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Survival characteristics of metastatic renal cell carcinoma patients treated with lymphokine-activated killer cells plus interleukin-2
SURVIVAL CHARACTERISTICS OF METASTATIC RENAL CELL CARCINOMA PATIENTS TREATED WITH LYMPHOKINE-ACTIVATED KILLER CELLS PLUS INTERLEUKIN-2 DERIC D. SCHOOF, PH.D. YASUNORI TERASHIMA, M.D., PH.D. STEVEN BATTER, M.D.
LINDA DOUVILLE, R.N. JEROME P RICHIE, M.D. TIMOTHY J. EBERLEIN, M.D.
From the Department of Surgery, Division of Surgical Oncology, Division of Urology, Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts ABSTRACTThe immunologic manipulation of patients with metastatic renal cell carcinoma using lymphokine-activated killer (LAK) cells in conjunction with systemic interleukin-2 (IL-2) has been examined under conditions in which the life-threatening toxicities associated with IL-2 treatment have been virtually eliminated. We have examined tumor regression in vivo as well as the survival characteristics of 12 patients with metastatic renal cell carcinoma following immunotherapy. Five of 12 (42%) patients experienced tumor regression exceeding 50 percent following treatment. To determine if immunotherapy had influenced the length of survival, all patients were followed until the time of death. Previous studies have characterized the length of survival of metastatic renal cell cancer patients according to a combination of risk factors unique for each patient. In this model, patients were categorized into risk groups based on the number of risk factors. Survival was found to be dependent on risk factors such as performance status, time from initial diagnosis, number of metastatic sites, recent weight loss, and prior cytotoxic chemotherapy. On completion of the LAK cell immunotherapy protocol, patients were categorized as nonresponders or responders. In addition, they were assigned to risk groups based on their unique profile of risk factors at the time of entry into the protocol. Using this model, we found the median survival of nonresponders (23 months) to be no different from responders (24 months), p >0.05. This was directly attributable to differences in risk factors which characterized members in these two response groups. However, the observed median survival of nonresponders following therapy was 1.9-fold longer than their projected survival based on the risk factors. Furthermore, the observed median survival of responders was 3.4-fold longer than projected from their risk factors. These results suggest that regardless of response status to therapy, cellular immunotherapy may play a role in mediating a significant palliative effect on the metabolic characteristics of these patients leading to extended survival.
One of the primary endpoints in most clinical trials for cancer therapy is tumor regression. Clinical reports on patients treated with cellular immunotherapy and biologic response modifiers such as interleukin-2 (IL-2) have used tu-
534
mor regression as the sole determinant in assessing the response status of a patient.1-3 Under these criteria, patients who fail to demonstrate tumor regression are classified as nonresponders and are assumed not to have derived UROLOGYI JUNE1993 I VOLUME41, NUMBER 6
TABLE I.
Characteristics
of the study population Survival
Case No. 1 2 3 4 5 6 7 8 9 10 11 12
Projected
Risk Group
Resp. to Ther. *
(mos) t
Observed Post Ther.
1 1 1 1 1 1 1 2 2 3 3 4
Yes No No No Yes No No Yes Yes No Yes No
12.8 12.8 12.8 12.8 12.8 12.8 12.8 7.7 7.7 5.3 5.3 3.4
241 13 11 8 19 33 25 30 6 23 >59 23
*Yes = partial or complete response; no = less than 50 percent regression of disease. TProjected median survival of patients assigned to risk groups as described.5 IIn this patient brain metastascs developed but otherwise patient had no evidence of systemic disease.
benefit from therapy. However, it is possible that cellular immunotherapy may influence the metabolic relationship between the host and the tumor leading to improved survival even though objective tumor regression was not observed. This is an area of human tumor immunobiology that deserves more study. To determine whether cellular immunotherapy influences the survival of patients with metastatic renal cell carcinoma, we have examined tumor regression and survival in patients with metastatic renal cell carcinoma treated with lymphokine-activated killer (LAK) cells plus systemic IL-2. Patients were treated under conditions in which the life-threatening toxicities associated with systemic IL-2 administration were virtually eliminated. Our results suggest that immunotherapy may exert a palliative influence on the tumor-bearing host which leads to increased survival regardless of whether objective tumor regression was observed. Material and Methods Twelve patients diagnosed with evaluable metastatic renal cell carcinoma were enrolled in a therapeutic trial of LAK cell immunotherapy plus systemic IL-2 at Brigham and Women’s Hospital.4 Entry criterion into the protocol included failure of all standard therapy or the lack of available standard therapy. Patients could not receive chemotherapy, radiation therapy, or hormonal therapy within one month prior to baseline evaluation. In addition, surgery or prior therapy with nitrosoureas or mitomycin C within the previous
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6
six weeks were exclusion criteria. All patients in this study had received prior chemotherapy, Patients were treated on a three-part protocol consisting of (1) systemic IL-2 administration, (2) generation of autologous LAK cells, and (3) infusion of LAK cells plus systemic IL-2 administration4 IL-2 was administered as an intravenous bolus at 30,000 IUlkg body weight every eight hours and was provided by the Robert Wood Johnson Pharmaceutical Research Institute, Raritan, N.J. All patients received three infusions of LAK cells. The mean number of peripheral blood mononuclear cells infused per course of treatment was 1.3 X lOlo. Patients were discharged from the hospital usually within forty-eight hours after the final dose of IL-2. All sites of evaluable tumor were measured prior to initiation of therapy and at two weeks and six weeks following completion of the protocol. Patients were then scanned by CT at three-month intervals until tumor recurrence or progression and were followed until death. A partial response (PR) to therapy was defined as a 50 percent or more decrease in the sum of the products of the longest perpendicular diameters of all measurable lesions. A complete response (CR) was recorded if all measurable tumor disappeared. Patients were categorized into one of five risk groups as described by Elson et aL5 Each patient was evaluated for several risk factors and assigned a score: (1) initial performance status-score = ECOG performance status; (2) time from initial diagnosis-score = 0 if >l year, 1 if < 1 year; (3) number of metastatic
535
Observed Survival Non-Responders
All Patients
.50 -
.25 -
0.0 0
I 30
15
I 45
I 60
0
Survival (months)
9
18
27
36
Survival (months)
FIGURE
1. Projected survival of all immunotherapy patients classified by risk model compared with observed survival of this patient population. As a group, survival of immunotherapy pat,ients was significantly greater than predicted by the risk model, p < 0.05, 2-sided.
FIGURE 2. Projected survival of immunotherapy patients classified as nonresponders compared with observed survival of this patient subpopulation. Survival of nonresponders was significantly greater than length of survival predicted by risk model, p < 0.1, 2-sided.
sites-score = 0 if there were 11 metastatic site, 1 if there were >l metastatic site; (4) weight loss-score = 0 if no weight loss in previous six months, 1 if weight loss occurred in previous six months; and (5) prior cytotoxic chemotherapy-score = 0 if no prior cytotoxic chemotherapy, 1 if cytotoxic chemotherapy was used. The number of risk factors was calculated by adding the assigned scores. Patients with 0 or 1 risk factor were assigned to risk group 1, patients with 2 risk factors were assigned to risk group 2, etc. Patients with 25 risk factors were assigned to risk group 5. In the event that a patient registered a 1 for number of metastatic sites, prior cytotoxic chemotherapy, and weight loss, the number of risk factors was calculated by subtracting 1 from the final score as described. 5 Survival curves were estimated by the Kaplan-Meier product-limit statistic.6 Comparison of survival curves for two groups at the p ~0.10 level was performed using the MantelHaenszel statistic7
mented in both patients assigned to group 2, and one of two patients assigned to group 3. To compare survival data of patients treated with cellular immunotherapy with patients having similar clinical features to their disease, we utilized prognostic factors which have been used to predict survival of patients with metastatic renal cell carcinoma. Patients were individually evaluated, scored for several risk factors, and assigned to one of five risk groups (Table I). The projected survival of each patient was determined according to the median survival established from a much larger series of patients as described in the material and methods sections5 We compared the observed survival for our patients with the projected survival predicted from this model. In this way, each individual patient served as their own control for purposes of determining survival. In this series of metastatic renal cell cancer patients, the projected median survival was twelve months, and the observed median survival was twenty-three months. When the survival curves of observed and projected survival were calculated, we observed a significant difference between these two groups, p < 0.05, 2sided (Fig. 1). These results demonstrated a statistically significant increase in survival for all patients treated with immunotherapy compared with the predicted survival of patients with similar disease characteristics. The projected survival of patients who were eventually classified as either responders or nonresponders to immunotherapy was compared. The projected median survival of nonresponders was
Results In this study, twelve consecutive patients with metastatic renal cell carcinoma were treated with cellular immunotherapy plus systemic IL-2 (Table I). Seven patients were assigned to risk group 1, two patients were assigned to group 2, two patients were assigned to group 3, and one patient was assigned to group 4. Two patients assigned to group 1 responded to immunotherapy by tumor regression. Interestingly, response to therapy also was docu-
536
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Observed Survival .25
.25
1
1
Prot:J;!,
Non-Responders 0.0
0.0
0
15
30
45
60
Survival (months)
I
I
I
I
1
0
15
30
45
60
Survival (months)
Projected survival of immunotherapy FIGURE 3. patients classified as responders compared with observed survival of this patient subpopulation. Survival of responders was significantly greater than length of survival predicted by risk model, p < 0.1, a-sided.
Observed survival of immunotherapy FIGURE 4. patients classified as nonresponders compared with observed survival of immunotherapy patients classijied as responders. Differences in survival between these two groups was not signijicantly different, p ~0.1, 2-sided.
12.8 months, and the projected median survival of responders, 7.7 months, were not significantly different, p >O.l, e-sided. When patients were classified according to response to therapy, we found that the observed survival of nonresponders was significantly longer than the projected survival of this patient subset (23 months versus 12 months), p = 0.09, 2-sided (Fig. 2). Similarly, the observed survival of responders was significantly longer than the projected survival of this patient subset (24 months versus 7 months), p = 0.09, 2-sided (Fig. 3). When the observed survival of responders was compared with the observed survival of nonresponders, we did not find a statistically significant difference in survival (24 months versus 23 months), p >O.l, 2-sided (Fig. 4). Overall, the observed median survival for nonresponders was 1.9-fold higher than the predicted median survival for this patient subset. For responders, the observed median survival was 3.4-fold higher than the predicted median survival.
reported that virtual elimination of lifethreatening toxicities could be accomplished by reducing the systemic dose of IL-2.g This has eliminated the need for intensive care unit admission which has contributed to a reduction in the expense of this therapeutic modality. Further reduction of non-life-threatening toxicities was noted by pretreating patients with ibuprofen prior to the start of immunotherapy. lo The dose reduction of IL-2 was compensated by extending the period of its administration following the adoptive transfer of LAK cells. This approach has not compromised response rates in patients with melanoma or metastatic renal cell carcinoma.Q This is consistent with our previous work which demonstrated that patients treated with low-dose IL-2 immunotherapy develop changes in their immunologic status which are qualitatively similar to those observed in patients who receive higher, more toxic doses of IL-2.l’ These changes include lymphocytosis, increased expression of lymphocyte activation markers,12 as well as circulating activated eosinophils. l3 These immunologic changes are observed regardless of whether or not the patient has had a clinical response. Despite extensive in vitro analysis of cytotoxicity, phenotype3J4.15 and in vivo lymphocyte countP or DR antigen expression on tumor,” predictors of response have not been identified. Barth and colleagues l8 have shown that noncytolytic tumor-infiltrating lymphocytes (TIL)
Comment Adoptive cellular immunotherapy continues to be associated with severe life-threatening toxicities and modest response rates that have considerably dampened enthusiasm for its routine use.8 The objective of this trial was to reduce the magnitude of the life-threatening toxicities associated with immunotherapy without sacrificing response rates. We have previously
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cells are capable of inducing a clinical response in mice, and that the response is predicted by the production of the cytokines TNF and IFN-7. A retrospective blinded examination of supernatants obtained from human LAK cell cultures used in immunotherapy has shown differences in IFN--r produced between responders and nonresponders (Schoof et al., lg), but additional work is needed to establish a reproducible predictor of clinical response for either lowdose or high-dose therapy. To further study the overall impact of cellular immunotherapy on patients with metastatic renal cell carcinoma, we have examined the survival characteristics of these patients. Previous studies have not examined the survival characteristics of responders and nonresponders to determine the possibility that therapy may influence survival in the absence of objective tumor regression. To explore this possibility, we categorized our patients into risk groups, following immunotherapy, according to the prognostic criteria used in a large series of patients with metastatic renal cell carcinoma.5 This approach provided a mechanism in which each patient could serve as their own unbiased control since projected survival was based on a control population equally matched for every risk factor. This method of comparison is preferable to using historical controls in which disease characteristics of the patients are not considered. If the survival of patients treated with immunotherapy was not influenced by this therapeutic modality, it would be expected that the observed survival of these patients would be no different from their projected survival. However, when the immunotherapy patient population was evaluated for objective response to therapy, it was found that both responders and nonresponders had longer survival than predicted by this risk model. In evaluating the reasons for this observation, it is interesting to note that the observed median survival of nonresponders following immunotherapy was 1.9fold higher than the predicted median survival of the nonresponder group. Patient selection bias is an unlikely explanation for the observed results since each patient serves as own control. An alternative proposal suggests an immunotherapy-induced palliative effect on patient survival. Further, the observed median survival in the patients who had clinical responses was 3.4-fold higher than the predicted median survival of patients in this group. This observation is more significant when the distri-
538
bution of risk factors in the responders is further analyzed. Previous work has shown that patients with metastatic renal cell carcinoma who have a greater number of risk factors also have reduced expected survival.5 In this series of immunotherapy patients, five were assigned to a risk group of 2 or higher. Three of these five patients experienced clinical responses to immunotherapy. For example, patient 11 had a projected median survival of approximately five months but has been free of disease for more than four years following cellular immunotherapy. Because of these differences in the unique disease characteristics of each patient, it is important to note that direct comparison of survival between responders and nonresponders is misleading and would best be addressed by a prospective randomized trial consisting of a treatment arm and control arm, stratified by risk factors in which survival was compared. The increased survival of patients treated with cellular immunotherapy who failed to register tumor regression is not unique to our study. Multiple infusions of activated peripheral blood mononuclear cells (over several months) have resulted in prolonged survival in a subset of patients receiving therapy in the absence of tumor regression.20 Although the immunobiology responsible for these observations is not understood, it may be possible that cytokine secretion by the adoptively transferred cell populations is capable of partially neutralizing the toxic effects that cachexia imposes on the patient.21 This is an area of investigation that requires closer examination because these results in addition to the data reported here, suggest the possibility that regulation of the metabolic toxicity caused by tumor-induced cachexia may provide a strategy for prolonging survival of the tumorbearing host. Such a strategy would likely require periodic maintenance cycles of immunotherapy. The minimal toxicity and expense of low-dose IL-2 plus LAK cell immunotherapy could conceivably play an important role in extending the survival of this patient population. In summary, we have shown that patients treated with LAK/IL-2 immunotherapy have prolonged survival regardless of clinical response using a risk model proposed by Elson et uE.~This observation is consistent with our previous studies which have shown that all patients treated with IL-2ILAK cell therapy showed the varying degrees of changes in immunologic
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status. Unlike chemotherapy where clinical response is directly related to therapeutic efficacy, it is apparent that low-dose IL-B/LAK cell immunotherapy is capable of inducing biologic responses which are not necessarily accompanied by changes in post-therapeutic tumor measurements, Response may, however, be measured in terms of the prolonged observed survival compared with the predicted survival. The present challenge is to identify parameters relevant to the host/tumor relationship that will make improvements in immunotherapy possible. Division of Surgical Oncology Division of Urology 75 Francis Street Boston, Massachusetts 02115 (DR. SCHOOF) ACKNOWLEDGMENT. Supported in part by NIH Grants CA09585 and CA45484, ACS-Faculty Research Award 407 (T. J. Eberlein), and The Robert Wood Johnson Pharmaceutical Research Institute, Raritan, New Jersey. References 1. Rosenberg SA, et al: Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients, Ann Surg 210: 474 (1989). 2. Rosenberg SA, et al: Combination therapy with interleukin2 and or-interferon for the treatment of patients with advanced cancer, J Clin Oncol 7: 1863 (1989). 3. West WH, et al: Constant-infusion recombinant interleukin2 in adoptive immunotherapy of advanced cancer, N Engl J Med 316: 898 (1987). 4. Schoof DD, et al: Adoptive immunotherapy ^. of human cancer using low-dose recombinant interleukin-2 and lymphokine-activated killer cells. Cancer Res 48: 5007 (1988). 5. Elson PJ, Witte RS, and Trump DL: Prognostic factors for survival in patients with recurrent or metastatic renal ‘cell carcinoma, Cancer Res 48: 7310 (1988). 6. Kaplan EL, and Meier P: Nonparametric estimation from incomplete observations, J Am Stat Assoc 53: 457 (1958).
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7. Mantel N: Evaluation of survival data and two new rank order statistics arising in consideration, Cancer Chemother Rep 50: 163 (1966). 8. Siegel JP, and Puri RK: Interleukin-2 toxicity, J Clin Oncol 9: 694 (1991). 9. Eberlein TJ, et al: A new regimen of interleukin-2 and lymphokine-activated killer cells. Efficacy without significant toxicity, Arch Intern Med 148: 2571 (1988). 10. Eberlein TJ, et al: Ibuprofen causes reduced toxic effects of interleukin-2 administration in patients with metastatic cancer, Arch Surg 124: 542 (1989). 11. Lotze MT, et al: In vivo administration of purified human interleukin-2. II. Halflife, immunologic effects, and expansion of peripheral lymphoid cells in vivo with recombinant IL-2, J Immunol 135: 2865 (1985). effects of systemic 12. Eberlein TJ, et al: Immunomodulatory low-dose recombinant interleukin-2 and lymphokine-activated killer cells in humans. Cancer Immunol Immunother 30: 145 (1989). 13. Silberstein DS, et al: Activation of eosinophils in cancer patients treated with IL-2 and IL-e-generated lymphokine-activated killer cells. I Immunol 142: 2162 (1989). 14. Rosenberg SA, et al: Observationsbn the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer, N Engl J Med 313: 1485 (1985). of 15. Rosenberg SA, et al: A progress report on the treatment 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone, N Engl J Med 316: 889 (1987). 16. Thompson JA, et al: Recombinant interleukin-2 toxicity, pharmacokinetics, and immunomodulatory effects in a phase I trial, Cancer Res 47: 4202 (1987). 17. Cohen PJ, et al: The immunopathology of sequential tumor biopsies in patients treated with interleukin-2. Correlation of response with T-cell infiltration and HLA-DR expression, Am J Path01 129: 208 (1987). 18. Barth RL Jr, Mule JJ, Spiess PJ, and Rosenberg SA: Interferon-y and tumor necrosis factor have a role in tumor regressions tumor-infiltrating lymphocytes, J Exmediated by murine CD8 per Med 173: 647 (1991). 19. Schoof DD, et al: Secondary cytokine production by lymphoid cells used in cellular immunotherapy, Surg Oncol 1: 163 (1992). 20. Osband ME, et al: Effect of autolymphocyte therapy on survival and quality of life in patients with metastatic renal-cell carcinoma, Lancet 335: 994 (1990). 21. Fearon K, and Carter D: Cancer cachexia, Ann Surg 208: 1 (1988).
539
LINDA DOUVILLE, R.N. JEROME P RICHIE, M.D. TIMOTHY J. EBERLEIN, M.D.
From the Department of Surgery, Division of Surgical Oncology, Division of Urology, Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts ABSTRACTThe immunologic manipulation of patients with metastatic renal cell carcinoma using lymphokine-activated killer (LAK) cells in conjunction with systemic interleukin-2 (IL-2) has been examined under conditions in which the life-threatening toxicities associated with IL-2 treatment have been virtually eliminated. We have examined tumor regression in vivo as well as the survival characteristics of 12 patients with metastatic renal cell carcinoma following immunotherapy. Five of 12 (42%) patients experienced tumor regression exceeding 50 percent following treatment. To determine if immunotherapy had influenced the length of survival, all patients were followed until the time of death. Previous studies have characterized the length of survival of metastatic renal cell cancer patients according to a combination of risk factors unique for each patient. In this model, patients were categorized into risk groups based on the number of risk factors. Survival was found to be dependent on risk factors such as performance status, time from initial diagnosis, number of metastatic sites, recent weight loss, and prior cytotoxic chemotherapy. On completion of the LAK cell immunotherapy protocol, patients were categorized as nonresponders or responders. In addition, they were assigned to risk groups based on their unique profile of risk factors at the time of entry into the protocol. Using this model, we found the median survival of nonresponders (23 months) to be no different from responders (24 months), p >0.05. This was directly attributable to differences in risk factors which characterized members in these two response groups. However, the observed median survival of nonresponders following therapy was 1.9-fold longer than their projected survival based on the risk factors. Furthermore, the observed median survival of responders was 3.4-fold longer than projected from their risk factors. These results suggest that regardless of response status to therapy, cellular immunotherapy may play a role in mediating a significant palliative effect on the metabolic characteristics of these patients leading to extended survival.
One of the primary endpoints in most clinical trials for cancer therapy is tumor regression. Clinical reports on patients treated with cellular immunotherapy and biologic response modifiers such as interleukin-2 (IL-2) have used tu-
534
mor regression as the sole determinant in assessing the response status of a patient.1-3 Under these criteria, patients who fail to demonstrate tumor regression are classified as nonresponders and are assumed not to have derived UROLOGYI JUNE1993 I VOLUME41, NUMBER 6
TABLE I.
Characteristics
of the study population Survival
Case No. 1 2 3 4 5 6 7 8 9 10 11 12
Projected
Risk Group
Resp. to Ther. *
(mos) t
Observed Post Ther.
1 1 1 1 1 1 1 2 2 3 3 4
Yes No No No Yes No No Yes Yes No Yes No
12.8 12.8 12.8 12.8 12.8 12.8 12.8 7.7 7.7 5.3 5.3 3.4
241 13 11 8 19 33 25 30 6 23 >59 23
*Yes = partial or complete response; no = less than 50 percent regression of disease. TProjected median survival of patients assigned to risk groups as described.5 IIn this patient brain metastascs developed but otherwise patient had no evidence of systemic disease.
benefit from therapy. However, it is possible that cellular immunotherapy may influence the metabolic relationship between the host and the tumor leading to improved survival even though objective tumor regression was not observed. This is an area of human tumor immunobiology that deserves more study. To determine whether cellular immunotherapy influences the survival of patients with metastatic renal cell carcinoma, we have examined tumor regression and survival in patients with metastatic renal cell carcinoma treated with lymphokine-activated killer (LAK) cells plus systemic IL-2. Patients were treated under conditions in which the life-threatening toxicities associated with systemic IL-2 administration were virtually eliminated. Our results suggest that immunotherapy may exert a palliative influence on the tumor-bearing host which leads to increased survival regardless of whether objective tumor regression was observed. Material and Methods Twelve patients diagnosed with evaluable metastatic renal cell carcinoma were enrolled in a therapeutic trial of LAK cell immunotherapy plus systemic IL-2 at Brigham and Women’s Hospital.4 Entry criterion into the protocol included failure of all standard therapy or the lack of available standard therapy. Patients could not receive chemotherapy, radiation therapy, or hormonal therapy within one month prior to baseline evaluation. In addition, surgery or prior therapy with nitrosoureas or mitomycin C within the previous
UROLOGY
/ JUNE 1993
/ VOLUME
41, NUMBER
6
six weeks were exclusion criteria. All patients in this study had received prior chemotherapy, Patients were treated on a three-part protocol consisting of (1) systemic IL-2 administration, (2) generation of autologous LAK cells, and (3) infusion of LAK cells plus systemic IL-2 administration4 IL-2 was administered as an intravenous bolus at 30,000 IUlkg body weight every eight hours and was provided by the Robert Wood Johnson Pharmaceutical Research Institute, Raritan, N.J. All patients received three infusions of LAK cells. The mean number of peripheral blood mononuclear cells infused per course of treatment was 1.3 X lOlo. Patients were discharged from the hospital usually within forty-eight hours after the final dose of IL-2. All sites of evaluable tumor were measured prior to initiation of therapy and at two weeks and six weeks following completion of the protocol. Patients were then scanned by CT at three-month intervals until tumor recurrence or progression and were followed until death. A partial response (PR) to therapy was defined as a 50 percent or more decrease in the sum of the products of the longest perpendicular diameters of all measurable lesions. A complete response (CR) was recorded if all measurable tumor disappeared. Patients were categorized into one of five risk groups as described by Elson et aL5 Each patient was evaluated for several risk factors and assigned a score: (1) initial performance status-score = ECOG performance status; (2) time from initial diagnosis-score = 0 if >l year, 1 if < 1 year; (3) number of metastatic
535
Observed Survival Non-Responders
All Patients
.50 -
.25 -
0.0 0
I 30
15
I 45
I 60
0
Survival (months)
9
18
27
36
Survival (months)
FIGURE
1. Projected survival of all immunotherapy patients classified by risk model compared with observed survival of this patient population. As a group, survival of immunotherapy pat,ients was significantly greater than predicted by the risk model, p < 0.05, 2-sided.
FIGURE 2. Projected survival of immunotherapy patients classified as nonresponders compared with observed survival of this patient subpopulation. Survival of nonresponders was significantly greater than length of survival predicted by risk model, p < 0.1, 2-sided.
sites-score = 0 if there were 11 metastatic site, 1 if there were >l metastatic site; (4) weight loss-score = 0 if no weight loss in previous six months, 1 if weight loss occurred in previous six months; and (5) prior cytotoxic chemotherapy-score = 0 if no prior cytotoxic chemotherapy, 1 if cytotoxic chemotherapy was used. The number of risk factors was calculated by adding the assigned scores. Patients with 0 or 1 risk factor were assigned to risk group 1, patients with 2 risk factors were assigned to risk group 2, etc. Patients with 25 risk factors were assigned to risk group 5. In the event that a patient registered a 1 for number of metastatic sites, prior cytotoxic chemotherapy, and weight loss, the number of risk factors was calculated by subtracting 1 from the final score as described. 5 Survival curves were estimated by the Kaplan-Meier product-limit statistic.6 Comparison of survival curves for two groups at the p ~0.10 level was performed using the MantelHaenszel statistic7
mented in both patients assigned to group 2, and one of two patients assigned to group 3. To compare survival data of patients treated with cellular immunotherapy with patients having similar clinical features to their disease, we utilized prognostic factors which have been used to predict survival of patients with metastatic renal cell carcinoma. Patients were individually evaluated, scored for several risk factors, and assigned to one of five risk groups (Table I). The projected survival of each patient was determined according to the median survival established from a much larger series of patients as described in the material and methods sections5 We compared the observed survival for our patients with the projected survival predicted from this model. In this way, each individual patient served as their own control for purposes of determining survival. In this series of metastatic renal cell cancer patients, the projected median survival was twelve months, and the observed median survival was twenty-three months. When the survival curves of observed and projected survival were calculated, we observed a significant difference between these two groups, p < 0.05, 2sided (Fig. 1). These results demonstrated a statistically significant increase in survival for all patients treated with immunotherapy compared with the predicted survival of patients with similar disease characteristics. The projected survival of patients who were eventually classified as either responders or nonresponders to immunotherapy was compared. The projected median survival of nonresponders was
Results In this study, twelve consecutive patients with metastatic renal cell carcinoma were treated with cellular immunotherapy plus systemic IL-2 (Table I). Seven patients were assigned to risk group 1, two patients were assigned to group 2, two patients were assigned to group 3, and one patient was assigned to group 4. Two patients assigned to group 1 responded to immunotherapy by tumor regression. Interestingly, response to therapy also was docu-
536
UROLOGY
/ JUNE1993
/ VOLUME41,NUMBERe
Observed Survival .25
.25
1
1
Prot:J;!,
Non-Responders 0.0
0.0
0
15
30
45
60
Survival (months)
I
I
I
I
1
0
15
30
45
60
Survival (months)
Projected survival of immunotherapy FIGURE 3. patients classified as responders compared with observed survival of this patient subpopulation. Survival of responders was significantly greater than length of survival predicted by risk model, p < 0.1, a-sided.
Observed survival of immunotherapy FIGURE 4. patients classified as nonresponders compared with observed survival of immunotherapy patients classijied as responders. Differences in survival between these two groups was not signijicantly different, p ~0.1, 2-sided.
12.8 months, and the projected median survival of responders, 7.7 months, were not significantly different, p >O.l, e-sided. When patients were classified according to response to therapy, we found that the observed survival of nonresponders was significantly longer than the projected survival of this patient subset (23 months versus 12 months), p = 0.09, 2-sided (Fig. 2). Similarly, the observed survival of responders was significantly longer than the projected survival of this patient subset (24 months versus 7 months), p = 0.09, 2-sided (Fig. 3). When the observed survival of responders was compared with the observed survival of nonresponders, we did not find a statistically significant difference in survival (24 months versus 23 months), p >O.l, 2-sided (Fig. 4). Overall, the observed median survival for nonresponders was 1.9-fold higher than the predicted median survival for this patient subset. For responders, the observed median survival was 3.4-fold higher than the predicted median survival.
reported that virtual elimination of lifethreatening toxicities could be accomplished by reducing the systemic dose of IL-2.g This has eliminated the need for intensive care unit admission which has contributed to a reduction in the expense of this therapeutic modality. Further reduction of non-life-threatening toxicities was noted by pretreating patients with ibuprofen prior to the start of immunotherapy. lo The dose reduction of IL-2 was compensated by extending the period of its administration following the adoptive transfer of LAK cells. This approach has not compromised response rates in patients with melanoma or metastatic renal cell carcinoma.Q This is consistent with our previous work which demonstrated that patients treated with low-dose IL-2 immunotherapy develop changes in their immunologic status which are qualitatively similar to those observed in patients who receive higher, more toxic doses of IL-2.l’ These changes include lymphocytosis, increased expression of lymphocyte activation markers,12 as well as circulating activated eosinophils. l3 These immunologic changes are observed regardless of whether or not the patient has had a clinical response. Despite extensive in vitro analysis of cytotoxicity, phenotype3J4.15 and in vivo lymphocyte countP or DR antigen expression on tumor,” predictors of response have not been identified. Barth and colleagues l8 have shown that noncytolytic tumor-infiltrating lymphocytes (TIL)
Comment Adoptive cellular immunotherapy continues to be associated with severe life-threatening toxicities and modest response rates that have considerably dampened enthusiasm for its routine use.8 The objective of this trial was to reduce the magnitude of the life-threatening toxicities associated with immunotherapy without sacrificing response rates. We have previously
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/ JUNE 1993
i
VOLUME
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cells are capable of inducing a clinical response in mice, and that the response is predicted by the production of the cytokines TNF and IFN-7. A retrospective blinded examination of supernatants obtained from human LAK cell cultures used in immunotherapy has shown differences in IFN--r produced between responders and nonresponders (Schoof et al., lg), but additional work is needed to establish a reproducible predictor of clinical response for either lowdose or high-dose therapy. To further study the overall impact of cellular immunotherapy on patients with metastatic renal cell carcinoma, we have examined the survival characteristics of these patients. Previous studies have not examined the survival characteristics of responders and nonresponders to determine the possibility that therapy may influence survival in the absence of objective tumor regression. To explore this possibility, we categorized our patients into risk groups, following immunotherapy, according to the prognostic criteria used in a large series of patients with metastatic renal cell carcinoma.5 This approach provided a mechanism in which each patient could serve as their own unbiased control since projected survival was based on a control population equally matched for every risk factor. This method of comparison is preferable to using historical controls in which disease characteristics of the patients are not considered. If the survival of patients treated with immunotherapy was not influenced by this therapeutic modality, it would be expected that the observed survival of these patients would be no different from their projected survival. However, when the immunotherapy patient population was evaluated for objective response to therapy, it was found that both responders and nonresponders had longer survival than predicted by this risk model. In evaluating the reasons for this observation, it is interesting to note that the observed median survival of nonresponders following immunotherapy was 1.9fold higher than the predicted median survival of the nonresponder group. Patient selection bias is an unlikely explanation for the observed results since each patient serves as own control. An alternative proposal suggests an immunotherapy-induced palliative effect on patient survival. Further, the observed median survival in the patients who had clinical responses was 3.4-fold higher than the predicted median survival of patients in this group. This observation is more significant when the distri-
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bution of risk factors in the responders is further analyzed. Previous work has shown that patients with metastatic renal cell carcinoma who have a greater number of risk factors also have reduced expected survival.5 In this series of immunotherapy patients, five were assigned to a risk group of 2 or higher. Three of these five patients experienced clinical responses to immunotherapy. For example, patient 11 had a projected median survival of approximately five months but has been free of disease for more than four years following cellular immunotherapy. Because of these differences in the unique disease characteristics of each patient, it is important to note that direct comparison of survival between responders and nonresponders is misleading and would best be addressed by a prospective randomized trial consisting of a treatment arm and control arm, stratified by risk factors in which survival was compared. The increased survival of patients treated with cellular immunotherapy who failed to register tumor regression is not unique to our study. Multiple infusions of activated peripheral blood mononuclear cells (over several months) have resulted in prolonged survival in a subset of patients receiving therapy in the absence of tumor regression.20 Although the immunobiology responsible for these observations is not understood, it may be possible that cytokine secretion by the adoptively transferred cell populations is capable of partially neutralizing the toxic effects that cachexia imposes on the patient.21 This is an area of investigation that requires closer examination because these results in addition to the data reported here, suggest the possibility that regulation of the metabolic toxicity caused by tumor-induced cachexia may provide a strategy for prolonging survival of the tumorbearing host. Such a strategy would likely require periodic maintenance cycles of immunotherapy. The minimal toxicity and expense of low-dose IL-2 plus LAK cell immunotherapy could conceivably play an important role in extending the survival of this patient population. In summary, we have shown that patients treated with LAK/IL-2 immunotherapy have prolonged survival regardless of clinical response using a risk model proposed by Elson et uE.~This observation is consistent with our previous studies which have shown that all patients treated with IL-2ILAK cell therapy showed the varying degrees of changes in immunologic
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status. Unlike chemotherapy where clinical response is directly related to therapeutic efficacy, it is apparent that low-dose IL-B/LAK cell immunotherapy is capable of inducing biologic responses which are not necessarily accompanied by changes in post-therapeutic tumor measurements, Response may, however, be measured in terms of the prolonged observed survival compared with the predicted survival. The present challenge is to identify parameters relevant to the host/tumor relationship that will make improvements in immunotherapy possible. Division of Surgical Oncology Division of Urology 75 Francis Street Boston, Massachusetts 02115 (DR. SCHOOF) ACKNOWLEDGMENT. Supported in part by NIH Grants CA09585 and CA45484, ACS-Faculty Research Award 407 (T. J. Eberlein), and The Robert Wood Johnson Pharmaceutical Research Institute, Raritan, New Jersey. References 1. Rosenberg SA, et al: Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients, Ann Surg 210: 474 (1989). 2. Rosenberg SA, et al: Combination therapy with interleukin2 and or-interferon for the treatment of patients with advanced cancer, J Clin Oncol 7: 1863 (1989). 3. West WH, et al: Constant-infusion recombinant interleukin2 in adoptive immunotherapy of advanced cancer, N Engl J Med 316: 898 (1987). 4. Schoof DD, et al: Adoptive immunotherapy ^. of human cancer using low-dose recombinant interleukin-2 and lymphokine-activated killer cells. Cancer Res 48: 5007 (1988). 5. Elson PJ, Witte RS, and Trump DL: Prognostic factors for survival in patients with recurrent or metastatic renal ‘cell carcinoma, Cancer Res 48: 7310 (1988). 6. Kaplan EL, and Meier P: Nonparametric estimation from incomplete observations, J Am Stat Assoc 53: 457 (1958).
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7. Mantel N: Evaluation of survival data and two new rank order statistics arising in consideration, Cancer Chemother Rep 50: 163 (1966). 8. Siegel JP, and Puri RK: Interleukin-2 toxicity, J Clin Oncol 9: 694 (1991). 9. Eberlein TJ, et al: A new regimen of interleukin-2 and lymphokine-activated killer cells. Efficacy without significant toxicity, Arch Intern Med 148: 2571 (1988). 10. Eberlein TJ, et al: Ibuprofen causes reduced toxic effects of interleukin-2 administration in patients with metastatic cancer, Arch Surg 124: 542 (1989). 11. Lotze MT, et al: In vivo administration of purified human interleukin-2. II. Halflife, immunologic effects, and expansion of peripheral lymphoid cells in vivo with recombinant IL-2, J Immunol 135: 2865 (1985). effects of systemic 12. Eberlein TJ, et al: Immunomodulatory low-dose recombinant interleukin-2 and lymphokine-activated killer cells in humans. Cancer Immunol Immunother 30: 145 (1989). 13. Silberstein DS, et al: Activation of eosinophils in cancer patients treated with IL-2 and IL-e-generated lymphokine-activated killer cells. I Immunol 142: 2162 (1989). 14. Rosenberg SA, et al: Observationsbn the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer, N Engl J Med 313: 1485 (1985). of 15. Rosenberg SA, et al: A progress report on the treatment 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone, N Engl J Med 316: 889 (1987). 16. Thompson JA, et al: Recombinant interleukin-2 toxicity, pharmacokinetics, and immunomodulatory effects in a phase I trial, Cancer Res 47: 4202 (1987). 17. Cohen PJ, et al: The immunopathology of sequential tumor biopsies in patients treated with interleukin-2. Correlation of response with T-cell infiltration and HLA-DR expression, Am J Path01 129: 208 (1987). 18. Barth RL Jr, Mule JJ, Spiess PJ, and Rosenberg SA: Interferon-y and tumor necrosis factor have a role in tumor regressions tumor-infiltrating lymphocytes, J Exmediated by murine CD8 per Med 173: 647 (1991). 19. Schoof DD, et al: Secondary cytokine production by lymphoid cells used in cellular immunotherapy, Surg Oncol 1: 163 (1992). 20. Osband ME, et al: Effect of autolymphocyte therapy on survival and quality of life in patients with metastatic renal-cell carcinoma, Lancet 335: 994 (1990). 21. Fearon K, and Carter D: Cancer cachexia, Ann Surg 208: 1 (1988).
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