Prophylactic cranial irradiation: Advantages and disadvantages

Annals of Oncology 3 (Suppl. 3): S51-S55, 1992. © 1992 Kluwer Academic Publishers. Printed in the Netherlands.

Original article Prophylactic cranial irradiation: Advantages and disadvantages W. T. Sause LDS and Cottonwood Hospitals, University of Utah Medical Center, Salt Lake City, Utah, U.S.A.

Introduction

Prophylactic irradiation to a potential sanctuary site demonstrates several important aspects of the pathophysiology of malignancies like childhood leukemias and small cell lung cancer (SCLC). Features that make treatment of a sanctuary site like the central nervous system (CNS) attractive in a particular disease are the high curability of the disease with systemic therapy, the high incidence of CNS relapse, the effectiveness of cranial irradiation, and the ability of this radiation to sterilize the CNS at doses that are not likely to produce a high incidence of late complications. Theoretically, acute lymphoblastic leukemia in childhood lends itself to such sanctuary-site treatment. Since the 1960s, acute lymphoblastic leukemia in children has been a potentially curable disease. Modern systemic chemotherapy cures more than 50% of children who present with this illness. In the 1960s, CNS relapses were noted to occur in approximately 40% to 60% of children following successful induction therapy. Clinical research conducted at the St Jude Children's Table I. Prevention of CNS relapse: Leukemia. Period

Therapy

CNS relapse (%)

1962-1965 1965-1967 1970-1971

12Gy None 24 Gy

40 60 7

Methotrexate Adapted from Poplack

ment schedules and avoiding the use of doxorubicin with irradiation. Prophylactic cranial irradiation delivered to those patients who obtain a complete remission in response to induction chemotherapy can reduce the incidence of CNS relapse and can usually be delivered with minimal CNS toxicity. Unfortunately, long-term disease control with systemic agents is poor. Until more effective systemic agents are developed, the role of prophylactic cranial irradiation is one of palliation rather than improving survival. Key words: small cell anaplastic carcinoma, prophylactic cranial irradiation, CNS relapse

Research Hospital demonstrated that modest radiation doses delivered to the cranial vault with intrathecal methotrexate reduced the incidence of initial CNS relapse to less than 10% (Table 1) [1]. Over the last 20 years, prognostic factors and radiation doses have been refined to provide maximal CNS sterilization with minimal neurologic toxicity. A similar treatment policy could be applied to anaplastic SCLC. SCLC represents a tumor that responds readily to cytotoxic chemotherapy, exhibits a high incidence of CNS relapse, is relatively radiosensitive, and modest radiation doses to the brain would be unlikely to cause late treatment sequelae in adults. Based on the clinical success observed in the treatment of acute lymphoblastic leukemia, prophylactic cranial irradiation (PCI) has been used in patients with anaplastic SCLC for a number of years. Unfortunately, the utility of PCI remains controversial.

Relapse pattern

Anaplastic SCLC has a high propensity for systemic spread. Early studies using only surgery and radiation were notable for the high incidence of systemic relapse. The development of systemic treatment in the 1970s has been responsible for improved median and 2-year survival in patients with this disease [2]. Ultimately, however, the brain represents a frequent relapse site and the majority of patients relapse. Several randomized and nonrandomized series have been published that attest to the relapse pattern of anaplastic SCLC

Downloaded from http://annonc.oxfordjournals.org/ at University of Chicago on July 13, 2015

Summary. Anaplastic small cell carcinoma of the lung is a disease that responds to multiagent systemic therapy. Unfortunately, a high incidence of central nervous system (CNS) relapse has been observed by many investigators. Cranial irradiation has been successfully used in acute lymphoblastic leukemia to reduce CNS relapse and improve survival. A similar application of prophylactic cranial irradiation in patients undergoing therapy for small cell anaplastic carcinoma of the lung has been noted to decrease CNS relapse from approximately 25% to approximately 5%. However, CNS toxicity has been noted to occur with CNS prophylaxis. We can reduce the incidence of CNS toxicity by using modern treat-

52

Dose-response relationship Anaplastic SCLC is a tumor that responds well to external-beam radiation. In sequential studies conducted by several investigators, a clinical dose-response relationship appears between the radiation dose deliv-

Table 2. PCI randomized trials. References

18] [91 |101 111] [12]

[13] |14]

% CNS relapse

Survival

With PCI

No PCI

0 0 17 9 0 4 5

36 16 24 13 27 18 21

NS NS NS NS NS NS NS

NS = not significant.

ered and intrathoracic tumor control. Arriagada et al. [15] were able to demonstrate improved intrathoracic control when doses escalated from 45 to 55 Gy, with 61% local control at 45 Gy vs. 82% at the 55-Gy dose. The Southwest Oncology Group (SWOG) was able to demonstrate an increase in local control when thoracic doses escalated from 30 to 45 Gy. In SWOG 76-28 [16], an increased number of relapses were noted at the lower dose. Choi [17], who analyzed chest relapses according to radiation dose delivered, also was able to document improved local control with escalating radiation doses (Table 3). Table 3. Intrathoracic control of anaplastic small cell lung cancer. References

[17]

Radiation dose (Gy)

% Control

45 55

61 82

30 50

61

The lowest possible dose necessary to sterilize the CNS remains somewhat controversial. The NCI has analyzed its results with therapeutic radiation for CNS metastases [18]. Thirty-seven of 61 patients achieved an objective response to radiation, with 32% exhibiting CR to treatment for clinically symptomatic brain relapses. Twenty-four of these 37 patients subsequently developed progressive CNS tumors. Patients received radiation in a variety of schedules, but those patients who were treated with more than 40 Gy had a median duration of response of 10 months, as opposed to 7 months for those who received less than 40 Gy. Komaki et al. [19], who analyzed results from the Medical College of Wisconsin, concluded that 10 2.5Gy fractions delivered in 2 weeks were as effective as 10 3-Gy fractions in 2 weeks for prophylactic cranial treatment. The group receiving 25 Gy experienced a 3% relapse rate compared with a 10% relapse rate in those receiving 30 Gy. The results of the NCI analysis suggest, but do not confirm, that 20 Gy in 10 fractions during induction therapy are similar to 24 Gy in 10 fractions delivered after initial chemotherapy. There appears to be a dose-response relationship

Downloaded from http://annonc.oxfordjournals.org/ at University of Chicago on July 13, 2015

and the ability of radiation therapy to reduce the incidence of early relapse [3]. A nonrandomized National Cancer Institute (NCI) series analyzed consecutive cohorts of patients treated with or without PCI [4]; 332 patients were analyzed. The analysis included patients treated from 1974 to 1980. In all, 136 patients had limited disease (LD), and 123 of the 332 had had a complete response (CR) to chemotherapy. A 42% incidence of CNS relapse occurred in the 176 patients who received no PCI. Of those treated with PCI, one group that received 24 Gy in eight fractions exhibited a 34% incidence of CNS relapse, while the group that received 20 Gy with induction chemotherapy experienced a 17% incidence. In the group with CRs to induction therapy, none who had received PCI experienced CNS relapse as the first site of recurrence, whereas 16% of those who received no PCI relapsed initially in the brain. The University of Maryland attempted a randomized trial of patients who initially experienced a CR to therapy [5]. An early analysis of this trial revealed that none of the 17 patients who had received PCI experienced CNS relapse while 31% of those not receiving PCI did. Randomization was discontinued at the time of these early analyses. When all patients who were entered into consecutive trials - conducted from 1975 through 1982 at the University of Maryland - were analyzed, 20% of those who received PCI (compared with 42% of those receiving no PCI) exhibited a CNS relapse. Only 1 patient treated with PCI experienced initial CNS relapse while 23% of the no-PCI group experienced initial CNS relapse [5]. From 1975 to 1979, the Radiation Therapy Oncology Group (RTOG) and Eastern Cooperative Oncology Group (ECOG) conducted a randomized trial of patients with LD anaplastic SCLC [6]. A total of 104 patients experienced CR to radiation therapy and were randomized to PCI vs. no PCI. Of the 104 patients, 11 developed brain metastases; only 2 of these 11 had been randomized to PCI. A recent University of Indiana analysis [7] revealed that of 38 CR patients who received PCI, 1 had an initial CNS relapse. Of 20 patients who did not receive PCI, 4 had brain relapses. Table 2 [8-14] lists various randomized trials and documents the incidence and reduction of CNS relapses with PCI. These trials represent a heterogeneous population of patients, including those with LD and extensive disease (ED), and those who did not as well as those who did experience CR to initial therapy. One consistent aspect of these reported series is a reduction in CNS relapses when PCI is used.

53

between radiation and control of anaplastic SCLC. In the treatment of subclinical CNS disease, the dose necessary for sterilization should be lower than that needed for overt disease. A dose greater than 20 Gy delivered in 10 fractions is probably necessary to prevent CNS relapse, but doses as high as 30 Gy in 10 fractions may be unnecessary. A complicating factor in the delivery of PCI is the timing of systemic chemotherapy, which may have a detrimental effect on normal tissue tolerance. Toxicity

Table 4. Neuret values for a variety of radiation schedules. Total dose (Gy)

Fraction size (Gy)

Tii

50 36 30 20 30 20

2 2.4 3 4 2 2.5

33 47 12 5 19 12

1)

Neuret

983 867 938 894 763 781

Adapted from Turrisi [22|.

Investigators from the University of Indiana recently reported an incidence of CNS toxicity as high as 63% in patients receiving PCI and doxorubicin-based chemotherapy concurrently. Radiation was delivered in fractions of 2.4 to 3 Gy, to a total dose of 30 to 36 Gy [7]. In the same issue of the Journal of Clinical Oncology, investigators from the Princess Margaret Hospital in Toronto analyzed late CNS sequelae following delivery of 20 Gy in five fractions applied between

Schema

Rduction chemotherapy

R E S

T A

G E

CR—-

PR. SD. PD ineligible

R A N D

O M

1 Z \ E

PCI25Gy/10Fx over 2-2 'Awk Follow-up evaluation q3mo years 1-2. q6mo years 3-5 Observation — > CNS — > TCI relapse

Randomization must be <24 wk after start of induction chemotherapy

Fig. 1. Schema of a prospective randomized trial by the Eastern Cooperative Oncology Group of prophylactic cranial irradiation (PCI) vs. observation in patients attaining a complete response (CR) to systemic treatment of the primary tumor. PR = partial response; SD = stable disease; PD = progressive disease; Fx = fraction; CNS = central nervous system; TCI = therapeutic cranial irradiation.

Downloaded from http://annonc.oxfordjournals.org/ at University of Chicago on July 13, 2015

Over the past 10 to 15 years we have developed more insight into the pathophysiology of normal tissue injury resulting from therapeutic radiation. The pathogenesis of radiation injury consists of vascular endothelial damage. In patients with anaplastic SCLC treated with PCI, the cause of CNS injury is multifactorial, but certain aspects of radiation delivery can be improved to minimize damage [20]. Clinical research conducted by Sheline [21] suggests an intricate relationship between total dose and fraction size and the development of CNS injury. The term 'neuret', coined by Sheline, is used to quantitate the probability of CNS toxicity. The formula is based on analysis of clinical data. As one approaches a neuret dose of 1,000, the incidence of CNS toxicity increases. Sheline has estimated that one could deliver approximately 52 Gy at 2 Gy per fraction and obtain an incidence of CNS necrosis of less than 1%. Turrisi [22] has calculated various neuret doses for CNS prophylaxis as demonstrated in Table 4 [22]. In SCLC, PCI at the usual dose of 30 Gy over 2 weeks results in a neuret of 938, a schedule close to CNS tolerance. If cytotoxic chemotherapy is given simultaneously, toxicity may be excessive.

chemotherapy cycles [23]. They concluded that the incidence of late CNS sequelae secondary to treatment was small and that prophylaxis delivered in this fashion was justified. Some investigators have reported a high incidence of changes on computed tomography (CT) and magnetic resonance imaging (MRI) following PCI. The NCI has extensively studied 15 patients with a minimum 6-year follow-up, 13 of whom received PCI [24]. At least 80% of these patients exhibited changes on neuropsychologic testing, CT, and MRI. These changes appeared to increase with longer follow-up. However, 9 of the 15 have returned to life-styles approximating those of their pretherapy lives. The issue of brain damage is further clouded by the incidence of CNS toxicity associated with any malignancy requiring systemic therapy. Investigators at St Jude Children's Research Hospital recently analyzed the incidence of CNS toxicity based on whether patients had received PCI [25], comparing those who had received intravenous and intrathecal methotrexate with those who had received intrathecal methotrexate and 18 Gy or 24 Gy of PCI. They were unable to detect any differences in verbal performance or full-scale IQs between treatment arms of the study. Patients with anaplastic SCLC exhibit a high incidence of CNS relapse; the relapse rate for patients in CR may be as high as 20% to 30%. PCI can substantially reduce the incidence of CNS relapse. The radiation dose necessary to influence the relapse pattern should be greater than 20 Gy delivered over 2 weeks. Some toxicity associated with the delivery of CNS prophylaxis appears to be related to the radiation dose per fraction and the timing of cytotoxic chemotherapy. Long-term sequelae have been noted on CT, MRI, and neuropsychologic testing in patients who have received PCI. It is difficult, however, to separate changes associated with age, underlying malignancy, and cytotoxic chemotherapy from those associated with the addition of PCI. The value of PCI in patients achieving a CR to systemic treatment has been poorly studied in a prospective, randomized fashion, and this is the intent of a current ECOG trial (Fig. 1).

54 Survival

Table 5. Survival of patients with limited anaplastic small cell lung cancer. Investigators

University of Pennsylvania SWOG NCI

Treatment

Median survival (mo)

EP + MDFRT EPV + RT EP + MDFRT

24 17 24

2-yr Survival

54

45 60

EP = etoposide/cisplatin; MDF = multiple daily fraction; RT radiation therapy; EPV = etoposide/cisplatin/vincristine.

Conclusion In summary, anaplastic SCLC represents a relatively radiosensitive disease that often responds to cytotoxic chemotherapy but exhibits a high incidence of CNS relapse. PCI-induced CNS toxicity may be minimized with modern techniques. Unfortunately, unlike acute lymphoblastic leukemia, anaplastic SCLC is rarely curable, and PCI is of limited value in the absence of improved systemic treatment.

References 1. Poplack DG. Acute lymphoblastic leukemia. In Pizzo PA, Poplack DG (eds): Principles and Practice of Pediatric Oncology. Philadelphia, Pa: JB Lippincott Co; 1989: 323-66.

Downloaded from http://annonc.oxfordjournals.org/ at University of Chicago on July 13, 2015

Unfortunately, these interesting clinical observations related to the use of PCI have not translated into improved survival. Prospective studies to date have not confirmed the ability of PCI to enhance survival in this group of patients (Table 2). Unlike acute lymphoblastic leukemia, it is possible to cure anaplastic SCLC with systemic therapy alone in an extremely small number of patients. Long-term follow-up analyses from the British Research Council report 7-year survival figures of less than 5% in LD patients [26]. PCI will not affect existing systemic disease and will not prevent 'reseeding' of the CNS in uncontrolled systemic disease. It will be valuable only if and when more favorable treatments for systemic disease become available. Recently reported trials from SWOG, the University of Pennsylvania, and the NCI suggest a substantial improvement in 2-year and median survival in LD patients treated with etoposide, cisplatin, and concurrent radiotherapy (Table 5) [16, 27, 28]. A phase III trial by ECOG and RTOG is attempting to confirm these encouraging results. Whether these patients will subsequently exhibit a high incidence of isolated CNS relapse and whether these remissions will be durable remain in question. If systemic and locoregional disease control can be improved, then perhaps PCI will have a major role in the management of this disease.

2. Feld R, Ginsberg RJ, Payne DG. Treatment of small cell lung cancer. In Roth JA, Ruckdeschel JC, Weisenburger TH (eds): Thoracic Oncology. Philadelphia, Pa: WB Saunders Co; 1989: 229-62. 3. Perez CA, Einhorn L, Oldham RK et al. for the Southeastern Cancer Study Group. Randomized 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 (11): 1200-8. 4. Rosen ST, Makuch RW, Lichter AS et al. 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 1983; 74: 615-24. 5. Aroney RS, Aisner J, Wesley MN et al. Value of prophylactic cranial irradiation given at complete remission in small cell lung carcinoma. Cancer Treat Rep 1983; 67 (7-8): 675-82. 6. Seydel HG, Creech R, Pagano M et al. Prophylactic versus no brain irradiation in regional small cell lung carcinoma. Am J Clin Oncol 1985; 8: 218-23. 7. Fleck JF, Einhorn LH, Lauer RC et al. Is prophylactic cranial irradiation indicated in small-cell lung cancer? J Clin Oncol 1990; 8 (2): 209-14. 8. Aisner J, Whitacre M, Van Echo DA et al. Combination chemotherapy for small cell carcinoma of the lung. Continuous versus alternating non-cross resistant combinations. Cancer Treat Rep 1982; 66: 221-30. 9. Beiler DD, Kane RC, Bernath AM et al. Low dose elective brain irradiation in small cell carcinoma of the lung. Int J Radiat Oncol Biol Phys 1979; 5: 941-5. 10. Cox JD, Petrovich Z, Paig C et al. Prophylactic cranial irradiation in patients with inoperable carcinoma of the lung. Cancer 1978; 42: 1135-40. 11. Hirsch FR, Hansen HH, Paulson OB et al. Development of brain metastases in small-cell anaplastic carcinoma of the lung. In Kay HEM, Whitehouse JMA (eds): CNS Complications of Malignant Disease. Baltimore, Md: University Park Press; 1979: 175-84. 12. Jackson DV, Richards F, Cooper MR et al. Prophylactic cranial irradiation in small cell carcinoma of the lung: a randomized study. JAMA 1977; 237: 2730-3. 13. Maurer LH, Tulloh M, Weiss RB et al. A randomized combined modality trial in small cell carcinoma of the lung: comparison of combination chemotherapy-radiation therapy versus cyclophosphamide-radiation therapy, effects of maintenance chemotherapy and prophylactic whole brain irradiation. Cancer 1980; 45: 30-9. 14. Seydel HG, Creech R, Pagano M et al. Combined modality treatment of regional small cell undifferentiated carcinoma of the lung. A cooperative study of the RTOG and the ECOG. Int J Radiat Oncol Biol Phys 1983; 9 (8): 1135-41. 15. Arriagada R, Le Chevalier T, Baldeyrou P et al. Alternating radiotherapy and chemotherapy schedules in small cell lung cancer, limited disease. Int J Radiat Oncol Biol Phys 1985; 11: 1461-7. 16. McCracken JD, Janaki LM, Taylor SB et al. Concurrent chemotherapy and radiotherapy for limited small-cell carcinoma of the lung: a Southwest Oncology Group study. Semin Oncol 1986; 13 (suppl 3): 31-6. 17. Choi NC. Reassessment of the role of radiation therapy relative to other treatments in small cell carcinoma of the lung. In Choi NC, Grillo HC, eds. Thoracic Oncology. New York, NY: Raven Press; 1983:233-56. 18. Carmichael J, Crane JM, Bunn PA et al. Results of therapeutic cranial irradiation in small cell lung cancer. Int J Radiat Oncol Biol Phys 1988; 14: 455-9. 19. Komaki R, Byhardt RW, Anderson T et al. What is the lowest effective biologic dose of prophylactic cranial irradiation? Am J Clin Oncol 1985; 8: 523-7. 20. Barendsen GW. Influence of fractionation on normal tissue tolerance. In Gutin PH, Leibel SA, Sheline GE (eds): Radiation

55

21.

22. 23.

24.

25.

mia who received 18-Gy, 24-Gy or no cranial irradiation. J Clin Oncol 1991; 9 (8): 1348-56. 26. Souhami RL, Law K. Longevity in small cell lung cancer. A report to the Lung Cancer Subcommittee of the United Kingdom Coordinating Committee for Cancer Research. Br J Cancer 1990; 61: 584-9. 27. Turrisi AT, Glover DJ. Concurrent twice-daily radiotherapy and platinum-etoposide chemotherapy in limited small cell lung cancer. Proc Am Soc Clin Oncol 1986; 5: 178 (Abstract). 28. Johnson BE, Grayson J, Woods E et al. Limited stage small cell lung cancer treated with concurrent etoposide/cisplatin plus bid chest radiotherapy. Proc Am Soc Clin Oncol 1989; 8: 228 (Abstract). Correspondence to: William T. Sause, MD Director, Radiation Therapy LDS Hospital Radiation Therapy Center 8th Ave and C St Salt Lake City, UT 84143, U.S.A.

Downloaded from http://annonc.oxfordjournals.org/ at University of Chicago on July 13, 2015

Injury to the Nervous System. New York, NY: Raven Press; 1991:57-67. Sheline GE. Irradiation injury of the human brain: a review of clinical experience. In Gilbert HA, Kagan AR (eds): Radiation Damage to the Nervous System, a Delayed Therapeutic Hazard. New York, NY: Raven Press; 1980: 39-58. Turrisi AT. Brain irradiation and systemic chemotherapy for small cell lung cancer: dangerous liaisons? J Clin Oncol 1990; 8 (2): 196-9. Lishner M, Feld R, Payne DG et al. Late neurological complications after prophylactic cranial irradiation in patients with small cell lung cancer: the Toronto experience. J Clin Oncol 1990; 8 (2): 215-21. Johnson BE, Patronas N, Hayes W et al. Neurologic, computed cranial tomographic, and magnetic resonance imaging abnormalities in patients with small-cell lung cancer: further follow-up of 6- to 13-year survivors. J Clin Oncol 1990; 8(1): 48-56. Mulhern RK, Fairclough D, Ochs J. A prospective comparison of neuropsychologic performance of children surviving leuke-