GOUGH ET ALll
CH E M 0 I M MUNOTHERAPY FOR METASTASES
CHEMOIMMUNOTHERAPY IN DISSEMINATED MELANOMA AND COLORECTAL CARCINOMA I.R. GOUGH. P.M. BOLTON. G.J.A. CLUNIEAND W. BURNETT Department of Surgery, University of Queensland, Brisbane. Non-specific immunotherapy with monthly intramuscular injection of Corynebacterlum parvum has been investigated by randomized clinical trials in patients with advanced cancer. Thirty-six patients with disseminatedmelanoma were treated witheitherimidazolecarboxamide(DT1C) aloneor DTlC plus C.parvum. A 19% objective response rate was observed. The mean survival time was slmiiar for both groups. Thirty-three patients with disseminated colorectal cancer were treated with either 5-fluorouracil (5FU) alone or 5FU plus C.parvum. No objective responses were observed. The mean survival time was similar for both groups. No advantage has been demonstrated in either tumour group by adding C.parvum to standard chemotherapy.
WHEN systemic metastases of melanoma or colorectal carcinoma are discovered, the life expectancy for the patient is relatively short. For both melanoma (Elias et alii, 1977) and colorectal carcinoma (Moertel and Reitemeir, 1969) the mean survival time is approximately six months. Disseminated melanoma has been relatively resistant to chemotherapy, but with dimethyltriazeno-i midazole-carboxamide (DTI C) objective response rates of 25% have been obtained (Luce, 1975). While combination chemotherapy is more effective than single agent chemotherapy in most h u m a n m a l i g n a n c i e s , t h i s has n o t b e e n demonstrated i n disseminated melanoma. Combinations of cyclophosphamide, vincristine, and procarbazine (Byrne, 1976), and of DTIC, bischloroethyl nitrosourea (BCNU), and vincristine (Cohen et alii, 1977; McKelvey et alii, 1977), are not superior to DTlC alone. Colorectal carcinoma is also relatively resistant to Chemotherapy. In a review of 2107 patients with disseminated colorectal cancer treated with 5fluorouracil (5FU) the response rate was 21% (Carter and Friedman, 1974). N o other single agent is as effective as 5FU (Moertel, 1975). Combinations of drugs have been disappointing, and most are less effective than 5FU alone. Recently, however, combinations incorporating 5FU and methylcyclohexyl-chloroethyl-nitrosourea ( m e t h y l CCNU) have been reported to give improved Reprints: I.R. Gough, Department of Surgery, Princess Alexandra Hospital, lpswich Road, Woolloongaba, Qld 4102.
296
’
response rates (Moertel, 1976), but survival times were not significantly affected. Although patients who respond objectively to chemotherapy tend t o survive longer in both these forms of malignancy (Moertel and Reitemeir, 1969; McKelvey et afii, 1977), there is no convincing evidence that chemotherapy influences overall survival. In the face of such disappointing results it is logical to test the addition of afurthertreatmentarm in the form of immunotherapy, since there is extensive experimental and some clinical evidence that a combination of immunotherapy and chemotherapy offers advantages over chemotherapy alone. Non-specific irnmunotherapy w i t h Bacifle Calrnette-Guerin (BCG) has been demonstrated to inhibit tumour growth i n experimental animals (Old et alii, 1959). BCG as an adjuvant to surgery has been reported to have an inhibitory effect o n the micrometastases of malignant melanoma (Eilber et alii, 1976), but when used in disseminated melanoma had no appreciable effect in terms of tumour regression or survival (El-Dorneiri et all;, 1977). BCG has been reported to increase the disease-free interval following surgery in patients with Dukes “C” colorectal carcinoma when compared with historical controls (Mavligit et alii, 1976), but has not been shown to influence the course of disseminated colorectal carcinoma. Corynebacteriurn parvurn has also been shown to be effective in animal tumour models when used alone (Woodruff et alii, 1974) and in combination VOL. 48-No.3, JUNE,1978 AUST.N.Z. J. SURG.
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CHEMOIMMUNOTHERAPY FOR METASTASES
with chemotherapy (Currie and Bagshawe, 1970; Fisheret alli, 1975). Israel (1976) has used C.parvum in association with combination chemotherapy i n a variety of advanced human cancers. He reported significant improvement in survival times of patients with oat cell or squamous cell carcinoma of the lung and with breast carcinoma, as compared with patients treated by chemotherapy alone. In March 1975 we started trials of standard chemotherapy versus chemoimmunotherapy in patients with disseminated melanoma or colorectal carcinoma. PATIENTS AND METHODS Patients who entered the trials had histologically proven disease, and while suffering f r o m disseminated cancer were in reasonable general health. The objectives and practical details of the trials were fully explained to the patients and their consent obtained. The patients were randomized to receive either chemotherapy alone or chemotherapy plus immunotherapy.
For melanoma, the chemotherapy was DTlC in a dose of 2.5 mg/kg per day to a maximum of 200 mg per day given by intravenous bolus injection on five consecutive days, and the course was repeated monthly. Patients randomized t o receive chemoimmunotherapy received DTlC on the same schedule and in addition were give C.parvum intramuscularly in a dose of 7 mg one week before starting chemotherapy and again on the fourth day of each monthly course of DTIC. For colorectal carcinoma, the chemotherapy was 5FU in a dose of 12.5 mg/kg given by weekly intravenous bolus i n j e c t i o n . Patients randomized t o receive chemoimmunotherapy received 5FU o n the same schedule and in addition were given C.parvum in a dose of 7 m g one week before starting chemotherapy and again at monthly intervals.
RESULTS Toxicity Treatment on the whole was well tolerated. DTlC produced nausea and vomiting following the first one or two doses of each course in the majority of patients. No significant bone marrow suppression was observed. The administration of 5FU was associated with occasional nausea and diarrhoea. Three patients experienced mild alopecia after six months of treatment. Three others developed leucopenia (peripheral white cell count less than 3,000/mm3) which required reduction of dose. Intramuscular C.parvum produced a local inflammatory response which many patients found painful for u p to 48 hours. C.parvum was best toleiated when given into the gluteal muscle mass rather than the quadriceps or deltoid. No abscess formation was observed. A pyrexia of up to 38°C was common 6 to 12 hours after the C.parvum injection, and some patients experienced mild anorexia and malaise. The treatment did not have to be discontinued because of toxicity in any patient, but was ceased if there was progression of disease or the patient entered a terminal stage of illness.
Ctinicaf Response In the melanoma trial, 36 patients have been followed for a minimum of three months. The numbers, mean age and sex ratio in both groups were similar (Table l).The distribution and extent of TABLE1 Chernoimmunotherapy Trial Melanoma
Randomization of Patients Chemotherapy
Number
20
16
Mean age
47
47
13 7
115
Male Female
The patients were reviewed at monthly intervals. Objective response was defined as a 50% or greater reduction in the area of all measurable tumour with no new or progressing lesions, the reduction in tumour size being sustained for at least one month. Stabilization was defined as no increase in tumour size or less than 50% regression over a three-month period. The Mann-Whitney test was used in statistical analysis of the survival times. The patients were also studied-by a series of tests for specific and nonspecific immune responses to their tumours and to therapy. Results of these studies will be reported separately. AUST. N.Z. J. SURG.VOL. 48-No. 3, JUNE,1978
Chemoimmunotherapy
metastatic disease was similar in the two groups, but five patients with cerebral metastases at the time of entry to the trial were in the chemotherapy alone group (Table 2). There were seven objective responses, a rate of 19%. Three of the responses were i n the chemotherapy group and four in the chemoimmunotherapy group. Objective responses were seen in four patients with metastases in skin, one with skin and lung, one with skin and lymph node, and one with lymph node metastases. Three of the seven responders died at 8% 10 and 15 months, and
297
GOUGH ET ALL1
CHEMOIMMUNOTHERAPY FOR METASTASES TABLE 2 Chemoimmunotherapy Trial . Melanoma Distribution of Metastases Chemotherapy (20)
Chemoimmunotherapy (16)
was reversed, but this would not be expected to have a significant effect on survival in disseminated c o l o r e c t a l carcinoma. T h e d i s t r i b u t i o n of metastases was similar, although as in the melanoma trial, there was a tendency for the patients in the chemotherapy group t o have more widespread disease (Table 5). No objective responses were observed in either treatment group.
9
12
Lung
10
7
Liver
5
2
Node
10
5
Cerebral
5
0
TABLE 5
Others
4
2
Chemoimmunotherapy Trial Colorectal Carcinoma Distribution of Metastases
Local
+
skin
four are still alive at 5%, 8%, 9 and 25 months. Two of the patients with skin metastases had an apparent complete remission of disease. The mean and median survival times of those patients who have died are shown in Table 3, and there was no significant difference between the two treatment groups (Mann-Whitney tests, P = 0.4). Seven patients still survive at times between 3 and 25 months from the start of therapy. TABLE 3 Chemoirnmunotherapy Trial Melanoma Survival Chemotherapy (20)
Chemoimmunotherapy (16)
16
13
Mean survival (months)
5
5.9
Median survival (months)
5
55
Dead
F k e of the patients had cerebral metastases at the time of entry t o the trial, and of the 29 patients who have died, 14 demonstrated cerebral metastases, a rate of 49%. It is thus apparent that neither DTlC alone nor DTlC plus C.parvum affects known cerebral metastases, and that neither drug offers protection against their development in patients with metastases originally in other sites. In the colorectal carcinoma trial, 33 patients were followed for a minimum of three months. The numbers, mean age, and sites of primary tumour in both groups were similar (Table 4). The sex ratio TABLE4 Chemoimmunotherapy Trial Colorectal Carcinoma Randomization of Patients Chemotherapy
Chemoimrnunotherapy
Number
19
14
Mean age
58
56
6:13
9:5
14
11
5
3
Male : female Primary in colon Primary in rectum
298
Chemotherapy (19)
Chemoimmunotherapy (14)
3
Local
11
Lung
2
2
Liver
12
10
Peritoneal
8
3
Other
5
2
In the 33 patients there were 24 with evaluable disease, i.e., a measurable tumour mass. There were nine patients who had metastatic disease proven at laparotomy but i n whom it was not possible subsequently to measure the disease in the postoperative period. Of those with evaluable disease, there were seven whose disease was regarded as stable, three being in the chemotherapy alone group and four in the chemoimmunotherapy group. The mean and median survival times of those patients who had died are shown in Table 6, and there was no significant difference between the two treatment groups (Mann-Whitney test, P = 9.3). TABLE 6 Chemoimmunotherapy Trial : Colorectal Carcinoma. Survival A
Chemothergpy (19)
Chemoimmunotherapy (14)
12
10
Mean survival (months)
5.6
4.9
Median survival (months)
5.5
5.5
Dead
DISCUSSION The administration of a killed vaccine of the anaerobic organism C.parvum has a strong stimulatory effect o n the reticuloendothelial system (Halpern et alii, 1963), and will inhibit the growth of experimental tumours (Woodruff and Boak, 1966). The antitumour properties of C.parvum in animals appear to be both non-specific, due to macrophage activation, and specific, due to stimulation of antitumour antibody production (Scott, 1974). T lymphocyte responses vary with the route of AUST.N.Z. J. SURG. Vo~.48-N0.3, JUNE,1978
CHEMOIMMUNOTHERAPY
GOUGH ET ALL1
F O R METASTASES
administration, activation occurring regional injection and depression systemic injection.
following following
In e x p e r i m e n t a I s y s t e ms n o n - spe c i f i c immunotherapy is most effective in an immunocompetent host with a small tumour burden, and therefore could not logically be expected to be effective when used alone in advanced human cancer patients suffering from immune depression and with major tumour burdens. The major clinical use of non-specific immunotherapy may therefore be after apparently curative surgery in patients with known poor prognosis or in association with Chemotherapy. C.parvum has been demonstrated to have an additive effect to chemotherapy in animal tumour systems. Currie and Bagshawe (1970) concluded that the timing of C.parvum administration relative to ghemotherapy was important in a mouse fibrosarcoma model, and that chemotherapy should be used firstto reduce turnour burden. However, Fisher and his colleagues (1975), using a mouse mammary carcinoma system, co n cl u d e d that th e chemotherapy-immunotherapy interval was not critical and that both agents could be administered simultaneously. Most experimental studies suggest that intravenous or intraperitoneal injection of C.parvum is superior to the intramuscular or subcutaneous route. However, Israel (1976) has used subcutaneous injections of C.parvum with combination chemotherapy in several types of advanced human cancer, and has shown that significant benefit can be derived by the addition of C.parvum to chemotherapy in such patients. The major advantage in these patients may have been due to the potent induction effect of C.parvurn on the production of bone marrow immunocyte precursors (Dimitrov et alii, 1975), so that the number and length of therapeutic interruptions for marrow depression, as measured by leucopenia, was halved in patients receiving C.parvum as compared with those receiving chemotherapy alone. The subcutaneous injection of C.parvurn leads to painful nodules at the site of injection, with occasional sterile abscesses, and some systemic upset in the form of chills and fever (Israel, 1976; Rao et alii, 1977). Intravenousadministration results in more major systemic reactions, with frequent rigors and pyrexia, nausea, vomiting, severe headaches, and transient severe hypertension (Woodruff et alii, 1975; Israel, 1976; Rao et alii, 1977). Although most of these workers suggested that the side effects of C.parvum were acceptable, our own experience of the severity of reactions AUST N.Z. J. SURG.VOL. 48-No. 3, JUNE,1978
following intravenous injection is such that we do not feel justified in using this route of administration to add to the already significant morbidity of treatment in patients with d isseminated disease. Intramuscular injection of C.parvum has been used by Woodruff and his colleagues (1975) and by Israel and Edelstein (1975). We have found that C.parvurn administered by this route is well tolerated, causing only slight local discomfort and mild pyrexia for 24 to 48 hours after injection. However, this trial has produced no evidence that intramuscular injection of C.parvum in thedoseand schedule utilized has had any effect on the course of the disease in patients suffering from disseminated melanoma or colorectal carcinoma. The objective response rate of 19% observed in patients suffering from disseminated melanoma is similar to that reported by other workers with DTlC alone (Luce, 1975). It was disappointing that no objective evidence of response was obtained in the patients with colorectal cancer. Objective response rates of approximately 20% have been reported by other workers using a similar dosage and schedule of administration of 5FU. The lack of response in this study may reflect the strictness of the criteria used. This trial has again emphasized the difficulty of treatment of cerebral metastases in malignant melanoma. It is known from animal pharmacokinetic studies (Loo et alii, 1968) that only a small proportion of an injected dose of DTlC crosses the blood-drain barrier, so it is not surprising that central nervous 'system metastases are unaffected by this drug. The, nitrosoureas, such as methylCCNU, have some activity against melanoma, and because they are lipid soluble are able to cross the blood-drain barrier. They have therefore been incorporated into several trial regimens, but evidence is lacking that they are effective alone or in combination for treating or delaying the development of CNS metastases (Comis and Carter, 1974). The survival time after the diagnosis of disseminated melanoma or colorectal carcinoma isshort, and it is therefore reasonable to question whether any therapy is justified at all. We have been concerned that the treatment offered should not be too toxicor unpleasant for the patients. It is possible that more intensive chemotherapy and immunotherapy schedules could have produced more favourable results, but at the risk of increased morbidity. Despite the disappointing overall results of this particular study, we believe that patients with advanced cancer benefit from the regular hospital visits and attention they receive during their participation in a clinical trial. We are convinced that
299
CH E M 0 IM M UNOTH ERAPY FOR METASTASES
carefully controlled clinical trials provide the only reliable way of determining genuine advances in the management of patients with disseminated cancer. ACKNOWLEDGEMENTS We wish to thank our colleagues at the Princes Alexandra and Royal Brisbane Hospitals who referred their patients, and gratefully acknowledge the financial assistance of the Queensland Cancer Fund and Cancer Research Fund of the Universityof Queensland.
REFERENCES BYRNE. M.J. (1976)Cancer (Philad.), 38: 1922. CARTER,S.K. and FRIEDMAN,M. (1974).Cancer Treatment Reviews, 1 : 1 1 1. COHEN.S.M.. GREENSPAN, E.M.. RATNER, L.H. and WEINER. M.J. (1977).Cancer (Philad.). 39: 41. COMIS. R.L. and CARTER.S.K. (1974), Cancer Treatment Reviews, 1: 285. CURRIE,G.A. and BAGSHAWE, K.D. (1970),Brit. med. J., 1: 541. DIMITROV.N., ANDRE,F.. ELIOPOULOS, G. and HALPERN.B.N. (1975),in Corynebacterium parvum. Applications in Experimental and Clinical Oncology. Plenum Publishing Corporation, New York. 1: 173. EILBER.F.R., MORTON,D.L., HOLMES.E.C.. SPARKS, F.C. and RAMMING. K.P. (1976),N. Engl. J. Med., 294: 237. EL-DOMEIRI,A.A., NIKA,8.. HSIA.W., CRISPEN,R.. SAEET.T.Y. and GUPTA.T.K.D. (1977),Arch. Surg., 1 1 2: 257. ELIAS.E.G.. DIDOLKAR, M.S., GOEL, I.P.. FORMEISTER. J.F., VALENZUELA. L.A., PICKREN.J.L. and MOORE,R.H. (1977). Surg. Gynec. Obstet., 144: 327.
300
GOUGH ET ALL1 FISHER,B., WOLMARK. N.. RUBIN.H. and SAFFER, E. (1975), J. flat. Cancer lnst., 55: 1147. HALPERN, B.N., PREVOT. A.R., BIOZZI,G., STIFFEL.C., MOUTON,D., MORARD.J.C., BOUTHILLIER,Y. and DECREUSEFOND, C. (1963),J. Reticdoendotbelid Soc., 1: 77. ISRAEL, L (1976), Ann. N.Y. Acad. Sci., 277: 241. ISRAEL,L. and EDELSTEIN. R. (1975),Lancet, 1: 979. LO0.T.L.. LUCE.J.K., JARDINE.J . H . ~ ~ ~ F RE., E 111(1968),Cancer I. Res., 28: 2448. LUCE,J.K. (1975),Seminars in Oncology, 2: 179. MAVLIGIT.G.M.. BURGESS.M.A., SEIBERT,G.B., JUBERT.A.V., MCBRIDE.C.M.. GEHAN, E.A.. GUTTERMAN.J.U., KHANKHANIAN. N.. SPEER.J.F., MARTIN,R.C., COPELAND. E.M. and HERSH.E.M. (1976).Lancet, 1: 871. MCKELVEY, E.M., LUCE. J.K., TALLEY, R.W., HERSH. E.M., HEWLITT.J.S. and MOON,T.E. (1977),Cancer (Philad.),
39: 1. MOERTEL. C.G. (1975),Cancer (Philad.), 36: 675. MOERTEL. C.G. (1976),J. Amer. med. Ass., 235: 2135. MOERTEL.C.G. and REITEMEIER. R.J. (1969). in Advanced Gastrointestinal Cancer, Harper and Row, New York: 3. OLD, L.J., CLARKE.D.A. and BENACERRAF. €3. (1959),Nature (Lond.), 184: 291. RAO.B.,WANEEO. H.J.. OCHOA,M.,LEWIS,J.L. and OETTGEN, H.F. (1977).Cancer (Philad.), 39: 514. SCOTT,M.T. (1974).Seminars in Oncology, 1: 367. WOODRUFF,M.F.A. and BOAK.J.L. (1966),Brit. J. Cancer,
20: 345. WOODRUFF. M.F.A., MCBRIDE,W.H. and DUNBAR.N. (1974), Clin. exp. Immunol., 17: 509. WOODRUFF. M.F.A.. CLUNIE,G.J.A., MCBRIDE, W.H., MCCORMACK. R.J.M., WALBAUM. P.R. and JAMES,K. (1975),in Corynebacterium Parvum, Plenum Publishing Company, New York: 383.
AUST. N.Z. J. SURG.V o ~ . 4 8 - N 0 . 3 , JUNE,1978
CH E M 0 I M MUNOTHERAPY FOR METASTASES
CHEMOIMMUNOTHERAPY IN DISSEMINATED MELANOMA AND COLORECTAL CARCINOMA I.R. GOUGH. P.M. BOLTON. G.J.A. CLUNIEAND W. BURNETT Department of Surgery, University of Queensland, Brisbane. Non-specific immunotherapy with monthly intramuscular injection of Corynebacterlum parvum has been investigated by randomized clinical trials in patients with advanced cancer. Thirty-six patients with disseminatedmelanoma were treated witheitherimidazolecarboxamide(DT1C) aloneor DTlC plus C.parvum. A 19% objective response rate was observed. The mean survival time was slmiiar for both groups. Thirty-three patients with disseminated colorectal cancer were treated with either 5-fluorouracil (5FU) alone or 5FU plus C.parvum. No objective responses were observed. The mean survival time was similar for both groups. No advantage has been demonstrated in either tumour group by adding C.parvum to standard chemotherapy.
WHEN systemic metastases of melanoma or colorectal carcinoma are discovered, the life expectancy for the patient is relatively short. For both melanoma (Elias et alii, 1977) and colorectal carcinoma (Moertel and Reitemeir, 1969) the mean survival time is approximately six months. Disseminated melanoma has been relatively resistant to chemotherapy, but with dimethyltriazeno-i midazole-carboxamide (DTI C) objective response rates of 25% have been obtained (Luce, 1975). While combination chemotherapy is more effective than single agent chemotherapy in most h u m a n m a l i g n a n c i e s , t h i s has n o t b e e n demonstrated i n disseminated melanoma. Combinations of cyclophosphamide, vincristine, and procarbazine (Byrne, 1976), and of DTIC, bischloroethyl nitrosourea (BCNU), and vincristine (Cohen et alii, 1977; McKelvey et alii, 1977), are not superior to DTlC alone. Colorectal carcinoma is also relatively resistant to Chemotherapy. In a review of 2107 patients with disseminated colorectal cancer treated with 5fluorouracil (5FU) the response rate was 21% (Carter and Friedman, 1974). N o other single agent is as effective as 5FU (Moertel, 1975). Combinations of drugs have been disappointing, and most are less effective than 5FU alone. Recently, however, combinations incorporating 5FU and methylcyclohexyl-chloroethyl-nitrosourea ( m e t h y l CCNU) have been reported to give improved Reprints: I.R. Gough, Department of Surgery, Princess Alexandra Hospital, lpswich Road, Woolloongaba, Qld 4102.
296
’
response rates (Moertel, 1976), but survival times were not significantly affected. Although patients who respond objectively to chemotherapy tend t o survive longer in both these forms of malignancy (Moertel and Reitemeir, 1969; McKelvey et afii, 1977), there is no convincing evidence that chemotherapy influences overall survival. In the face of such disappointing results it is logical to test the addition of afurthertreatmentarm in the form of immunotherapy, since there is extensive experimental and some clinical evidence that a combination of immunotherapy and chemotherapy offers advantages over chemotherapy alone. Non-specific irnmunotherapy w i t h Bacifle Calrnette-Guerin (BCG) has been demonstrated to inhibit tumour growth i n experimental animals (Old et alii, 1959). BCG as an adjuvant to surgery has been reported to have an inhibitory effect o n the micrometastases of malignant melanoma (Eilber et alii, 1976), but when used in disseminated melanoma had no appreciable effect in terms of tumour regression or survival (El-Dorneiri et all;, 1977). BCG has been reported to increase the disease-free interval following surgery in patients with Dukes “C” colorectal carcinoma when compared with historical controls (Mavligit et alii, 1976), but has not been shown to influence the course of disseminated colorectal carcinoma. Corynebacteriurn parvurn has also been shown to be effective in animal tumour models when used alone (Woodruff et alii, 1974) and in combination VOL. 48-No.3, JUNE,1978 AUST.N.Z. J. SURG.
GOUGH ET ALll
CHEMOIMMUNOTHERAPY FOR METASTASES
with chemotherapy (Currie and Bagshawe, 1970; Fisheret alli, 1975). Israel (1976) has used C.parvum in association with combination chemotherapy i n a variety of advanced human cancers. He reported significant improvement in survival times of patients with oat cell or squamous cell carcinoma of the lung and with breast carcinoma, as compared with patients treated by chemotherapy alone. In March 1975 we started trials of standard chemotherapy versus chemoimmunotherapy in patients with disseminated melanoma or colorectal carcinoma. PATIENTS AND METHODS Patients who entered the trials had histologically proven disease, and while suffering f r o m disseminated cancer were in reasonable general health. The objectives and practical details of the trials were fully explained to the patients and their consent obtained. The patients were randomized to receive either chemotherapy alone or chemotherapy plus immunotherapy.
For melanoma, the chemotherapy was DTlC in a dose of 2.5 mg/kg per day to a maximum of 200 mg per day given by intravenous bolus injection on five consecutive days, and the course was repeated monthly. Patients randomized t o receive chemoimmunotherapy received DTlC on the same schedule and in addition were give C.parvum intramuscularly in a dose of 7 mg one week before starting chemotherapy and again on the fourth day of each monthly course of DTIC. For colorectal carcinoma, the chemotherapy was 5FU in a dose of 12.5 mg/kg given by weekly intravenous bolus i n j e c t i o n . Patients randomized t o receive chemoimmunotherapy received 5FU o n the same schedule and in addition were given C.parvum in a dose of 7 m g one week before starting chemotherapy and again at monthly intervals.
RESULTS Toxicity Treatment on the whole was well tolerated. DTlC produced nausea and vomiting following the first one or two doses of each course in the majority of patients. No significant bone marrow suppression was observed. The administration of 5FU was associated with occasional nausea and diarrhoea. Three patients experienced mild alopecia after six months of treatment. Three others developed leucopenia (peripheral white cell count less than 3,000/mm3) which required reduction of dose. Intramuscular C.parvum produced a local inflammatory response which many patients found painful for u p to 48 hours. C.parvum was best toleiated when given into the gluteal muscle mass rather than the quadriceps or deltoid. No abscess formation was observed. A pyrexia of up to 38°C was common 6 to 12 hours after the C.parvum injection, and some patients experienced mild anorexia and malaise. The treatment did not have to be discontinued because of toxicity in any patient, but was ceased if there was progression of disease or the patient entered a terminal stage of illness.
Ctinicaf Response In the melanoma trial, 36 patients have been followed for a minimum of three months. The numbers, mean age and sex ratio in both groups were similar (Table l).The distribution and extent of TABLE1 Chernoimmunotherapy Trial Melanoma
Randomization of Patients Chemotherapy
Number
20
16
Mean age
47
47
13 7
115
Male Female
The patients were reviewed at monthly intervals. Objective response was defined as a 50% or greater reduction in the area of all measurable tumour with no new or progressing lesions, the reduction in tumour size being sustained for at least one month. Stabilization was defined as no increase in tumour size or less than 50% regression over a three-month period. The Mann-Whitney test was used in statistical analysis of the survival times. The patients were also studied-by a series of tests for specific and nonspecific immune responses to their tumours and to therapy. Results of these studies will be reported separately. AUST. N.Z. J. SURG.VOL. 48-No. 3, JUNE,1978
Chemoimmunotherapy
metastatic disease was similar in the two groups, but five patients with cerebral metastases at the time of entry to the trial were in the chemotherapy alone group (Table 2). There were seven objective responses, a rate of 19%. Three of the responses were i n the chemotherapy group and four in the chemoimmunotherapy group. Objective responses were seen in four patients with metastases in skin, one with skin and lung, one with skin and lymph node, and one with lymph node metastases. Three of the seven responders died at 8% 10 and 15 months, and
297
GOUGH ET ALL1
CHEMOIMMUNOTHERAPY FOR METASTASES TABLE 2 Chemoimmunotherapy Trial . Melanoma Distribution of Metastases Chemotherapy (20)
Chemoimmunotherapy (16)
was reversed, but this would not be expected to have a significant effect on survival in disseminated c o l o r e c t a l carcinoma. T h e d i s t r i b u t i o n of metastases was similar, although as in the melanoma trial, there was a tendency for the patients in the chemotherapy group t o have more widespread disease (Table 5). No objective responses were observed in either treatment group.
9
12
Lung
10
7
Liver
5
2
Node
10
5
Cerebral
5
0
TABLE 5
Others
4
2
Chemoimmunotherapy Trial Colorectal Carcinoma Distribution of Metastases
Local
+
skin
four are still alive at 5%, 8%, 9 and 25 months. Two of the patients with skin metastases had an apparent complete remission of disease. The mean and median survival times of those patients who have died are shown in Table 3, and there was no significant difference between the two treatment groups (Mann-Whitney tests, P = 0.4). Seven patients still survive at times between 3 and 25 months from the start of therapy. TABLE 3 Chemoirnmunotherapy Trial Melanoma Survival Chemotherapy (20)
Chemoimmunotherapy (16)
16
13
Mean survival (months)
5
5.9
Median survival (months)
5
55
Dead
F k e of the patients had cerebral metastases at the time of entry t o the trial, and of the 29 patients who have died, 14 demonstrated cerebral metastases, a rate of 49%. It is thus apparent that neither DTlC alone nor DTlC plus C.parvum affects known cerebral metastases, and that neither drug offers protection against their development in patients with metastases originally in other sites. In the colorectal carcinoma trial, 33 patients were followed for a minimum of three months. The numbers, mean age, and sites of primary tumour in both groups were similar (Table 4). The sex ratio TABLE4 Chemoimmunotherapy Trial Colorectal Carcinoma Randomization of Patients Chemotherapy
Chemoimrnunotherapy
Number
19
14
Mean age
58
56
6:13
9:5
14
11
5
3
Male : female Primary in colon Primary in rectum
298
Chemotherapy (19)
Chemoimmunotherapy (14)
3
Local
11
Lung
2
2
Liver
12
10
Peritoneal
8
3
Other
5
2
In the 33 patients there were 24 with evaluable disease, i.e., a measurable tumour mass. There were nine patients who had metastatic disease proven at laparotomy but i n whom it was not possible subsequently to measure the disease in the postoperative period. Of those with evaluable disease, there were seven whose disease was regarded as stable, three being in the chemotherapy alone group and four in the chemoimmunotherapy group. The mean and median survival times of those patients who had died are shown in Table 6, and there was no significant difference between the two treatment groups (Mann-Whitney test, P = 9.3). TABLE 6 Chemoimmunotherapy Trial : Colorectal Carcinoma. Survival A
Chemothergpy (19)
Chemoimmunotherapy (14)
12
10
Mean survival (months)
5.6
4.9
Median survival (months)
5.5
5.5
Dead
DISCUSSION The administration of a killed vaccine of the anaerobic organism C.parvum has a strong stimulatory effect o n the reticuloendothelial system (Halpern et alii, 1963), and will inhibit the growth of experimental tumours (Woodruff and Boak, 1966). The antitumour properties of C.parvum in animals appear to be both non-specific, due to macrophage activation, and specific, due to stimulation of antitumour antibody production (Scott, 1974). T lymphocyte responses vary with the route of AUST.N.Z. J. SURG. Vo~.48-N0.3, JUNE,1978
CHEMOIMMUNOTHERAPY
GOUGH ET ALL1
F O R METASTASES
administration, activation occurring regional injection and depression systemic injection.
following following
In e x p e r i m e n t a I s y s t e ms n o n - spe c i f i c immunotherapy is most effective in an immunocompetent host with a small tumour burden, and therefore could not logically be expected to be effective when used alone in advanced human cancer patients suffering from immune depression and with major tumour burdens. The major clinical use of non-specific immunotherapy may therefore be after apparently curative surgery in patients with known poor prognosis or in association with Chemotherapy. C.parvum has been demonstrated to have an additive effect to chemotherapy in animal tumour systems. Currie and Bagshawe (1970) concluded that the timing of C.parvum administration relative to ghemotherapy was important in a mouse fibrosarcoma model, and that chemotherapy should be used firstto reduce turnour burden. However, Fisher and his colleagues (1975), using a mouse mammary carcinoma system, co n cl u d e d that th e chemotherapy-immunotherapy interval was not critical and that both agents could be administered simultaneously. Most experimental studies suggest that intravenous or intraperitoneal injection of C.parvum is superior to the intramuscular or subcutaneous route. However, Israel (1976) has used subcutaneous injections of C.parvum with combination chemotherapy in several types of advanced human cancer, and has shown that significant benefit can be derived by the addition of C.parvum to chemotherapy in such patients. The major advantage in these patients may have been due to the potent induction effect of C.parvurn on the production of bone marrow immunocyte precursors (Dimitrov et alii, 1975), so that the number and length of therapeutic interruptions for marrow depression, as measured by leucopenia, was halved in patients receiving C.parvum as compared with those receiving chemotherapy alone. The subcutaneous injection of C.parvurn leads to painful nodules at the site of injection, with occasional sterile abscesses, and some systemic upset in the form of chills and fever (Israel, 1976; Rao et alii, 1977). Intravenousadministration results in more major systemic reactions, with frequent rigors and pyrexia, nausea, vomiting, severe headaches, and transient severe hypertension (Woodruff et alii, 1975; Israel, 1976; Rao et alii, 1977). Although most of these workers suggested that the side effects of C.parvum were acceptable, our own experience of the severity of reactions AUST N.Z. J. SURG.VOL. 48-No. 3, JUNE,1978
following intravenous injection is such that we do not feel justified in using this route of administration to add to the already significant morbidity of treatment in patients with d isseminated disease. Intramuscular injection of C.parvum has been used by Woodruff and his colleagues (1975) and by Israel and Edelstein (1975). We have found that C.parvurn administered by this route is well tolerated, causing only slight local discomfort and mild pyrexia for 24 to 48 hours after injection. However, this trial has produced no evidence that intramuscular injection of C.parvum in thedoseand schedule utilized has had any effect on the course of the disease in patients suffering from disseminated melanoma or colorectal carcinoma. The objective response rate of 19% observed in patients suffering from disseminated melanoma is similar to that reported by other workers with DTlC alone (Luce, 1975). It was disappointing that no objective evidence of response was obtained in the patients with colorectal cancer. Objective response rates of approximately 20% have been reported by other workers using a similar dosage and schedule of administration of 5FU. The lack of response in this study may reflect the strictness of the criteria used. This trial has again emphasized the difficulty of treatment of cerebral metastases in malignant melanoma. It is known from animal pharmacokinetic studies (Loo et alii, 1968) that only a small proportion of an injected dose of DTlC crosses the blood-drain barrier, so it is not surprising that central nervous 'system metastases are unaffected by this drug. The, nitrosoureas, such as methylCCNU, have some activity against melanoma, and because they are lipid soluble are able to cross the blood-drain barrier. They have therefore been incorporated into several trial regimens, but evidence is lacking that they are effective alone or in combination for treating or delaying the development of CNS metastases (Comis and Carter, 1974). The survival time after the diagnosis of disseminated melanoma or colorectal carcinoma isshort, and it is therefore reasonable to question whether any therapy is justified at all. We have been concerned that the treatment offered should not be too toxicor unpleasant for the patients. It is possible that more intensive chemotherapy and immunotherapy schedules could have produced more favourable results, but at the risk of increased morbidity. Despite the disappointing overall results of this particular study, we believe that patients with advanced cancer benefit from the regular hospital visits and attention they receive during their participation in a clinical trial. We are convinced that
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carefully controlled clinical trials provide the only reliable way of determining genuine advances in the management of patients with disseminated cancer. ACKNOWLEDGEMENTS We wish to thank our colleagues at the Princes Alexandra and Royal Brisbane Hospitals who referred their patients, and gratefully acknowledge the financial assistance of the Queensland Cancer Fund and Cancer Research Fund of the Universityof Queensland.
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