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Neurological sequelae in long-term survivors of small cell lung cancer
Int. J. Radiation
Biol.
Phys., Vol. 34, No. 5, pp. 1181- 1183, 1996 Copyright 0 1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/96 $15.00 + .oO
SO360-3016(%)00069-7
ELSEVIER
l
Oncology
Editorial NEUROLOGICAL
SEQUELAE IN LONG-TERM SURVIVORS SMALL CELL LUNG CANCER RITSUKO
OF
M.D., F.A.C.R.
KOMAKI,
Department of Radiotherapy (Box 97), The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 USA van Oosterhout and his colleagues (17) have analyzed central nervous system (CNS) effects of chemotherapy and prophylactic cranial irradiation (PCI) among 5 1 patients with small cell lung cancer (SCLC) who survived 2 years or longer. Evaluations included neurological and neuropsychological tests, cranial computerized tomography (CT), or magnetic resonance imaging (MRI) . There were three groups: Group 1 treated by chemotherapy alone (2 1 patients), Group 2 treated by chemotherapy followed by PC1 ( 19 patients), and Group 3 treated by concurrent or alternating chemotherapy and PC1 ( 11 patients). Comparison between them and a control group of 29 people of similar age without cancer was done for neuropsychological aspects. The authors found that there was no significant difference in neuropsychological tests among the three groups, although there was more white matter abnormality found in Group 3. Mean neuropsychometric results among treated patients were significantly worse compared to the control group. Therefore, they concluded that there was no significant neurological toxicity from PCI, and marked neuropsychological differences between treated patients and the control group suggested that cognitive impairment might be related to SCLC itself, emotional distress, or deteriorated physical condition. Their intention to compare different treatment groups is well appreciated. However, if the control group had had cancer other than SCLC rather than no malignancy, speculation about cognitive impairment due to patient emotional distress or physical deterioration would have been eliminated. Second, neuropsychological assessment and findings of CT or MRI among patients who were not 2-year survivors were never mentioned. Third, this is a retrospective study without comparison between patients’ pre- and posttreatment trend of neuropsychological assessment and brain CT or MRI findings. Finally, an important point missing from their conclusion is that concur-
rent or alternating chemotherapy and PC1 achieved significantly longer median survivals (7.8 years vs. 4.15.4 years), which might have influenced white matter abnormalities in Group 3. In the United States, there will be approximately 40,000 patients diagnosed with SCLC in 1996. One quarter of them will live long enough to manifest brain metastasis (9, 10). Nugent and his colleagues ( 14) first reported brain metastasis in 80% of patients who were alive 2 years after treatment for SCLC without PCI. Multiple randomized studies have shown that PC1 reduced brain metastasis as the first site of failure among patients with limited SCLC without significant improvement in survival ( 1, 3, 5, 8, 12, 16). However, a recent randomized study (2) reported a significant reduction in brain metastasis and significant improvement in brain metastasis-free survival among patients with limited SCLC who had a complete response and received PCI. Although 2 years is rather short to assess neuropsychological toxicities, this 300 patient study found that neuropsychological abnormalities were not significantly different between the two groups who received PC1 compared to those who did not receive PCI. We have reported ( 10) a pre-PC1 neuropsychological study among 30 patients with limited SCLC who achieved complete response (29 patients) or partial response ( 1 patient). This study revealed a strikingly high incidence of cognitive deficiency (97%)) although this deficiency was not obvious clinically nor to the patients. Our objective was to distinguish the cause of cognitive deficiency from chemotherapy- or disease-related vs. a paraneoplastic syndrome. Two groups with SCLC treated with or without chemotherapy were compared. No difference in cognitive deficiency was found between them. We concluded that cognitive deficiency among patients with SCLC was due to disease rather than treatment (13).
Accepted for publication 16 January 1996. 1181
1182
I. J. Radiation
Oncology
0 Biology
0 Physics
Other recent articles (4, 11, 15) on PC1 for SCLC patients who achieved CR suggest that PC1 reduced brain metastasis, possibly improved long-term survival and was not significantly correlated to neurological toxicity. Liengswangwong and his colleagues ( 11) reported a retrospective study of 43 patients who achieved CR and 24 received PC1 with total doses of 25-36 Gy in lo16 fractions after completion of chemotherapy. Patient characteristics and chemotherapy were similar between the PC1 group and 19 patients who did not receive PCI. Two-year survival rates with freedom-from-relapse in the CNS was 93% in the PC1 group compared to 47% in the no-PC1 group (p = 0.001). CNS relapse was encountered in only 2 of 24 PC1 patients compared to 7 of 19 patients without PC1 (p = 0.003). Comparison of 2-year actuarial overall survivals also showed a significant difference between the PC1 and no-PC1 groups: 50% vs. 21%, respectively (p = 0.001). The authors reported five patients who were still alive at the time of their analysis and all of them received PC1 without late neurological sequelae. Ohonoshi and his colleagues ( 15 ) have reported a study of 46 patients with SCLC who achieved CR and were randomized to receive PC1 vs. observation. Their median follow-up was 8.5 years and there was a significant reduction of brain metastasis among the PC1 group compared to the no-PC1 group: 5/23 (22%) vs. 12/23 (52%), respectively (p = 0.05 ) . Their 5-year and median survivals were also better among the PC1 group: 22% vs. 13% and 21 vs. 15 months, respectively, although the differences were not statistically significant (p = 0.097). Late neurological toxicity was infrequent in both groups.
Volume
34. Number
5. 1996
More detailed neuropsychological studies before and after treatment (6, 10) suggest that cognitive deficiency among patients with limited SCLC might be due to a paraneoplastic syndrome or disease-related phenomena. An interesting study reported by Dalmau and his colleagues ( 7 ) shows that patients with neuroendocrine-related tumors and paraneoplastic encephalopathy ( PEM ) or paraneoplastic sensory neuropathy (PSN) developed high titers of antibodies, anti-Hu, against neuronal proteins in their tumors, usually SCLC. They concluded that tumors associated with anti-Hu are more indolent than those without. They analyzed the sera of 109 patients with neuroblastoma (NB ) for anti-Hu, correlated anti-Hu titers and survival, coexpression of Hu antigens and major histocompatibility proteins (MHC) . They performed similar analyses in 26 patients with SCLC. They found that most NB patients (78% ) and all SCLC patients expressed Hu antigen. This study suggests that patients who developed anti-Hu in their serum lived longer with possible neurosequelae associated with PEM/PSN. As van Oosterhout and his colleagues’ study ( 17) showed, white matter abnormality was more frequently seen in the patients who lived longer after more intensive concurrent or alternating chemotherapy and PCI. Late neurological sequelae must be investigated further without preconception of treatment-related complications. Detailed neuropsychological studies before and after treatment correlated with patient characteristics, tumor histology, stage, brain MRI or MR spectroscopy, and detection of immunological or molecular biomarkers might lead us to prevention of neurological complications.
REFERENCES 1. Aisner, J.; Whitacre, M.; Van Echo, D. A.; Wiemik, P. H. Combination chemotherapy for small cell carcinoma of the lung : Continuous vs. alternating non-cross resistant combinations. Cancer Treat. Rep. 66:221-230; 1982. 2. Arriagada, R.; Le Chevalier, T.; Borie, F.; Riviere, A.; Chomy, P.; Monnet, I.; Tardivon, A.; Viader, F.; Tarayre, M.; Benhamou, S. Prophylactic cranial irradiation for patients with small cell lung cancer in complete remission. J. Natl. Cancer Inst. 87: 183- 190; 1995. 3. Beiler, D. D.; Kane, R. C.; Bemath, E. M.; Cashdollar, M. R. Low dose elective brain irradiation in small cell carcinoma of the lung. Int. J. Radiat. Oncol. Biol. Phys 5:941-945; 1979. 4. Belani, C. P.; Whitacre, M.; Aisner, J. Redefinition of outcome of long-term survivors with small cell lung cancer (abstract). Proc. Am. Sot. Clin. Oncol. 13:A1088; 1994. 5. Cox, J. D.; Stanley, K.; Petrovich, Z.; Paig, C.; Yesner, R. Cranial irradiation in cancer of the lung of all cell types. J. Am. Med. Assoc. 245:469-472; 1981. 6. Cull, A.; Gregor, A.; Hopwood, P.; Macbeth, F.; KarnickaMlodkowska, H.; Thatcher, N.; Burt, P.; Stout, R.; Stepniewska, K.; Stewart, M. Neurological and cognitive impairment in long-term survivors of small cell lung cancer. Eur. J. Cancer 30A: 1067- 1074; 1994. 7. Dalmau, J.; Graus, F.; Cheung, N. K.; Rosenblum, M. K.;
8.
9.
10.
11.
12.
Ho, A.; Canete, A.; Delattre, J. Y.; Thompson, S. J.; Posner, J. B. Major histocompatibility proteins, anti-Hu antibodies, and paraneoplastic encephalomyelitis in neuroblastoma and small cell lung cancer. Cancer 75:99-109; 1995. Jackson, D. V., Jr.; Richards, F., II; Cooper, M. R.; Ferree, C.; Muss, H. B.; White, D. R.; Spurr, C. L. Prophylactic cranial irradiation in small cell carcinoma of the lung. A randomized study. J. Am. Med. Assoc. 237:2730-2733; 1977. Komaki, R.; Cox, J. D.; Whitson, W. Risk of brain metastasis from small cell carcinoma of the lung related to length of survival and prophylactic irradiation. Cancer Treat. Rep. 65:811-814; 1981. Komaki, R.; Meyers, C. A.; Shin, D. M.; Garden, A. S.; Byrne, K.; Nickens, J. A.; Cox, J. D. 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. Liengswangwong, V.; Bonner, J. A.; Shaw, E. G. Foote, R. L.; Frytak, S.; Richardson, R. L.; Creagan, E. T.; Eagan, R. T.; Su, J. Q. Prophylactic cranial irradiation in limitedstage small cell lung cancer. Cancer 75:1302- 1309; 1995. Maurer, L. H.; Tulloh, M.; Weiss, R. B.; Blom, J.; Leone, L.; Glidewell, 0.; Pajak, T. F. Randomized combined modality trial in small cell carcinoma of the lung : Comparison
Neurological sequelaein SCLC 0 R. KOMAKI of combinationchemotherapy-radiationtherapy versuscyclophosphamide-radiation therapy effects of maintenance chemotherapy and prophylactic whole brain irradiation. Cancer45:30-39; 1980. 13. Meyers, C. A.; Byrne, K. S.; Komaki, R. Cognitive deficits in patients with small cell lung cancer before and after chemotherapy.Lung Cancer 12:231-235; 1995. 14. Nugent, J. L.; Bunn, P. A.; Matthews, M. J.; Ihde, 0. C.; Cohen, M. H.; Gazdar, A.; Minna, J. D. CNS metastases in smallcell bronchogeniccarcinoma:Increasingfrequency and changing pattern with lengthening survival. Cancer 44:1845-1893; 1979. 15. Ohonoshi,T.; Ueoka,H.; Kawahara,S.; Kiura, K.; Kamei, H.; Hiraki, Y.; Segawa,Y.; Hi&i, S.; Kimura, I. Compara-
1183
tive study of prophylacticcranialirradiationin patientswith small cell lung cancer achieving a completeresponse:A long-term follow-up result. Lung Cancer10:47-54; 1993. 16. Seydei, H. G.; Creech,R.; Pagano,M.; Salazar,0.; Rubin, P.; Concannon,J.; Carbone,P.; Mohiuddin, M.; Perez, C.; Matthews, M. Combinedmodality treatmentof smallcell undifferentiatedcarcinomaof the lung. A cooperativestudy of the RTOG and ECOG. Int. J. Radiat.Oncol. Biol. Phys. 9:1135-1141; 1983. 17. van Oosterhout,A. G. M.; Ganzevles,P. G. J.; Wilmink, J. T.; deGeus,B. W. J.; van Vonderen,G. M. W.; Twijnstra, A. Sequelaein long-term survivors of smallcell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 34(5):1037- 1044: 1996.
Biol.
Phys., Vol. 34, No. 5, pp. 1181- 1183, 1996 Copyright 0 1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/96 $15.00 + .oO
SO360-3016(%)00069-7
ELSEVIER
l
Oncology
Editorial NEUROLOGICAL
SEQUELAE IN LONG-TERM SURVIVORS SMALL CELL LUNG CANCER RITSUKO
OF
M.D., F.A.C.R.
KOMAKI,
Department of Radiotherapy (Box 97), The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 USA van Oosterhout and his colleagues (17) have analyzed central nervous system (CNS) effects of chemotherapy and prophylactic cranial irradiation (PCI) among 5 1 patients with small cell lung cancer (SCLC) who survived 2 years or longer. Evaluations included neurological and neuropsychological tests, cranial computerized tomography (CT), or magnetic resonance imaging (MRI) . There were three groups: Group 1 treated by chemotherapy alone (2 1 patients), Group 2 treated by chemotherapy followed by PC1 ( 19 patients), and Group 3 treated by concurrent or alternating chemotherapy and PC1 ( 11 patients). Comparison between them and a control group of 29 people of similar age without cancer was done for neuropsychological aspects. The authors found that there was no significant difference in neuropsychological tests among the three groups, although there was more white matter abnormality found in Group 3. Mean neuropsychometric results among treated patients were significantly worse compared to the control group. Therefore, they concluded that there was no significant neurological toxicity from PCI, and marked neuropsychological differences between treated patients and the control group suggested that cognitive impairment might be related to SCLC itself, emotional distress, or deteriorated physical condition. Their intention to compare different treatment groups is well appreciated. However, if the control group had had cancer other than SCLC rather than no malignancy, speculation about cognitive impairment due to patient emotional distress or physical deterioration would have been eliminated. Second, neuropsychological assessment and findings of CT or MRI among patients who were not 2-year survivors were never mentioned. Third, this is a retrospective study without comparison between patients’ pre- and posttreatment trend of neuropsychological assessment and brain CT or MRI findings. Finally, an important point missing from their conclusion is that concur-
rent or alternating chemotherapy and PC1 achieved significantly longer median survivals (7.8 years vs. 4.15.4 years), which might have influenced white matter abnormalities in Group 3. In the United States, there will be approximately 40,000 patients diagnosed with SCLC in 1996. One quarter of them will live long enough to manifest brain metastasis (9, 10). Nugent and his colleagues ( 14) first reported brain metastasis in 80% of patients who were alive 2 years after treatment for SCLC without PCI. Multiple randomized studies have shown that PC1 reduced brain metastasis as the first site of failure among patients with limited SCLC without significant improvement in survival ( 1, 3, 5, 8, 12, 16). However, a recent randomized study (2) reported a significant reduction in brain metastasis and significant improvement in brain metastasis-free survival among patients with limited SCLC who had a complete response and received PCI. Although 2 years is rather short to assess neuropsychological toxicities, this 300 patient study found that neuropsychological abnormalities were not significantly different between the two groups who received PC1 compared to those who did not receive PCI. We have reported ( 10) a pre-PC1 neuropsychological study among 30 patients with limited SCLC who achieved complete response (29 patients) or partial response ( 1 patient). This study revealed a strikingly high incidence of cognitive deficiency (97%)) although this deficiency was not obvious clinically nor to the patients. Our objective was to distinguish the cause of cognitive deficiency from chemotherapy- or disease-related vs. a paraneoplastic syndrome. Two groups with SCLC treated with or without chemotherapy were compared. No difference in cognitive deficiency was found between them. We concluded that cognitive deficiency among patients with SCLC was due to disease rather than treatment (13).
Accepted for publication 16 January 1996. 1181
1182
I. J. Radiation
Oncology
0 Biology
0 Physics
Other recent articles (4, 11, 15) on PC1 for SCLC patients who achieved CR suggest that PC1 reduced brain metastasis, possibly improved long-term survival and was not significantly correlated to neurological toxicity. Liengswangwong and his colleagues ( 11) reported a retrospective study of 43 patients who achieved CR and 24 received PC1 with total doses of 25-36 Gy in lo16 fractions after completion of chemotherapy. Patient characteristics and chemotherapy were similar between the PC1 group and 19 patients who did not receive PCI. Two-year survival rates with freedom-from-relapse in the CNS was 93% in the PC1 group compared to 47% in the no-PC1 group (p = 0.001). CNS relapse was encountered in only 2 of 24 PC1 patients compared to 7 of 19 patients without PC1 (p = 0.003). Comparison of 2-year actuarial overall survivals also showed a significant difference between the PC1 and no-PC1 groups: 50% vs. 21%, respectively (p = 0.001). The authors reported five patients who were still alive at the time of their analysis and all of them received PC1 without late neurological sequelae. Ohonoshi and his colleagues ( 15 ) have reported a study of 46 patients with SCLC who achieved CR and were randomized to receive PC1 vs. observation. Their median follow-up was 8.5 years and there was a significant reduction of brain metastasis among the PC1 group compared to the no-PC1 group: 5/23 (22%) vs. 12/23 (52%), respectively (p = 0.05 ) . Their 5-year and median survivals were also better among the PC1 group: 22% vs. 13% and 21 vs. 15 months, respectively, although the differences were not statistically significant (p = 0.097). Late neurological toxicity was infrequent in both groups.
Volume
34. Number
5. 1996
More detailed neuropsychological studies before and after treatment (6, 10) suggest that cognitive deficiency among patients with limited SCLC might be due to a paraneoplastic syndrome or disease-related phenomena. An interesting study reported by Dalmau and his colleagues ( 7 ) shows that patients with neuroendocrine-related tumors and paraneoplastic encephalopathy ( PEM ) or paraneoplastic sensory neuropathy (PSN) developed high titers of antibodies, anti-Hu, against neuronal proteins in their tumors, usually SCLC. They concluded that tumors associated with anti-Hu are more indolent than those without. They analyzed the sera of 109 patients with neuroblastoma (NB ) for anti-Hu, correlated anti-Hu titers and survival, coexpression of Hu antigens and major histocompatibility proteins (MHC) . They performed similar analyses in 26 patients with SCLC. They found that most NB patients (78% ) and all SCLC patients expressed Hu antigen. This study suggests that patients who developed anti-Hu in their serum lived longer with possible neurosequelae associated with PEM/PSN. As van Oosterhout and his colleagues’ study ( 17) showed, white matter abnormality was more frequently seen in the patients who lived longer after more intensive concurrent or alternating chemotherapy and PCI. Late neurological sequelae must be investigated further without preconception of treatment-related complications. Detailed neuropsychological studies before and after treatment correlated with patient characteristics, tumor histology, stage, brain MRI or MR spectroscopy, and detection of immunological or molecular biomarkers might lead us to prevention of neurological complications.
REFERENCES 1. Aisner, J.; Whitacre, M.; Van Echo, D. A.; Wiemik, P. H. Combination chemotherapy for small cell carcinoma of the lung : Continuous vs. alternating non-cross resistant combinations. Cancer Treat. Rep. 66:221-230; 1982. 2. Arriagada, R.; Le Chevalier, T.; Borie, F.; Riviere, A.; Chomy, P.; Monnet, I.; Tardivon, A.; Viader, F.; Tarayre, M.; Benhamou, S. Prophylactic cranial irradiation for patients with small cell lung cancer in complete remission. J. Natl. Cancer Inst. 87: 183- 190; 1995. 3. Beiler, D. D.; Kane, R. C.; Bemath, E. M.; Cashdollar, M. R. Low dose elective brain irradiation in small cell carcinoma of the lung. Int. J. Radiat. Oncol. Biol. Phys 5:941-945; 1979. 4. Belani, C. P.; Whitacre, M.; Aisner, J. Redefinition of outcome of long-term survivors with small cell lung cancer (abstract). Proc. Am. Sot. Clin. Oncol. 13:A1088; 1994. 5. Cox, J. D.; Stanley, K.; Petrovich, Z.; Paig, C.; Yesner, R. Cranial irradiation in cancer of the lung of all cell types. J. Am. Med. Assoc. 245:469-472; 1981. 6. Cull, A.; Gregor, A.; Hopwood, P.; Macbeth, F.; KarnickaMlodkowska, H.; Thatcher, N.; Burt, P.; Stout, R.; Stepniewska, K.; Stewart, M. Neurological and cognitive impairment in long-term survivors of small cell lung cancer. Eur. J. Cancer 30A: 1067- 1074; 1994. 7. Dalmau, J.; Graus, F.; Cheung, N. K.; Rosenblum, M. K.;
8.
9.
10.
11.
12.
Ho, A.; Canete, A.; Delattre, J. Y.; Thompson, S. J.; Posner, J. B. Major histocompatibility proteins, anti-Hu antibodies, and paraneoplastic encephalomyelitis in neuroblastoma and small cell lung cancer. Cancer 75:99-109; 1995. Jackson, D. V., Jr.; Richards, F., II; Cooper, M. R.; Ferree, C.; Muss, H. B.; White, D. R.; Spurr, C. L. Prophylactic cranial irradiation in small cell carcinoma of the lung. A randomized study. J. Am. Med. Assoc. 237:2730-2733; 1977. Komaki, R.; Cox, J. D.; Whitson, W. Risk of brain metastasis from small cell carcinoma of the lung related to length of survival and prophylactic irradiation. Cancer Treat. Rep. 65:811-814; 1981. Komaki, R.; Meyers, C. A.; Shin, D. M.; Garden, A. S.; Byrne, K.; Nickens, J. A.; Cox, J. D. 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. Liengswangwong, V.; Bonner, J. A.; Shaw, E. G. Foote, R. L.; Frytak, S.; Richardson, R. L.; Creagan, E. T.; Eagan, R. T.; Su, J. Q. Prophylactic cranial irradiation in limitedstage small cell lung cancer. Cancer 75:1302- 1309; 1995. Maurer, L. H.; Tulloh, M.; Weiss, R. B.; Blom, J.; Leone, L.; Glidewell, 0.; Pajak, T. F. Randomized combined modality trial in small cell carcinoma of the lung : Comparison
Neurological sequelaein SCLC 0 R. KOMAKI of combinationchemotherapy-radiationtherapy versuscyclophosphamide-radiation therapy effects of maintenance chemotherapy and prophylactic whole brain irradiation. Cancer45:30-39; 1980. 13. Meyers, C. A.; Byrne, K. S.; Komaki, R. Cognitive deficits in patients with small cell lung cancer before and after chemotherapy.Lung Cancer 12:231-235; 1995. 14. Nugent, J. L.; Bunn, P. A.; Matthews, M. J.; Ihde, 0. C.; Cohen, M. H.; Gazdar, A.; Minna, J. D. CNS metastases in smallcell bronchogeniccarcinoma:Increasingfrequency and changing pattern with lengthening survival. Cancer 44:1845-1893; 1979. 15. Ohonoshi,T.; Ueoka,H.; Kawahara,S.; Kiura, K.; Kamei, H.; Hiraki, Y.; Segawa,Y.; Hi&i, S.; Kimura, I. Compara-
1183
tive study of prophylacticcranialirradiationin patientswith small cell lung cancer achieving a completeresponse:A long-term follow-up result. Lung Cancer10:47-54; 1993. 16. Seydei, H. G.; Creech,R.; Pagano,M.; Salazar,0.; Rubin, P.; Concannon,J.; Carbone,P.; Mohiuddin, M.; Perez, C.; Matthews, M. Combinedmodality treatmentof smallcell undifferentiatedcarcinomaof the lung. A cooperativestudy of the RTOG and ECOG. Int. J. Radiat.Oncol. Biol. Phys. 9:1135-1141; 1983. 17. van Oosterhout,A. G. M.; Ganzevles,P. G. J.; Wilmink, J. T.; deGeus,B. W. J.; van Vonderen,G. M. W.; Twijnstra, A. Sequelaein long-term survivors of smallcell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 34(5):1037- 1044: 1996.