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Decision Analysis for Prophylactic Cranial Irradiation for Patients With Small-Cell Lung Cancer

J. Jack Lee, B. Nebiyou Bekele, Xian Zhou, Scott B. Cantor, Ritsuko Komaki, Jin Soo Lee

From the Department of Biostatistics & Applied Mathematics, and Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Research Institute and Hospital, National Cancer Center Korea, Gyeonggi-do, Republic of Korea

Address reprint requests to J. Jack Lee, PhD, Department of Biostatistics & Applied Mathematics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 447, Houston, TX 77030-4009; e-mail: jjlee{at}mdanderson.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix 1 Appendix 2 Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: Prophylactic cranial irradiation (PCI) has been shown to provide survival benefit in patients with limited disease small-cell lung cancer (LD-SCLC) who have achieved complete response. However, PCI may also produce long-term neurotoxicity (NT). The benefits and risks of PCI in LD-SCLC are evaluated.

METHODS: We developed a decision-analytic model to compare quality-adjusted life expectancy (QALE) in a cohort of SCLC patients who do or do not receive PCI by varying survival rates and the frequency and severity of PCI-related NT. Sensitivity analyses were applied to examine the robustness of the optimal decision.

RESULTS: At current published survival rates (26% 5-year survival rate with PCI and 22% without PCI) and a low NT rate, PCI offered a benefit over no PCI (QALE = 4.31 and 3.70 for mild NT severity; QALE = 4.09 and 3.70 for substantial NT severity, respectively). With a moderate NT rate, PCI was still preferred. If the PCI survival rate increased to 40%, PCI outperformed no PCI with a mild NT severity. However, no PCI was preferred over PCI (QALE = 5.72 v 5.47) with substantial NT severity. Two-way sensitivity analyses showed that PCI was preferred for low NT rates, mild NT severity, and low long-term survival rates. Otherwise, no PCI was preferred.

CONCLUSION: The current data suggest PCI offers better QALE than no PCI in LD-SCLC patients who have achieved complete response. As the survival rate for SCLC patients continues to improve, NT rate and NT severity must be controlled to maintain a favorable benefit-risk ratio for recommending PCI.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix 1 Appendix 2 Authors' Disclosures of... Author Contributions REFERENCES

 
The brain is recognized as a frequent site of metastasis in small-cell lung cancer (SCLC) patients. Approximately 14% to 24% of SCLC patients have demonstrable CNS metastases at initial presentation, usually in combination with other extrathoracic sites.^1,2 Even after initial response to chemotherapy, the incidence of clinically detectable brain metastases increased with increased length of survival and reaches 50% at 2 years.^3,4 With autopsy cases included, CNS metastases can be as high as 80% at 2 years.⁵ Moreover, treatment of brain metastases is unsatisfactory—only about half of patients achieve a useful palliation after whole-brain irradiation, and median survival is less than 3 months after metastasis to the brain.⁶ In considering the poor outcome of patients who developed brain metastases, Hansen⁷ proposed prophylactic brain irradiation, later renamed prophylactic cranial irradiation (PCI), for all patients with SCLC.

During the last three decades, there has been much debate on whether and how PCI should be used in the management of SCLC. The point of contention centers on the determination of the risks of short-term and long-term toxicity and benefits of reduction in brain metastasis and prolonging overall survival by PCI. Because of the intense research^8-31 and two recent meta-analyses,^32,33 a general consensus has been reached in the following areas: PCI is recommended for patients with limited disease (LD) SCLC who have achieved complete response (CR); the commonly accepted dose of PCI ranges from 24 to 36 Gy, with once-daily or twice-daily fractions equal to 2 to 3 Gy/d; PCI and concomitant chemotherapy can increase toxicity and should be avoided; PCI significantly reduces the risk of brain metastasis by approximately 50% (hazard ratio, 0.46³² and 0.48³³); PCI prolongs survival (hazard ratio for mortality, 0.84³² and 0.82³³); and acute radiation-induced toxicities are typically mild and resolved within a few months.

Despite the above-described advancements, only limited data on long-term PCI toxicities are available.^23-29 To date, there are no reliable data to estimate the frequency and severity of the long-term toxicities induced by PCI. PCI is now routinely recommended for those patients who achieved CR to chemotherapy. These patients may be at increased risk of chronic neurotoxicity (NT) because they have a greater potential for long-term survival. Moreover, as more effective chemotherapy and combined chemoradiation improves the overall outcome and long-term survival of SCLC patients, the potential risk of chronic NT will be greater and the quality of life (QOL) becomes a more important consideration among the long-term survivors.

The purpose of this study was to explore the benefits and risks of PCI in LD-SCLC patients who have achieved CR. We examine the benefit-risk ratio of PCI by varying the cure fraction, NT rate, and the severity of NT. We postulate that in those subpopulations with higher cure fractions (we use 5-year survival as a surrogate for cure fraction), there will be increased risk and severity of NT, thus making the optimal decision uncertain. We use a decision-analysis framework to model the trade-off between survival and NT. The benefit of PCI is assessed by varying the long-term survival rate and the rate and severity of NT using a simulation. Given that PCI has become a standard treatment for LD-SCLC patients who have achieved CR, it is no longer ethical to conduct randomized controlled trials including an arm with no PCI. The decision-theoretic framework, then, is established to provide an analytic assessment of the overall value of PCI. The implications and future directions are also discussed.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix 1 Appendix 2 Authors' Disclosures of... Author Contributions REFERENCES

 
We examined the quality-adjusted life expectancy (QALE) for patients receiving PCI and compared their QALE with patients not receiving PCI after considering the impact of NT on QOL.³⁴ A decision-analytic model was used to compare QALE in the groups treated with PCI and no PCI using a large cohort (N = 100,000) of simulated patients. To incorporate the impact of chronic NT on the QOL of PCI-treated patients, QALE was calculated based on the following assumptions.

Survival Functions
Results from reported meta-analyses^32,33 were used to determine the benefit of PCI therapy relative to no PCI. The relative failure rate (RFR) of PCI to no PCI at 5 years was estimated at 94.2% (81% and 86% for PCI and no PCI, respectively). Because heterogeneous patient populations were included in the meta-analyses, 5-year survival rates for PCI patients with LD were obtained from a recently reported Intergroup SCLC study.³⁵ Specifically, the 5-year survival rate for the PCI group was 26% and, with the RFR of 94.2%, we calculated the updated no PCI 5-year survival rate to be 22%. Survival times in our simulation were modeled using a truncated log-normal distribution in the first 15 years. After 15 years, the survival distribution of long-term lung cancer survivors³⁶ was assumed. The 5-year relative benefit of PCI to no PCI was held constant in our study. The log-normal assumption fit well with the survival data for the LD-SCLC patients who have achieved CR.³⁷

Assumptions for the Onset and Frequency of NT
It is a challenge to provide an accurate estimate of the onset and frequency of NT induced by PCI. Fifteen percent to more than 90% of the SCLC patients show cognitive dysfunction and impairment of neuropsychological assessment before PCI.^27,38 Chemotherapy, aging, paraneoplastic syndromes, micrometastases, and so on can complicate the issue further. Significant NTs were reported when PCI was used in the past. For example, one study showed that 63% of the patients receiving PCI had NT occurring as late as 54 months after irradiation.^39-41 Most severe toxicities were associated with high PCI dose of more than 40 Gy and/or concomitant chemotherapy. Since then, the PCI regimen has been modified. Recent literature showed that PCI-induced NT is much reduced. In fact, two randomized trials showed that there was no noticeable NT within the first 2 years of PCI. There were, however, no sufficient data to estimate the long-term toxicity.^26,29 A recent report indicating that among the nine patients who survived for more than 5 years after PCI, two had impairment of memory and two had dizziness. One of eight patients underwent computed tomography or magnetic resonance imaging showed a mild cortical atrophy in the brain.⁴²

We explored various possibilities of NT rates and, among them, two cases were studied in depth: the low NT rate model and the moderate NT rate model, corresponding to 30% and 50% latent NT rates, respectively. Given that most patients do not survive long enough to experience NT, when the 5-year survival rate for PCI group was 26%, a 30% latent NT rate resulted in 7.8% of the observed NT and a 50% latent NT rate resulted in a 13% of the observed NT. These assumptions are consistent with the results showing a 5-year NT of 10%.²⁴ The functional form of NT rate is listed in Appendix 1.

Assumption for the Effect of NT on QOL
Because NT is degenerative in nature, we constructed a decreasing QOL utility function, with a utility of 1 corresponding to a fully functional life without NT after patients were treated for their SCLC and achieved CR, and a utility of 0 corresponding to death. Patients who developed NT after PCI will have a utility between 0 and 1 depending on the severity of NT. We study two different settings depicting a case in which utility decreases only mildly and another case in which utility decreases substantially over time using mixtures of exponential functions (Appendix 2). The minimum utility for the mildly and substantially decreasing cases were set at 0.7 and 0.4, respectively. The average QOL utility functions during years after PCI treatment are plotted in Figure 1. For the low NT rate (Fig 1A), scenarios 1 and 2 showed that average QOL utility decreased to 0.91 and 0.82 by year 15 with mild and substantial NT, respectively. Similarly, for the moderate NT rate (Fig 1B), scenarios 3 and 4 illustrated that the average QOL utility decreased to 0.85 for the mild NT case and 0.70 for the substantial NT case by 15 years. Consistent with clinical observation, the average utility decline in the first 2 years was minimal in all scenarios.

View larger version (8K): [in this window] [in a new window]   Fig 1. Utility functions reflecting average quality of life (QOL) over time for four scenarios with low and moderate neurotoxicity (NT) rates and mild and substantial severity of NT. The average QOL utility decreases by 15 years after prophylactic cranial irradiation (PCI) for scenarios 1, 2, 3, and 4 are 91%, 82%, 85%, and 70%, respectively.

where U_ij is the utility for the ith patient on the jth day for i=1,...,N_pci and j=1,...,S_i.

We obtain the QALE by taking the average of the QALY values for all patients receiving PCI

Sensitivity Analysis
Sensitivity analysis was conducted by varying the parameters of simulation studies to provide a comprehensive assessment of the benefit-risk ratio of PCI. The values and ranges of parameters evaluated were 5-year survival rates in the no-PCI groups (22% or 36%, and in a more general case, ranging from 10% to 70%); latent NT rate (30% and 50% corresponding to low and moderate observed NT, respectively, and in a more general case, ranging from 10% to 70%); and decrease of utility function (mildly or substantially decreasing utility cases, as described). Multiple scenarios were generated by varying the cure rate, latent NT rate, and NT severity level. By varying the 5-year survival rate in the no-PCI group and the latent NT rate, two-way sensitivity analysis was performed to evaluate the benefit-risk of PCI and no PCI using QALE as the outcome measure. A wide range of parameters were evaluated; thus, the findings from each scenario could be viewed as results obtained from specific subpopulations or from future SCLC patients with better survival outcome.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix 1 Appendix 2 Authors' Disclosures of... Author Contributions REFERENCES

 
Quality-Adjusted Survival and QALE
Quality-adjusted survival curves for various NT rates and 5-year survival rates are shown in Figures 2 and 3 for the low and moderate NT rate, respectively. Estimated survival curves for PCI without NT were included for reference purposes. Figure 2A shows that for scenario 1, with low NT rate and mild NT severity, PCI is always better than no PCI when the 5-year survival rate is 22% in the no-PCI group (26% in the PCI group) even after adjusting for NT. The QALE (in QALYs) of the PCI group is 16% better than that in the no-PCI group (4.31 for PCI v 3.70 for no PCI). Figure 2B showed that the QALE of the PCI group is 9% better than that of the no-PCI group (6.22 for PCI v 5.72 for no PCI) when the cure rate in the no-PCI group increased to 36%. With substantial NT deficit, benefit in QALE of PCI was 11% compared with that of no PCI (4.09 for PCI v 3.70 for no PCI) with 22% cure rate (Fig 2C). The loss in benefit of the PCI, however, can be seen in Figure 2D when the cure rate in the no-PCI group increased to 36% with substantial NT. QALE for the PCI group was only 2% better than that of the no-PCI group (5.85 for PCI v 5.72 for no PCI). Note that the quality-adjusted survival curves of PCI and no PCI crossed after 11 years, indicating the loss of benefit of PCI in long-term survivors. In summary, with a low NT rate, PCI is better than no PCI in all scenarios depicted in Figure 2 except for long-term survivors after 11 years (Fig 2D). As the 5-year survival rate increases or the severity of NT increases, the benefit of PCI over no PCI becomes less evident.

View larger version (22K): [in this window] [in a new window]   Fig 2. Quality-adjusted survival curves for prophylactic cranial irradiation (PCI) and no-PCI groups with a latent 30% neurotoxicity (NT) rate. Mildly decreasing utility assuming (A) 22% cure rate and (B) 36% cure rate in the no PCI group. Substantially decreasing utility assuming (C) 22% cure rate and (D) 36% cure rate in the no PCI group.

View larger version (22K): [in this window] [in a new window]   Fig 3. Quality-adjusted survival curves for prophylactic cranial irradiation (PCI) and no PCI groups with a latent 50% neurotoxicity (NT) rate. Mildly decreasing utility assuming (A) 22% cure rate and (B) 36% cure rate in the no PCI group. Substantially decreasing utility assuming (C) 22% cure rate and (D) 36% cure rate in the no PCI group. QALE, quality-adjusted life expectancy.

Two-Way Sensitivity Analysis
Figure 4A gives a contour plot showing the regions in which no PCI is preferred (gray-shaded area) or PCI is preferred (open area without shading) when utility is assumed to decrease mildly during 15 years. In this case, at current 5-year survival rates of 22% for the no-PCI group, it is clear that PCI is overwhelmingly preferred versus no PCI except in extreme cases when the latent NT rate and the survival rate are extremely high (for example, when both of them are > 60%). In all cases when the latent NT rate is less than 54% or 5-year survival rate is less than 46%, PCI is preferred.

View larger version (9K): [in this window] [in a new window]   Fig 4. Two-way sensitivity analysis by varying 5-year survival rate in no PCI group and latent neurotoxicity rate with (A) mildly decreasing utility, and (B) substantially decreasing utility, respectively. The white, open area indicates the region where PCI is preferred; the gray, shaded area indicates where no PCI is preferred.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix 1 Appendix 2 Authors' Disclosures of... Author Contributions REFERENCES

 
The current study has addressed key points relevant to the issues that physicians should consider before recommending PCI therapy to SCLC patients who have achieved CR. Under various scenarios we showed that the benefit of PCI relative to no PCI depends on the rate and severity of NT and the cure fraction. Our analysis supports the current standard practice of giving PCI to LD-SCLC patients who have achieved CR, assuming that the NT rate is low and the toxicity is mild. As the 5-year survival rates increase due to improved therapies, PCI may have inferior QALE relative to no PCI. Furthermore, there may be subsets of patients, who because of their baseline characteristics (such as younger patients and females), having higher cure potential than the average patients. A better understanding of the extent and severity of long-term NT would permit us to better delineate the most appropriate treatment options for those patients.

As reported in the literature, increase in the total dose and higher dose fractionation reduces the CNS relapse rate. However, because higher dose fractions potentially are associated with increased risk of NT, a total dose of 24 to 36 Gy given during 2 to 3 weeks has become more widely recommended.^46,53 How the modification of total dose and dose fraction schedule will affect efficacy and the rates of NT is unclear, but perhaps the ongoing Radiation Therapy Oncology Group study (RTOG 0212) will help clarify the issue. The latent NT rate and the severity of toxicity are also critical in determining the relative benefit of administering PCI. Our analysis suggests that, with the current survival rate, if we have mildly decreasing utility, PCI is always preferred. But with substantially decreased utility, no PCI can yield higher QALE if the latent NT rate is 53% or higher.

PCI is a cost-effective treatment, which improves the QOL-adjusted survival for LD-SCLC patients who achieved CR and is considered a standard treatment for this patient population.^43-53 Our decision analysis conforms to the prevailing view that the benefit of PCI outweighs the risk and offers better QALE based on the current data. As the systematic therapy continues to improve, however, it is possible that PCI may result in inferior QALE when the cure fractions are substantially higher than the current level (eg, when 5-year survival of the no-PCI group is greater than 43% with substantial NT at a 30% latent NT rate).

The validity of our decision analysis depends on the assumptions of the models and their parameters. The assumption that RFR of the PCI group is 94.2% of the no-PCI group could vary. Because of the inherent nature of PCI (ie, because its therapeutic effect is localized to the irradiated brain without any conceivable effects on the systemic disease), one may consider the PCI effect as a constant rather than a fixed proportion in long-term survivors. As the cure rate increases, the fixed-proportion assumption on RFR could err on the side of favoring PCI. Conversely, one may argue that the effect of PCI should be more pronounced, particularly in LD-SCLC patients, because a higher proportion of treatment failure occurs in the brain compared with that in patients with more extensive diseases. In addition, assumptions on the long-term toxicity of PCI, including the frequency and severity of toxicity and the QOL measures in patients, may vary as well. The long-term toxicity data should be documented prospectively and systematically to provide more specific information in evaluating the risk and benefit of PCI.

In summary, the role of PCI in SCLC patients needs to be reviewed critically as survival rates increase, especially for those patients who have achieved CR, and therefore have a greater potential for long-term survival. Additional efforts are needed to increase the effectiveness of tumor control while reducing the long-term toxicity to make PCI as safe and effective as possible. In addition, with the increasing understanding of the molecular profile and its association with the likelihood of developing brain metastasis and/or the susceptibility to PCI-induced NT in patients with SCLC, tailored treatment regimens can be developed to maximize the efficacy while minimizing the potential toxicity.^54,55

	Appendix 1

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix 1 Appendix 2 Authors' Disclosures of... Author Contributions REFERENCES

 
We assumed that the cumulative probability of neurotoxicity (NT) at time t follows a generalized logistic function

The functional form presented above has the following properties resembling the clinical observations:

1. The cumulative NT rate of NT is relatively low within the first 2 years after PCI treatment, whereas the frequency begins to increase more noticeably after 2 years.
   
2. The cumulative NT rate begins to plateau after 6 years.
   
3. The latent maximum cumulative NT rate is denoted as . reaches 0.30 or 0.50, corresponding to the low and moderate NT rate cases, respectively. Note that depicts the latent NT rate (ie, the proportion of long-term survivors receiving PCI who would eventually experience NT). With 26% of overall survival in 5 years, = 0.30 depicts only 7.8% of the long-term patients who survive long enough to experience the onset of NT for the low NT rate case and = 0.50 depicts the 13% observed NT rate for the moderate NT rate case.
   

	Appendix 2

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix 1 Appendix 2 Authors' Disclosures of... Author Contributions REFERENCES

 
We define the average utility function and utility functions used in the analysis. The utility function is a nonincreasing function over time made up with three parts: a constant of 1 (full utility) before the onset of NT, a decreasing function between the onset of NT and 15 years after that by a piecewise exponential function, and a constant nadir of utility after 15 years since the onset of NT.

Let c_i to be the number of survival days before the onset of NT and let d_i be the number of survival days after onset of NT for the ith patient for i = 1,...,M. The total unadjusted survival time for patient i is S_i = c_i+d_i. Furthermore, define U_ij to be the utility of the ith patient on the jth day. The average utility function is equal to

For the mildly decreasing utility case, U_ij is

For the substantially decreasing utility case, U_ij is

Note that for patients with dementia, average preference scores (utility-like measures) ranged from 0.35 to 0.60.⁵⁶ Therefore, in practical terms, our assumption of the substantial NT can be interpreted that eventually the NT will result in a state similar to dementia. Conversely, the worst case of the mild NT will result in a status midway between a fully functional life and dementia.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix 1 Appendix 2 Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix 1 Appendix 2 Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: J. Jack Lee, B. Nebiyou Bekele, Scott B. Cantor, Jin Soo Lee Data analysis and interpretation: J. Jack Lee, B. Nebiyou Bekele, Xian Zhou, Scott B. Cantor, Ritsuko Komaki, Jin Soo Lee Manuscript writing: J. Jack Lee, B. Nebiyou Bekele, Xian Zhou, Scott B. Cantor, Jin Soo Lee Final approval of manuscript: J. Jack Lee, B. Nebiyou Bekele, Xian Zhou, Scott B. Cantor, Ritsuko Komaki, Jin Soo Lee

 

	ACKNOWLEDGMENTS

 
We thank Craig Stevens, MD, PhD, and Bonnie S. Glisson, MD, for their helpful comments.

	NOTES

 
Supported in part by the National Cancer Institute Grants No. CA16672 and CA91844, and the Department of Defense Grants No. DAMD17-01-1-0689, DAMD17-02-1-0706, and W81XWH-04-1-0142.

J.J.L. and B.N.B. contributed equally to the work.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix 1 Appendix 2 Authors' Disclosures of... Author Contributions REFERENCES

 
1. Argiris A, Murren JR: Staging and clinical prognostic factors for small-cell lung cancer. Cancer J 7:437-447, 2001[Medline]

2. Hochstenbag MMH, Twijnstra A, Wilmink JT, et al: Asymptomatic brain metastases (BM) in small cell lung cancer: MR-imaging is useful at initial diagnosis. J Neurooncol 48:243-248, 2000[CrossRef][Medline]

3. Bunn PA, Nugent JL, Matthews MJ: Central nervous system metastases in small cell lung carcinoma. Semin Oncol 5:314-322, 1978[Medline]

4. Komaki R, Cox JD, Whitson W: Risk of brain metastases from small carcinoma of the lung related to length of survival and prophylactic irradiation. Cancer Treat Rep 65:811-814, 1981[Medline]

5. Nugent JL, Bunn PA, Matthews MJ, et al: CNS metastases in small cell bronchogenic carcinoma: Increasing the frequency and changing pattern with lengthening of survival. Cancer 44:1885-1893, 1979[CrossRef][Medline]

6. Carmichael J, Crane JM, Bunn PA, et al: Results of therapeutic cranial irradiation in small cell lung cancer. Int J Radiat Oncol Biol Phys 14:455-459, 1988[Medline]

7. Hansen HH: Should initial treatment of small cell carcinoma include systemic chemotherapy and brain irradiation? Cancer Chemother Rep 34:239-241, 1973

8. Jackson DV Jr, Richards FII, Copper MR, et al: Prophylactic cranial irradiation in small cell carcinoma of the lung: A randomized study. JAMA 237:2730-2733, 1977[Abstract/Free Full Text]

9. Cox JD, Petrovich Z, Paig C, et al: Prophylactic cranial irradiation in patients with inoperable carcinoma of the lung: Preliminary report of a cooperative trial. Cancer 42:1135-1140, 1978[CrossRef][Medline]

10. 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 5:941-945, 1979[Medline]

11. Hansen HH, Dombernowsky P, Hirsch FR, et al: Prophylactic irradiation in bronchogenic small cell carcinoma: A comparative trial of localized versus extensive radiotherapy including prophylactic cranial irradiation in patients receiving combination chemotherapy. Cancer 46:279-284, 1980[CrossRef][Medline]

12. Maurer LH, Tulloh M, Weiss RB, et al: A randomized combination 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 45:30-39, 1980[CrossRef][Medline]

13. Eagan RT, Frytak S, Lee RE, et al: A case for preplanned thoracic and prophylactic whole brain radiation therapy in limited small cell lung cancer. Cancer Clin Trials 4:261-266, 1981[Medline]

14. Catane R, Schwade JG, Yarr I, et al: Follow-up neurological evaluation in patients with small cell lung carcinoma treated with prophylactic cranial irradiation and chemotherapy. Int J Radiat Oncol Biol Phys 7:105-109, 1981[Medline]

15. Katsenis AT, Karpasitis N, Giannakakis D, et al: Elective brain irradiation in patients with small-cell carcinoma of the lung: Preliminary report, in Protifex G (ed): Lung Cancer: Etiology, Epidemiology, Prevention, Early Diagnosis, Treatment. Amsterdam, The Netherlands, Excerpta Medica, 1982, pp 277-284

16. Moutain CF, Vincent R, Wilson HE, et al: Intensive chemotherapy and radiotherapy of small cell carcinoma of the lung-regional disease. Abstracts of the Third World Conference on Lung Cancer, Tokyo, Japan, pp 153, May 17-20, 1982 (abstr)

17. 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 67:675-682, 1983[Medline]

18. Seydel HG, Creech R, Pagano M, et al: Prophylactic versus no brain irradiation in regional small cell lung carcinoma. Am J Clin Oncol 8:218-223, 1985[Medline]

19. Johnson BE, Becker B, Goff WB II, et al: Neurologic, neuropsychologic, and computed cranial tomography scan abnormalities in 2- to 10-year survivors of small-cell lung cancer. J Clin Oncol 3:1659-1667, 1985[Abstract/Free Full Text]

20. Lee JS, Umsawasdi T, Lee YY, et al: Neurotoxicity in long-term survivors of small cell lung cancer. Int J Radiat Oncol Biol Phys 12:313-321, 1986[Medline]

21. Laukkanen E, Klonoff H, Allan B, et al: The role of prophylactic brain irradiation in limited stage small cell lung cancer: Clinical, neuropsychologic, and CT sequelae. Int J Radiat Oncol Biol Phys 14:1109-1117, 1988[Medline]

22. Niiranen A, Holsti P, Salmo M: Treatment of small cell lung cancer: Two-drug versus four-drug chemotherapy and loco-regional irradiation with or without prophylactic cranial irradiation. Acta Oncol 28:501-505, 1989[Medline]

23. Ohonoshi T, Ueoka H, Kawahara S, et al: Comparative study of prophylactic cranial irradiation in patients with small cell lung cancer achieving a complete response: A long-term follow-up result. Lung Cancer 10:47-54, 1993[CrossRef][Medline]

24. Shaw EG, Su JQ, Eagan RT, et al: Prophylactic cranial irradiation in complete responders with small-cell lung cancer: Analysis of the Mayo Clinic and North Central Cancer Treatment Group data bases. J Clin Oncol 12:3227-3232, 1994

25. Cull A, Gregor A, Hopwood P, et al: Neurological and cognitive impairment in long-term survivors of small cell lung cancer. Eur J Cancer 30:1067-1074, 1994[CrossRef]

26. Arriagada R, Le Chevalier T, Borie F, et al: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. J Natl Cancer Inst 87:183-190, 1995[Abstract/Free Full Text]

27. Komaki R, Meyers CA, Shin DM, et al: Evaluation of cognitive function in patients with limited small cell lung cancer prior to and shortly following prophylactic cranial irradiation. Int J Radiat Oncol Biol Phys 33:179-182, 1995[CrossRef][Medline]

28. Wagner H, Kim K, Turrisi A: A randomized phase III study of prophylactic cranial irradiation versus observation in patients with small cell lung cancer achieving a complete response: Final report of an incomplete trial by the Eastern Cooperative Oncology Group and Radiation Therapy Oncology Group (E3589/R92-01). Proc Am Soc Clin Oncol 15:376, 1996

29. Gregor A, Cull A, Stephens RJ, et al: Prophylactic cranial irradiation is indicated following complete response to induction therapy in small cell lung cancer: Results of a multicenter randomized trial. Eur J Cancer 33:1752-1758, 1997[CrossRef][Medline]

30. Laplanche A, Monnet I, Santos-Miranda S, et al: Controlled clinical trial of prophylactic cranial irradiation for patients with small cell lung cancer in complete remission. Lung Cancer 21:193-201, 1998[CrossRef][Medline]

31. Fonseca R, O'Neill BP, Foote RL, et al: Cerebral toxicity in patients treated for small cell carcinoma of the lung. Mayo Clin Proc 74:461-465, 1999[Abstract]

32. Auperin A, Arriagada R, Pignon JP, et al: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. N Engl J Med 341:476-484, 1999[Abstract/Free Full Text]

33. Meert AP, Paesmans M, Berghmans T, et al: Prophylactic cranial irradiation in small cell lung cancer: A systematic review of the literature with meta-analysis. BMC Cancer 1:5-13, 2001[CrossRef][Medline]

34. Billingham LJ, Abrams KR: Simultaneous analysis of quality of life and survival data. Stat Methods Med Res 11:25-48, 2002[Abstract/Free Full Text]

35. 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[Abstract/Free Full Text]

36. National Center for Health Statistics: Vital statistics of the United States, 1995, preprint of Vol II, Mortality, Part A, Sec 6, life tables. Hyattsville, MD, National Center for Health Statistics, 1998

37. Tai P, Tonita J, Yu E, et al: Twenty-year follow-up study of long-term survival of limited-stage small-cell lung cancer and overview of prognostic and treatment factors. Int J Radiat Oncol Biol Phys 56:626-633, 2003[CrossRef][Medline]

38. Kanard A, Frytak S, Jatoi A: Cognitive dysfunction in patients with small-cell lung cancer: Incidence, causes, and suggestions on management. J Support Oncol 2:127-132, 2004[Medline]

39. Minna JD, Higgins GA, Glatstein EJ: Cancer of the lung, in Devita VT, Hellman SJ, Rosenberg SA (eds): Cancer: Principles & Practice of Oncology (ed 2). Philadelphia, PA, J.B. Lippincott, 1985, pp 507-597

40. Fleck JF, Einhorn LH, Lauer RC, et al: Is prophylactic cranial irradiation indicated in small-cell lung cancer? J Clin Oncol 8:209-214, 1990[Abstract]

41. Kurup A, Hanna NH: Treatment of small cell lung cancer. Crit Rev Oncol Hematol 52:117-126, 2004[Medline]

42. Cao K-J, Huang H-Y, Tu M-C, et al: Long-term results of prophylactic cranial irradiation for limited-stage small-cell lung cancer in complete remission. Chin Med J 118:1258-1262, 2005[Medline]

43. Tai THP, Yu E, Dickof P, et al: Prophylactic cranial irradiation revisited: Cost-effectiveness and quality of life in small-cell lung cancer. Int J Radiat Oncol Biol Phys 52:68-74, 2002[CrossRef][Medline]

44. Vines EF, Le Pechoux C, Arriagada R: Prophylactic cranial irradiation in small cell lung cancer. Semin Oncol 30:38-46, 2003[Medline]

45. Le Pechoux C, Arriagada R: Prophylactic cranial irradiation in small cell lung cancer. Hematol Oncol Clin North Am 18:355-372, 2004[CrossRef][Medline]

46. Pottgen C, Eberhardt W, Stuschke M: Prophylactic cranial irradiation in lung cancer. Curr Treat Options Oncol 5:43-50, 2004[Medline]

47. Arriagada R, Le Chevalier T, Riviere A, et al: Patterns of failure after prophylactic cranial irradiation in small-cell lung cancer: Analysis of 505 randomized patients. Ann Oncol 13:748-754, 2002[Abstract/Free Full Text]

48. Chua YJ, Steer C, Yip D: Recent advances in management of small-cell lung cancer. Cancer Treat Rev 30:521-543, 2004[CrossRef][Medline]

49. Sorensen JB: The role of prophylactic brain irradiation in small cell lung cancer treatment. Monaldi Arch Chest Dis 59:128-133, 2003[Medline]

50. Kotalik J, Yu E, Markman BR, et al: Practice guideline on prophylactic cranial irradiation in small-cell lung cancer. Int J Radiat Oncol Biol Phys 50:309-316, 2001[CrossRef][Medline]

51. Turrisi AT III: Limited stage small cell lung cancer: Treatment and therapy. Curr Treat Options Oncol 4:61-64, 2003[Medline]

52. Simon M, Argiris A, Murren JR: Progress in the therapy of small cell lung cancer. Crit Rev Oncol Hematol 49:119-133, 2004[Medline]

53. Jackman DM, Johnson BE: Small-cell lung cancer. Lancet 366:1385-1396, 2005[CrossRef][Medline]

54. Bubb RS, Komaki R, Hachiya T, et al: Association of Ki-67, p53, and bcl-2 expression of the primary non-small-cell lung cancer lesion with brain metastatic lesion. Int J Radiat Oncol Biol Phys 53:1216-1224, 2002[CrossRef][Medline]

55. Milas I, Komaki R, Hachiya T, et al: EGFR, COX-2 and BAX expression in the primary non-small cell lung cancer and brain metastases. Clin Cancer Res 9:1070-1076, 2003[Abstract/Free Full Text]

56. Wimo A, Mattson B, Krakau I: Cost-utility analysis of group living in dementia Care. Int J Technol Assess Health Care 11:49-65, 1995[Medline]

Submitted February 10, 2006; accepted April 17, 2006.

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