Thoracic Radiation Therapy for Limited-Stage Small-Cell Lung Cancer: Unanswered Questions

comprehensive revie w Thoracic Radiation Therapy for Limited-Stage Small-Cell Lung Cancer: Unanswered Questions Corinne Faivre-Finn,1 Paul Lorigan,2 Catharine West,3 Nick Thatcher2 Abstract The role of thoracic radiation therapy (RT; TRT) is now established in the management of limited-stage small-cell lung cancer (SCLC). There is increasing evidence in the literature in favor of early concurrent chemoradiation therapy, and a gold standard of care for patients with a good performance status is twice-daily TRT (45 Gy in 3 weeks) with concurrent cisplatin/etoposide. Five-year survival rates > 20% can be expected with this combined-modality approach. Although current clinical trials are exploring the efficacy of new chemotherapeutic strategies for the disease, essential questions related to the optimization of TRT remain unanswered. In particular, the optimal RT dose, fractionation, and treatment volume have not been defined. This review highlights the need for well-designed multinational trials aimed at the optimization and standardization of RT for limited-stage SCLC. These trials should integrate translational research studies to investigate the molecular basis of RT resistance and to develop biomarker profiles of prognosis. Clinical Lung Cancer, Vol. 7, No. 1, 23-29, 2005

Key words: Chemoradiation therapy, Cisplatin, Concurrent therapy, Etoposide, Fractionation, Sequential therapy

Introduction

Combination chemotherapy alone is associated with intrathoracic failure rates of 75%-90%. The addition of thoracic irradiation reduces the risk of intrathoracic failure to 30%-60% but does not always translate into a survival advantage.2-7 However, 2 metaanalyses published in 1992 show a statistically significant advantage associated with the addition of TRT to chemotherapy.8,9 The reduction in the rate of local relapses with TRT is 50%, and the absolute long-term survival gain is approximately 5%. There was a trend toward a greater reduction in mortality among younger patients: the relative risk of death in the combined-therapy group compared with the chemotherapy group ranged from 0.72 for patients < 55 years of age (95% CI, 0.56-0.93) to 1.07 for patients > 70 years of age (95% CI, 0.70-1.64).8 Although the role of TRT is now well established in the management of limited-stage SCLC, several important questions remain unanswered:

At the time of diagnosis, approximately 30% of patients with small-cell lung cancer (SCLC) will have tumors confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes.1 These patients are designated as having limitedstage disease, and most long-term disease-free survivors come from this group. However, despite excellent response rates to chemotherapy and radiation therapy (RT), the majority of patients will have local relapse and/or with distant metastasis. In patients with limited-stage disease, a median survival of 16-24 months with current forms of treatment can be reasonably expected. Radiation therapy plays an important role in the management of limited-stage SCLC. Randomized trials have shown that thoracic RT (TRT) and prophylactic cranial irradiation (PCI) improve tumor control and overall survival (OS). 1Clinical Oncology Department 2Medical Oncology Department 3Academic Department of Radiation Oncology

Christie Hospital NHS Trust, Manchester, UK Submitted: Feb 17, 2005; Revised: Apr 27, 2005; Accepted: Jun 9, 2005 Address for correspondence: Corinne Faivre-Finn, MD, PhD, Christie Hospital, Wilmslow Rd, Withington, Manchester M20 4BX, UK Fax: 44-161-4468142; e-mail: [email protected]

• What is the optimal total radiation dose? • What is the optimal radiation fractionation? • What is the optimal timing of radiation? • What is the optimal sequencing of radiation? • What is the optimal volume of radiation? • Is elective nodal irradiation necessary?

Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1525-7304, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.

Clinical Lung Cancer July 2005

23

Thoracic RT for Limited-Stage SCLC Table 1

Timing and Sequencing of Thoracic Radiation Therapy10-18

Study

Number Timing of of Patients Thoracic RT

Prophylactic Cranial Irradiation

Survival , %

Median Survival (Months)

Murray et al, 199310

308

Day 22 (C) Day 106 (C)

Yes Yes

20 (5-Year) 11 (5-Year)

21.2 16

Lebeau et al, 199311

156

Day 30 (C) Day 36 (A)

Yes Yes

6 (3-Year) 11 (3-Year)

13.5 14

Work et al, 199712

199

Day 1 (A) Day 120 (A)

Yes Yes

10.8 (5-Year) 12 (5-Year)

10.5 12

Gregor et al, 199713

334

Day 43 (A) Day 99 (S)

Not mandatory –

12 (3-Year) 15 (3-Year)

14 15

Jeremic et al, 199714

103

Day 1 (C) Day 43 (C)

Yes Yes

30 (5-Year) 15 (5-Year)

34 26

Perry et al, 199815

270

Day 1 (C) Day 64 (C)

Yes Yes

6.6 (5-Year) 12.8 (5-Year)

13 14.5

Skarlos et al, 200116

81

Day 1 (C) Day 64 (C)

CR only –

22 (3-Year) 13 (3-Year)

17.5 17

Takada et al, 200217

228

Day 2 (C) After cycle 4 (S)

In CR or near CR –

23.7 (5-Year) 18.3 (5-Year)

27.2 19.7

James et al, 200318

325

Day 22 (C) Day 106 (C)

Yes Yes

16 (3-Year) 20 (3-Year)

13.5 15.1

Abbreviations: A = alternating; C = concurrent; S = sequential

• Can conformal RT decrease the toxicity of concurrent chemoradiation therapy? • Is twice-daily concurrent chemoradiation therapy the “gold standard”? • Can we identify patients likely to respond to RT? This article is not exhaustive. Other authors have published excellent reviews on TRT and SCLC. Our aim is to provide an up-to-date view of recent developments and future directions.

Difficulties in Interpreting Limited-Stage Small-Cell Lung Cancer Clinical Trials Before interpreting the results of clinical trials that address the above questions in limited-stage SCLC, several general remarks should be made. The survival benefit expected with the introduction of improved RT is small (in the order of 5%-10%) but worthwhile. Significant statistical differences between treatment arms can be demonstrated only by large randomized controlled trials. The majority of the trials done in this field were unfortunately underpowered because of the small number of patients included (Table 1).10-18 For example, the Takada et al trial comparing concurrent to sequential chemoradiation therapy included only 228 patients and was powered to detect a 50% improvement in median survival.17 The poor compliance to treatment in some SCLC trials can represent a major obstacle in demonstrating a small treatment effect. Indeed, among the trials comparing early versus late thoracic irradiation, significant reductions in chemotherapy doses were reported.12,13,15 These trials failed to show the superiority of early thoracic irradiation. In contrast, the Intergroup study comparing twice-daily with once-daily early tho-

24

Clinical Lung Cancer July 2005

racic RT did not allow for chemotherapy delays or dose reductions during the first 5 weeks of treatment.19 This could explain the improved survival results. Most randomized clinical trials addressing the role of thoracic RT to date have used 2-dimensional radiation planning and delivery. Reviews of trials in lung cancer have suggested suboptimal tumor coverage, probably as a result of the unavailability of computed tomography (CT)–based treatment planning.20 Consequently, if we assume that such errors were equally distributed among the arms, the apparent differences between treatments can become minimal. Finally, it is important to be aware of the variability in trial designs and populations studied when comparing different clinical trials. Indeed, the definition of early thoracic RT, the number of cycles of chemotherapy, the type of chemotherapy agents delivered, and the use of PCI are extremely variable.

Total Dose of Radiation Therapy Historically, SCLC is treated with lower doses of radiation than non–small-cell lung carcinoma, because patients receive initial chemotherapy and SCLC is considered to be a radiationsensitive disease.21 Indeed, in vitro irradiation of SCLC lines has generally shown a greater intrinsic radiation sensitivity than adenocarcinoma or squamous cell lung cancer cell lines. However, although improved chemotherapy increases the control of distant metastases, low-dose schedules, such as 30 Gy in 10 fractions, are associated with a high frequency of local failure.22 In a randomized trial, 37.5 Gy was superior to 25 Gy in terms of local control.23 In addition, retrospective studies suggest that TRT doses of ≥ 50 Gy can translate into improved progressionfree survival,22,24,25 but an impact on OS has yet to be demonstrated. In a phase I study of TRT given concurrently with cisplatin and etoposide, the maximum tolerated doses were 45 Gy in 30 fractions over 3 weeks and ≥ 70 Gy in 35 fractions over 7 weeks for daily RT.26 Thoracic RT commenced at the start of the fourth cycle of chemotherapy. The dose-limiting toxicity was grade ≥ 4 esophagitis, seen in 2 of 7 patients (29%) receiving twice-daily RT and 2 of 6 patients (33%) receiving oncedaily RT. No grade ≥ 3 pneumonitis was observed. A landmark study by Turrisi et al showed that 45 Gy given twice a day over 3 weeks was superior to 45 Gy delivered once a day over 5 weeks in terms of local control and OS.19 For patients receiving twice-daily RT, the 5-year survival rate was 26% versus 16% in the once-daily arm (P = 0.04). As expected, the toxicity was higher in the twice-daily arm, with 27% of patients experiencing grade 3 esophagitis compared with 11% in the once-daily arm (P < 0.001). It is unclear whether the bet-

Corinne Faivre-Finn et al Table 2

Phase III Randomized Controlled Trials of Hyperfractionated Thoracic Radiation Therapy14,17,19,30

Study

No. of Patients

Chemotherapy Regimen

Radiation Therapy Regimen

5-Year Survival, %

Grade 3/4 Esophagitis, %

Bonner et al30

262

Cisplatin/Etoposide

48 Gy, 1.5 Gy twice daily, weeks 13-14 and 17-18 50.4 Gy, 1.8 Gy once daily, weeks 13-18

22 21

12.3 5.3

Takada et al17

228

Cisplatin/Etoposide

45 Gy, 1.5 Gy twice daily, weeks 1-3 45 Gy, 1.5 Gy twice daily after week 10

23.7 18.3

9 4

Jeremic et al14

103

Carboplatin/Etoposide

54 Gy, 1.5 Gy twice daily, weeks 1-4 54 Gy, 1.5 Gy twice daily, weeks 6-9

30 15

15 13

Turrisi19

417

Cisplatin/Etoposide

45 Gy, 1.5 Gy twice daily, weeks 1-3 45 Gy, 1.8 Gy once daily, weeks 1-5

26 16

32 16

ter results in the twice-daily arm are explained by the increase in the total dose of radiation or by the use of altered fractionation leading to a shorter overall treatment time. Indeed, the study of Turrisi et al reported a high rate of local thoracic relapse in the once-daily arm: 52% versus 36% in the twicedaily arm (P = 0.06). This observation suggests that the dose in the once-daily arm was suboptimal. Doses ≥ 60 Gy should be evaluated against the regimen of the twice-daily arm of the Turrisi et al study to demonstrate a dose effect in the management of limited-stage SCLC. We may need to move away from the concept that intrinsic radiation sensitivity correlates with high local control rates. Doses similar to the doses given to non–small-cell cancers may be necessary to improve local control and OS.

Radiation Fractionation Conventional RT fractionation can be modified by hyperfractionation (RT given more than once a day) and/or acceleration (shortening of the overall treatment time). The use of small doses per fraction will diminish late normal tissue damage. An advantage of accelerated RT is the ability to avoid the detrimental effects of accelerated tumor cell repopulation,22,28 which occurs in limited-stage SCLC.29 The main disadvantages of hyperfractionation for patients are inconvenience and increased acute toxicity, mainly radiation esophagitis. Accelerated RT is also associated with increased acute toxicity. Studies on SCLC cell lines showed a small “shoulder” on radiation survival curves and low surviving fractions at 2 Gy.21 These observations suggest that SCLC could be sensitive to, and thus benefit from, the lower doses used in hyperfractionated RT. Table 2 summarizes the randomized phase III studies involving hyperfractionated TRT in patients with limited-stage SCLC. Five-year survival rates > 20% are reported with twicedaily RT with concurrent chemotherapy. Two phase III randomized trials compared hyperfractionated with conventional once-daily fractionated TRT. Turrisi et al compared 45 Gy given twice daily (1.5 Gy per fraction) over 3 weeks or once daily (1.8 Gy per fraction) over 5 weeks.19 Radiation was given concurrently starting with the first cycle of chemotherapy. Twice-daily RT improved 5-year OS (26% vs. 16% in the oncedaily arm) but increased the rate of grade 3 radiation esophagitis. However, there were no other significant differences in acute toxicity between the 2 arms and no long-term esophageal stric-

tures. The North Central Cancer Treatment Group also compared twice-daily with once-daily fractionation, but the design of the study was different.30,31 Thoracic RT was given concurrently with the fourth and fifth cycles of chemotherapy. Patients were randomized to receive 48 Gy in 32 fractions in the twicedaily arm with a 2.5-week split after the initial 24 Gy or 50.4 Gy in 28 fractions in the once-daily arm. The twice-daily RT took as long to deliver as conventional once-daily RT in this study (overall RT treatment time was 38 days in both arms), resulting in no overall acceleration in the hyperfractionated arm. Potential weaknesses in this approach are that tumor repopulation is likely to occur during the break in treatment29 and the delay in starting TRT allows for chemotherapy-resistant clones to develop. No differences in local control or OS were reported in this trial. This finding highlights the importance of overall treatment time in determining local control and survival. A phase III prospective randomized trial comparing hyperfractionated accelerated twice-daily RT with a daily dose administered at or near the maximum tolerated dose should clarify whether the total dose delivered is as important as the overall treatment time in the management of limited-stage SCLC.

Sequencing and Timing of Thoracic Radiation Therapy Numerous clinical trials have explored the optimal timing and sequencing of TRT. Chemotherapy and RT can be delivered concurrently, sequentially, or as alternating treatment. Traditionally, TRT has been given sequentially after completion of chemotherapy, mainly because some of the chemotherapy drugs, such as doxorubicin and methotrexate, used before the cisplatin and etoposide era were associated with high complication rates when given concurrently with TRT. A number of questions are raised when considering the optimal timing of chemotherapy and RT.

Is Early Radiation Therapy Better than Late Radiation Therapy? Early TRT could be better than delayed TRT for a number of reasons. Early delivery of RT could reduce the emergence of chemotherapy-resistant tumor cells that would subsequently be responsible for treatment failure, and early treatment could minimize the capacity of tumors to undergo accelerated repopulation. The advantage of delayed RT includes the possibility of irradiat-

Clinical Lung Cancer July 2005

25

Thoracic RT for Limited-Stage SCLC ing a smaller volume of normal tissue if the postchemotherapy volume is treated, resulting in less toxicity. Furthermore, the increased toxicity associated with early concurrent treatment could compromise the chance of maintaining the dose intensity of the chemotherapy and/or the total number of cycles delivered.12,15 Nine randomized phase III trials10-18 have addressed this question and are summarized in Table 1. They will not be detailed in this review article, because other authors have extensively done this.32,33,34 These 9 trials all have different designs and variable definitions of limited-stage disease, which makes comparison difficult. The definition of early RT is also variable, but the latest start date was day 57 after the first cycle of chemotherapy.13 It is important to note that not all patients received PCI, which could have a bearing on the survival figures. In the National Cancer Institute of Canada (NCIC) trial, 308 eligible patients received cyclophosphamide/doxorubicin/vincristine alternating with a platinum agent and etoposide every 3 weeks for 3 cycles of each regimen.10 Patients were randomized to receive early (week 3, concurrent with cycle 2) or late thoracic irradiation (week 15, concurrent with cycle 6). Progression-free survival and OS were superior in the early thoracic irradiation arm. The trials by Jeremic et al and Takada et al showed a trend in this direction.14,17 It should be noted that in the trial of Jeremic et al, the difference in survival between early and late TRT was almost significant on univariate analysis (P = 0.052) and significant on multivariate analysis (P = 0.027). However, 6 trials did not show any difference in outcome between patients treated with early versus late RT.11-13,15,16,18 The 1992 metaanalyses evaluating the role of TRT in adddition to chemotherapy failed to identify the optimal timing of TRT.8 The London Lung Group Study 8 was reported at the 2003 World Lung Cancer meeting after the publication of the aforementioned reviews on SCLC.18 This study replicated the NCIC study10 and randomized 325 patients to receive early or late chemoradiation but failed to demonstrate an advantage for early concurrent chemoradiation. The survival rates at 3 years were 13% in the early RT arm and 20% in the late RT arm (P = 0.18). The corresponding figures in the NCIC study are 29.7% and 21.5% (P = 0.008). However, more patients in the late TRT arm of the study of James et al18 received 6 cycles of chemotherapy and PCI, which could, in part, explain the results. When comparing the results of these 9 clinical trials, it appears that the best results have been seen with early concurrent TRT.10,14,17 The 20% 5-year survival milestone has generally been achieved with early thoracic irradiation. In 2004, 2 metaanalyses evaluated the timing of TRT in combined modality therapy. The first one, by Fried et al, included randomized trials published after 1985 addressing the timing of RT relative to chemotherapy.35 Early RT was defined as < 9 weeks after initiation of chemotherapy, and late RT was defined as ≥ 9 weeks after initiation of chemotherapy. Seven trials were included (N = 1524), and there was a suggestion of heterogeneity among studies in the risk difference analysis. The 2-year OS benefit for early TRT compared with late TRT for all studies was 5.2% (95% CI, 0.6%-9.7%; P = 0.03). This improvement in 2-year survival is similar to the benefit of adding TRT or PCI to chemotherapy. The number needed to treat (NNT) to see a

26

Clinical Lung Cancer July 2005

benefit was 20. Studies using platinum agent–based chemotherapy showed a 2-year OS benefit for early TRT compared with late TRT of 9.8% (95% CI, 3.8%-15.9%; P = 0.002) yielding an NNT of 10.2, again favoring early TRT. Corresponding figures for studies employing hyperfractionated RT and platinum agent–based chemotherapy are 16.7% (95% CI, 7.4%-26.0%; P < 0.001) with an NNT of 6. No benefit was seen in favor of early TRT if once-daily fractionation and non–platinum agent–based chemotherapy were used. This metaanalysis did not take into account the London Lung Group study.18 The authors present a revised analysis of 3-year OS in the discussion of the article, including the London Lung Group study. Revised results show that the OS advantage for early TRT in patients receiving platinum agent–based chemotherapy is less pronounced for patients treated with once-daily RT. The authors concluded that there is sufficient evidence to support the use of early TRT as a component of a combined-modality approach specifically with a platinum agent–based hyperfractionated regimen. A recent Cochrane review compared the effect of early versus late TRT, stratified for overall treatment time of chest irradiation and for administration of RT with or without concurrent chemotherapy, on local tumor control and OS.36 Early RT was defined as starting within 30 days of initiation of chemotherapy, and late RT was defined as starting chest irradiation ≥ 30 days after initiation of chemotherapy. Seven randomized controlled clinical trials were included (N = 1514). There was no significant 2- or 3-year OS benefit in favor of early versus late TRT with cisplatin (odds ratio [OR], 0.73%; 95% CI, 0.5-1.03; test for overall effect, z = 1.81; P = 0.07) or non–cisplatin-based chemotherapy (OR, 1.97; 95% CI, 1.10-3.53; test for overall effect, z = 0.81; P = 0.42). There was a 5-year survival benefit in favor of early TRT and cisplatin-based chemotherapy (OR, 0.64%; 95% CI, 0.44-0.92; test for overall effect, z = 2.40; P = 0.02), but it is important to note that the London Lung Group study was not included in the 5-year survival analysis, because only the 3-year survival data were available.18 The effect of the overall treatment time of chest radiation on survival was also analyzed. Five studies delivered the radiation with an overall treatment time of < 30 days,10,14,16-18 and, in 2 studies, the overall treatment time was > 30 days.12,15 A significant association between overall treatment time and OS was found in favor of an overall treatment time of < 30 days at 5 years but not at 2 years. The authors reported that no firm conclusion can be drawn as to whether the overall treatment time of chest RT affects survival and that it is unclear whether the timing of chest RT (beginning within 30 days after the start of chemotherapy or later) affects long-term survival.

Should Chemoradiation Therapy Be Used Sequentially or Concurrently? If we accept, as discussed in the previous paragraph, that early TRT is superior to delayed treatment, the optimal treatment sequencing is concurrent.10,14,17 To our knowledge, the Japan Clinical Oncology Group Study is the only trial that randomized patients between sequential and concurrent chemoradiation therapy.17 All patients received 4 cycles of cisplatin/etopo-

Corinne Faivre-Finn et al

Radiation Target Volume The radiation target volume is another source of controversy. There are 2 main questions.

Is Elective Nodal Irradiation Necessary? This question has not been addressed by a prospective study. Some authors favor fields that include the primary lesion, both hilar regions, the entire mediastinum, and both supraclavicular areas.37 Using limited fields relies on systemic therapy to treat microscopic involvement of locoregional lymph nodes. In the study of Turrisi et al, the elective radiation was limited to the gross tumor (as defined by CT) and the bilateral mediastinal and ipsilateral hilar lymph nodes. Irradiation of uninvolved supraclavicular fossae was not carried out. In a Dutch pilot study, the volume of irradiation was limited to the gross tumor volume (primary tumor and involved nodes) with a margin of 2 cm.38 One of the main arguments in favor of this approach is the significant reduction of complications caused by combined chemoradiation therapy, including radiation esophagitis and pneumonitis. The use of modern imaging techniques such as CT and positron emission tomography should allow more accurate definition of tumor volume. At present, it appears more appropriate to deliver a higher radiation dose to the macroscopic disease and involved nodes rather than trying to treat extended volumes, which poses the risk of compromising local control, although there is a paucity of data on this approach in limited-stage SCLC.

If Thoracic Radiation Is Started After Several Cycles of Chemotherapy, Should We Treat with the Pre- or Postchemotherapy Volume? In a retrospective review of data from the North Central Cancer Treatment Group and the Mayo Clinic, half the analyzed patients received RT at the prechemotherapy volume, and the other half received RT at the postchemotherapy volume.

Figure 1

ACTOR Trial: Phase II Trial of TRT in Limited-Stage SCLC Treated Concurrently with Etoposide/Cisplatin Once-Daily TRT D1

Limited-Stage SCLC

side every 3 weeks (sequential arm) or 4 weeks (concurrent arm). Thoracic RT began on day 2 of the first cycle of chemotherapy in the concurrent arm and after the fourth cycle in the sequential arm. Two hundred thirty-one patients received hyperfractionated TRT (45 Gy in 30 fractions over 3 weeks). The 5-year survival rates were 18.3% in the sequential arm and 23.7% in the concurrent arm, suggesting an advantage for the concurrent treatment (P = 0.097). However, the difference was not statistically significant, probably because of the small sample size. The results in the concurrent arm are consistent with the 26% 5-year survival rate reported in the study by Turrisi et al,19 despite the fact that the chemotherapy dose intensity was inferior in the concurrent arm compared with the sequential arm. The increase in the chemotherapy interval from 3 weeks to 4 weeks resulted in a decrease in dose intensity of 33% in the concurrent arm. The grade 3/4 esophagitis rate was much lower in the concurrent arm of the Japanese study17 compared with the concurrent hyperfractionated arm of the Turrisi et al study19 (9% and 32%, respectively), perhaps reflecting the longer cycle length.

R A N D O M I Z E

D3

D21 D24

D43 D45

D64 D66

RT 66 Gy/45 days/33 fractions

Twice-Daily TRT D1

D3

D21 D24

D43 D45

RT 45 Gy/19 days/30 fractions

D64 D66

R E S T A G E

SD, PR, CR→PCI

If < SD → No PCI

Chemotherapy Radiation Therapy

The majority of the local recurrences were reported to be “infield failures” and supported the use of postchemotherapy volume.39 A Southwest Oncology Group trial randomized patients exhibiting a partial response or stable disease after chemotherapy to receive wide-volume RT or reduced-volume RT followed by further chemotherapy.40 The wide-volume fields included the prechemotherapy tumor volume plus the mediastinum, and the reduced-volume fields included the postchemotherapy tumor volume with a margin of 2 cm. All patients received split-course RT (30 Gy in 10 fractions over a period of 2 weeks followed by 2 weeks rest and 30 Gy in 12 fractions over 2 weeks). The local recurrence rate was similar in both arms: 32% for the prechemotherapy-volume arm and 28% for the postchemotherapy-volume arm. A study by Arriagada et al compared target volumes including a 1-1.5–cm margin to target volumes with < 1 cm margin. There was no difference in terms of local recurrence rates between the 2 arms.41 The results of these 3 studies suggest it is appropriate to treat the postchemotherapy tumor volume.

Evaluating the Response to Chemoradiation Therapy The evaluation of the response to combined chemoradiation therapy is an important endpoint for clinical trials in limitedstage SCLC and is another area of controversy in the management of this disease. After the combined treatment is completed, residual tissue might still be present at the site of the initial disease, and the significance of this is uncertain without repeat biopsies or surgical resection. Endpoints for multimodality clinical trials in stage III non–small-cell lung cancer (NSCLC) were discussed at the 1994 International Adjuvant Lung Cancer Trial consensus conference.42 The group agreed on 2 definitions of local control: (a) complete disappearance of all radiographic abnormalities by chest film and CT (complete disappearance of all abnormalities on CT is rare) or (b) residual radiographic abnormality (or abnormalities) assessed by chest CT at 3 and 6 months after completion of thoracic radiation therapy, which then remains stable for an additional ≥ 6 months. These definitions could be extrapolated to SCLC. Positron emission tomography scanning could be useful in the assessment of local control, but, unfortunately, we lack data on its use in SCLC multimodality treatment response.

Clinical Lung Cancer July 2005

27

Thoracic RT for Limited-Stage SCLC Table 3

Current Clinical Trials in Limited-Stage SCLC

PDQ Designation

Treatment

LLCG-STUDY 12

Phase III chemotherapy/RT with or without thalidomide

CAN-NCIC-BR20

Phase II chemotherapy/RT with or without ZD6474

CALGB-30206

Phase II cisplatin and irinotecan followed by carboplatin/etoposide and RT

RTOG-0241

Phase I irinotecan/cisplatin and thoracic RT

Conclusions and Future Directions

NCCTG-N9923

Phase II topotecan/paclitaxel before and after high-dose thoracic RT with concurrent cisplatin/etoposide/amifostine

Although RT plays a critical role in the management of limited-stage SCLC, essential questions related to the optimization of TRT remain unanswered. To date, efforts to improve outcome have focused largely on optimizing systemic therapy. There is the paradox of new drugs, such as taxanes, topoisomerase I inhibitors, and gemcitabine,52,53,54 being explored and integrated into limited-stage SCLC treatment strategies while important issues regarding the optimal delivery of definitive RT have not been addressed. Based on recent metaanalysis data, RT should be started no later than the third cycle of chemotherapy, but it is unclear whether it should commence with the first or second cycle of chemotherapy. The trend toward the increasing use of conformal RT with no elective nodal irradiation could be associated, in the future, with a decrease in acute toxicity, but this should be explored within the context of randomized trials. It will be important that these studies examine patterns of failure and the delivery of inadvertent doses to adjacent areas. There is a clear need for more data exploring and optimizing the delivery of RT in terms of the overall treatment time and total tumor dose. A gold standard of care for patients with limited-stage SCLC with a good performance status is twice-daily TRT (45 Gy in 3 weeks) with concurrent cisplatin/etoposide. We have recently started a randomized phase II study comparing the better arm of the study of Turrisi et al (45 Gy in 30 fractions over 3 weeks)19 with a higher dose of RT delivered once daily (66 Gy in 33 fractions), both given with concurrent cisplatin/etoposide (Figure 1). Radiation therapy is given conformally with no elective nodal irradiation. Patients who show a complete response receive PCI. The primary endpoint of the study is the rate of grade 3/4 esophagitis. If the toxicity in the once-daily arm is acceptable, a phase III study comparing these 2 arms should follow. Several trials are currently under way without elective nodal irradiation, which will provide important data on radiation target volume. The role of conformal RT in the management of limited-stage SCLC has not been established yet. More data are also needed on the long-term toxicity of chemoradiation therapy and on the best tools for assessing and predicting toxicity.55 To facilitate intertrial comparisons, there should be a move toward the use of the same assessment tools, such as the Common Toxicity Criteria version 3.56 The ongoing clinical trials in limited-stage SCLC listed in the National Cancer Institute Physician Data Query directory are summarized in Table 3. Most of those trials are phase I/II, with an interest focused on chemoradiation therapy involving new drugs such as irinotecan, thalidomide, and vascular endothelial

SWOG-S0222 RTOG-0239

Phase II induction tirapazamine/cisplatin/etoposide with concurrent thoracic RT followed by consolidation cisplatin/etoposide Phase II cisplatin/etoposide combined with accelerated high-dose thoracic RT

Abbreviations: CALGB = Cancer and Leukemia Group B; NCCTG = North Central Cancer Treatment Group; PDQ = Physician Data Query; RTOG = Radiation Therapy Oncology Group; SWOG = Southwest Oncology Group

Translational Research Translational research is required to increase our understanding of the biology of limited-stage SCLC and to develop methods for identifying patients who are likely to respond to RT. There is evidence that tumor proliferation and accelerated repopulation may be important. A study of 215 patients with limited-stage SCLC showed gaps in RT-compromised survival.29 A recent metaanalysis examined the expression of Ki-67 as a marker of proliferation in lung cancer.43 Ki-67 expression was an adverse prognostic factor for survival in NSCLC, but only 1 study for patients with SCLC was included in the metaanalysis, highlighting the relative lack of biologic data available for SCLC. The molecular basis of accelerated repopulation in SCLC should be explored to highlight potential biomarkers of prognosis. In head and neck squamous cell carcinoma, the potential of molecular profiles to predict RT response has been demonstrated.44 Profiles were identified that were associated with a good response to accelerated hyperfractionated or conventional RT. Whether these profiles can be extrapolated to other tumor sites or whether a SCLC-specific profile should be developed needs to be established. There is also a need to investigate the potential importance of hypoxia and reoxygenation during treatment in SCLC.45,46 Tumor hypoxia is now recognized to be an important factor driving tumor progression and limiting the success of therapy, but its role in SCLC has not been explored. Because tumor reoxygenation during treatment could stimulate accelerated repopulation,47,48 the potential for SCLC to reoxygenate during RT is of interest. Although SCLC is generally considered to be radiation-sensitive, the development of resistance after treatment is a recognized problem. Thus, an important area of research is to study the molecular mechanisms underlying the development of radiation resistance. For example, activation of AKT and mitogen-activated protein kinase pathways is linked with the development of radiation resistance in SCLC.49 Associated with these mechanistic stud-

28

ies is the need to explore novel radiation sensitization strategies such as those involving PI3K-AKT pathway inhibitors.50 Recent advances in molecular biology are enabling the identification of gene expression profiles associated with NSCLC.51 Similar studies are required for limited-stage SCLC. Microarray technology should aid the identification of new biomarkers of prognosis and therapeutic targets. The development of this information for the prediction of response to RT and integration into routine management will be a translational challenge of the next decade.

Clinical Lung Cancer July 2005

Corinne Faivre-Finn et al growth factor inhibitors. It is of interest to note that most chemoradiation therapy trials deliver a higher dose of RT compared with doses used in previous clinical trials. However, there is an unmet need for well-designed chemoradiation therapy trials aimed at the optimization and standardization of RT for limited-stage SCLC. With the decreasing incidence of SCLC seen during the past decade, these trials will need to be multicenter in design and increasingly multinational to ensure that an adequate statistical power is achieved. It is important that translational research be integrated into new trials to address important issues such as the molecular basis of treatment resistance and the development of biomarker profiles of prognosis.

References 1. Matthews MJ, Kanhouwa S, Pickren J, et al. Frequency of residual and metastatic tumour in patients undergoing curative surgical resection for lung cancer. Cancer Chemother Rep 3 1973; 4:63-67. 2. Mira J, Livingstone R, Moore T. Influence of chest radiotherapy in frequency and patterns of chest relapse in disseminated small cell lung Cancer 1982; 50:1266-1272. 3. Bleehan N, Bunn P, Cox J. Role of radiation therapy in small cell anaplastic carcinoma of the lung. Cancer Treat Rep 1983; 67:11-19. 4. Goodman G, Livingstone R. Small cell lung cancer. Curr Probl Cancer 1989; 13:7-55. 5. Perez C, Einhorn R, Oldham F, et al. Randomised trial of radiotherapy to the thorax in limited small cell carcinoma of the lung treated with multiagent chemotherapy and elective brain irradiation: A preliminary report. J Clin Oncol 1984; 2:1200-1208. 6. Perry M, Eaton WC, Propert KJ, et al. Chemotherapy with or without radiation therapy in limited stage small cell lung cancer. N Engl J Med 1987; 316:912-918. 7. Bunn PA, Lichter AS, Makuch RW, et al. Chemotherapy alone or chemotherapy with chest radiation therapy in limited-stage small-cell lung cancer. Ann Intern Med 1987; 106:655-662. 8. Pignon JP, Arriagada R, Idhe D, et al. A meta-analysis of TRT for small-cell lung cancer. N Engl J Med 1992; 327:1618-1622. 9. Warde P, Payne D. Does thoracic irradiation improve survival and local control in limited-stage small-cell lung cancer. J Clin Oncol 1992; 10:890-895. 10. Murray N, Coy P, Pater JL, et al. Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1993; 11:336-344. 11. Lebeau B, Urban T, Brechot JM, et al. A randomized clinical trial comparing concurrent and alternating thoracic irradiation for patients with limited small cell lung carcinoma. "Petites Cellules" Group. Cancer 1999; 86:1480-1487. 12. Work E, Nielsen OS, Bentzen SM, et al. Randomized study of initial versus late chest irradiation combined with chemotherapy in limited-stage small-cell lung cancer. Aarhus Lung Cancer Group. J Clin Oncol 1997; 15:3030-3037. 13. Gregor A, Drings P, Burghouts J, et al. Randomized trial of alternating versus sequential radiotherapy/chemotherapy in limited-disease patients with small-cell lung cancer: a European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group Study. J Clin Oncol 1997; 15:2840-2849. 14. Jeremic B, Shibamoto Y, Acimovic L, et al. Initial versus delayed accelerated hyperfractionated radiation therapy and concurrent chemotherapy in limited small-cell lung cancer: a randomized study. J Clin Oncol 1997; 15:893-900. 15. Perry MC, Herndon JE III, Eaton WL. Thoracic radiation therapy added to chemotherapy for small-cell lung cancer: an update of Cancer and Leukemia Group B Study 8083. J Clin Oncol 1998; 16:2466-2467. 16. Skarlos DV, Samantas E, Briassoulis E, et al. Randomized comparison of early versus late hyperfractionated thoracic irradiation concurrently with chemotherapy in limited disease small-cell lung cancer: a randomized phase II study of the Hellenic Cooperative Oncology Group (HeCOG). Ann Oncol 2001; 12:1231-1238. 17. Takada M, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 2002; 20:3054-3060. 18. James LE, Spiro S, O,Donnell KM, et al. A randomised study of timing of thoracic irradiation in small cell lung cancer-study 8. Lung Cancer 2003; 41(suppl 2):S23 (Abstract #70). 19. Turrisi AT, Kim K, Blum R, et al. Twice daily compared to once-daily thoracic radiotherapy in limited-stage small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999; 340:265-271. 20. Emami B. Three-Dimensional Conformal Radiation Therapy In Bronchogenic Carcinoma. Semin Radiat Oncol 1996; 6:92-97. 21. Carney DN, Mitchell JB, Kinsella TJ. In vitro radiation and chemotherapy sensitivity of established cell lines of human small cell lung cancer and its large cell morphological variants. Cancer Res 1983; 43:2806-2811. 22. Choi NC, Carey RW. Importance of radiation dose in achieving improved loco-regional tumour control in limited stage small-cell lung carcinoma: an update. Int J Radiat Oncol Biol Phys 1989; 17:307-310. 23. Coy P, Hodson I, Payne D, et al. The effect of dose of thoracic irradiation on recurrence in patients with limited-stage small-cell lung cancer. In initial results of a Canadian multicentre randomised trial. Int J Radiat Oncol Biol Phys 1988; 14:219-226. 24. Roof K, Fidias P, Lynch T. Radiation dose escalation in limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys 2003; 57:701-708. 25. Miller K, Marks L, Sibley G, et al. Routine use of approximately 60 Gy once-daily tho-

racic irradiation for patients with limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys 2003; 56:355-359. 26. Choi NC, Herndon JE, Rosenman J, et al. Phase I study to determine the maximum tolerated dose of radiation in standard daily and hyperfractionated-accelerated twicedaily radiation schedules with concurrent chemotherapy for limited-stage small-cell lung cancer. J Clin Oncol 1998; 16:3528-3536. 27. Maciejewski B, Withers HR, Taylor JMG, et al. Dose fractionation and regeneration in radiotherapy for cancer of the oral cavity and oropharynx: tumour dose-response and repopulation. Int J Radiat Oncol Biol Phys 1989; 16: 831-843. 28. Withers HR, Taylor JMG, Maciejewski B. The hazard of accelerated tumour clonogen repopulation during radiotherapy. Acta Oncol 1988; 27: 131-146. 29. Videtic GM, Fung K, Tomiak AT, et al. Using treatment interruptions to palliate the toxicity from concurrent chemoradiation for limited small cell lung cancer decreases survival and disease control. Lung Cancer 2001; 33:249-258. 30. Bonner JA, Sloan JA, Shanahan TG et al. Phase III comparison of twice-daily splitcourse irradiation versus once-daily irradiation for patients with limited stage small-cell lung carcinoma. J Clin Oncol 1999; 17:2681-2691. 31. Schild SE, Bonner JA, Shanahan TG et al. Long-term results of a phase III trial comparing once-daily radiotherapy with twice-daily radiotherapy in limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004; 59:943-951. 32. Turrisi AT, Sherman CA. The treatment of limited small cell lung cancer: a report of the progress made and future prospects. Eur J Cancer 2002; 38:279-291. 33. De Ruysscher D, Vansteenkiste J. Chest radiotherapy in limited-stage small cell lung cancer: facts, questions, prospects. Radiother Oncol 2000; 55:1-9. 34. Curran WJ. Combined-modality therapy for limited-stage small cell lung cancer. Semin Oncol 2001; 28:14-22. 35. Fried B, Morris D, Hensing T, et al. Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited stage small-cell lung cancer. J Clin Oncol 2004; 22:4785-4793. 36. Pijls-Johannesma MCG, De Ruysscher DKM, Rutten I, et al. Early versus late chest radiotherapy for limited stage small cell lung cancer. Cochrane Database Syst Rev 2004, Issue 4; Art. No: CD004700. 37. Perez C, Purdy J, Razek A. Radiation therapy of carcinoma of the lung and oesophagus. In Levitt S, Tapely N, eds. Technological Basis of Radiation Therapy: Practical Clinical Implications. Philadelphia: Lea & Febiger, 1984. 38. Belderbos J, van Meerbeeck J, Weenink C. Concurrent radiation therapy in small cell lung cancer (SCLC) LD: preliminary results from a Dutch pilot study. Lung Cancer 2000; 29(suppl 1):96 (Abstract #315). 39. Liengswangwong V, Bonner JA, Shaw EG, et al. Limited-stage small-cell lung cancer: patterns of intra-thoracic recurrence and the implication for thoracic radiotherapy. J Clin Oncol 1994; 12:496-502. 40. Kies MS, Mira JG, Crowley JJ, et al. Multimodal therapy for limited small-cell lung cancer: a randomized study of induction combination chemotherapy with or without thoracic radiation in complete responders; and with wide-field versus reduced-field radiation in partial responders: a Southwest Oncology Group Study. J Clin Oncol 1987; 5:592-600. 41. Arriagada R, Pellae-Cosset B, Ladron de Guevara JC, et al. Alternating radiotherapy and chemotherapy schedules in limited small cell lung cancer: analysis of local chest recurrences. Radiother Oncol 1991; 20:91-98. 42. Green MR, Cox JD, Ardizzoni A, et al. Endpoints for multimodal clinical trials in stage III non-small cell lung cancer (NSCLC): a consensus report. Lung Cancer 1994; 11(suppl 3):S11-S13. 43. Martin B, Paesmans M, Mascaux C, et al. Ki-67 expression and patients survival in lung cancer: systematic review of the literature with meta-analysis. Br J Cancer 2004; 91:2018-2025. 44. Buffa FM, Bentzen SM, Daley FM, et al. Molecular marker profiles predict locoregional control of head and neck squamous cell carcinoma in a randomized trial of continuous hyperfractionated accelerated radiotherapy. Clin Cancer Res 2004; 10:3745-3754. 45. Prosnitz RG, Yao B, Farrell CL, et al. Pretreatment anemia is correlated with the reduced effectiveness of radiation and concurrent chemotherapy in advanced head and neck cancer. Int J Radiat Oncol Biol Phys 2005; 61:1087-1095. 46. Corry J, Rischin D. Strategies to overcome accelerated repopulation and hypoxia--what have we learned from clinical trials? Semin Oncol 2004; 31:802-808. 47. Jones B, Dale RG Estimation of tumour hypoxic fraction from clinical data sets compatible with accelerated repopulation. Acta Oncol 1998; 37:263-268. 48. Sheridan MT, West CM, Cooper RA et al. Pretreatment apoptosis in carcinoma of the cervix correlates with changes in tumour oxygenation during radiotherapy. Br J Cancer 2000; 82:1177-1182. 49. Kraus AC, Ferber I, Bachmann SO, et al. In vitro chemo- and radio-resistance in small cell lung cancer correlates with cell adhesion and constitutive activation of AKT and MAP kinase pathways. Oncogene 2002; 21:8683-8695. 50. Riesterer O, Tenzer A, Zingg D, et al. Novel radiosensitizers for locally advanced epithelial tumors: inhibition of the PI3K/Akt survival pathway in tumor cells and in tumor-associated endothelial cells as a novel treatment strategy? Int J Radiat Oncol Biol Phys 2004; 58(2):361-368. 51. Meyerson M, Franklin WA, Kelley MJ. Molecular classification and molecular genetics of human lung cancers. Semin Oncol 2004; 31:4-19. 52. Bunn PA, Kelly K. A phase I study of cisplatin, etoposide, and paclitaxel in small cell lung cancer. Semin Oncol 1997; 24:144-148. 53. Greco FA. Hainsworth JD. Paclitaxel, carboplatin, and oral etoposide in the treatment of small cell lung cancer. Semin Oncol 1996; 23:7-10. 54. Kinoshita A, Fukuda M, Kuba M, et al. Phase I study of irinotecan and cisplatin with concurrent thoracic radiotherapy in limited-stage small-cell lung cancer. Proc Am Soc Clin Oncol 2000; 19:511a (Abstract #1999). 55. Trotti A, Colevas AD, Setser A, et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003; 13:176-181. 56. National Cancer Institute. Common Terminology Criteria for Adverse Events v3.0. Available at: http://ctep.cancer.gov/reporting/ctc.html. Accessed January 25, 2005.

Clinical Lung Cancer July 2005

29