatment Response
Group I (n ⫽ 98)
Group II (n ⫽ 97)
CR PR SD PD
54 (55%) 29 (30%) 11 (11%) 4 (4%)
58 (60%) 27 (28%) 10 (10%) 2 (2%)
RESULTS Between January 1992 and December 1994, a total of 198 patients were enrolled onto this study at the University Hospital, Kragujevac, Yugoslavia. Three patients (Group I, 1; Group II, 2) were excluded from the study due to heart attack on the second day of the treatment, voluntarily discontinuation of the treatment during the first weekend of
p ⫽ 0.68 by Fisher’s exact test. Abbreviations: CR ⫽ complete response; PR ⫽ partial response; SD ⫽ stable disase; PD ⫽ progression of disease.
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Fig. 1. Overall survival: Group I (solid line) and Group II (dotted line).
Acute high-grade (ⱖ 3) toxicity is shown in Table 3. There was no difference in the incidence of various nonhematologic toxicities between the two treatment groups, but patients treated with the weekend CHT had significantly higher hematologic toxicity (p ⫽ 0.0046). There were 4 patients with Grade 3 and 3 patients with Grade 4 leukopenia and 3 patients with Grade 3 and 2 with Grade 4 trombocytopenia in Group I. Corresponding figures for Group II were 8 patients with Grade 3 and 5 with Grade 4 leukopenia, and 10 patients with Grade 3 and 4 with Grade 4 trombocytopenia. Only 1 patient treated with weekend CHT experienced Grade 3 anemia. Late high-grade toxicity was not different between the two treatment groups (Table 3). Interruptions during the treatment course were noted in 6 (6%) patients in Group I (range, 7–10 days; median 8 days) and in 21 (21%) patients in Group II (range, 7–15 days; median,
Fig. 2. Local progression-free survival: Group I (solid line) and Group II (dotted line)
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Fig. 3. Distant metastasis-free survival: Group I (solid line) and Group II (dotted line).
11 days) (p ⫽ 0 .0018). The mean and SD for the periods of interruption was 8.2 ⫾ 1.2 days in Group I and 11.3 ⫾ 2.4 days in Group II (p ⫽ 0.0055, t test). The analysis of the relationship between weight loss and either survival or toxicity showed that there was no difference in survival. Only the difference in hematologic toxicity (acute) in patients with no weight loss was significant between Groups I and II (Fisher exact test, p ⫽ 0.0027). The difference in hematologic toxicity in patients with weight loss between the two groups was insignificant (Fisher exact test, p ⫽ 0.081). There were no differences in other toxicities when groups of patients were stratified according to the weight loss. DISCUSSION RT and CHT are considered the standard of care for patients with unresectable lung cancer. The optimal sequence/timing of these two modalities has been debated. The initial positive study published by Dillman et al. (22) and later confirmed by RTOG (11), show that induction CHT followed by RT was better than RT alone. Other studies have suggested that concurrent CHT with RT is better than RT alone. More recent trials have attempted to combine and compare concurrent with sequential programs. Trying to build on the results of CALGB 8433 study (22) that became the strongest advocate of efficacy of that approach, Clamon et al. (23) compared the same induction CHT consisting of cisplatin/vinblastine followed by standard RT (60 Gy in 30 daily fractions) with or without concurrent 100 mg/m2/week of carboplatin. There was no difference between the radiosensitized and nonradiosensitized groups regarding overall survival (MST: 13.4 vs. 13.5 months; 4-year survival: 13% vs. 10%; p ⫽ 0 .74). These results show a more sobering picture about induction cisplatin/vinblastine followed by standard RT that does not necessarily obtain good and
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Table 3. High Grade (ⱖ3) toxicity Acute high grade
Late high grade
Group I
Group II
Group I
Group II
Toxicity
Grade
(n ⫽ 98)
(n ⫽ 97)
(n ⫽ 98)
(n ⫽ 97)
Bronchopulmonary
3 4 3 4 3 4 3 3
8 4 11 4 7 5 0 2
9 4 12 5 19 9 0 3
6 3 6 3 – – 2 1
6 2 6 2 – – 2 1
Esophageal Hematologic Osseous Gastric
consistent results, being inferior in the study of Clamon et al. (23) to that expected from the previous two studies (10, 11, 22). Furthermore, the results of the study of Clamon et al. (23) are not different from those obtained by Hfx RT alone in the RTOG/ECOG study (11). Most recently, Furuse et al. (24) compared concurrent vs. sequential split course RT and mitomycin C, vindesine, and cisplatin in patients with unresectable Stage III NSCLC. The MST was significantly higher in the concurrent group (16.5 vs. 13.3 months; p ⫽ 0.040) as well as long-term survival (5-year survival rates: 16% vs. 9%). While the results of the sequential group are similar to those of previously published studies on the induction cisplatin/vinblastine plus standard RT (10, 11, 22) and those of the French multi-institutional study (9), the results of the concurrent group appear favorable in terms of both MST and long-term survival, offering additional evidence about effectiveness of concurrent RT/CHT in locally advanced NSCLC. Also, Ball et al. (25) evaluated standard (60 Gy in 30 daily fractions in 6 weeks) vs. accelerated Hfx RT (60 Gy in 30 fractions in 3 weeks) with or without concurrent carboplatin (70 mg/m2) given during either Weeks 1 and 5 (standard RT) or Week 1 (accelerated Hfx RT). For the 41 patients with Stage III disease treated with standard RT/ carboplatin, the MST was 17.0 months and estimated 1- and 2-year survivals were 63% and 29%, respectively, while the 5-year survival was 8%. Results of the current study appear to be similar to that of Ball et al. (25) regarding the MST (17 vs. 20 and 22 months), but 5-year survival appears superior in our study, results showing 20% and 23% for our two groups, respectively. Because the total carboplatin doses in the studies of Ball et al. (25) and in our study are similar (700 mg/m2 vs. 725 mg/m2), it seems that another possible explanation for our better long-term results may lie in our high-dose Hfx RT that may have had some advantage over the standard RT in the study of Ball et al. (25) as shown during the RTOG 8311 study (26). Other possible explanations may lie in the addition of etoposide and the more protracted way of administration of carboplatin/etoposide, as we used it in a low-dose, daily fashion. The MST of the standard RT/carboplatin of the study of Ball et al. (25) compares favorably to that of the study of Clamon et al. (23)
(17 vs. 13.5 months) and is similar to that of the Furuse et al. study (24) (16.5 months). In our continuous efforts to optimize the treatment approach in Stage III NSCLC, we underwent a Phase III trial of Hfx RT and concurrent low-dose, daily carboplatin/etoposide with or without weekend CHT consisting of carboplatin/etoposide doses higher than those given daily. No difference was seen in either overall survival, local control, or distant metastasis control. While the results obtained in the Hfx RT/low-dose, daily carboplatin/etoposide group appear to be similar to those obtained during our previous study (17), the results of the weekend approach appear to be somewhat inferior to those obtained during the initial Phase II study (MST: 22 vs. 25 months; 5-year survival: 23% vs. 29%) (18), which may not come as a surprise owing to the well-established worldwide experience when a Phase II study enters “a Phase III life.” Although not different in various nonhematologic aspects, hematologic toxicity was significantly higher with the weekend CHT, which gives another perspective to the overall results. One of the possible explanations for the lack of significant difference favoring the weekend approach may be the small difference in the total doses of both drugs we used. Although not in a usual way of administration, the total doses of both carboplatin and etoposide were higher in Group II for a total of 620 mg, which may roughly equal 350 mg/m2 or one full cycle of both drugs when given in a more conventional way (e.g., carboplatin, 350 mg/m2, Day 1; etoposide, 120 mg/m2, Days 1–3). It seems, therefore, that the effect of this “additional cycle,” as an advantage of the weekend CHT, may not be large, at least not as anticipated from the results of the previous Phase II study using the same regimen (18). In the light of existing toxicities, it is questionable whether any additional weekend CHT dose may substantially improve results without causing more toxicities, principally hematologic ones. However, the introduction of newer, “third generation” (27) drugs may be a reasonable approach. Initial experience with newer drugs (28 –31) raises hopes about applicability in this treatment setting and the possibility of concurrent administration with high-dose RT.
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Another explanation for the lack of significant difference favoring the weekend approach may lie in the possibility of less radiosensitizing effects because less amount of CHT was given on weekdays to Group II patients, and they received 40% less CHT on weekdays (30 mg vs. 50 mg per day), and in closer proximity to the Hfx RT than did Group I. Consistent with this possibility, Group II patients had a 1-month shorter median time to local progression than did Group I patients (Fig. 2). Conversely, although not significantly different, the MTDM was 4 months longer in Group II compared with Group I (Fig. 3), which suggests better systemic effects. This study has again showed that concurrent RT/CHT is a viable and efficient treatment approach in patients with Stage III NSCLC. With high-dose Hfx RT and low-dose daily platinum-based CHT, it is now possible to achieve an MST of 20 months and a 5-year survival of 20%. Toxicity can be tolerated well even with no bone marrow support when no additional but only low-dose, daily CHT is offered to these patients. The main aim of the RT and concurrent low-dose, daily CHT is improvement in local tumor control. This may be even further improved with the use of sophisticated tools of treatment
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planning and delivery (32–34) and possibly fortified with the introduction of new drugs (27–31). It is possible that local tumor control higher than we are achieving in Stage III NSCLC now, may be followed with a significant improvement in the distant metastasis control. This could happen, providing adequate time sequence, i.e., that there is enough time for improved local control to materialize in an improvement in the distant metastasis control, by simply making tumors that are now more locally controlled to be less prone to disseminate. An improvement in local tumor control could lead to better distant metastasis control and, therefore, to more substantial improvement in overall survival. As we have just seen this in the study on the use of high-dose Hfx RT and concurrent low-dose, daily CDDP in advanced head and neck cancer (35), this possibility may become a reality in Stage III NSCLC as well. Nevertheless, improved local control may not necessarily lead to better control of distant metastasis; it may, in fact, lead to a higher risk of distant metastasis, because patients with good local control live longer to manifest distant metastasis, indicating the need for better systemic treatment.
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31. 32. 33.
34. 35.
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in favorable patients with Radiation Therapy Oncology group stage III nonsmall cell lung carcinoma. Report of Radiation Therapy Oncology Group 83-11. J Clin Oncol 1990;8:1543– 1555. Greco FA, Hainsworth JD. Multidisciplinary approach to potentially curable non-small cell carcinoma of the lung. Oncology 1997;1:27–36. Mauer AM, Masters GA, Haraf DJ, et al. Phase I study of docetaxel with concomitant thoracic radiation therapy. J Clin Oncol 1998;16:159 –164. Herscher LL, Hahn SM, Kroog G, et al. Phase I study of paclitaxel as a radiation sensitizer in the treatment of mesothelioma, and non-small-cell lung cancer. J Clin Oncol 16:635– 641. Masters GA, Haraf DJ, Hoffman PC, et al. Phase I study of vinorelbine, cisplatin, and concomitant thoracic radiation in the treatment of advanced chest malignancies. J Clin Oncol 16:1998:2157–2163. Vokes EE, Gregor A, Turrisi AT. Gemcitabine and radiation therapy for non-small cell lung cancer. Semin Oncol 1998; 25(Suppl. 4):66 – 69. Graham MV, Purdy JA, Emami B, et al. Preliminary results of a prospective trial using three dimensional radiotherapy for lung cancer. Int J Radiat Oncol Biol Phys 1995;33:993–1000. Robertson JM, Ten Haken RK, Hazuka MB, et al. Dose escalation for non-small cell lung cancer using conformal radiation therapy. Int J Radiat Oncol Biol Phys 1997;37: 1079 –1085. Tsai JS, Wazer DE, Ling MN, et al. Dosimetric verification of the dynamic intensity-modulated radiation therapy of 92 patients. Int J Radiat Oncol Biol Phys 1998;40:1213–1220. Jeremic B, Shibamoto Y, Milicic B, et al. Hyperfractionated radiation therapy with or without concurrent low-dose cisplatin in locally advanced squamous cell carcinoma of the head and neck: A prospective randomized trial. J Clin Oncol 2000; 18:1458 –1464.
PII S0360-3016(00)01546-7
CLINICAL INVESTIGATION
Lung
HYPERFRACTIONATED RADIATION THERAPY AND CONCURRENT LOWDOSE, DAILY CARBOPLATIN/ETOPOSIDE WITH OR WITHOUT WEEKEND CARBOPLATIN/ETOPOSIDE CHEMOTHERAPY IN STAGE III NON–SMALLCELL LUNG CANCER: A RANDOMIZED TRIAL BRANISLAV JEREMIC, M.D., PH.D.,* YUTA SHIBAMOTO, M.D., D. M.SC.,† LJUBISA ACIMOVIC, M.D., M.SC.,‡ BILJANA MILICIC, M.D., M.SC.,* SLOBODAN MILISAVLJEVIC, M.D.,‡ NEBOJSA NIKOLIC, M.D.,* ALEKSANDAR DAGOVIC, M.D.,* JASNA ALEKSANDROVIC, M.D.,* AND GORDANA RADOSAVLJEVIC-ASIC, M.D., PH.D.§ Departments of *Oncology and ‡Surgery, University Hospital, Kragujevac, Yugoslavia; †Department of Oncology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan; §Institute for Lung Disease and TB, Belgrade, Yugoslavia Purpose: To investigate whether the addition of weekend chemotherapy consisting of carboplatin/etoposide to hyperfractionated radiation therapy (Hfx RT) and concurrent daily carboplatin/etoposide offers an advantage over the same Hfx RT/daily carboplatin/etoposide. Methods and Materials: A total of 195 patients (Group I, 98; Group II, 97) were treated with either Hfx RT to a total tumor dose of 69.6 Gy via 1.2 Gy b.i.d. fractionation and daily 50 mg each of carboplatin and etoposide during the RT course (Group I) or the same Hfx RT with daily carboplatin/etoposide consisting of 30 mg each of carboplatin and etoposide and with weekend (Saturdays and Sundays) 100 mg each of carboplatin and etoposide during the RT course (Group II). Results: No difference was found regarding median survival time and 5-year survival rates (20 vs. 22 months and 20% vs. 23%; p ⴝ 0.57). Median time to local progression was 20 and 19 months, respectively, while 5-year local progression-free survival rates were 28% and 27%, respectively (p ⴝ 0.66). Also, there was no difference regarding either median time to distant metastasis and 5-year distant metastasis-free survival (21 vs. 25 months and 29% vs. 34%, p ⴝ 0.29). There was no difference in the incidence of various nonhematologic toxicities between the two treatment groups, but patients treated with the weekend CHT had significantly more high-grade (> 3) hematologic toxicity (p ⴝ 0.0046). Late high-grade toxicity was not different between the two treatment groups. Conclusion: The addition of weekend carboplatin/etoposide did not improve results over those obtained with Hfx RT and concurrent low-dose, daily carboplatin/etoposide, but it led to a higher incidence of acute high-grade hematologic toxicity. © 2001 Elsevier Science Inc. Non–small-cell lung cancer, Radiotherapy, Hyperfractionation, Chemotherapy, Carboplatin, Etoposide.
INTRODUCTION Stage III non–small-cell lung cancer (NSCLC) represents one of the major challenges in thoracic oncology. Numerous studies of radiation therapy (RT) alone revealed distant metastasis to be an important pattern of failure (1–3). To improve treatment outcome, a number of strategies addressing this issue evolved in the last two decades. They include various combinations of RT and chemotherapy (CHT) with (4 – 8) or without (9 –14) surgery. The combination of the former two methods mostly concentrates around two approaches, assumed to be of the greatest benefit, namely, induction (neoadjuvant) CHT followed by RT and concur-
rent RT/CHT, although possibilities for alternating RT/CHT clearly exist. Expecting an improvement in survival obtained through an improvement in the distant metastasis control, induction CHT followed by radical, standard fraction RT became increasingly used owing to the results of the Cancer and Leukemia Group B (CALGB) Study 8433 (10) and the French multi-institutional study (9). They showed that induction CHT and standard fraction, radical RT are superior to RT alone. This largely affected the “standards of practice” around the world and led to the recommendations about its wider applicability (15). To further extend this issue, preliminary results of a joint Radiation Therapy On-
Reprint requests to: Dr. Branislav Jeremic, Department of Radiation Oncology, University Hospital, Hoppe-Seyler-Strasse 3, D-72076 Tuebingen, Germany. Tel: ⫹49-7071-298-2165; Fax: ⫹49-7071-295-894; E-mail: [email protected]
This study was supported in part by the Grant-in-Aid for Scientific Research (B) from the Japanese Ministry of Education, Science and Culture (10557087, 11470190, 11877152) Accepted for publication 30 October 2000. 19
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cology Group (RTOG)/Eastern Cooperative Oncology Group (ECOG) study also showed an advantage for the same (as CALGB 8433) induction CHT (two cycles of cisplatin and vinblastine) followed by standard fraction radical RT over not just the same radical RT, but high-dose hyperfractionated (Hfx) RT as well (11). This approach, however, while being successful in addressing the issue of distant metastasis, does not successfully address the issue of the control of the local (intrathoracic) disease, which has been shown to be as low as 17% after 1 year when pathologic evaluation was used (9). The local tumor control, however, is the major focus of the concurrent RT/CHT regimens. Both approaches carry an increase in the toxicity, which appeared somewhat higher in concurrent regimens. Our previous studies in Stage III NSCLC showed that high-dose Hfx RT can be successfully combined with concurrent chemotherapy consisting of carboplatin and etoposide (16, 17). We have identified a regimen consisting of 69.6 Gy via 1.2 Gy b.i.d. fractionation and 50 mg of daily dose of both carboplatin and etoposide as an efficient treatment regimen (median survival time [MST] ⫽ 22 months; 4-year survival ⫽ 23%) with acceptable toxicity (17), much lower than that observed when higher doses of platinating agents alone or with other agents are used (12–14, 16). However, the issue of controlling the distant metastasis may not have been properly addressed by that study design, which led us to opening a Phase II study on the use of somewhat lower daily dose of carboplatin/etoposide (reduced from 50 mg each to 30 mg each of carboplatin and etoposide, both given daily) but with somewhat higher weekend (Saturdays and Sundays) doses of both carboplatin and etoposide (100 mg each), to optimize the treatment of presumed micrometastasis present from the outset (18). Because the early experience with the latter approach was favorable, we underwent a prospective randomized trial in which we compared the high-dose Hfx RT and concurrent low-dose carboplatin/etoposide with the same approach including lower daily doses of carboplatin/etoposide and higher weekend doses of carboplatin/etoposide as applied in our Phase II study (18). METHODS AND MATERIALS Eligibility criteria included age of 18 years or older, histologically or cytologically confirmed, advanced NSCLC classified as Stage IIIA or IIIB by the International System (19), a Karnofsky performance status (KPS) score of at least 50%, and no previous therapy. Patients were excluded if they had postoperative thoracic recurrence or a history of any prior or concurrent cancer (except that of the skin), unless the patient had shown no evidence of disease for more than 5 years. Patients with malignant pleural effusion were also excluded. The pretreatment evaluation included medical history, physical examination, complete blood count, biochemical screening tests, postero-anterior and lateral chest radiographs, and computed tomography (CT) scans of the thorax and upper abdomen as well as abdominal
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ultrasound and bone radionuclide scan. Brain CT scan and pulmonary function tests were strongly recommended and performed when possible. No patient underwent mediastinoscopy for the purpose of staging. The patients were randomly divided into the following groups: Group I, Hfx RT with 1.2 Gy twice daily with a total dose of 69.6 Gy and carboplatin and etoposide, both given as 50 mg daily during the RT course, Mondays to Fridays. In Group II, the same Hfx RT regimen was administered with daily CHT consisting of 30 mg each of carboplatin and etoposide during the RT course (Mondays to Fridays), plus weekend CHT consisting of 100 mg each of carboplatin and etoposide, both given on Saturdays and Sundays during the RT course. The weekly dose for carboplatin and etoposide was 250 mg in Group I, while, in the Group II, it was 350 mg. This study was performed after approval was obtained from the Institutional Ethics Committee. Informed consent was obtained from all patients. The patients were examined at the end of Hfx RT, every month for 6 months after the completion of Hfx RT, every 2 months for 2 years thereafter, and every 4 months thereafter. Complete blood counts, biochemical tests, and chest radiographs were performed at each visit. Pathologic verifications were not performed routinely but were recommended if signs of tumor persistence or recurrence were present. Restaging at the time of any progression was performed by using all procedures outlined above and radiography of the bones, whenever necessary. RT was administered with 6 –10 MV photons using linear accelerators. The primary tumor was encompassed with a minimum 2-cm margin, as was the entire mediastinum from the suprasternal notch to a level 6 cm below the carina (upper and middle lobe lesions) or to the diaphragm (lower lobe lesions); the ipsilateral hilum was encompassed with a 2-cm margin and the contralateral hilum with a 1-cm margin. The ipsilateral supraclavicular fosse was included in the treatment field only when the primary tumor was located in the upper or middle lobe. The initial target volume was treated with a minimum dose of 50.4 Gy through anteroposterior/postero-anterior (AP-PA) fields, after which the RT field was reduced but included all detectable tumors (total dose, 69.6 Gy), using the combination of an anterior, lateral, and/or posterior oblique fields. Doses were specified at middepth at the central axis for parallel-opposed fields or at the intersection of the central axes for other techniques. The maximum dose to the spinal cord was 50.4 Gy. The maximum dose used was 21.6 Gy for the contralateral lung, 45.6 Gy for the entire heart, and 60 Gy for the esophagus. Two daily fractions of 1.2 Gy were administered 5 times a week with an interfraction interval of 4.5– 6 h. An interfraction interval of 4.5–5.0 h or 5.5– 6.0 h was nonrandomly assigned to each patient and under no circumstance was it allowed to change from the shorter to the longer interval and vice versa. Daily CHT was administered as a short i.v. infusion during the intervals between the two daily RT fractions, 3– 4 h after the first one (i.e., 1–2 h before the second one). The weekend CHT was
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also administered as short (30 min) i.v. infusion. No dose corrections were made for lung inhomogenities. No dose modification of either RT or CHT was allowed during treatment, but only temporary interruptions in the treatment course due to toxicity were allowed. The criteria for treatment response were as follows: complete response (CR) was defined as the disappearance for at least 4 weeks of all measurable or evaluable disease and the absence of new lesions. For measurable disease, partial response (PR) was defined as a 4-week reduction of more than 50% of the sum of the products of the cross-sectional diameters of all measurable lesions, together with the absence of new lesions. For evaluable lesions, PR was defined as a decrease in tumor size for at least 8 weeks. Stable disease (SD) was defined as a reduction of less than 50% or an increase of less than 25% in the sum of the products of the cross-sectional diameters of all measurable lesions and no clear pattern of either regression or progression of disease for at least 8 weeks. Progression of disease (PD) was defined as an increase of more than 25% in the sum of the products of the cross-sectional diameters of measured lesions, together with increase in evaluable disease or the appearance of new lesions. 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 (20). Statistical tests were based on a two-sided significance level. To allow detection of an increase in the 2-year survival rate from 30% to 50%, with a significance of 0.05 and a power of 80% (21), randomization of 192 patients was planned. With the same significance and power, this number of patients could also allow detection of a 1.6-fold increase in the MST. No interim analysis was planned during the trial and no early stopping rules were used. Differences between pairs of groups in response rate and incidence of toxicity were evaluated by Fisher’s Exact unless otherwise noted. Survival and relapse-free survival rates were calculated from the date of randomization by the Kaplan–Meier method, and differences between pairs of groups in survival curves were analyzed by the log–rank test. In calculating local progression-free and distant metastasis-free survival rates, patients who developed either type of failure were considered at risk for the other endpoint and censored at the time of last evaluation. All these statistical analyses were carried out by one of us (Y.S.), using the computer program HALBAU 4 (Gendaisuugakusha, Kyoto, Japan).
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Table 1. Patients characteristics Group I Group II Total (n ⫽ 98) (n ⫽ 97) (n ⫽ 195)
Characteristic Gender Age (years) KPS
Weight loss Stage
M F median range 50 60 70 80 90 100 ⬎5% ⱕ5% IIIA IIIB
Interfraction interval (h) 4.5 5.0 5.5 6.0
63 35 59 41–69 8 9 11 24 29 17 46 52 51 47
65 32 59 45–69 8 9 9 23 28 20 43 54 52 45
128 67 59 41–69 16 18 20 47 57 37 89 106 103 92
23 30 21 24
24 31 19 23
47 61 40 47
KPS ⫽ Karnofsky performance status.
treatment, and finding of second (concurrent) cancer before the start of treatment. Therefore, a total of 195 patients (Group I, 98; Group II, 97) were fully evaluable for response, survival, and toxicity. All patients completed treatment as planned, and no patient was lost to follow-up. Patient characteristics are given in Table 1. Response to treatment is given in Table 2. There was no difference in either CR or overall (CR ⫹ PR) response rates between the two treatment groups (p ⫽ 0.68). No difference was found regarding overall survival (MST: 20 vs. 22 months; 1-, 2-, 3-, and 5-year survival rates: 80%, 47%, 29%, and 20%, respectively vs. 78%, 49%, 34%, and 23%, respectively; p ⫽ 0.57) (Fig. 1). No difference was seen in local tumor control. The median time to local progression was 20 and 19 months, respectively, while 2- and 5-year local progression-free survival rates were 37% and 28%, respectively vs. 44% and 27%, respectively (p ⫽ 0.66) (Fig. 2). Also, there was no difference regarding distant metastasis control, with the median time to distant metastasis being 21 and 25 months, respectively, and 2- and 5-year distant metastasis-free survival being 45% and 29% vs. 51% and 34%, respectively (p ⫽ 0 .29) (Fig. 3). Table 2. Response to treatment Response
Group I (n ⫽ 98)
Group II (n ⫽ 97)
CR PR SD PD
54 (55%) 29 (30%) 11 (11%) 4 (4%)
58 (60%) 27 (28%) 10 (10%) 2 (2%)
RESULTS Between January 1992 and December 1994, a total of 198 patients were enrolled onto this study at the University Hospital, Kragujevac, Yugoslavia. Three patients (Group I, 1; Group II, 2) were excluded from the study due to heart attack on the second day of the treatment, voluntarily discontinuation of the treatment during the first weekend of
p ⫽ 0.68 by Fisher’s exact test. Abbreviations: CR ⫽ complete response; PR ⫽ partial response; SD ⫽ stable disase; PD ⫽ progression of disease.
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Fig. 1. Overall survival: Group I (solid line) and Group II (dotted line).
Acute high-grade (ⱖ 3) toxicity is shown in Table 3. There was no difference in the incidence of various nonhematologic toxicities between the two treatment groups, but patients treated with the weekend CHT had significantly higher hematologic toxicity (p ⫽ 0.0046). There were 4 patients with Grade 3 and 3 patients with Grade 4 leukopenia and 3 patients with Grade 3 and 2 with Grade 4 trombocytopenia in Group I. Corresponding figures for Group II were 8 patients with Grade 3 and 5 with Grade 4 leukopenia, and 10 patients with Grade 3 and 4 with Grade 4 trombocytopenia. Only 1 patient treated with weekend CHT experienced Grade 3 anemia. Late high-grade toxicity was not different between the two treatment groups (Table 3). Interruptions during the treatment course were noted in 6 (6%) patients in Group I (range, 7–10 days; median 8 days) and in 21 (21%) patients in Group II (range, 7–15 days; median,
Fig. 2. Local progression-free survival: Group I (solid line) and Group II (dotted line)
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Fig. 3. Distant metastasis-free survival: Group I (solid line) and Group II (dotted line).
11 days) (p ⫽ 0 .0018). The mean and SD for the periods of interruption was 8.2 ⫾ 1.2 days in Group I and 11.3 ⫾ 2.4 days in Group II (p ⫽ 0.0055, t test). The analysis of the relationship between weight loss and either survival or toxicity showed that there was no difference in survival. Only the difference in hematologic toxicity (acute) in patients with no weight loss was significant between Groups I and II (Fisher exact test, p ⫽ 0.0027). The difference in hematologic toxicity in patients with weight loss between the two groups was insignificant (Fisher exact test, p ⫽ 0.081). There were no differences in other toxicities when groups of patients were stratified according to the weight loss. DISCUSSION RT and CHT are considered the standard of care for patients with unresectable lung cancer. The optimal sequence/timing of these two modalities has been debated. The initial positive study published by Dillman et al. (22) and later confirmed by RTOG (11), show that induction CHT followed by RT was better than RT alone. Other studies have suggested that concurrent CHT with RT is better than RT alone. More recent trials have attempted to combine and compare concurrent with sequential programs. Trying to build on the results of CALGB 8433 study (22) that became the strongest advocate of efficacy of that approach, Clamon et al. (23) compared the same induction CHT consisting of cisplatin/vinblastine followed by standard RT (60 Gy in 30 daily fractions) with or without concurrent 100 mg/m2/week of carboplatin. There was no difference between the radiosensitized and nonradiosensitized groups regarding overall survival (MST: 13.4 vs. 13.5 months; 4-year survival: 13% vs. 10%; p ⫽ 0 .74). These results show a more sobering picture about induction cisplatin/vinblastine followed by standard RT that does not necessarily obtain good and
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Table 3. High Grade (ⱖ3) toxicity Acute high grade
Late high grade
Group I
Group II
Group I
Group II
Toxicity
Grade
(n ⫽ 98)
(n ⫽ 97)
(n ⫽ 98)
(n ⫽ 97)
Bronchopulmonary
3 4 3 4 3 4 3 3
8 4 11 4 7 5 0 2
9 4 12 5 19 9 0 3
6 3 6 3 – – 2 1
6 2 6 2 – – 2 1
Esophageal Hematologic Osseous Gastric
consistent results, being inferior in the study of Clamon et al. (23) to that expected from the previous two studies (10, 11, 22). Furthermore, the results of the study of Clamon et al. (23) are not different from those obtained by Hfx RT alone in the RTOG/ECOG study (11). Most recently, Furuse et al. (24) compared concurrent vs. sequential split course RT and mitomycin C, vindesine, and cisplatin in patients with unresectable Stage III NSCLC. The MST was significantly higher in the concurrent group (16.5 vs. 13.3 months; p ⫽ 0.040) as well as long-term survival (5-year survival rates: 16% vs. 9%). While the results of the sequential group are similar to those of previously published studies on the induction cisplatin/vinblastine plus standard RT (10, 11, 22) and those of the French multi-institutional study (9), the results of the concurrent group appear favorable in terms of both MST and long-term survival, offering additional evidence about effectiveness of concurrent RT/CHT in locally advanced NSCLC. Also, Ball et al. (25) evaluated standard (60 Gy in 30 daily fractions in 6 weeks) vs. accelerated Hfx RT (60 Gy in 30 fractions in 3 weeks) with or without concurrent carboplatin (70 mg/m2) given during either Weeks 1 and 5 (standard RT) or Week 1 (accelerated Hfx RT). For the 41 patients with Stage III disease treated with standard RT/ carboplatin, the MST was 17.0 months and estimated 1- and 2-year survivals were 63% and 29%, respectively, while the 5-year survival was 8%. Results of the current study appear to be similar to that of Ball et al. (25) regarding the MST (17 vs. 20 and 22 months), but 5-year survival appears superior in our study, results showing 20% and 23% for our two groups, respectively. Because the total carboplatin doses in the studies of Ball et al. (25) and in our study are similar (700 mg/m2 vs. 725 mg/m2), it seems that another possible explanation for our better long-term results may lie in our high-dose Hfx RT that may have had some advantage over the standard RT in the study of Ball et al. (25) as shown during the RTOG 8311 study (26). Other possible explanations may lie in the addition of etoposide and the more protracted way of administration of carboplatin/etoposide, as we used it in a low-dose, daily fashion. The MST of the standard RT/carboplatin of the study of Ball et al. (25) compares favorably to that of the study of Clamon et al. (23)
(17 vs. 13.5 months) and is similar to that of the Furuse et al. study (24) (16.5 months). In our continuous efforts to optimize the treatment approach in Stage III NSCLC, we underwent a Phase III trial of Hfx RT and concurrent low-dose, daily carboplatin/etoposide with or without weekend CHT consisting of carboplatin/etoposide doses higher than those given daily. No difference was seen in either overall survival, local control, or distant metastasis control. While the results obtained in the Hfx RT/low-dose, daily carboplatin/etoposide group appear to be similar to those obtained during our previous study (17), the results of the weekend approach appear to be somewhat inferior to those obtained during the initial Phase II study (MST: 22 vs. 25 months; 5-year survival: 23% vs. 29%) (18), which may not come as a surprise owing to the well-established worldwide experience when a Phase II study enters “a Phase III life.” Although not different in various nonhematologic aspects, hematologic toxicity was significantly higher with the weekend CHT, which gives another perspective to the overall results. One of the possible explanations for the lack of significant difference favoring the weekend approach may be the small difference in the total doses of both drugs we used. Although not in a usual way of administration, the total doses of both carboplatin and etoposide were higher in Group II for a total of 620 mg, which may roughly equal 350 mg/m2 or one full cycle of both drugs when given in a more conventional way (e.g., carboplatin, 350 mg/m2, Day 1; etoposide, 120 mg/m2, Days 1–3). It seems, therefore, that the effect of this “additional cycle,” as an advantage of the weekend CHT, may not be large, at least not as anticipated from the results of the previous Phase II study using the same regimen (18). In the light of existing toxicities, it is questionable whether any additional weekend CHT dose may substantially improve results without causing more toxicities, principally hematologic ones. However, the introduction of newer, “third generation” (27) drugs may be a reasonable approach. Initial experience with newer drugs (28 –31) raises hopes about applicability in this treatment setting and the possibility of concurrent administration with high-dose RT.
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Another explanation for the lack of significant difference favoring the weekend approach may lie in the possibility of less radiosensitizing effects because less amount of CHT was given on weekdays to Group II patients, and they received 40% less CHT on weekdays (30 mg vs. 50 mg per day), and in closer proximity to the Hfx RT than did Group I. Consistent with this possibility, Group II patients had a 1-month shorter median time to local progression than did Group I patients (Fig. 2). Conversely, although not significantly different, the MTDM was 4 months longer in Group II compared with Group I (Fig. 3), which suggests better systemic effects. This study has again showed that concurrent RT/CHT is a viable and efficient treatment approach in patients with Stage III NSCLC. With high-dose Hfx RT and low-dose daily platinum-based CHT, it is now possible to achieve an MST of 20 months and a 5-year survival of 20%. Toxicity can be tolerated well even with no bone marrow support when no additional but only low-dose, daily CHT is offered to these patients. The main aim of the RT and concurrent low-dose, daily CHT is improvement in local tumor control. This may be even further improved with the use of sophisticated tools of treatment
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planning and delivery (32–34) and possibly fortified with the introduction of new drugs (27–31). It is possible that local tumor control higher than we are achieving in Stage III NSCLC now, may be followed with a significant improvement in the distant metastasis control. This could happen, providing adequate time sequence, i.e., that there is enough time for improved local control to materialize in an improvement in the distant metastasis control, by simply making tumors that are now more locally controlled to be less prone to disseminate. An improvement in local tumor control could lead to better distant metastasis control and, therefore, to more substantial improvement in overall survival. As we have just seen this in the study on the use of high-dose Hfx RT and concurrent low-dose, daily CDDP in advanced head and neck cancer (35), this possibility may become a reality in Stage III NSCLC as well. Nevertheless, improved local control may not necessarily lead to better control of distant metastasis; it may, in fact, lead to a higher risk of distant metastasis, because patients with good local control live longer to manifest distant metastasis, indicating the need for better systemic treatment.
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