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Prophylactic Cranial Irradiation in Small-Cell Lung Cancer

Emory University School of Medicine, Department of Radiation Oncology, Atlanta, Georgia, USA

Correspondence: Richard H. Matthews, M.D., Ph.D., Associate Professor of Radiation Oncology, Emory University, 2841 Hawthorne Dr. NE, Atlanta, Georgia 30345, USA. Telephone: 770-493-6964 or 404-616-3947; Fax: 770-492-0284; e-mail: blmatthews{at}mindspring.com

	ABSTRACT

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Prophylactic cranial irradiation is now known to improve survival to a significant degree in small-cell lung cancer (SCLC) patients; this is in addition to its established role in preventing the disabling symptoms of brain metastases. New information indicates that it confers a survival benefit for limited or extensive stage SCLC patients gaining a complete response in the chest. A review of causes of cerebral dysfunction as a complication indicates that such problems can be due to suboptimal radiation fractionation, chemotherapy, or an inappropriate combination of prophylactic brain irradiation with chemotherapy. Optimum treatment with prophylactic brain irradiation has been shown not to cause adverse effects with detailed psychometric testing. Several additional sources of information can be drawn together to suggest a dose-response pattern for prophylactic brain irradiation, leading to the recommendation that a dose of 25-36 Gy is optimal, delivered in 2-3 Gy daily fractions after the completion of chest irradiation and chemotherapy. This will be better defined in future clinical trials.

Key Words. Prophylactic cranial irradiation • Small-cell lung cancer • Brain metastases • Survival

	INTRODUCTION

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At the time of initial diagnosis, 10% to 14% of patients with small-cell lung cancer (SCLC) have detectable brain metastases [1]. At the time of death, at least one-third (33% to 42%) of patients harbor clinically recognized brain metastases, and approximately 50% of patients have brain metastases when sent to postmortem examination [2]. The frequency of brain metastases increases as survival time increases [3, 4]. Moreover, patients with extensive-stage disease at presentation are more likely than those with limited-stage disease to develop brain metastases at two years (47% versus 69%) [3]. With improvements in systemic and local therapy yielding improved overall survival rates at five years, recurrence in the central nervous system has become an increasing problem that affects approximately 50% of patients two years after diagnosis. Improving survival may be seen as an initial step in dealing with SCLC that then increases the concern for the quality of life of the surviving patients.

Brain metastasis impairs the quality of life and shortens survival [5]. Patients developing brain metastases often require hospitalization. The treatment of clinically established brain metastases is only partially satisfactory; perhaps about half achieve meaningful palliation by radiation [6, 7] or chemotherapy, and median survival is only four to six months [8]. Results from other clinical problems, such as the prophylactic cranial irradiation (PCI) of children with acute lymphocytic leukemia (ALL) [9], led to the initiation of PCI into the treatment of SCLC more than 20 years ago. The original argument for its use was based not upon a survival benefit, but upon prevention of the morbidity associated with clinically evident brain metastases. Data permitting a more complete evaluation of the benefits and problems associated with PCI have been gathered in the last few years.

	IMPACT OF PCI ON SURVIVAL IN SCLC

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In the 1980s, clinical trials comparing the treatment of SCLC patients in complete remission with and without PCI consistently revealed a significant decrease in the incidence of brain metastasis, with no increase in overt neurological complications. The results, however, remained inconclusive with regard to the benefit in terms of overall survival. In addition, the safety of PCI was questioned at that time, largely on the basis of possible toxic effects on neurocognitive functions.

Despite arguments against the use of PCI, there was a substantial increase in the absolute number of patients at risk for relapse in the brain with improving control of disease in the chest. It was clear that the risks and benefits of PCI needed to be formally assessed in a prospective randomized trial. This view was echoed in the retrospective reviews that continued to appear from around the world in the early 1990s [10-12], which uniformly demonstrated decreased overt brain metastases, but only sometimes suggested improved survival. The methodological shortcomings of the early investigations and growing concern about cost and hazard versus benefits of PCI led to the design and launch of a new wave of randomized trials in the late 1980s and early 1990s. These have now been completed and involved more than 1,000 patients in all. The three large studies (approximately 300 patients each) had consistent results [13-16]. Two of these studies, PCI85 (a trial originating in France) and UK02 (a British trial), incorporated prospective neurocognitive assessment in their design [13, 14]. There was a suggestion of improved survival in the PCI group in each case, but the difference was not statistically significant. No individual randomized trial has conclusively shown a survival benefit for PCI. However, none of these trials was large enough to provide sufficient power to detect moderate differences in survival.

The PCI Overview Collaborative Group was established to conduct a meta-analysis of trials using PCI and to make recommendations for clinical practice. The report of this meta-analysis was published recently in The New England Journal of Medicine [17] and should establish a new standard of practice for appropriately selected patients. Trials eligible for consideration in the meta-analysis were limited to those in which patients had been treated with systemic chemotherapy (with or without thoracic radiation) to a complete clinical response, and in which patients were subsequently randomized either to receive or not to receive PCI. Patients with known brain metastases were thus excluded. The Group identified seven trials meeting these strict criteria, three of which were large (including > 200 patients) and four were small (including 55 patients). Accrual for these studies ranged from 1977 to 1994. PCI treatments were generally 24 to 40 Gy, administered in fractions of 2-3 Gy per day. The principal study endpoint was survival. The meta-analysis demonstrated a statistically significant improvement in survival with the use of PCI. At three years, 20.7% of patients treated with PCI were alive, in contrast to 15.3% of the controls (p = .01). The estimated magnitude of benefit is 5.4% in absolute terms at three years, and the survival advantage persisted over time. As a percent gain over control, this represents a 35% increase in the proportion of surviving patients, an appreciable gain. Several PCI regimens were used in the studies included, and more uniform use of the more successful regimens may readily augment further the survival benefit. There was a significant increase in disease-free survival at three years from 13.3% in the control group to 22.1% in the PCI group (p < .0001). PCI was associated with an absolute decrease of 25.3% in the cumulative incidence of brain metastasis at three years, from 58.6% in the control group to 33.3% in the treatment group (p < .0001) [17]. Several prior studies had established that PCI decreases the risk of brain metastases. The reduction of clinically detectable brain metastases was a persistent effect in the meta-analysis, consistent with an interpretation that PCI works by eliminating microscopic metastatic deposits in the brain. The important new finding in the meta-analysis is that there was a highly significant improvement in overall survival and disease-free survival associated with PCI, and that the benefits were consistent among subgroups defined by age, performance status, limited versus extensive stage, and type of induction therapy.

	NEUROCOGNITIVE DYSFUNCTIONS—NATURE AND CAUSATIVE FACTORS

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One may examine radiation effects on brain in various circumstances to anticipate possible problems, since there is a more limited body of information dealing with adverse effects in the case of PCI. Crossen et al. [18] conducted a wide-ranging review of neurological and neurocognitive adverse effects noted in patients after cranial irradiation in various settings: brain necrosis, seizures, or dementia reported sometimes after high-dose irradiation for primary gliomas, learning deficits in children receiving moderate dose cranial irradiation as treatment for ALL, an interaction between chemotherapy and radiation, and abnormalities in psychometric testing showing up more readily than positive findings on clinical examination. Johnson and coworkers studied long-term survivors of SCLC [19, 20] finding a decline in neurocognitive function with some correlation with abnormalities on CT scan. Problems were more frequent when chemotherapy was given at the time of cranial irradiation, or large radiation fraction size was employed. Harris and Levene [21] had studied visual complications associated with irradiation of pituitary adenomas and craniopharyngiomas, finding that such complications did not occur at daily fractions of 2 Gy, but did occur with notable incidence at daily fraction sizes of 2.5 or 3 Gy. An animal histological study associated axonal loss in white matter bundles with use of 4 Gy x 5 fractions, a regimen for PCI which had been in vogue in some Canadian centers [22]. Some authors such as Fleck et al. [23] had recommended against PCI, finding limited efficacy at reducing brain metastases and occurrence of significant complications in neurological and cognitive functions. Examination of their treatment details reveals treatment plans which would not be recommended today; one plan called for split-course irradiation in proximity to chemotherapy, and the other delivered 10 fractions of 3 Gy each at the same time as a chemotherapy regimen including Adriamycin. Administration of Adriamycin at the same time as radiation is now known to have major toxic effects on several vital organs including heart, liver, and brain. Contemporaneous with Fleck et al., a group from Princess Margaret Hospital continued to advocate PCI, finding it to be efficacious at reducing brain metastases, and finding neurological complications to be few, and possibly associated with other factors such as chemotherapy [24]. It should be noted that these conclusions appear to be based on clinical findings rather than upon formal psychometric testing. Turrisi editorialized on the differences between the two foregoing studies with conflicting results at the time of publication, pointing to the "dangerous liaison" between chemotherapy and PCI as a probable basis for the major differences in the results [25]. An earlier study from M.D. Anderson Hospital had associated neurotoxicity of PCI with administration of methotrexate or procarbazine after PCI [26]. There were two published studies in 1995 in which psychometric testing was done before and after PCI, one by an M.D. Anderson group and the second by a Dutch group [27, 28]. PCI consisted of 10 fractions of 2.5 Gy in one study and 15 fractions of 2 Gy in the other, and PCI was given after completion of all chemotherapy in both cases. Both studies reported a measurable deficit in neurocognitive function prior to PCI, which did not worsen further after PCI. The hazard that deficits in objectively measured neurocognitive function may be associated with chemotherapy rather than with PCI properly administered is perhaps best underlined by a study carried out by Schagen et al. [29] which does not involve cranial irradiation at all; psychometric testing was done on breast cancer patients with the finding that there was an adverse effect on those patients receiving adjuvant CMF chemotherapy.

Two of the largest randomized trials included in the recently published meta-analysis did incorporate formal assessment of neurocognitive function by psychometric testing before and after PCI. The PCI85 trial (a trial originating in France) was the first major randomized study that addressed this area [13], being published in 1995. In each treatment center, initial neurocognitive tests and follow-up assessments were performed by the same neurologist. The strict black-and-white categorization of examination results as either normal or abnormal may explain why only 41% of the patients had a normal examination at the time of randomization, after induction chemotherapy but before PCI. The results of testing over five years of follow-up in PCI85 showed no differences in neurocognitive function between patients receiving PCI and those not receiving it. The UK02 trial (a British trial) [14] was the second large randomized trial to include formal assessment of neurocognitive functioning. Psychometric testing was done at randomization and every six months afterwards. Impairment was defined using standard deviations from age-matched controls. Up to 40% of patients showed significant abnormalities on individual tests before PCI. Impairments were not found related to age, gender, previous therapy, or treatment center and were evenly distributed between the PCI and control arms of the study. Psychometric evaluations done in follow-up showed no adverse effects of PCI compared to the control arm of the study. Taken together, these two large studies suggest that with objective psychometric testing, 40%-60% of SCLC patients have abnormalities in neurocognitive functioning, and that when managed as it was in these studies, PCI does nothing to worsen the condition.

If PCI given in an optimum fashion does not have an adverse effect on neurocognitive function, but about half of the SCLC patients have deficits before PCI measurable by psychometric testing, what has caused such deficits? One possible area of concern is an effect from the chemotherapy regimens used to gain survival, as mentioned above. However, the nature of the neurocognitive deficits noted suggests frontal-subcortical dysfunction. This is also the region of the brain involved in paraneoplastic encephalopathy.

	WHAT IS THE OPTIMUM REGIMEN?

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We still do not know entirely how best to integrate PCI with chemotherapy in patients with SCLC. Although we have some useful information, the optimal dose of radiation, the best fractionation, and the duration and timing of PCI have not been clearly determined. There is evidence, however, that the risks are highest when chemotherapy (especially with neurotoxic drugs such as nitrosoureas) is given simultaneously with PCI (especially with large fraction sizes) [19].

The UK02 trial, which initially compared higher dose versus lower dose versus observation, confirmed the effectiveness of PCI in reducing the rate of occurrence of brain metastases. Interestingly, among patients randomized in the three-arm part of the study, the significant advantage of PCI was seen only with the higher dose level (36 Gy in 18 fractions, hazard ratio [HR], 0.16; 95% CI, 0.07 to 0.36); the low-dose PCI (24 Gy in 12 fractions, 2 Gy per fraction) had effects similar to those seen in the control group (HR, 0.71; 95% CI, 0.36 to 1.43) [14]. In the PCI85 trial [13], however, patients who underwent PCI with a total dose of 24 Gy delivered in eight, rather than 12 fractions, had significantly better results than those of their control group (HR, 0.45), although this hazard ratio is not as low as that reported for 36 Gy in 18 fractions.

A common misconception is that 24 Gy in 12 fractions is a safe and effective prophylactic regimen. The UK02 study [14] demonstrated this dose and fraction scheme in fact leads to little or no effect. A common regimen used in practice is 30 Gy in 10 fractions. The concern about possible toxicities of 2.5 Gy and 3.0 Gy fractions has not been studied sufficiently in controlled trials. At this time, dose schedules including 24 Gy in 3 Gy fractions [13], 25 Gy in 2.5 Gy fractions, and 36 Gy in 18 fractions as used by the UK02 study are reasonably well established as having some impact in reducing brain metastases, and would be considered as being within the standard of care today. Gregor compared six regimens for PCI recently [30], and 36 Gy in 18 fractions had the most favorable hazard ratio of the six (Table 1).

	CONCLUSIONS

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There is a high propensity for SCLC survivors to develop brain metastasis. The impact of brain metastases on socioeconomic issues and the quality of life of patients is significantly worse than the impact of failure at other metastatic sites [5]. Patients with brain relapse spend significant time hospitalized and suffer loss of independence. In this setting, the prevention of brain metastases and improved quality of life become desirable. PCI is a practical, useful, and apparently safe method, when properly employed, of reducing the risk of brain metastasis in patients with SCLC.

PCI significantly reduces the rate of appearance of brain metastases, especially in patients achieving good response to induction chemotherapy, and there is no significant evidence of serious morbidity associated with properly applied PCI (i.e., soon after chemotherapy and in moderate fraction size). A meta-analysis confirmed the survival benefit in both limited and extensive SCLC patients in complete remission.

The optimal radiation dose and schedule has not been clearly defined. Doses of less than 30 Gy in 2-Gy fractions may be suboptimal, but effectiveness could be increased with the use of larger fractions. Regimens such as 24 Gy in eight fractions or 30 Gy in 10 fractions have been commonly used in practice. Doses of 25 Gy in 10 fractions and 36 Gy in 18 fractions are also within the standard of care. The optimum radiation schedule will probably become the subject of future trials. What is the best plan to use while awaiting the outcome of further trials? The present authors would recommend that on the basis of all presently available data, 36 Gy in 18 fractions is most supportable at this time in terms of proven efficacy at reducing brain metastasis while maintaining minimal risk of serious complications.

Timing of PCI is also critical. The best practice is to introduce PCI as early as feasible after completing chemotherapy. Delaying PCI beyond six months from diagnosis appears to have an adverse effect.

Objective psychometric testing is important in assessing neurocognitive morbidity. Psychometric testing should be done at various points, before and after chemotherapy, and before and after PCI is carried out. Further research is needed to determine the etiology of cognitive impairment in patients with SCLC from the time of their first presentation in order to make plans to counter this problem.

With these observations as a guide, we propose the following: A) PCI should now be considered part of the standard treatment of patients with SCLC in complete remission; B) PCI should be withheld until completion of chemotherapy, then given without excess delay, and C) conservative total doses and fractionation schemes should be used (e.g., a dose of 25-36 Gy, delivered in 2-3 Gy daily fractions; 36 Gy in 2 Gy fractions may be the most supportable regimen at present.)

See Prophylactic Cranial Irradiation In Small-Cell Lung Cancer: Is It Still Controversial or Is It A No-Brainer? by Andrew T. Turrisi, III.

 

	ACKNOWLEDGMENTS

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The authors thank Ms. Kam Wong for her capable assistance in preparing the manuscript.

	REFERENCES

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Prophylactic Cranial Irradiation in Small-Cell Lung Cancer: Is It Still Controversial or Is It a No-Brainer?

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This Article Abstract Full Text (PDF) eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Related articles in The Oncologist Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yang, G. Y. Articles by Matthews, R. H. Search for Related Content PubMed PubMed Citation Articles by Yang, G. Y. Articles by Matthews, R. H.