Concurrent versus sequential radiotherapy for small cell lung cancer

Concurrent

Versus

Hiroko

Tsukada,

Sequential Radiotherapy Cell Lung Cancer

Akira

Yokoyama,

and the Japan Clinical Two

meta-analyses

therapy

plus

apy lung

have

radiotherapy Cancer and I to

1984

concurrent controlled tional trial,

the

resistance, two modalities

early Leukemia failed

in to

Cancer Institute and the Japan

showed

that

early

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the

show

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20%

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for

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three timing

early

recent (the Na-

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delayed

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is achievable For the present,

of thoracic regimen

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Takada,

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of limited-stage likelihood

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the course of treatment. Group B trial performed

chemoradiation. trials of thoracic

radiotherapy. of cisplatinletoposide

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alone in the treatment cancer. To minimize

of chemotherapy integration of the

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chemotherapy

Koichi Oncology

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surearly con-

with standard

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therapy. Semin Oncol28 @uppI Saunders Company.

4):23-26.

Copyright

0 2001

by MB.

N THE TREATMENT of limited-stage small cell lung cancer (SCLC), chest recurrence is observed in more than half of patients after chemotherapy-induced remission.1 Therefore, it seems reasonable to add thoracic radiotherapy to systemic chemotherapy for the treatment of this disease. As a result, a number of randomized trials comparing chemotherapy alone with combined chemotherapy and radiotherapy were conducted in the early- and mid-1980s. Although most found significant improvement in local control with combined treatment, no survival advantage was confirmed. However, two meta-analyses of these studies have found a small but statistically significant increase in survival for treatment with thoracic radiotherapy plus chemotherapy compared with chemotherapy alone.zx3 The timing of radiotherapy and chemotherapy varied from study to study among trials in these meta-analyses. Despite indirect comparisons of early versus late radiotherapy and of sequential versus nonsequential radiotherapy conducted in one meta-analysis, the optimal schedule for integration of the two modalities remains unclear.2 Drug resistance is a major factor limiting the I

Semmors in Oncology,

Vol 28, No 2, Suppl 4 (April),

200 I: pp 23-26

for Small Nagahiro

Saijo,

Group

effectiveness of cancer chemotherapy. Because the primary tumor is the most heterogeneous portion, it is the most likely repository of de novo resistant cells. Elimination of many cancer cells in the primary tumor in the shortest time is the optimal way to minimize the likelihood of emergence of chemotherapy resistance. Theoretically, the most promising way to combine chemotherapy and radiotherapy is to introduce radiotherapy early in the course of treatment. The likelihood that thoracic radiotherapy would eliminate chemoresistant cells evolving in the primary tumor should depend on the interval between use of these two modalities.4x5 The Cancer and Leukemia Group B addressed the importance of timing of radiotherapy in a randomized trial.’ Patients were randomly assigned to receive initial radiotherapy plus chemotherapy (group 1, n = 125), delayed radiotherapy plus chemotherapy (group 2, n = 145), or chemotherapy alone (group 3, n = 129). The difference in treatment between group 1 and group 2 was a delay in radiotherapy of 9 weeks. Chemotherapy consisted of cyclophosphamide, etoposide, and vincristine, with doxorubicin subsequently replacing etoposide in alternate cycles only after the completion of radiotherapy in both arms. Chemotherapy was given every 3 weeks for 18 months. The thoracic radiotherapy was composed of 40 Gy in 4 weeks, followed by a lo-Gy boost directed against residual disease. Although there was no significant difference in either complete response rate or survival between the initial and delayed radiotherapy arms, hematologic toxicity was more severe in the initial arm. Unfortunately, the interpretation of this study is confounded because po-

From the Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan. Address rep& requeststo Hiroko Tsukada, MD, Department of Internal Medicine, Niigata Cancer Center Hospital, 2-15-3 Kawagishi-cho, Niigata, Japan 951-8566. Copyright 0 2001 by WB. Saunders Company 0093~7754/01/2802-0404$35.00/O doi:10.1053/sonc.2001.25741 23

TSUKADA

24

Median Range Sex Male Female

64 30-74

6.5 39-74

NS

93 (82) 21 (18)

91 (80)

NS

IO8 (95)

108 (95)

23 (20)

PS O-I 2 Weight Loss/b
6 (5)

6 (5)

IO2 (93)

104 (95)

8 (7)

6 (5)

NS

months NS

tential differences in outcome from the timing of radiotherapy may have been obscured by unplanned attenuation in chemotherapy doses caused by toxicity after the first cycle. In an attempt to solve the problems of increased incidence and severity of toxicity when chemotherapy and radiotherapy are administered concurrently, combined use of cisplatin plus etoposide (PE) has largely replaced the older regimens using anthracyclines, nitrosoureas, or cyclophosphamide. The toxicity of a concurrent PE regimen and radiotherapy is tolerable and does not compromise subsequent systemic treatment.+8 Furthermore, both platinum and etoposide have been suggested to enhance the effect of radiotherapy. The group at the National Cancer Institute of Canada first showed an advantage of early administration of thoracic radiotherapy using this combination.4 The chemotherapy used consisted of cyclophosphamide, doxorubicin, and vincristine alternating with PE. Patients were randomized to receive early (n = 155) or late (n = 153) radiotherapy. The only difference in treatment between the two arms was a delay in radiotherapy of 12 weeks. Although complete response rates did not differ significantly between the two arms, progression#free survival (P = .036) and overall survival (P = .008) were significantly superior in the early

ET AL

radiotherapy arm. Furthermore, patients in the late radiotherapy arm had a higher risk of brain metastases (P = .006). Because both arms in this study included concurrent treatment, the difference was exclusively timing. On the other hand, the Japan Clinical Oncology Group compared an early concurrent schedule with conventional sequential radiotherapy after chemotherapy.6,7 The Japan Clinical Oncology Group used a relatively small number of chemotherapy cycles with accelerated hyperfractionated radiotherapy. Standard eligibility criteria were used in selecting patients for this study. To enroll, patients had to be less than 75 years of age with histologically documented limited-disease SCLC, have an Eastern Cooperative Oncology Group performance status of 0 to 2, have measurable or evaluable disease, and adequate organ function. Between 1991 and 1995, 231 patients were enrolled and 228 proved eligible. Patient characteristics are listed in Table 1.7 The majority of patients were male with good performance status and minimal weight loss. Both groups received four cycles of the PE regimen (cisplatin 80 mg/m2 on day 1, etoposide 100 mg/m’ on days 1 to 3) given at 3-week intervals on the sequential arm (arm S) or 4-week intervals on the concurrent arm (arm C). Radiation therapy consisted of 45 Gy given in 30 fractions for 15 treatment days (1.5 Gy twice daily). It was started on day 2 of the first cycle for arm C and after the fourth cycle for arm S (Fig 1). Patients could receive more than 90% of their planned dose intensity in both arms. Complete response rates were not significantly different

Concurrent

thoracic

irradiation arm 12 16wk.s

Etoposide

Sequential

thoraoic

irradiation

100 mgMdays

l-

arm

Fig I. Study design of a phase 111 study of concurrent versus sequential thoracic radiotherapy for limited-stage small cell lung cancer treated with PE.’ Both groups received four cycles of PE given at 3-week intervals on the sequential arm or 4-week intervals on the concurrent arm. Radiation therapy consisted of 45 Gy in 30 fractions with I .5 Gy twice daily started on day 2 of the first cycle for the concurrent arm and after the fourth cycle for the sequential arm. CDDP, cisplatin.

RADIOTHERAPY

FOR

SMALL

CELL

LUNG

25

CANCER

I 0

12

Fig 2. Overall versus sequential cell lung cancer

24

survival thoracic treated

36

48 Months

60

84

96

of a phase III study of concurrent radiotherapy for limited-stage small with PE.’ Median survival time was

21.2 months on the concurrent arm versus 19.5 sequential arm. Two-year survival was 55.3% on arm versus 35.4% on the sequential arm and ~~~30.9% on the concurrent arm versus 20.7% tial at-m. Overall survival .0570) on the concurrent

72

was marginally arm.

superior

months on the the concurrent 3-year survival on the sequen(log

rank,

P =

between the two arms (27.2% in arm S, 40.4% in arm C). Overall survival was marginally (P = .0570) better in arm C. The 2-year survival rate was 35.4% in arm S versus 55.3% in arm C (Fig 2). There was no significant difference in relapse pattern between the two arms. Grade 3 or 4 leukopenia (I’ = .OOOl ) and thrombocytopenia (P = .0006) were more common in arm C (Table 2).7 However, there was no significant difference between the arms in the incidence of grade 3 or 4 esophagitis, infection, or treatment-related death. Four cycles of PE plus concurrent twice-daily thoracic radiotherapy could be administered with acceptable toxicity. Jeremic et a15 offered additional evidence that early radiotherapy is superior to delayed radiotherapy. They used accelerated hyperfractionated radiotherapy (1.5 Gy twice daily to a total of 54 Gy) plus concurrent daily carboplatin and etoposide (30 mg each), and four sequential cycles of PE chemotherapy (cisplatin 30 mg/m’ and etoposide 120 mg/m2 on days 1 to 3). Patients on the initial radiotherapy arm (n = 52) received concurrent chemoradiation at weeks 1 to 4, and patients on the delayed arm (n = 51) at weeks 6 to 9. Both complete response rates (early v delayed = 90% v 82%; P = .023) and overall survival (5,year sure viva1 rate, 30% v 15%, P = .027) were significantly better in the initial radiotherapy arm. Recently, the final report of an Eastern Coop-

erative Oncology Group-Radiation Therapy Oncology Group-Southwest Oncology Group intergroup trial was published.8 In this larger-scale study, four cycles of PE chemotherapy were administered concurrently with 45 Gy of thoracic radiation (nearly the same schedule as in the Japanese study). Overall, 2- and 5-year survival rates were 44% and 23%, respectively, which exceeded those of any previously reported large, randomized trial of chemoradiation for limited-stage SCLC.8 These studies showed that a long-term survival rate greater than 20% is achievable using early integrated chemoradiation for limited-stage SCLC. An alternating schedule was proposed as another strategy for early administration of radiotherapy. The theoretical advantages of this method are decreased additive toxicity and assurance of better drug dose intensity .9 However, in the European Organization for Research and Treatment of Cancer randomized trial, these advantages were not successfully shown in the clinical setting.lO A French study suggested that an alternating schedule was superior to a concurrent schedule with respect to pulmonary toxicity. However, the Z-year survival rate was 17% in the alternating group of that study,ll which is less than half the rate for early concurrent administration of thoracic radiotherapy with a PE-based regimen (Fig 3).4-T In a Danish trial, an alternating schedule was used and 199 patients were randomly allocated to initial radiotherapy or late radiotherapy delayed by

Table

2. Phase

Sequential

Thorkic

Small

Cell

Lung

111 Study

OF Concurrent

Radietherapy Cancer

Etoposide:

far

Treated Grade

Leukopenia Grade 314 Grade 4

Cisplatin

and

3/4 Taxi&f

Sequential

No. Patients

With

Versus Limited-Stage

Concurrent

(W

F)

I I4

II3

P V&e

99 (86.8)

58 (5 I .3)

42 (36.8)

IO (8.8)

Thrombocytopenia Anemia

41 (36.0)

29 (25.7)

60 (52.6)

46 (40. I)

NS

Esophagitis FWW

IO (8.8)

4 (3.5)

NS

2Q.8)

2 (1.8)

NS

6 (5.3)

I (0.9)

NS

3 (2.6)

4 (3.5)

NS

Infection Treatment-related

death

,000 I ,006

26

TSUKADA

ET AL

REFERENCES PE-Based

CALGB’

FMlCe” EORTC”

Fig

3.

Long-term

rack radiotherapy Two-year survival significantly higher PE-based regimen.

Regime:,

NCI-C’ Denmark”

survival

rate

Jeremic’ JCOG’”

according

to timing

Intergroup” of tho-

for limited-stage small cell lung cancer. rate for early thoracic irradiation was not than that for late irradiation with a nonThe randomized trials using PE-based reg

imens (except for the Danish trial) support the concept that the optimal integration of chemotherapy and thoracic irradiation is early chemoradiation. PE, cisplatin plus etoposide; C, concurrent; tion.

S, sequential;

A,

alternating;

TI, thoracic

irradia-

18 weeks.12The timing of radiotherapy had no significant effect on survival. However, the 2-year survival rate was only about 20% in both arms. CONCLUSIONS

Three controlled trials have shown that early concurrent chemoradiation is superior to delayed or sequentialradiotherapy. The recent EasternCooperative Oncology Group-Radiation Therapy Oncology Group-Southwest Oncology Group in, tergroup trial confirmed the conclusions of these three trials. A long-term survival rate of more than 20% for limited-stage SCLC appearsto be achievd able with early concurrent chemoradiation. Although three other trials failed to show the advane tage of early radiotherapy on survival, actual delivery of chemotherapy wasinadequate in one of thesenegative trials. In addition, the short median survivals in these negative trials suggestthat poor prognosismay have obscured the benefit of early radiotherapy in the study population. For the present, early concurrent administration of thoracic radiotherapy with a PE-basedregimen should be the standard approach for treatment of limitedstageSCLC.

1. Perry MC, Eaton WL, Propert KJ, et al: Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N Engl J Med 316:912-918, 1987 2. Pignon JP, Arriagada R, Ihde DC, et al: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327:1618-1624, 1992 3. Warde P, Payne D: Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 10:890-895, 1992 4. 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. J Clin Oncol 11:336-344, 1993 5. 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 15:893x900, 1997 6. Takada M, Fukuoka M, Furuse K, et al: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited stage small-cell 1ung cancer: Preliminary results of the Japan Clinical Oncology Group (JCOG). Proc Am Sot Clin Oncol 15:372a, 1996 (abstr 1103) 7. Goto K, Nishiwaki Y, Takada M, et al: Final results of a phase III study of concurrent versus sequential thoracic radio, therapy in combination with cisplatin and etoposide for limited-stage small cell lung cancer: The Japan Clinical Oncology Group (JCOG) Study. Proc Am Sot Clin Oncol 18:468a, 1999 (abstr 1805) 8. Turrisi AT, Kim K, Blum R, et al: Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340:265-271, 1999 9. Arriagada R, Le Chevalier T, Baldeyrou P, et al: Alternating radiotherapy and chemotherapy schedules in small cell lung cancer limited disease. Int J Radiat 0x01 Biol Phys 11:1461,1467, 1985 10. Gregor A, Drings P, Burghouts J, et al: Randomized trial of alternating versus sequential radiotherapy/chemotherapy in limited-disease patients with small-zell lung cancer: A European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group Study. J Clin Oncol 15:2840-2849, 1997 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. Cancer 86:1480-1487, 1999 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. J Clin Oncol 15:3030-3037, 1997