Europ. J. CancerVol. 13, pp. 1169 1173. Pergamon Press 1977. Printed in Great Britain
Tumour Regression and Survival of Patients with Disseminated Malignant Melanoma Treated with Chemotherapy and Specific Active Immunotherapy* D. W. HEDLEY, T. J. McELWAIN and G. A. CURRIE Departments of Tumour Immunology and Medicine, Royal Marsden Hospital and Chester Beatty Research Institute, Belmont, Sutton, Surrey, United Kingdom
Abstract--We have treated 59 patients with disseminated or inoperable malignant melanoma with a combination of chemotherapy (D. T.I.C. ) and immunotherapy (comprising irradiated allogeneic melanoma cells plus BCG) and have followed their progress for a minimum often months. Objective tumour regression was observed in 44% of the patients but most of these patients relapsed despite continued treatment, the longest complete regression lasting 21 months. Patients with disease confined to the skin, lymph nodes or lungs had a higher regression rate (19/34 as against 7/25) and survived longer than those with visceral, osseous or cerebral metastases. Complete regressions were commoner in women but the overall regression rate was the same in both sexes. By comparison of these results with literature controls andfrom the inexorable decline in the survival curves we conclude that despite its apparent effect on objective regression rate this form of combination immunotherap.~chemotherapy has little or no worthwhile effect on survival.
INTRODUCTION
a n o m a cells admixed with BCG can lead to predictable changes in some measurable parameters of host responses to m a l i g n a n t melanoma, i.e., can evoke the appearance of tumourdirected cytotoxic lymphocytes and the disappearance of inhibitory factors from the serum. This form of i m m u n i z a t i o n was tested in a group of patients receiving cytotoxic c h e m o t h e r a p y in an uncontrolled study and we noted an objective regression rate higher than that anticipated from historical and literature controls [8]. We have extended these observations and here report a study of 59 patients which indicates that, while the objective regression rate remains high, there appears to be no significant effect on survival and that some patients relapse while on treatment. We also describe several features of the patients which seem to have prognostic significance.
THE OVERALLresults of cytotoxic c h e m o t h e r a p y in the treatment of the "final c o m m o n p a t h w a y " of malignant m e l a n o m a are disappointing. At present D T I C (5, 3, 3-dimethyl-l-triazeno imidazole 4-carboxamide) is the most active single agent providing objective regression in about 20 o/~ of treated patients [ 1] but with little or no effect on survival. D r u g combinations, some including D T I C , have so far proved to be disappointing since they produce more side effects t h a n D T I C alone but no significant increase in overall regression rate [14]. I m m u n o t h e r a p y is being evaluated in m a n y centres [5], but so far is of little or no proven value. O u r own studies have indicated [6-8] that i m m u n i z a t i o n with irradiated mel-
Accepted 29 April 1977.
MATERIAL AND METHODS
*This work was supported by a programme grant from the Medical Research Council and the Cancer Research Campaign.
Patients
Between M a y 1973 and October 1975 a total 1169
1170
D. W. Hedle~, T. j . 3/IcElwain and G. A. Currie
of 66 patients referred to the R o y a l Marsden Hospital, Sutton, with disseminated or inoperable m a l i g n a n t m e l a n o m a were treated with the combined c h e m o - i m m u n o t h e r a p y protocol. Seven started this t r e a t m e n t at a very a d v a n c e d stage of their disease and either died before completing the first course or were too ill to attend for further treatment. T h e remaining 59 patients were treated for a m i n i m u m of 6 weeks, none were w i t h d r a w n before 6 weeks since regression often occurred after 2 or 3 courses. T h e r e were 26 men with a m e a n age of 45.9 and 33 w o m e n with a m e a n age of 48.2 yr. Patients varied considerably in the a m o u n t of t u m o u r present and the sites of overt dissemination at the start of medical treatment, but could be divided into two broad groups: those with disease confined to skin, l y m p h nodes or lungs (34 cases---lung disease was included in this group since it was our earlier experience that disease confined to the lungs regressed as frequently as nodal or cutaneous metastases) and those with visceral, cerebral or bone metastases (25 cases), since prognosis is known to be particularly bad in the latter group [4]. All patients have been followed up to death or tbr a m i n i m u m of 10 months, and we present data on the regression rate, duration of regression and survival from the start of c h e m o - i m m u n o t h e r a p y . Since this was an extended pilot study there were no concurrent control patients, the shape of the survival curve leading us to a b a n d o n a tbrmal controlled trial. O u r regression and survival data were c o m p a r e d to those obtained in recently published studies from other centres [2, 4]. Furthermore our own historical survival d a t a are similar to those reported by E i n h o r n and colleages [2].
Treatment Protocol (a) Chemotherapy. All patients received D T I C everv 4 weeks. Initially the dose used was 2.5 mg/kg intravenously daily fbr live consecutive days c o m b i n e d with Vincristine 1.4 rag/ I n 2 intravenously on the first day. Because of some cases of neurotoxicity and lack of evidence of any clear cut benefit from the addition ofvincristine [9] this agent was not used in the last 27 patients and the dose of D T I C was increased to 250 m g / m 2 for 5 days. T h e r e were few serious adverse reactions and no deaths attributed to the D T I C , although vomiting for a few hr after the injection was c o m m o n . O n e patient developed t h r o m b o c y t o p e n i c p u r p u r a on D T I C 2 5 0 m g / m 2 but tolerated a reduced dose. (b) Immunotherapy. This consisted of 2 x 107 irradiated allogeneic m a l i g n a n t m e l a n o m a cells
plus 50/lg of percutancous Glaxo BCG by i n t r a d e r m a l injection as previously described [8]. This " i m m u n o t h e r a p y " was given m i d w a y between c h e m o t h e r a p y courses. Alternating c h e m o t h e r a p y and i m m u n o t h e r a p y was continued either until it was obvious that the disease was unresponsive or until the patient had been in complete remission for at least 6 months.
RESULTS Tile clinical effect of t r e a t m e n t was j u d g e d to be (a) no response; (b) partial regression or (c) complete regression. Partial regression is defined as a decrease in the m e a n d i a m e t e r of measurable lesions of 50°'o for at least 30 days in tile absence of disease progression elsewhere or tile presence of static disease elsewhere. Patients with less than 500'o regression or whose disease r e m a i n e d static were included amongst the nonresponders. F u r t h e r m o r e , patients who showed more than 50°,0 regression of some lesions while other lesions were progressing were regarded as non-responders. Using these criteria 33 (56~}'0) of" the 59 evaluable cases did not respond to treatment. O f the 25 responders 6 went into complete regression and 20 had partial regressions (i.e., overall regression rate = 44"i, ).
Regression rate according to extent of metastases Although the overall response rate (of evaluable cases) in males and females was similar (males 11/26, females 1 5 / 3 3 ) o n l y 1 male patient achieved complete regression c o m p a r e d to 5 females. This difference was not related to the extent of the disease since regression of visceral and even bone metastases were seen in the w o m e n whereas m a n y men with skin and nodal involvement did not achieve complete regression.
Regression rate according to extent of metastases In patients with disease confined to skin, l y m p h nodes or lungs, the regression rate was 56°i, (19/34). This is exactly twice that of patients with visceral disease, 28°Jo (7/25), in whom there was only one complete regression. T a b l e 1 lists the sites of overt metastasis at the start o f c h e m o - i m m u n o t h e r a p y and the n u m b e r of patients in w h o m disease regression took place. In several patients disease regressed at some sites while remaining static at others. T a b l e 2 summarises the regression rates according to sex and the presence or absence of visceral metastases.
1171
Tumour Regression and Survival of Patients with Disseminated Malignant Melanoma Table 1. Sites oJ metastasis at the start ~ chemoimmunotherapy and the number of patients in whom regression was seen
Site
Number of patients with involvement
Number of patients with disease regression
37 27 21 10 16 6 3 1 2 1
18 (49%) 14 (52%) 9 (43o,o) 2 (20%) 5 (31% ) 1 0 0 1 0
Skin Lymph nodes Lungs Bone Liver Brain Bowel Nasal mucosa Salivary gland Adrenal
Table 2.
Men and women Men Women
Regressionrates according to sex and the presence or absence of visceral metastases
All sites
Visceral disease
Disease confined to skin, lymph nodes or lungs
26/59 (44%) 11/26 15/33
7/25 (28%) 3/12 4/13
19/34 (56%) 8/t4 11/20
Regression rate according to duration of history The interval between primary excision and the start of chemo-immunotherapy for surgically incurable disease ranged from 2 to 300 months, the median being 47 months in patients who showed disease regression and 28 months in those who did not. A test for the mean (log) duration of history showed no significant difference-t =0.72, degrees of freedom (d.f.) 53, P < 0 . 5 . Regression rate according to age The mean age of all patients was 47 yr, of regressors 54 yr and of non-regressors 42 yr. These results were tested by Chi square analysis which showed that the difference was significant
with which a regression became evident and its duration, except that the 2 regressions noted after 3 months were only of short duration. Duration of regression All patients who achieved complete regression have since relapsed, with a median regression length of 12 months. Three patients relapsed while still on treatment. The 20 patients achieving partial regression have now all relapsed despite continuing on the full treatment protocol. Partial regressions were sustained for a shorter period (median 3 months) than complete regressions. In patients with visceral, cerebral or bone disease the median duration of regression was 3 months whereas in those with nodal, pulmonary or cutaneous deposits it was 6.5 months. Survivalfrom the start of chemo-immunotherapy Patients showing disease regression lived longer than those who did not (Fig. 1 ). None of the non-responders survived tbr more than 9 months from the start of chemoimmunotherapy, whereas 6 out of the 26 remitters are still alive 10, 14, 18, 18, 25 and 28 months after the start of treatment. Figures 2 and 3 divide the patients into those with visceral, cerebral or bone involvement and those with disease confined to skin, lymph nodes or lung. The survival curves tbr patients with visceral disease show a very poor prognosis which is improved only slightly in those with disease regression. This group includes one complete regression, a patient who had multiple osteolytic bone deposits in addition to lung, skin and regional and distant lymph node involvement. Those patients with metastases confined to skin, lymph node or lung showed longer median survival in those achieving disease regression (15 months) compared to 6 months in non-remitters. The pronounced shoulder in the survival curve 1.0
0.75
/
(X2 =9.5, d.f. = 3 , P < 0.05) This difference in mean age between regressors and non-regressors was almost exactly the same in the men as in the women.
~'~
response (25 patients)
~
no response
132patients)
0.5
2 0.25
Intervalfrom start of treatment to start of regression All but two regressions had become clinically detectable by the third month of treatment, 9 of these occurring within the first 4 weeks. There was no significant correlation between the speed
~
3
Fig. 1.
2 -
6
9
12 15 Months
18
21
24
Survival curves (life table)for all patients.
i 27
1172
D. W . Hedley, T. j . M c E l w a i n and G. A. Currie 1.0
response(I patients) o---o no response(18 patientsl
0.75 g
0.5
0.25
i
3
6
9
12
24
M0nlhs
F@ 2. Survival curves (lij'e tables)jbr patients with overt visceral, osseous or cerebral metaslasea.
"•
I.O
~
0.75
~
response(18 patientsl
0.5 o 0.25
i
i
i
3
6
9
r~
i
12
i
t
i
t
i
15
18
21
24
27
Months
eig. 3.
Survival curves (lije table )jbr patients with disease limited to skin, lymph nodes or lung.
of responders in this group (Fig. 3) is the main difference between its shape and that of all responders (Fig. 1 ), and this plus the absence of a tail of survivors suggests that the improved survival of patients with disease limited to skin, node or lung may be a function of the disease rather than the treatment, i.e., treatment was started earlier because metastases at these sites are more easily detected.
DISCUSSION Despite widespread enthusiasm tor immunotherapy as a form of cancer treatment, there is little convincing clinical evidence of its eftkctiveness and the rationale behind many of the forms of treatment in current use remains poorly defined. This extended pilot study confirms our earlier findings [8] which suggested that specific active
immunotherapy increases the overall objective regression rate, but the shape of the survival curves, with the complete absence of any tail, shows that this treatment is incapable of significantly improving survival in patients with advanced disease. The median survival times achieved are very similar to those described by other authors [2, 4] and closely resemble the fgures published by De Vita and Fisher [10]. Indeed, all of the patients who had partial objective regressions relapsed while continuing treatment with alternating immunotherapy and chemotherapy. Such results are reminiscent of the effects of unsuccessful cytotoxic chemotherapy in other tumours such as colorectal cancer where objective regressions can be achieved but are not associated with significant prolongation of life. The overall regression rate of 44~!,b is about twice that achieved in most large series using chemotherapy alone and was obtained with a relatively non-toxic regime. Although regressions were seen most frequently in patients with disease confned to the skin, lymph nodes or the lungs, we do not believe that the selection of patients alone can account for the high regression rate since we obtained a rate of 19/34 (56°i,) in this group and 7/25 (28°~,) in those with visceral, cerebral and bone metastases, both figures being substantially higher than those reported for the effects of chemotherapy alone in such patients [1, 2]. Newlands and his colleagues [11] have reported a study in which specific active immunotherapy combined with chemotherapy was compared with chemotherapy alone in similar patients to our own. Their results clearly demonstrated the absence of any effect on survival despite showing an ettEct of immunotherapy on the regression rate, which was 4 out of l 7 (23°~) in patients receiving chemotherapy alone and 9 out of 19 (47 ° o ) in patients receiving chemotherapy plus immunotherapy. In our hands the combined treatment induced 56% regressions in patients with skin, lymph node and lung disease. The fact that the chemoimmunotherapy protocol can produce such regressions of overt disease at least raises the hope that it might be of value as an adjunct to surgery and prevent or delay the appearance of subclinical metastases. Such a trial is currently in progress.
Acknowledgements--We thank Professor M. R. Alderson of the Division of Epidemiologyfor statistical advice and recognizewith gratitude the enthusiasticcollaboration of'the manv clinicianswho reI~'rrcdpatients to our Unit.
Turnout Regression and Survival of Patients with Disseminated Malignant Melanoma REFERENCES
1. J. K. LucE, Chemotherapy of malignant melanoma. Cancer (Philad.) 30, 1604 (1972). 2. L . H . EINHORN, M. A. BURGESS,C. VALLEJOS,G. P. BODEY,J. GUTTERNAN,G. MAVLIGIT,E. M. HERSH,J. K. LUCE, E. FREI, E.J. FREIREICHandJ. A. GOTTLIEB, Prognostic correlations and response to treatment in advanced metastatic malignant melanoma. CancerRes. 34, 1995 (1974). 3. J . H . MooN, S. GAILANI, M. R. COOPER, D. M. HAYES,V. g. REGE,J. BLOM,G.
4.
5.
6. 7. 8.
9.
10. 11.
FALKSON, P. MAURICE, K. BRUNNER, O. GLIDEWELL and J. F. HOLLAND, Comparison of the combination of 1,3-bis(2-chloroethyl) 1-nitrosourea (BCNU) and vincristine with two dose schedules of5-(3,3-dimethyl-1 -triazino) imidazole 4carboxaminde (DTIC) in the treatment of disseminated malignant melanoma. Cancer (Philad.) 35, 368 (1975). J . J . CONSTANZI,V. K. VAITKEVICIUS,J. M. Q UAGLIANA,B. HOOGSTRATEN,C. A. COLTMAN and F. C. DELANEY, Combination chemotherapy for disseminated malignant melanoma. Cancer (Philad.)35, 342 (1975). Leading Article, Malignant melanoma and immunotherapy. Brit. reed. J. 2, 831 (1976). G.A. CURRIE, F. LEJEUNE and G. H. FAIRLEY, Immunisation with irradiated tumour cells and specific lymphocyte cytotoxicity in malignant melanoma. Brit. reed. J. 2, 305 (1971). G.A. CURRIE, Effect of active immunisation with irradiated tumour cells on specific serum inhibitors of cell-mediated immunity in patients with disseminated cancer. Brit. J. Cancer28, 25 (1973). G . A . CURRIE and T. J. McELWAIN, Active immunotherapy as an adjunct to chemotherapy in the treatment of disseminated malignant melanoma: a pilot study. Brit. J. Cancer31, 143 (1975). D.L. AHMANN,R. G. HAHN and H. F. BISEL, Evaluation of 1-(2-chloroethyl-3-4methylcyclohexyl)-l-nitrosourea (Methyl-CCNU, NSC 45388) a.nd vincristine (NSC 67574) in palliation of disseminated malignant melanoma. Cancer (Philad.) 33, 615 (1974). V.T. DE VITA and R. I. FISHER,Natural history of malignant melanoma as related to therapy. Cancer Treat. Reps. 60, 153 (1976). E.S. NEWLANDS,C.J. OON,J. T. ROBERTS,P. ELLIOTT,R. F. MOULD,C. TOPHAM, F . J . F . MADDEN, K. A. NEWTONand G. WESTBURY,Clinical trial of combination chemotherapy and specific active immunotherapy in disseminated melanoma. Brit. J. Cancer34, 174 (1976).
1173
Tumour Regression and Survival of Patients with Disseminated Malignant Melanoma Treated with Chemotherapy and Specific Active Immunotherapy* D. W. HEDLEY, T. J. McELWAIN and G. A. CURRIE Departments of Tumour Immunology and Medicine, Royal Marsden Hospital and Chester Beatty Research Institute, Belmont, Sutton, Surrey, United Kingdom
Abstract--We have treated 59 patients with disseminated or inoperable malignant melanoma with a combination of chemotherapy (D. T.I.C. ) and immunotherapy (comprising irradiated allogeneic melanoma cells plus BCG) and have followed their progress for a minimum often months. Objective tumour regression was observed in 44% of the patients but most of these patients relapsed despite continued treatment, the longest complete regression lasting 21 months. Patients with disease confined to the skin, lymph nodes or lungs had a higher regression rate (19/34 as against 7/25) and survived longer than those with visceral, osseous or cerebral metastases. Complete regressions were commoner in women but the overall regression rate was the same in both sexes. By comparison of these results with literature controls andfrom the inexorable decline in the survival curves we conclude that despite its apparent effect on objective regression rate this form of combination immunotherap.~chemotherapy has little or no worthwhile effect on survival.
INTRODUCTION
a n o m a cells admixed with BCG can lead to predictable changes in some measurable parameters of host responses to m a l i g n a n t melanoma, i.e., can evoke the appearance of tumourdirected cytotoxic lymphocytes and the disappearance of inhibitory factors from the serum. This form of i m m u n i z a t i o n was tested in a group of patients receiving cytotoxic c h e m o t h e r a p y in an uncontrolled study and we noted an objective regression rate higher than that anticipated from historical and literature controls [8]. We have extended these observations and here report a study of 59 patients which indicates that, while the objective regression rate remains high, there appears to be no significant effect on survival and that some patients relapse while on treatment. We also describe several features of the patients which seem to have prognostic significance.
THE OVERALLresults of cytotoxic c h e m o t h e r a p y in the treatment of the "final c o m m o n p a t h w a y " of malignant m e l a n o m a are disappointing. At present D T I C (5, 3, 3-dimethyl-l-triazeno imidazole 4-carboxamide) is the most active single agent providing objective regression in about 20 o/~ of treated patients [ 1] but with little or no effect on survival. D r u g combinations, some including D T I C , have so far proved to be disappointing since they produce more side effects t h a n D T I C alone but no significant increase in overall regression rate [14]. I m m u n o t h e r a p y is being evaluated in m a n y centres [5], but so far is of little or no proven value. O u r own studies have indicated [6-8] that i m m u n i z a t i o n with irradiated mel-
Accepted 29 April 1977.
MATERIAL AND METHODS
*This work was supported by a programme grant from the Medical Research Council and the Cancer Research Campaign.
Patients
Between M a y 1973 and October 1975 a total 1169
1170
D. W. Hedle~, T. j . 3/IcElwain and G. A. Currie
of 66 patients referred to the R o y a l Marsden Hospital, Sutton, with disseminated or inoperable m a l i g n a n t m e l a n o m a were treated with the combined c h e m o - i m m u n o t h e r a p y protocol. Seven started this t r e a t m e n t at a very a d v a n c e d stage of their disease and either died before completing the first course or were too ill to attend for further treatment. T h e remaining 59 patients were treated for a m i n i m u m of 6 weeks, none were w i t h d r a w n before 6 weeks since regression often occurred after 2 or 3 courses. T h e r e were 26 men with a m e a n age of 45.9 and 33 w o m e n with a m e a n age of 48.2 yr. Patients varied considerably in the a m o u n t of t u m o u r present and the sites of overt dissemination at the start of medical treatment, but could be divided into two broad groups: those with disease confined to skin, l y m p h nodes or lungs (34 cases---lung disease was included in this group since it was our earlier experience that disease confined to the lungs regressed as frequently as nodal or cutaneous metastases) and those with visceral, cerebral or bone metastases (25 cases), since prognosis is known to be particularly bad in the latter group [4]. All patients have been followed up to death or tbr a m i n i m u m of 10 months, and we present data on the regression rate, duration of regression and survival from the start of c h e m o - i m m u n o t h e r a p y . Since this was an extended pilot study there were no concurrent control patients, the shape of the survival curve leading us to a b a n d o n a tbrmal controlled trial. O u r regression and survival data were c o m p a r e d to those obtained in recently published studies from other centres [2, 4]. Furthermore our own historical survival d a t a are similar to those reported by E i n h o r n and colleages [2].
Treatment Protocol (a) Chemotherapy. All patients received D T I C everv 4 weeks. Initially the dose used was 2.5 mg/kg intravenously daily fbr live consecutive days c o m b i n e d with Vincristine 1.4 rag/ I n 2 intravenously on the first day. Because of some cases of neurotoxicity and lack of evidence of any clear cut benefit from the addition ofvincristine [9] this agent was not used in the last 27 patients and the dose of D T I C was increased to 250 m g / m 2 for 5 days. T h e r e were few serious adverse reactions and no deaths attributed to the D T I C , although vomiting for a few hr after the injection was c o m m o n . O n e patient developed t h r o m b o c y t o p e n i c p u r p u r a on D T I C 2 5 0 m g / m 2 but tolerated a reduced dose. (b) Immunotherapy. This consisted of 2 x 107 irradiated allogeneic m a l i g n a n t m e l a n o m a cells
plus 50/lg of percutancous Glaxo BCG by i n t r a d e r m a l injection as previously described [8]. This " i m m u n o t h e r a p y " was given m i d w a y between c h e m o t h e r a p y courses. Alternating c h e m o t h e r a p y and i m m u n o t h e r a p y was continued either until it was obvious that the disease was unresponsive or until the patient had been in complete remission for at least 6 months.
RESULTS Tile clinical effect of t r e a t m e n t was j u d g e d to be (a) no response; (b) partial regression or (c) complete regression. Partial regression is defined as a decrease in the m e a n d i a m e t e r of measurable lesions of 50°'o for at least 30 days in tile absence of disease progression elsewhere or tile presence of static disease elsewhere. Patients with less than 500'o regression or whose disease r e m a i n e d static were included amongst the nonresponders. F u r t h e r m o r e , patients who showed more than 50°,0 regression of some lesions while other lesions were progressing were regarded as non-responders. Using these criteria 33 (56~}'0) of" the 59 evaluable cases did not respond to treatment. O f the 25 responders 6 went into complete regression and 20 had partial regressions (i.e., overall regression rate = 44"i, ).
Regression rate according to extent of metastases Although the overall response rate (of evaluable cases) in males and females was similar (males 11/26, females 1 5 / 3 3 ) o n l y 1 male patient achieved complete regression c o m p a r e d to 5 females. This difference was not related to the extent of the disease since regression of visceral and even bone metastases were seen in the w o m e n whereas m a n y men with skin and nodal involvement did not achieve complete regression.
Regression rate according to extent of metastases In patients with disease confined to skin, l y m p h nodes or lungs, the regression rate was 56°i, (19/34). This is exactly twice that of patients with visceral disease, 28°Jo (7/25), in whom there was only one complete regression. T a b l e 1 lists the sites of overt metastasis at the start o f c h e m o - i m m u n o t h e r a p y and the n u m b e r of patients in w h o m disease regression took place. In several patients disease regressed at some sites while remaining static at others. T a b l e 2 summarises the regression rates according to sex and the presence or absence of visceral metastases.
1171
Tumour Regression and Survival of Patients with Disseminated Malignant Melanoma Table 1. Sites oJ metastasis at the start ~ chemoimmunotherapy and the number of patients in whom regression was seen
Site
Number of patients with involvement
Number of patients with disease regression
37 27 21 10 16 6 3 1 2 1
18 (49%) 14 (52%) 9 (43o,o) 2 (20%) 5 (31% ) 1 0 0 1 0
Skin Lymph nodes Lungs Bone Liver Brain Bowel Nasal mucosa Salivary gland Adrenal
Table 2.
Men and women Men Women
Regressionrates according to sex and the presence or absence of visceral metastases
All sites
Visceral disease
Disease confined to skin, lymph nodes or lungs
26/59 (44%) 11/26 15/33
7/25 (28%) 3/12 4/13
19/34 (56%) 8/t4 11/20
Regression rate according to duration of history The interval between primary excision and the start of chemo-immunotherapy for surgically incurable disease ranged from 2 to 300 months, the median being 47 months in patients who showed disease regression and 28 months in those who did not. A test for the mean (log) duration of history showed no significant difference-t =0.72, degrees of freedom (d.f.) 53, P < 0 . 5 . Regression rate according to age The mean age of all patients was 47 yr, of regressors 54 yr and of non-regressors 42 yr. These results were tested by Chi square analysis which showed that the difference was significant
with which a regression became evident and its duration, except that the 2 regressions noted after 3 months were only of short duration. Duration of regression All patients who achieved complete regression have since relapsed, with a median regression length of 12 months. Three patients relapsed while still on treatment. The 20 patients achieving partial regression have now all relapsed despite continuing on the full treatment protocol. Partial regressions were sustained for a shorter period (median 3 months) than complete regressions. In patients with visceral, cerebral or bone disease the median duration of regression was 3 months whereas in those with nodal, pulmonary or cutaneous deposits it was 6.5 months. Survivalfrom the start of chemo-immunotherapy Patients showing disease regression lived longer than those who did not (Fig. 1 ). None of the non-responders survived tbr more than 9 months from the start of chemoimmunotherapy, whereas 6 out of the 26 remitters are still alive 10, 14, 18, 18, 25 and 28 months after the start of treatment. Figures 2 and 3 divide the patients into those with visceral, cerebral or bone involvement and those with disease confined to skin, lymph nodes or lung. The survival curves tbr patients with visceral disease show a very poor prognosis which is improved only slightly in those with disease regression. This group includes one complete regression, a patient who had multiple osteolytic bone deposits in addition to lung, skin and regional and distant lymph node involvement. Those patients with metastases confined to skin, lymph node or lung showed longer median survival in those achieving disease regression (15 months) compared to 6 months in non-remitters. The pronounced shoulder in the survival curve 1.0
0.75
/
(X2 =9.5, d.f. = 3 , P < 0.05) This difference in mean age between regressors and non-regressors was almost exactly the same in the men as in the women.
~'~
response (25 patients)
~
no response
132patients)
0.5
2 0.25
Intervalfrom start of treatment to start of regression All but two regressions had become clinically detectable by the third month of treatment, 9 of these occurring within the first 4 weeks. There was no significant correlation between the speed
~
3
Fig. 1.
2 -
6
9
12 15 Months
18
21
24
Survival curves (life table)for all patients.
i 27
1172
D. W . Hedley, T. j . M c E l w a i n and G. A. Currie 1.0
response(I patients) o---o no response(18 patientsl
0.75 g
0.5
0.25
i
3
6
9
12
24
M0nlhs
F@ 2. Survival curves (lij'e tables)jbr patients with overt visceral, osseous or cerebral metaslasea.
"•
I.O
~
0.75
~
response(18 patientsl
0.5 o 0.25
i
i
i
3
6
9
r~
i
12
i
t
i
t
i
15
18
21
24
27
Months
eig. 3.
Survival curves (lije table )jbr patients with disease limited to skin, lymph nodes or lung.
of responders in this group (Fig. 3) is the main difference between its shape and that of all responders (Fig. 1 ), and this plus the absence of a tail of survivors suggests that the improved survival of patients with disease limited to skin, node or lung may be a function of the disease rather than the treatment, i.e., treatment was started earlier because metastases at these sites are more easily detected.
DISCUSSION Despite widespread enthusiasm tor immunotherapy as a form of cancer treatment, there is little convincing clinical evidence of its eftkctiveness and the rationale behind many of the forms of treatment in current use remains poorly defined. This extended pilot study confirms our earlier findings [8] which suggested that specific active
immunotherapy increases the overall objective regression rate, but the shape of the survival curves, with the complete absence of any tail, shows that this treatment is incapable of significantly improving survival in patients with advanced disease. The median survival times achieved are very similar to those described by other authors [2, 4] and closely resemble the fgures published by De Vita and Fisher [10]. Indeed, all of the patients who had partial objective regressions relapsed while continuing treatment with alternating immunotherapy and chemotherapy. Such results are reminiscent of the effects of unsuccessful cytotoxic chemotherapy in other tumours such as colorectal cancer where objective regressions can be achieved but are not associated with significant prolongation of life. The overall regression rate of 44~!,b is about twice that achieved in most large series using chemotherapy alone and was obtained with a relatively non-toxic regime. Although regressions were seen most frequently in patients with disease confned to the skin, lymph nodes or the lungs, we do not believe that the selection of patients alone can account for the high regression rate since we obtained a rate of 19/34 (56°i,) in this group and 7/25 (28°~,) in those with visceral, cerebral and bone metastases, both figures being substantially higher than those reported for the effects of chemotherapy alone in such patients [1, 2]. Newlands and his colleagues [11] have reported a study in which specific active immunotherapy combined with chemotherapy was compared with chemotherapy alone in similar patients to our own. Their results clearly demonstrated the absence of any effect on survival despite showing an ettEct of immunotherapy on the regression rate, which was 4 out of l 7 (23°~) in patients receiving chemotherapy alone and 9 out of 19 (47 ° o ) in patients receiving chemotherapy plus immunotherapy. In our hands the combined treatment induced 56% regressions in patients with skin, lymph node and lung disease. The fact that the chemoimmunotherapy protocol can produce such regressions of overt disease at least raises the hope that it might be of value as an adjunct to surgery and prevent or delay the appearance of subclinical metastases. Such a trial is currently in progress.
Acknowledgements--We thank Professor M. R. Alderson of the Division of Epidemiologyfor statistical advice and recognizewith gratitude the enthusiasticcollaboration of'the manv clinicianswho reI~'rrcdpatients to our Unit.
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