Inr J Rodumon Onmlo~y Bw/. Phys, Vol Pnnted I” the U.S.A. All&hts reserved.

24. pp. 43-48 Copyright

0360.3016/92 $5.00 t .OO $1 1992 Pergamon Press Ltd.

??Clinical Original Contribution

A REAPPRAISAL

OF THE ROLE OF PROPHYLACTIC CRANIAL LIMITED SMALL CELL LUNG CANCER

IRRADIATION

IN

M. ROSENSTEIN, M.D., PH.D.,’ J. ARMSTRONG, M.R.C.P.I.,’ M. KRIS, M.D.,* B. SHANK, M.D., PH.D.,~ H. SCHER, M.D.,* D. FASS, M.D.,’ L. HARRISON, M.D.,’ Z. FUKS, M.D.’ AND S. LEIBEL, M.D.’ ‘Department

of Radiation Oncology, Memorial Sloan-Kettering Cancer Center (MSKCC), New York; and 2Division of Solid Tumor Oncology, Department of Medicine, (MSKCC) and 3Department of Radiation Oncology, Mount Sinai Medical Center, New York

The use of prophylactic cranial irradiation in limited stage small cell lung cancer remains controversial. Prospective trials have demonstrated that PCI can reduce central nervous system relapse rates, but the impact on survival remains questionable except for the possible evidence of a beneficial effect for long term survivors. With higher rates of thoracic control now obtainable with hyperfktionated radiation and concomitant chemotherapy, it becomes important to analyze the benefit of PC1 in that setting. Before 1982, we included PC1 in the management of all patients with limited stage small cell lung cancer; thereafter, we discontinued its use. This report compares the outcome of the two treatment approaches and addresses the role of PC1 among patients who achieve durable local control. There were 36 limited stage small cell lung cancer patients treated with PC1 from 1979-1982 and 26 patients treated without PC1 from 1985-1989. Induction chemotherapy was followed in both groups by thoracic irradiation (45 Cy). The PC1 patients received 30 Gy to the whole brain in 10 fractions. Both groups received maintenance chemotherapy. Of complete responders, brain failure was the first failure in 18% (4/22) of PCI (+) versus 45% (10/22) of PC1 (-) (p = .04). Survival at 2 years was 42% for PC1 (+) versus 13% for PC1 (-) (p < .05). When the analysis was limited to those patients permanently controlled in the thorax; there were 25% (4/16) brain failures PC1 (+) versus 70% (7/10) PC1 (-) (p = .03). For this same subset the 2-year survival was 56% PC1 (+) versus 14% PC1 (-) (p < .05). There were no 5 year survivors without PC1 compared to 38% (6/16) with PCI. These data suggest that PC1 appears to be effective in enhancing survival of patients who achieve durable thoracic control. Prospective trials are necessary to evaluate the use of PC1 combined with therapeutic regimens with a documented ability to achieve high rates of sustained control of thoracic disease. Prophylactic

cranial irradiation, Limited stage small cell lung cancer, Thoracic radiation, Hyperfractionation.

INTRODUCTION

added to the consolidative phase of multiple prospective clinical trials. While PC1 decreases the incidence of CNS relapse, this treatment has failed to provide a consistent survival benefit (4, 10, 18, 25, 32). This, in part, may be explained by the generally poor control of chest disease achieved in these trials. This study was undertaken to retrospectively assess the overall influence of PC1 on survival and, more specifically, to address the value of PC1 for patients who achieve durable thoracic control. In view of the emerging reports of successful radiotherapeutic strategies to enhance thoracic control (6, 8, 13, 24, 28, 29, 34, 36), a reappraisal of the role of PC1 is warranted.

Small cell lung cancer (SCLC) comprises 20% of all primary lung malignancies and has been considered to be highly responsive to both radiation and chemotherapy. While there have been significant gains in short-term response rates in SCLC, long term cures remain the exception, and are largely confined to patients with limited stage small cell lung cancer (LSSCLC) (1). Analysis of the patterns of failure in patients with LSSCLC demonstrate that approximately 50% of patients will ultimately fail in the central nervous system (5). Brain failure (BF) is a morbid and often fatal sequela in patients treated for cure with multimodality therapy. The use of chemotherapy capable of crossing the blood brain barrier has had little impact on the prevention of these relapses (15, 27, 35). To improve the long-term outcome of patients with LSSCLC, PC1 for subsets of patients has been

METHODS

AND

MATERIALS

Twenty-six patients with LSSCLC were treated without PC1 at Memorial Sloan-Kettering Cancer Center -

Reprint requests to: John Armstrong,

M.R.C.P.I.

Accepted 43

for publication

23 January

1992.

44

1. J. Radiation Oncology 0 Biology 0 Physics

(MSKCC) between 1985 and 1989 and were retrospectively compared to 36 patients treated from 1979 to 1982 with PC1 (33). These 62 patients represent all patients with LSSCLC treated on protocol during these time periods. PC1 was abandoned in the later series due to concerns over increased toxicity and lack of proven therapeutic benefit. Criteria for eligibility to both protocols included LSSCLC with histologic confirmation of malignancy, no prior malignancy other than cutaneous carcinoma, performance status adequate for aggressive combined modality therapy, no evidence of congestive heart failure or history of angina pectoris, and the capability of giving informed consent. Limited stage small cell lung cancer was defined as disease confined to the mediastinum, ipsilateral hemithorax, and ipsilateral/contralateral supraclavicular nodes. Patients with pleural effusions were excluded. Initial evaluation included physical exam, complete blood and chemistry profile, bone scan, bone marrow biopsy and CT scans of the chest and abdomen. When indicated, CT scan of the brain, lumbar puncture, or other studies were performed.

Treatment

Induction for both groups was two alternating cycles of CAV (cytoxan [CTX], adriamycin, and vincristine [VCR]) and (c-DDP + VP-16) for a total of four cycles of induction chemotherapy. Consolidation consisted of TI for both groups, and concomitant CTX and VCR in the PC1 (+) group. Maintenance included CAV alternating with c-DDP + VP-16 in both groups, plus CCNU, methotrexate, and procarbazine for PC1 (+) patients (Table 1).

Table 1. Comparison

Drue Induction Cyclophosphamide Adriamycin Vincristine

of chemotherapy

dosages

PC1 (+)

PC1 (-)

me/M2

ma/M2

1200 50 1.2

1000 45 1.4

CDDP VP-16 Consolidation Vincristine Cyclophosphamide

60 120*

120 120

1.4 500

-

Maintenance CCNU Methotrexate Procarbazine

80 30 100

-

Cytoxan Adriamycin Vincristine

1000 30 1.4

750 30 1.2

50 120

120 100

CDDP VP-16

* Given 3 times, 2 days apart during each cycle.

Volume 24, Number I. 1992

Consolidation for the PC1 (-) patients who achieved a CR or partial response (PR) to chemotherapy consisted of 45 Gy thoracic irradiation (TI) given in 1.5 Gy fractions twice daily (bid) 4 to 6 hr apart 4 days per week over 15 days beginning 1 week after completion of induction chemotherapy. Patients receiving PC1 were consolidated with 45 Gy TI in 2.5 Gy fractions once daily fractions with concomitant CTX (500 mg/M2) and VCR (1.4 mg/M2) on days 1 and 15 and PC1 consisting of 30 Gy in 3 Gy fractions. Prophylactic cranial irradiation was administered during consolidative chemotherapy. Thoracic irradiation was performed using lo- 15 mv photons with a three to four field plan. Treatment planning CT scans and computer planning with lung density corrections were employed. Maintenance chemotherapy in the PC1 (+) patients consisted of three phases: (I) CCNU 80 mg/M2 on day 1, MTX 30 mg/M2 on day 1, 8, 15, and 22, and procarbazine 100 mg/M2 on day 1- 14 inclusive. (2) CTX, 1000 mg/M2 on day 1, Doxorubicin, 30 mg/MZ on day 1, and VCR 1.4 mg/M2 on day 1. (3) c-DDP, 50 mg/M2 on day 1 and VP-16 120 mg/M2 on day 4, 6 and 8. Patients remaining in CR initiated maintenance approximately 10 weeks after consolidation while partial responders continued therapy without a treatment break. Cycles were continued until disease progression or the patient was disease free for one year. Prophylactic cranial irradiation (-) patients were randomized to receive two or six cycles of maintenance chemotherapy after completion of induction chemotherapy and radiation. Patients were treated with one course of CAV (CTX, 750 mg/M2, VCR, 1.2 mg/M2 and Adriamycin 30 mg/M2) alternated every 6 weeks with c-DDP 120 mg/M2 on Day 1 and VP- 16 100 mg/M2 on Day 2, 4, and 6. Patients randomized to receive six cycles of chemotherapy received one maintenance cycle of both combinations, while patients randomized to ten cycles completed two additional cycles of each combination. This study continues to accrue patients; however, preliminary analysis confined to the limited stage patients demonstrates that duration of maintenance therapy does not appear to influence survival (data not shown).

Statistics

Survival, local control, and freedom from thoracic progression were measured from the initiation of therapy to death. Survival was compared for that subset of patients who achieved a CR in the thorax with or without PCI. In addition, survival was compared between patients remaining controlled locally treated with or without PCI. Freedom from thoracic progression was measured from initiation of therapy to disease progression. All survival curves are calculated according to the method of Kaplan and Meier (19). Patients dying from causes other than LSSCLC, including secondary malignancies, were censored. Differences in survival and control rates were assessed by Log Rank analysis. Fisher’s exact test was used

Prophylactic cranial irradiation in small cell lung cancer 0 M.

Table 2. Patient characteristics

Number F:M (% female) Median age Median KPS

to assess

significance

in

PC1 (+)

PC1 (-)

36 15:21 (42%) 57 80%

26 lo:16 (38%) 60 90%

the distribution of characteristics

45

ROSENSTEINet al.

(22/36) versus 85% (22/26) in the PC1 (+) and PC1 (-) groups, respectively. In these two subgroups, BF occurred in 23% (5/22) of the PC1 (+) patients, versus 50% ( 1 l/22) of the PC1 (-) patients (p = .04). The brain was the first site of failure in 18% (4/22) of the PC1 (+) versus 45% ( 10/22) of the PC1 (-) patients (p = .04). The brain was the only site of failure in 9% (2/22) of the PC1 (+) patients versus 26% (6/26) of the PC1 (-) patients (p = .I). Survival at 2 years was 42% for the PC1 (+) versus 13% for the PC1 (-) patients who achieved a CR in the thorax (p = .05).

between groups. RESULTS Patient characteristics The distribution of patient characteristics and prognostic factors between the PC1 (+) and PC1 (-) patients are summarized in Table 2. Both groups are well matched for prognostic variables. Efects of PCI on BF The overall distribution of central nervous system failures are summarized in Table 3a. Failures were documented by CT scan once clinical suspicion warranted it. The incidence of BF was 20% (7/36) and 58% (15/26) in the PC1 (+) and PC1 (-) groups, respectively (p = .OOl). The CNS was the first site of failure in 14% (5/36) and 46% ( 12/26), respectively (p = .004). Furthermore, the central nervous system was the only site of failure in three patients (8%) in the PC1 (+) group versus seven patients (27%) in the PC1 (-) group (p = .04). BF and survival in patients achieving a CR in the thorax The distribution of BF in patients achieving a CR in the chest is detailed in Table 3b. The CR rate was 6 1%

BF and survival in patients controlled in the thorax While survival was significantly improved in patients receiving PCI, this same group had significantly improved thoracic control, which resulted in enhanced freedom from disease progression in the thorax. Presumably, this was due to concomitant thoracic radiation and consolidative chemotherapy in these patients. To control for this confounding factor, only CR patients who never failed in the thorax were analyzed. The CR rate in the chest was higher for PC1 (-) patients compared to PC1 (+) patients, however, freedom from thoracic progression was 45% in the PC1 (-) group compared to 73% (16/22) in the PC1 (+) group. In patients controlled in the thorax, there were 25% (4/16) BF in the PC1 (+) group versus 70% (7/10) in the PC1 (-) group (p = .03). For this same subset, 2-year survival was 56% PC1 (+) versus 14% PC1 (-) (p < .05) (Fig. 1). There were no 5-year survivors without PC1 compared to 6116 with PCI. Three of the 6 long term survivors developed secondary malignancies and did not die of LSSCLC and were censored from analysis. Permanent neurotoxicity occurred in three PC1 (+) patients. One patient developed short-term memory deficits and ataxia. This has been clinically stable and he is alive seven years since initiation of treatment. A second patient became demented and ataxic 2 years after initiation of

Table 3. The effect of PC1 on BF PC1 (+) no. = 36 No.

PC1 (-) no. = 26 (%)

No.

(%)

n

P

(27) (46) (58)

10 17 22

.04 .004 .oo 1

16 8 14

.04 .1 .04

26 11

.05 .03

All patients

a. Brain only site failure Brain-first failure All brain failures

3 5 7

(8) (14) (20)

I 12 15 Patients

b. CR in thorax Brain failures Brain-only site failure Brain-first failure

22 5 2 4

I;:; (9) (18)

C.

* Patients

never failed in chest.

16 4

(73) (25)

(85) (50) (27) (45)

22 11 6 10 Patients

Durable local control* Brain failure

with CR in chest

10 7

controlled

in chest (45) (70)

46

1. J. Radiation Oncology 0 Biology 0 Physics

Volume 24. Number I. 1992

SCLC: SURVIVAL OF CRs REMAINING CONTROLLED IN THE CHEST

P c 0.05

7

-PCI a

TIME (YEARS) Fig. 1. Survival distribution

of PC1 (+) versus PC1 (-) patients

therapy. A CT scan showed ventricular dilation and atrophy of periventricular white matter. She died of non small cell lung cancer 2.5 years after initiation of treatment. The third patient developed optic atrophy and subsequently died of acute non-lymphocytic leukemia 6 years after initial treatment. DISCUSSION The use of PC1 in the management of LSSCLC remains controversial. Many retrospective (9, 20, 30, 32) as well as prospective trials (3, 4, 10, 17, 18, 25, 32) have shown that PC1 effectively reduces the overall incidence of brain failures, but no clear survival advantage has been demonstrated. Many of the prospective trials may be criticized for including mixed histologies, inadequate patient numbers, patients with extensive disease, or patients never achieving a CR in the thorax. In addition, a low rate of thoracic control was achieved in these trials due, in part, to the use of low doses of thoracic irradiation and variable chemotherapy. Consequently, the definitive prospective trial has not as yet been completed. We included PC1 in the management of all patients with LSSCLC treated at MSKCC between 1979 and 1982 (33). It was evident from our own early experience, as well as others, that PC1 can lead to profound neurologic toxicity and ultimate debility (7, 11, 12, 14, 17, 21, 22, 23, 31). Reported side effects include abnormalities of

who achieved

thoracic

control.

mental function, CT evidence of white matter atrophy, seizures, dementia, ataxia, and psychomotor disturbances. It is not clear, however, if many of these debilities are the result of a paraneoplastic process or a manifestation of radiation interaction with drugs capable of crossing the blood brain barrier (CCNU, procarbazine, or methotrexate). Because of the absence of a proven benefit and concern over these potential toxicities, PC1 was eliminated from consolidative treatment at MSKCC beginning in 1985. The dramatic increase in CNS relapse following this change in policy prompted us to reappraise this decision and forms the basis for this study. This retrospective analysis clearly demonstrates that PC1 decreases overall CNS relapse as well as the incidence of first failures in the CNS, not unlike most other studies to date. Prophylactic cranial irradiation (+) patients also received maintenance chemotherapy with procarbazine, CCNU, and methotrexate; however, these agents when used without PC1 have not impacted on BF and is an unlikely explanation for the differences observed here (15, 27, 35). A recent randomized control of twelve versus six courses of chemotherapy demonstrated a modest improvement in survival in patients achieving a complete response to initial chemotherapy (26) however, no statistically significant delay in brain metastases as first site of failure was observed further suggesting that the duration of maintenance chemotherapy has no effect on BF.

Prophylactic cranial irradiation in small cell lung cancer 0 M. ROSENSTEIN et al.

Survival at 2 years was 42% for the PC1 (+) patients compared to 13% for the PC1 (-) patients (p < .05), however, other factors in addition to PC1 may be operative. The method of TI (OD vs BID), administering concomitant chemotherapy during TI, or the duration of maintenance chemotherapy had no effect on distant metastases outside the CNS (2). The improvement in survival in PC1 (+) patients was confounded, however, by the enhanced freedom from thoracic progression observed in patients receiving OD TI compared to BID TI, 57% versus 15%, respectively. These differences in thoracic control form the basis of a separate report (2). When analyzing CRs not failing in the thorax, there was a significant decrease in BF in the PC1 (+) patients which translated into significantly improved survival and the potential for cure (Fig. 1). There were no long-term survivors among patients who did not receive prophylactic cranial irradiation in this series. As the potential for long-term cure of patients with LSSCLC now exists ( 12,23), methods to prevent the longterm consequences of therapy require analysis. As is the case with other normal tissues, a reduction in fraction size should result in a decrease in long-term toxicity, and possibly an increase in therapeutic ratio ( 16). While Komaki has demonstrated comparable CNS control rates in patients treated with 30 Gy in 10 fractions compared to 25 Gy in 10 fractions, it is not clear if this has resulted in reduced neurotoxicity (20). It has been suggested that 30

41

Gy in conventional fractionation may further reduce CNS toxicity, but these doses have no proven efficacy in controlling brain failure ( 16). Additional studies are required to determine if PC1 in lower doses per fraction given without potentially neurotoxic agents would decrease neurotoxicity while maintaining CNS control. In summary, the data suggest that the overall difference in survival of the two populations is due to inferior thoracic control and increased central nervous system relapse in PC1 (-) patients. We have attempted to control for the confounding issue of thoracic failure, and showed that PC1 (+) patients had significantly enhanced survival. As this is not a prospective randomized trial and other therapeutic differences exist between the two groups, these results are not conclusive. Nevertheless, it appears that PC1 could best benefit that subgroup of LSSCLC patients that achieves long-term CRs in the mediastinum. In view of the high degree of durable thoracic control now achievable with twice daily thoracic irradiation and concomitant chemotherapy (36) PC1 will become an increasingly important issue in patient management. Since 86% of patients receiving twice daily thoracic irradiation achieved a CR in the thorax, it appears reasonable to administer PC1 during TI. Until a subgroup (42%) ([26/62] patients in this series) of CRs achieving durable thoracic control are prospectively identifiable, we recommend that if PC1 is used, it should be given to all LSSCLC patients achieving a CR in the chest.

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Volume 24, Number 1. 1992

28. Perez, C.; Einhorn, L.; Oldham, R.; Greco, F.; Gohen, H.; Silverman, H.; Krauss, S.; Homback, N.; Comas, F.; Omura, G.; Salter, M.; Keller, J.; Mclaren, J.; Kellermeyer, R.; Storaasli, J.; Birch, R.; Dandy, M. Randomized trial of radiation therapy 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. 2: 1200-1208;1984. 29. Perry, M.; Eaton, W.; Propert, K.; Ware, J.: Zimmer, B.; Chaninian, A.; Skarin, A.; Carey, R.; Kreisman, H.; Faulkner, C.; Comis, R.; Green, R. Chemotherapy with or without radiation therapy in limited small cell carcinoma of the lung. N. Engl. J. Med. 316:912-918;1987. 30. Rosen, S.; Makuch, R.; Lichter, A.; Ihde, D.: Matthews, M.; Minna, J.; Glatstein, E.; Bunn, P. Role of prophylactic cranial irradiation in prevention of central nervous system metastases in small cell lung cancer: Potential benefit restricted to patients with complete response. Am. J. Med. 74:6 15624;1983. 31. Scher, H.; Hilaris, B.; Wittes, R. Long term follow-up of combined modality therapy in small cell carcinoma (SCLC) of the lung. Proc. Am. Sot. Clin. Oncol. 2: 199;1983. 32. Seydel, H.; Crech, R.; Pagano, M.; Salazar, 0.; Rubin, P.; Concannon. J.; Carbone, P.; Mohuiddin, M.; Perez, C.: Matthews, M. Combined modality treatment of regional small undifferentiated carcinoma of the lung: a cooperative study of the RTOG and ECOG. Int. J. Radiat. Oncol. Biol. Phys. 9:1135-1141;1983. 33. Shank, B.; Natale, R.; Hilaris, B.; Wittes, R. Treatment of small cell carcinoma of the lung with combined high dose mediastinal irradiation, whole brain prophylaxis and chemotherapy. Int. J. Radiat. Oncol. Biol. Phys. 7:469475;1981. 34. Souhami, R.; Geddes, D.; Spiro. S.; Harper. P.; Tobias, J.; Mantel], B.; Fearon, F.; Bradbury, 1. Radiotherapy in smallcell cancer of the lung treated with combination chemotherapy: a controlled trial. Br. Med. J. 288: 1643-l 646; 1984. 35. Tattersal, M. H.; Fox, R. M.; Woods, R. L. A randomized trial of high dose methotrexate in small cell lung cancer treated by combination chemotherapy. Second World Congress on Lung Cancer, Copenhagen, June 9-13; 1980. 36. Turrisi, A.; Glover, D. J.; Mason, B. A preliminary report: Concurrent twice-daily radiotherapy plus platinum-etoposide chemotherapy for limited small cell lung cancer. lnt. J. Radiat. Oncol. Biol. Phys. 15: 183-187;1988.

A reappraisal of the role of prophylactic cranial irradiation in limited small cell lung cancer.

The use of prophylactic cranial irradiation in limited stage small cell lung cancer remains controversial. Prospective trials have demonstrated that P...
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