Neurological Research A Journal of Progress in Neurosurgery, Neurology and Neurosciences
ISSN: 0161-6412 (Print) 1743-1328 (Online) Journal homepage: http://www.tandfonline.com/loi/yner20
Immunotherapy for recurrent malignant glioma: an interim report on survival Marylou Ingram, J. Galen Buckwalter, Deane B. 'Skip' Jacques, Donald B. Freshwater, Richard M. Abts, Geza B. Techy, Koichi Miyagi, C. Hunter Shelden, Robert W. Rand & Linda Ward English To cite this article: Marylou Ingram, J. Galen Buckwalter, Deane B. 'Skip' Jacques, Donald B. Freshwater, Richard M. Abts, Geza B. Techy, Koichi Miyagi, C. Hunter Shelden, Robert W. Rand & Linda Ward English (1990) Immunotherapy for recurrent malignant glioma: an interim report on survival, Neurological Research, 12:4, 265-273, DOI: 10.1080/01616412.1990.11739955 To link to this article: http://dx.doi.org/10.1080/01616412.1990.11739955
Published online: 23 Jul 2016.
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Citing articles: 18 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=yner20 Download by: [NUS National University of Singapore]
Date: 04 April 2017, At: 08:56
Immunotherapy for recurrent malignant glioma: an interim report on survival Marylou Ingram*, j. Galen Buckwaltert, Deane B. 'Skip' jacques+, Donald B. Freshwater§,,, Richard M. Abtsll, Geza B. Techy*, Koichi Miyagi*,**, C. Hunter Shelden*, Robert W. Rand+ and Linda Ward English+ *Experimental and Clinical Immunotherapy Laboratory, and tsiostatistics, Huntington Medical Research Institutes, (HMRI) Pasadena, CA, *Neurosciences Institute, Hospital of the Good Samaritan, Los Angeles, CA, §Experimental Neurosurgery Laboratory, HMRI, fDepartment of Neurosurgery, Huntington Memorial Hospital (HMH), Pasadena, CA, 0Departnient of Pathology, HMH, CA, USA, **Present address: Department of Neurosurgery, University of the Ryukyus School of Medicine, Nishihara, Uehara 207, Okinawa, japan '
We present interim survivial data for a group of 83 adult patients with recurrent malignant glioma treated by implanting stimulated autologous lymphocytes into the tumour bed following surgical debulking. The patients were treated 6 months or more prior to data analysis. Fifty-nine patients were male and 24 female. The mean age for the entire group was 48.4 years and the mean Karnofsky rating (KR) was 67.2. Eight of the patients had grade II tumours, 33 had grade Ill tumours and 42 had grade IV tumours. Statistical analysis focuses on tumour grade, KR and patient age, factors that have been shown to affect survival in previous studies. Multifactorial analyses are employed to identify interrelationships among factors related to survival. Seven patients (8%) did not respond to immunotherapy, 76 (92 %) had a good initial response. Twenty-five patients (30.1 %) are living and 18 (22 %) have shown no evidence of recurrence. Results are evaluated in the light of those obtained in trials of other experimental therapies for recurrent malignant gliomas. It is concluded that the present protocol offers a safe and comparatively effective treatment option. Keywords: Immunotherapy, malignant gliomas, interleukin-2, clinical trial, stimulated autologous lymphocytes Malignant glial tumours continue to be one of the most predictable of diseases in terms of vital prognosis \ In spite of advances in diagnostic and treatment procedures these tumours usually have a fatal outcome. Median survival time from initial diagnosis appears to be in the range of 8-13 months. Survival times for tumours that recur after conventional treatment are much shorter. We present here the interim results of an ongoing phase 1-11 clinical trial of an experimental immunotherapy procedure for glial tumours that recurred after conventional therapy. For convenience we refer to this trial as the Huntington Medical Research Institutes (HMRI) brain tumour immunotherapy trial. Major emphasis is placed on identifying patient and tumour characteristics that predict survival and on statistically evaluating correlations within our own data. No consistent predi ctors of increased survival time following treatment for recurrence have been identifi ed in previously reported clinical trials in which patients similar to those in the HMRI trial were treated according to other experimental protocols and evaluated in terms of survival 1 - 12 . Nevertheless, several factors had some effect on survival in at least one study. These include tumour grade, patient age, extent of infiltration, Karnofsky performance rating (KR), interval between operations and completeness of tumour removal, all of which warrant consideration when evaluating the effectiveness of the various treatment protocols. The present analysis focuses on th e effect of tumour grade, patient age and KR. Address fo r re prints: Dr M. Ing ram, Hunt ington Me di cal Re search In stitutes, 99 N. El Molino Avenu e, Pasad e na, CA 91101 , USA.
METHOD Design and preliminary results of the extend ed phase 1- 11 (non-randomized) HMRI trial of adoptive immunotherapy for recurrent or residual malignant glioma have been described previously, including major changes that were made in the evolving protocol 13' 14 • Brief ly, the protocol used in the present study involves implanting cultured , autologous stimulated lymphocytes (ASL) into the tumour bed followin g surgical debulking of recurrent tumours. Th e lymphocytes are initially activated by exposure to phytohaemagglutinin, then cultured for approximately 1 week in the presence of interleukin-2 (IL-2). Whereas lymphokine-activated killer (LAK) cells are derived from a minority population of peripheral blood lymphocyt es that already bear surface receptors for IL-2, th e ASL must be indu ced to express such receptors by preliminary exposure to processed antigen or mitogen (PHA in the HMRI protocol). Most LAK cell protocols require repeated systemic administration of IL-2. Virtually all T lymphocytes respond to PHA, hence ASL represent a broader spectrum of cells than do LAK cells. I L-2 is not administered system ically in the HMRI protocol. Instead it is included in th e cell implant in an amount consist ent with the concentration required to mai ntain comparable numbers of cells in vitro. LAK cells and ASL differ morphologically as well as serologically and can also be distinguished on the basis of their cytotoxicity forcertain widel y used target cell lines 13 - 16 • The HMRI protocol calls for repeat immunoth erapy at th e first clinical or radiolog ical sign of recurrence. The trial began in Febru ary 1985 and at the tim e of data analysis a total of 97 p ati ent s had b een treat ed . Eig hty-
© 1990 Butterworth- Heinemann 0161 - 641 2/90/04026S -09
Neurological Research, 1990, Volume 12, December
265
Immunotherapy for malignant glioma: M. Ingram eta/
eight patients treated at least 6 months prior to data analysis form the subject pool for the present interim report. The protocol was reviewed and approved by the Huntington Memorial Hospital Institutional Review Board and by the US Food and Drug Administration (BB IND 2185). The patients were accepted for the experimental treatment only after the procedure had been thoroughly discussed with them and they had given signed informed consent. Patients eligible for the trial were male or female and between the ages of 18 and 75 years with a documented history of recurrent malignant glioma and evidence of recurrence by CT scan and/or clinical signs following conventional therapy (surgical removal of tumour followed by standard radiation therapy and/or chemotherapy). Other criteria were: Karnofsky performance rating (KR) of 60 or better, tumour accessible to (partial) removal and not crossing the midline or invading the basal ganglia. Exclusion criteria include significant cardiovascular, pulmonary, hepatic, or other major organ disease, neurological disease not related to glioma, hepatitis or H IV positive serum test, significant abnormality in standard coagulation profile, significant infectious disease, primary malignancy of sites other than the central nervous system (excluding basal cell carcinoma of the skin), pregnancy or lactation, significant abnormality of serum chemistry or blood count (except for lymphopenia, which is common in these patients, most of whom require steroids). Some exceptions were made in accepting patients, especially early in the series. Thirteen patients had KR less than 60. One patient had received radiation therapy but no prior surgery or biopsy. All patients except two were adults. The two paediatric patients treated are not included in the patients analysed in this report. Two pati'Emts with metastatic intracranial melanoma were treated but are also excluded from this analysis. Twenty patients had received chemotherapy. Five patients died from pulmonary embolism. Three of them who died within 6 weeks of treatment and are not evaluable are excluded from the group. The exclusions reported resulted in a total of 83 evaluable glioma patients.
Tumour grading The following histological criteria were used in grading the recurrent tumours:
Grade I (none included in the HMRI treatment group) -
diffuse small astrocytes cellularity slightly increased over normal cell nuclei slightly enlarged and hyperchromatic capillaries slightly increased in number without endothelial pro I iferation mitotic figures rarely found
Grade II -
definite increased cellularity, diffuse cell nuclei definitely enlarged and hyperchromatic tendency of small tumour cells to occur in clumps of two or three cells
266 Neurological Research, 1990, Volume 12, December
-
tumour cells may form small zone around blood vessels - capillaries increased in number without endoth~lial proliferation - gemistocytic astrocytes may be present - mitotic figures difficult to find Grade Ill -
marked hypercell u larity pleomorphic hyperchromatic cells occasional giant cell formation increased capillaries with endothelial proliferation moderate numbers of mitotic figures areas of necrosis usually present
Grade IV - marked hypercellularity - marked pleomorphism and hyperchromatism - frequent giant cell formation - marked vascularity with prominent endothelial proliferation - mitotic figures easily found - areas of necrosis present
RESUlTS Demographic data for all 83 patients are presented in Table 1. Toxicity No significant toxic effects of the immunotherapy procedure per se have been observed. Adverse effects were those associated with surgery, namely wound infections, adverse reactions to antibiotics used to treat wound infections, spinal fluid leakage requiring a shunt, deep vein thrombosis and pulmonary embolism. Transient fever (38.5- 39°C), common amongst post-neurosurgical patients, was observed in many patients during the first few days after surgery. Moderate postoperative nausea was seen occasionally. A comprehensive neuropsychological evaluation of the effects of the treatment .procedure was conducted on a subset of 20 patients 17•18 • This will be the subject of a separate report. Results suggest that any neuropsychological deficits are probably explained as sequelae of the surgical procedure with no consistent evidence of neuropsychological deficits associated with generalized toxicity. The majority of patients were discharged from the hospital within 1 week of treatment. Where appropriate, patients were discharged to the rehabilitation unit for additional therapies. Table 1:
Patient characteristics
No. of patients Males Females
83
Mean age (years) (range)
48.4 (19-74)
Tumour Grade Grade Grade
8 33
grade II Ill IV
Mean KR (range)
59 24
42
67.2 (40- 90)
Immunotherapy for malignant glioma: M. Ingram eta/
Table 2:
Descriptive statistics for response groups Tumour grade
Sex Response No response Recurrence in 2-4 months Recurrence in 4-8 months Recurrence in 8-12 months Recurrence in 1 year + No recurrence
M
F
II
Ill
IV
Mean age (years) (range)
Mean KR" (range)
Mean survival (weeks) b (ra nge)
7
0
0
2
5
49.7 (27- 69)
62.9 (50- 80)
13.6 (3-31 )
11
3
0
4
10
54.3 (33-74)
61.4 (40- 80)
24.6 (14-52)
16
10
9
16
49.2 (19-71)
67.3 (50-80)
36.1 (22- 70)
8
3
5
5
48. 9 (36- 62)
70.0 (60-80)
67.1 (40-125)
6 11
7
5 8
1 5
52.0 (35- 62) 40.3 (25- 63)
62.9 (50- 70) 72.8 (60- 90)
98.4 (65 - 146) 81.4 (27 -146)
1 5
"Pretreatment KR. bAfter initial immunotherapy for recurrent tumour.
Response to therapy (Table 2) A patient was considered to have a positive initial response to treatment if, 2 months after treatment, the tumour either decreased in size or showed no enlargement relative to its size on a reference CT scan taken 1-2 days postoperatively and the patient remained clinically stable or improved. Patients who showed continued tumour enlargement and/or clinical deterioration during the first 2 months after treatment are considered nonresponders. Survival of these patients corresponds to that reported for patients whose recurrence is not treated. Recurrence of disease after immunotherapy occurred in the majority of patients. Twenty-five patients (30.1 %) were alive at th e time of data analysis. Characteristics of response groups (Table 2) Analysis of variance (ANOVA) indicates a significant difference between the response groups for age (P < 0.03) and mean survival time (P < 0.001). While the mean survival times for the different response groups are generally in the expected direction, the lower survival time for the no recurrence group, compared with the group that recurred after 1 year, reflects the shorter time on study of a few individuals in the no recurrence group. The mean age of the different response groups shows no clear pattern, although the no recurrence group is younger than any other. The KR differences among the response groups are significant (P = 0.05). Chi-sq uare analysis indicated that th e frequency distribution of tumour grades across response groups was statistically significant (P = 0.05). Five of the eight (62.5%) grade II patients, eight of 33 (24.2%) grade Ill patients, but only five of 42 (12.0%) grade IV patients have yet to show evidence of recurrence. There was no statistically significant difference between m ales and femal es with respect to response groups. Survival times (figures 1 and 2) The statistical program BMD: P1 L13 was used to estimate survival curves. The median survival time from initial surgery is 89.6 weeks and 25% of the patients are estim at ed to survive 151.0 weeks (range 25-511 weeks). Only 80 patients are represented in this estimate; patients who died or had in itial surgery less than 52 weeks prior
to data analysis are excluded. Twenty-three (28.8%) of these patients were alive at the time of writing. The estimated median survival after immunotherapy for recurrent tumours is 43.3 weeks (range 3-146 weeks) for all 83 patients as shown in Figure 1. It is estimated that 25% of the patients will survive at least 99.0 weeks after immunotherapy. Factors affecting survival Sex (Table 3). The Mantel-Cox statistic was used to determine the level of difference between the groups because of its sensitivity to late events when few patients are left in the studl 9 • This statistic was used throughout this study because of our interest in long-term survivors and the factors that influ ence long-term survival.
100
80
01
c > > L.
60
:::l
.,"' 01
...."'c
., .,0..u
40
L.
20
oL-~-L-L~~--L-~~~_L~_J~~~~~-
o
8
16 24 32 40 48 56 64 72 80 88 961041121 20128
Time surv ived (weeks) Figure 1: Survival of entire group of 83 patients after treatment for rec urrence.
Neurological Research, 1990, Volume 12, December 267
Immunotherapy for malignant g lioma: M . Ingram eta/
Table 3: Survival statistics by sex, tumour grade, age and KR Median survival (weeks)
Variable
No. of patients
Percentage of total
No. alive
Female Male
24 59
28.9 71 .1
9 16
37.5 27.1
45.1 42.7
Grade II Ill IV
8 33 42
9.6 39.8 50.6
5 12 8
62.5 36.4 19.5
N/A* 57.7 33.5
Age (years)
ISSN: 0161-6412 (Print) 1743-1328 (Online) Journal homepage: http://www.tandfonline.com/loi/yner20
Immunotherapy for recurrent malignant glioma: an interim report on survival Marylou Ingram, J. Galen Buckwalter, Deane B. 'Skip' Jacques, Donald B. Freshwater, Richard M. Abts, Geza B. Techy, Koichi Miyagi, C. Hunter Shelden, Robert W. Rand & Linda Ward English To cite this article: Marylou Ingram, J. Galen Buckwalter, Deane B. 'Skip' Jacques, Donald B. Freshwater, Richard M. Abts, Geza B. Techy, Koichi Miyagi, C. Hunter Shelden, Robert W. Rand & Linda Ward English (1990) Immunotherapy for recurrent malignant glioma: an interim report on survival, Neurological Research, 12:4, 265-273, DOI: 10.1080/01616412.1990.11739955 To link to this article: http://dx.doi.org/10.1080/01616412.1990.11739955
Published online: 23 Jul 2016.
Submit your article to this journal
View related articles
Citing articles: 18 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=yner20 Download by: [NUS National University of Singapore]
Date: 04 April 2017, At: 08:56
Immunotherapy for recurrent malignant glioma: an interim report on survival Marylou Ingram*, j. Galen Buckwaltert, Deane B. 'Skip' jacques+, Donald B. Freshwater§,,, Richard M. Abtsll, Geza B. Techy*, Koichi Miyagi*,**, C. Hunter Shelden*, Robert W. Rand+ and Linda Ward English+ *Experimental and Clinical Immunotherapy Laboratory, and tsiostatistics, Huntington Medical Research Institutes, (HMRI) Pasadena, CA, *Neurosciences Institute, Hospital of the Good Samaritan, Los Angeles, CA, §Experimental Neurosurgery Laboratory, HMRI, fDepartment of Neurosurgery, Huntington Memorial Hospital (HMH), Pasadena, CA, 0Departnient of Pathology, HMH, CA, USA, **Present address: Department of Neurosurgery, University of the Ryukyus School of Medicine, Nishihara, Uehara 207, Okinawa, japan '
We present interim survivial data for a group of 83 adult patients with recurrent malignant glioma treated by implanting stimulated autologous lymphocytes into the tumour bed following surgical debulking. The patients were treated 6 months or more prior to data analysis. Fifty-nine patients were male and 24 female. The mean age for the entire group was 48.4 years and the mean Karnofsky rating (KR) was 67.2. Eight of the patients had grade II tumours, 33 had grade Ill tumours and 42 had grade IV tumours. Statistical analysis focuses on tumour grade, KR and patient age, factors that have been shown to affect survival in previous studies. Multifactorial analyses are employed to identify interrelationships among factors related to survival. Seven patients (8%) did not respond to immunotherapy, 76 (92 %) had a good initial response. Twenty-five patients (30.1 %) are living and 18 (22 %) have shown no evidence of recurrence. Results are evaluated in the light of those obtained in trials of other experimental therapies for recurrent malignant gliomas. It is concluded that the present protocol offers a safe and comparatively effective treatment option. Keywords: Immunotherapy, malignant gliomas, interleukin-2, clinical trial, stimulated autologous lymphocytes Malignant glial tumours continue to be one of the most predictable of diseases in terms of vital prognosis \ In spite of advances in diagnostic and treatment procedures these tumours usually have a fatal outcome. Median survival time from initial diagnosis appears to be in the range of 8-13 months. Survival times for tumours that recur after conventional treatment are much shorter. We present here the interim results of an ongoing phase 1-11 clinical trial of an experimental immunotherapy procedure for glial tumours that recurred after conventional therapy. For convenience we refer to this trial as the Huntington Medical Research Institutes (HMRI) brain tumour immunotherapy trial. Major emphasis is placed on identifying patient and tumour characteristics that predict survival and on statistically evaluating correlations within our own data. No consistent predi ctors of increased survival time following treatment for recurrence have been identifi ed in previously reported clinical trials in which patients similar to those in the HMRI trial were treated according to other experimental protocols and evaluated in terms of survival 1 - 12 . Nevertheless, several factors had some effect on survival in at least one study. These include tumour grade, patient age, extent of infiltration, Karnofsky performance rating (KR), interval between operations and completeness of tumour removal, all of which warrant consideration when evaluating the effectiveness of the various treatment protocols. The present analysis focuses on th e effect of tumour grade, patient age and KR. Address fo r re prints: Dr M. Ing ram, Hunt ington Me di cal Re search In stitutes, 99 N. El Molino Avenu e, Pasad e na, CA 91101 , USA.
METHOD Design and preliminary results of the extend ed phase 1- 11 (non-randomized) HMRI trial of adoptive immunotherapy for recurrent or residual malignant glioma have been described previously, including major changes that were made in the evolving protocol 13' 14 • Brief ly, the protocol used in the present study involves implanting cultured , autologous stimulated lymphocytes (ASL) into the tumour bed followin g surgical debulking of recurrent tumours. Th e lymphocytes are initially activated by exposure to phytohaemagglutinin, then cultured for approximately 1 week in the presence of interleukin-2 (IL-2). Whereas lymphokine-activated killer (LAK) cells are derived from a minority population of peripheral blood lymphocyt es that already bear surface receptors for IL-2, th e ASL must be indu ced to express such receptors by preliminary exposure to processed antigen or mitogen (PHA in the HMRI protocol). Most LAK cell protocols require repeated systemic administration of IL-2. Virtually all T lymphocytes respond to PHA, hence ASL represent a broader spectrum of cells than do LAK cells. I L-2 is not administered system ically in the HMRI protocol. Instead it is included in th e cell implant in an amount consist ent with the concentration required to mai ntain comparable numbers of cells in vitro. LAK cells and ASL differ morphologically as well as serologically and can also be distinguished on the basis of their cytotoxicity forcertain widel y used target cell lines 13 - 16 • The HMRI protocol calls for repeat immunoth erapy at th e first clinical or radiolog ical sign of recurrence. The trial began in Febru ary 1985 and at the tim e of data analysis a total of 97 p ati ent s had b een treat ed . Eig hty-
© 1990 Butterworth- Heinemann 0161 - 641 2/90/04026S -09
Neurological Research, 1990, Volume 12, December
265
Immunotherapy for malignant glioma: M. Ingram eta/
eight patients treated at least 6 months prior to data analysis form the subject pool for the present interim report. The protocol was reviewed and approved by the Huntington Memorial Hospital Institutional Review Board and by the US Food and Drug Administration (BB IND 2185). The patients were accepted for the experimental treatment only after the procedure had been thoroughly discussed with them and they had given signed informed consent. Patients eligible for the trial were male or female and between the ages of 18 and 75 years with a documented history of recurrent malignant glioma and evidence of recurrence by CT scan and/or clinical signs following conventional therapy (surgical removal of tumour followed by standard radiation therapy and/or chemotherapy). Other criteria were: Karnofsky performance rating (KR) of 60 or better, tumour accessible to (partial) removal and not crossing the midline or invading the basal ganglia. Exclusion criteria include significant cardiovascular, pulmonary, hepatic, or other major organ disease, neurological disease not related to glioma, hepatitis or H IV positive serum test, significant abnormality in standard coagulation profile, significant infectious disease, primary malignancy of sites other than the central nervous system (excluding basal cell carcinoma of the skin), pregnancy or lactation, significant abnormality of serum chemistry or blood count (except for lymphopenia, which is common in these patients, most of whom require steroids). Some exceptions were made in accepting patients, especially early in the series. Thirteen patients had KR less than 60. One patient had received radiation therapy but no prior surgery or biopsy. All patients except two were adults. The two paediatric patients treated are not included in the patients analysed in this report. Two pati'Emts with metastatic intracranial melanoma were treated but are also excluded from this analysis. Twenty patients had received chemotherapy. Five patients died from pulmonary embolism. Three of them who died within 6 weeks of treatment and are not evaluable are excluded from the group. The exclusions reported resulted in a total of 83 evaluable glioma patients.
Tumour grading The following histological criteria were used in grading the recurrent tumours:
Grade I (none included in the HMRI treatment group) -
diffuse small astrocytes cellularity slightly increased over normal cell nuclei slightly enlarged and hyperchromatic capillaries slightly increased in number without endothelial pro I iferation mitotic figures rarely found
Grade II -
definite increased cellularity, diffuse cell nuclei definitely enlarged and hyperchromatic tendency of small tumour cells to occur in clumps of two or three cells
266 Neurological Research, 1990, Volume 12, December
-
tumour cells may form small zone around blood vessels - capillaries increased in number without endoth~lial proliferation - gemistocytic astrocytes may be present - mitotic figures difficult to find Grade Ill -
marked hypercell u larity pleomorphic hyperchromatic cells occasional giant cell formation increased capillaries with endothelial proliferation moderate numbers of mitotic figures areas of necrosis usually present
Grade IV - marked hypercellularity - marked pleomorphism and hyperchromatism - frequent giant cell formation - marked vascularity with prominent endothelial proliferation - mitotic figures easily found - areas of necrosis present
RESUlTS Demographic data for all 83 patients are presented in Table 1. Toxicity No significant toxic effects of the immunotherapy procedure per se have been observed. Adverse effects were those associated with surgery, namely wound infections, adverse reactions to antibiotics used to treat wound infections, spinal fluid leakage requiring a shunt, deep vein thrombosis and pulmonary embolism. Transient fever (38.5- 39°C), common amongst post-neurosurgical patients, was observed in many patients during the first few days after surgery. Moderate postoperative nausea was seen occasionally. A comprehensive neuropsychological evaluation of the effects of the treatment .procedure was conducted on a subset of 20 patients 17•18 • This will be the subject of a separate report. Results suggest that any neuropsychological deficits are probably explained as sequelae of the surgical procedure with no consistent evidence of neuropsychological deficits associated with generalized toxicity. The majority of patients were discharged from the hospital within 1 week of treatment. Where appropriate, patients were discharged to the rehabilitation unit for additional therapies. Table 1:
Patient characteristics
No. of patients Males Females
83
Mean age (years) (range)
48.4 (19-74)
Tumour Grade Grade Grade
8 33
grade II Ill IV
Mean KR (range)
59 24
42
67.2 (40- 90)
Immunotherapy for malignant glioma: M. Ingram eta/
Table 2:
Descriptive statistics for response groups Tumour grade
Sex Response No response Recurrence in 2-4 months Recurrence in 4-8 months Recurrence in 8-12 months Recurrence in 1 year + No recurrence
M
F
II
Ill
IV
Mean age (years) (range)
Mean KR" (range)
Mean survival (weeks) b (ra nge)
7
0
0
2
5
49.7 (27- 69)
62.9 (50- 80)
13.6 (3-31 )
11
3
0
4
10
54.3 (33-74)
61.4 (40- 80)
24.6 (14-52)
16
10
9
16
49.2 (19-71)
67.3 (50-80)
36.1 (22- 70)
8
3
5
5
48. 9 (36- 62)
70.0 (60-80)
67.1 (40-125)
6 11
7
5 8
1 5
52.0 (35- 62) 40.3 (25- 63)
62.9 (50- 70) 72.8 (60- 90)
98.4 (65 - 146) 81.4 (27 -146)
1 5
"Pretreatment KR. bAfter initial immunotherapy for recurrent tumour.
Response to therapy (Table 2) A patient was considered to have a positive initial response to treatment if, 2 months after treatment, the tumour either decreased in size or showed no enlargement relative to its size on a reference CT scan taken 1-2 days postoperatively and the patient remained clinically stable or improved. Patients who showed continued tumour enlargement and/or clinical deterioration during the first 2 months after treatment are considered nonresponders. Survival of these patients corresponds to that reported for patients whose recurrence is not treated. Recurrence of disease after immunotherapy occurred in the majority of patients. Twenty-five patients (30.1 %) were alive at th e time of data analysis. Characteristics of response groups (Table 2) Analysis of variance (ANOVA) indicates a significant difference between the response groups for age (P < 0.03) and mean survival time (P < 0.001). While the mean survival times for the different response groups are generally in the expected direction, the lower survival time for the no recurrence group, compared with the group that recurred after 1 year, reflects the shorter time on study of a few individuals in the no recurrence group. The mean age of the different response groups shows no clear pattern, although the no recurrence group is younger than any other. The KR differences among the response groups are significant (P = 0.05). Chi-sq uare analysis indicated that th e frequency distribution of tumour grades across response groups was statistically significant (P = 0.05). Five of the eight (62.5%) grade II patients, eight of 33 (24.2%) grade Ill patients, but only five of 42 (12.0%) grade IV patients have yet to show evidence of recurrence. There was no statistically significant difference between m ales and femal es with respect to response groups. Survival times (figures 1 and 2) The statistical program BMD: P1 L13 was used to estimate survival curves. The median survival time from initial surgery is 89.6 weeks and 25% of the patients are estim at ed to survive 151.0 weeks (range 25-511 weeks). Only 80 patients are represented in this estimate; patients who died or had in itial surgery less than 52 weeks prior
to data analysis are excluded. Twenty-three (28.8%) of these patients were alive at the time of writing. The estimated median survival after immunotherapy for recurrent tumours is 43.3 weeks (range 3-146 weeks) for all 83 patients as shown in Figure 1. It is estimated that 25% of the patients will survive at least 99.0 weeks after immunotherapy. Factors affecting survival Sex (Table 3). The Mantel-Cox statistic was used to determine the level of difference between the groups because of its sensitivity to late events when few patients are left in the studl 9 • This statistic was used throughout this study because of our interest in long-term survivors and the factors that influ ence long-term survival.
100
80
01
c > > L.
60
:::l
.,"' 01
...."'c
., .,0..u
40
L.
20
oL-~-L-L~~--L-~~~_L~_J~~~~~-
o
8
16 24 32 40 48 56 64 72 80 88 961041121 20128
Time surv ived (weeks) Figure 1: Survival of entire group of 83 patients after treatment for rec urrence.
Neurological Research, 1990, Volume 12, December 267
Immunotherapy for malignant g lioma: M . Ingram eta/
Table 3: Survival statistics by sex, tumour grade, age and KR Median survival (weeks)
Variable
No. of patients
Percentage of total
No. alive
Female Male
24 59
28.9 71 .1
9 16
37.5 27.1
45.1 42.7
Grade II Ill IV
8 33 42
9.6 39.8 50.6
5 12 8
62.5 36.4 19.5
N/A* 57.7 33.5
Age (years)
