Recurrent malignant melanoma: effect of adjuvant immunotherapy on survival PETER B. MCCULLOCH, MD, FRCP[C]; PETER B. DENT, MD, FRCP[C]; MORRIS BLAJCHMAN, MD, FRCP[C]; WILLIAM M. MUIRHEAD, MB, FRCP[C], DMRT; ROBERT A. PRICE, B ENG
Twenty-nine patients referred consecutively to a cancer clinic because of recurrent metastatic malignant melanoma were given 5 mg of Connaught Laboratories bacillus Calmette-Guerin (BCG) by multiple cutaneous puncture at weekly and later at monthly intervals. Eight were also treated with autologous tumour vaccine and three with intralesional BCG. This group was compared with a retrospective control group of 54 patients treated with surgery and radiotherapy alone after recurrence. Prognostic features such as site of primary and of first metastasis, disease-free interval, age and sex were similar in the two groups. However, the median survival from the time of first recurrence was 12 months in the control group but 21 months in the BCG-treated group. The major improvement was in patients with disease limited to the regional lymph nodes: the median survival was 16 months in the control group but over 32 months in the BCG-treated group. Autologous tumour vaccine appeared to have no effect on survival. Serial testing of immunocompetence did not offer any prognostic advantage, although the results of some tests correlated well with extent of disease. Vingt-neuf patients vus consecutivement en consultation dans une clinique From the Hamilton clinic of the Ontario Cancer Treatment and Research Foundation, and McMaster University, Hamilton Presented in part to the American Association for Cancer Research, May 1975 Reprint requests to: Dr. P.B. McCulloch, Hamilton clinic. Ontario Cancer Treatment and Research Foundation, 711 Concession St., Hamilton, Ont. L8V 1C3
d'oncologie pour un m6lanome maim dissemin6 en rechute ont re.u 5 mg de bacille Calmette-Guerin (BCG) des Laboratoires Connaught par ponction percutan6e multiple, hebdomadairement au debut, puis a Intervalle d'un mols par Ia suite. Huit patients ont aussi ete traites a l'aide d'un vaccin antitumoral autologue et trois ont re.u des injections de BCG dans les l6sions. Ce groupe a et6 compare de fa9on r6trospective a un groupe temoin compos6 de 54 patients traites par chirurgie et radiotherapie seules apres recidive. Les elements de pronostic tels que le foyer de Ia lesion primaire et de Ia premiere metastase, l'intervalle de remission, l'Age et le sexe etalent semblabies chez les deux groupes. Toutefois, Ia survie mediane a partir de Ia premiere r6cidive a 6t6 de 12 mois chez le groupe temoin mais de 21 mois chez le groupe traite au BCG. La principale amelioration a touch6 les patients dont Ia maladie se limitait aux ganglions lymphatiques regionaux: Ia survie m6diane a 6t6 de 16 mois pour le groupe t6moin par rapport a 32 mois pour le groupe BCG. Le vaccin antitumoral autologue semble n 'avoir eu aucun effet sur Ia survie. Des epreuves s6riees du statut immunitaire ne semblent avoir offert aucun avantage diagnostique, bien que les resultats de quelques tests aient montre une bonne corr6lation avec l'6tendue de Ia maladie.
Immunologic stimulation may be of benefit in human cancer.1 Bacillus Calmette-Gu6rin (BCG) is the most commonly used immunotherapeutic agent in treating human and animal malig-
nant disease.1 It has shown promise in studies of malignant melanoma,34 acute myelogenous leukemia6'7 and lung cancer.8 Several studies have also demonstrated that intralesional injections of BCG into cutaneous melanoma deposits often produce regression of injected lesions and occasionally of distant noninjected lesions.2 Administration of autologous or allogeneic tumour cells, modified in various ways, has also been shown to be of benefit in human malignant disease.9'10 Two American groups have published controlled studies purporting to show benefit from BCG immunotherapy on rates of recurrence and survival in recurrent malignant melanoma. The Houston group3 presented a preliminary report of a study of 16 patients with disease limited to regional lymph nodes, 5 of whom benefited greatly from treatment with the Tice strain of BCG; however, the minimum follow-up was only 1 year, and various strains and doses of BCG were used. The treatment was also moderately toxic in that most patients had a fever, with a temperature of up to 38.8 0C, lasting 24 to 48 hours after the injection. The Los Angeles group has published reports of two studies in similar patients with regional lymph node metastases. In the first study4 67 such patients were treated and compared with 34 controls not selected at random. No clinical data were presented for the controls. The minimum follow-up was less than 6 months, and the median follow-up, less than 16 months. In the second study5 84 such patients were treated with BCG, but once again the minimum follow-up was less than 16 months and the median follow-up, about 20 months. The 42 controls in
CMA JOURNAL/JULY 9, 1977/VOL. 117 33
a
controlled
manner,
with
a
Table I-Criteria for staging of malignant melanoma* Stage
Criterion Primary melanoma only; no metastases II Local recurrence within 3 cm of primary Ill Regional metastases more than 3 cm from primary Intradermal ("in transit" metasA tases) B Regional lymph nodes AB Intradermal and regional lymph nodes IV Distant hematogenous metastases *System of the University of Texas M.D. Anderson Hospital and Tumor Institute at Houston.
Table Il-Details of two groups of patients with malignant melanoma Treatment group; no. (and %) of patients Immunotherapy (n = 29) Control (n = 54)
Datum Site of primary Head and neck Limb Trunk Eye Unknown Site of first metastasis Skin Lymph nodes Lung Other viscera
4 (14) 10 (34) 13 (45) 1(3) 1 (3)
8 (15) 22 (41) 17 (31) 6(11) 1 (2)
5 18 2 4
9 (17) 33 (61) 1 (2) 11(20)
Clinical Ill III III IV
2 (7)1 18(62) 1-69% 0 (0) j 9 (31)
5 (9)1 30(56) 1-70% 3 (5) J 16 (30)
stage at time of first metastasis A B AB
(17) (62) (7) (14)
Time interval between appearance of primary and metastasis Syr Mean (mo) Median (mo) Sex distribution Males Females
4 (14) 18(62) 3(10) 4(14) 24 18
10 (18) 23(43) 16(30) 5 (9) 20 26
15 (52) 14 (48)
21(39) 33 (61)
Mean age at time of first appearance of metastasis (yr)
46
47
Gross residual tumour present after surgical treatment of first recurrence
17 (59)
23 (43)
BCG-treated group and 12 months for the control group (Fig. 1). This difference is significant at the 5% level by the chi-square method of Mantel.14 Survival was prolonged from the time of diagnosis of the primary by 10 months in the BCG-treated group over the controls, and the 5-year survival from the time of diagnosis of the primary was 45% in the BCG-treated group as opposed to 26% in the control group. There was no improvement in survival for patients with stage IV disease at the time of the first recurrence (median survival, approximately 4 months). However, the median survival from the time of first recurrence for controls with stage III disease (Fig. 2) was 16 months. For immunotherapy patients with stage III disease the median survival has not yet been reached at 32 months. The difference between these survival curves is also significant at the 5% level. Eleven of the immunotherapy patients were treated with the chemotherapeutic agent 5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide (DTIC) in single doses of 850 mg/in2 intravenously every 4 weeks for two doses.15 Three patients responded with measurable regressions lasting 2, 7 and 10 months. When these responders were excluded, the survival curve for the remaining 26 matched the survival curve in Fig. 1. Thus, although the chemotherapy produced objective and subjective remissions it did not influence the prolongation of survival of the whole group. In addition to BCG, eight of the patients received autologous tumour vaccine containing 10. irradiated cells treated with Vibrio cholerae neuramin100
idase (Behringwerke), 5 units per 1O cells, for 30 minutes at 37 0C. The cells were then washed and resuspended in 0.2 ml of Hanks' buffered saline solution containing 0.05 mg of live BCG vaccine and injected subcutaneously in two sites. Survival in these patients was not altered and the curves closely matched that of the overall group in Fig. 1. In three of the immunotherapy patients 0.1 to 0.5 mg of the same BCG was injected intralesionally on several occasions, resulting in inflammation and regression of the injected lesions in all three. In one patient uninjected lesions also became inflamed and regressed, and biopsy of the residual pigmented areas revealed only pigmentladen macrophages. The dose of BCG given to all 29 patients (5 mg) produced only local inflammation, with no systemic toxicity. One patient had transient episodes of fever after 10 months of therapy, but died 4 months later with disseminated malignant melanoma and no evidence of mycobacterial infection at auLopsy. Discussion The prognosis for survival in recurrent malignant melanoma is bleak; most series show a long-term survival of 10 to 15% and apparent cure only if all recurrent disease is completely resected. The median survival from time of primary diagnosis in our control group was 24 and 42 months, respectively, for men and women; these figures are almost identical to those of the group at M.D. Anderson Institute in Houston1' (23 and 44 months), de-
0--c 30G treated(29)
.
100
spite the use of various chemotherapeutic regimens in the latter group that were not used in our control group. Our finding of a beneficial effect of BCG immunotherapy in patients with recurrent malignant melanoma supports the previous observations of the Houston group3 and the Los Angeles group.4'5 This benefit seems to be limited to patients without distant metastases. The very poor prognosis of patients with metastases is usually not improved by immunotherapy; however, within this group we and others4 have found that some patients with abdominal, pulmonary and even central nervous system masses have a prolonged survival following surgery and chemoimmunotherapy. The most striking improvement was in patients with disease limited to the regional lymph nodes (stage III). In these patients, even when complete resection was not possible, a significant survival advantage appears to have been conferred by immunotherapy when this group is compared with our control group and with other control groups in the literature. This improved survival seems to be attributable to nonspecific immune stimulation plus reduction of tumour mass by repeated surgery. Specific immune stimulation with an autologous tumour vaccine did not appear to provide additional benefits. Chemotherapy with DTIC, while relieving symptoms and producing objective regression of disease, did not affect overall survival when this treatment was restricted to patients with gross symptomatic disease. A recent study by Pinsky and colleagues17 of the Memorial Sloan-Ket-
20
.ontrol (54) 90
90 .
80
4,
24
80
O.0.0 . 23
70
70
21
0 7o
Survival
60
Oh
0246
12
18
%
60
Survival
. 17
24
30
36
months from recurrence FIG. 1-Survival curves for 83 patIents with malignant melanoma. Numbers beside curves represent numbers of patients at risk of recurrence. Difference between curves significant at 5% leveL
0246
12
18
24
30
36
months from recurrence FIG. 2-Survival curves for 58 patIents with stage III disease. Numbers beside curves represent numbers of patients at risk of recurrence. Difference between curves significant at 5% level.
CMA JOURNAL/JULY 9, 1977/VOL. 117 35
The Royal College of Physicians
and Surgeons of Canada
Examinations The examinations of the Royal College are held in September of each year. Candidates wishing to sit for the examinations should note the following: 1. Every candidate for admission to the examinations must submit an application for assessment of training. 2. Candidates in training in Canada should apply for preliminary assessment of training at least one year before the date on which they expect to sit for the examinations, that Is to say not later than September 1st of the preceding year. Candidates who have had training outside of Canada should submit their initial application for assessment at lesst eighteen months before they expect to sit for the examinations, that is by March 1st of the preceding year. Only candidates whose assessment of credentials Is complete will be accepted to sit for the examinations. 3. Candidates who desire to sit for an examination, having complied with the above requirement of preliminary assessment of training, must notify the College in writing of their intent before February 1st of the year of the examination. Upon receipt of this notice of intent, the evaluation of the candidate's performance during training will be added to the previously completed assessment of credentials. Each candidate will then receive notification as to eligibility together with an application formfor admission. to the examination which he will complete and return. 4. The following documents may be obtained from the College office: (a) Application forms for assessment oftraining. (b) General Information booklet on training requirements and examinations. (c) Specific requirements for training and regulations relating to the examinations of each specialty. Requests should indicate the specialty or specialties of Interest to the applicant. (d) Listing of specialty training programmes in Canada accreditedby the College. 5. Address all enquiries to: Division of Training and Evaluation ROYAL COLLEGE OF PHYSICIANS AND SURGEONS OF CANADA 74 Stanley Avenue Ottawa, Ontario KIM 1P4 Tel.: (613) 746-8177
tering Cancer Center, New York, failed in established disease, and its immunoto confirm a beneficial effect of BCG suppressive potential is relatively low. in patients with stage III disease. These Controlled randomized studies are unauthors reported a median survival of der way in Canada to assess the role 32 months from the time of first recur- of chemoimmunotherapy with DTIC rence for both controls and BCG- and Connaught Laboratories BCG in treated patients; in contrast, the me- early (stages I, II and III) malignant dian survival for our controls was 16 melanoma. months, which is similar to that reWe thank Dr. Charles Dunnett for the ported by the Houston group,16 and statistical Dr. Silvio Landi of the median survival for BCG-treated Connaught analysis, Laboratories for supplying the patients has not been reached at 32 BCG, the nurses of the immunotherapy months. There are a number of major ciinic of the Hamilton clinic for their differences between the study of Piasky unfailing enthusiasm, Mrs. Sharon D'Anand associates and ours that may ac- gelo and Mrs. Cheryl lacobucci for typing count for the differences. Their pa- the manuscript, and the Ontario Cancer tients all received prophylactic lymph- Treatment and Research Foundation for adenectomy as primary treatment, so supplying the funds. recurrence would have been diagnosed References earlier and the survival time after re1. BAKER MA, TAUB RN: Immunotherapy of currence increased in their control human cancer. Prog Allergy 17: 227. 1973 group as compared with ours. The fail- 2. BAST RC JR, ZBAR B, BoRsos T, et al: BCG and cancer. N Engi I Med 290: 1458, 1974 ure of BCG to prolong survival in their 3. GUTrERMAN JU, MCBRIDE C, Faassascn EJ. Ct at: Active immunotherapy with B.C.G. for patients may be due to the fact that a recurrent malignant melanoma. Lancea' 1: different strain of BCG (Tice) was used 1208, 1973 MORTON DL, EILBER FR, HOLMES EC, et al: in a lower dose than in the studies of 4. BCG immunotherapy of malignant melanoma: summary of a seven-year experience. Ann the Los Angeles group4'5 and the study Surg 180: 635, 1974 of Gutterman and colleagues.6 BCG 5. ESLBER FR, MORTON DL, HOLMES EC, et al: Adjuvant immunotherapy with BCG in treatvaccination in the limbs draining the ment of regional-lymph-node metastases from malignant melanoma. N Engi I Med 294: 237. afeas of lymph node resection was 1976 omitted in the study of Pinsky and as- 6. GUlTERMAN JU, HERSH EM, RODRIGUEZ V. et at: Chemoimmunotherapy of adult acute sociates, whereas all four limbs were leukaemia. Prolongation of remission in myeloblastic leukaemia with B.C.G. Lancet 2: treated by us and by the Houston and 1974 Los Angeles groups. Finally, none of 7. 1405, VOGLER WR, CHAN YK: Prolonging remission myeloblastic in leukaemia by Tice-strain bacilthe patients of Pinsky and associates lus Calmette-Gu6rin. Lancet 2: 128, 1974 MS. MAyER C, KAUSEL 11W: had residual disease, compared with 8. MCKNEALLY Regional immunotherapy of lung cancer with 25% of our patients. It is conceivable intrapleural B.C.G. Lancet 1: 377, 1976 9. Pows its R: Immunotherapy for acute myethat a small amount of tumour antigen logenous leukemia using irradiated and Unirradiated leukemia cells. Cancer 34 (suppl may be necessary for optimal benefit 4): 1558, 1974 from nonspecific immunotherapy. 10. Bstxitss JG, HOLLAND .75, YAms 3W. et al: Chemotherapy of acute myelocytic leukemia Studies of tumour-specific and nonwith neuraminidase treated allogeneic leukemic cells. Proc Am Assoc Cancer Res 16: specific immunologic function were 121, 1975 carried out in patients receiving BCG 11. Luca JK, MCBRIDE CN, FRIE E In: Melanoma, in Cancer Medicine, HOLLAND JF, immunotherapy.18 Data on nonspecific FREt E III (eds), Philadelphia, Lea & Febiger, 1973, p 1823 immune competence showed that with 12. MACKIE RM, CARFRAE DC, COCHRAN AJ: increasing severity of disease there was Assessment of prognosis in patients with malignant Lancet 2: 455, 1972 a significant decrease in circulating 13. FAIRORIEVE melanoma. J: Selective criteria for surgical removal of the endocrine glands in advanced lymphocyte counts and in vitro rebreast cancer. Surg Gynecol Obstee 120: 371, sponses to suboptimal concentrations 1965 MANTEL N: Evaluation of survival data and of phytohemagglutinin. BCG therapy, 14. two new rank order statistics arising in its consideration. Cancer Chemother Rep 50: however, produced no significant 163, 1966 change in the degree of nonspecific 15. COWAN DH, BEROSAGEL DE: Intermittent treatment of metastatic malignant melanoma immunoreactivity in these patients. In with high dose 5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide. Cancer Chemother another study1' we found that patients Rep 55: 1971 with stage IV disease demonstrated a 16. EINHORN 175, LH, BURGESS MA, VALLEJOS C, et Prognostic al: correlations and response lower level of reactivity in indirect imto treatment in advanced metastatic malignant Cancer Res 34: 1995, 1974 munofluorescent tests for antibody 17. melanoma. PINsKY CM, HIRSHAUT Y, WANESO 113, et al: Randomized trial of BCG (percutaneous adagainst the membrane of cultured melaministration). A surgical .uvant immunonoma cells than patients with more limtherapy for patients with melanoma, stage II. Ann NY Acad Sd 277: 187, ited disease. The effect of BCG im- 18. Lul VK, KARPucHAs J, Dit.tT1976PB, et al: munotherapy on this feature has not Cellular immunocompetence in melanoma: effect of extent of disease and immunotheryet been evaluated. apy. Br I Cancer 32: 323, 1975 19. DENT PB, LsAo 5K, MCCULLOCH PB, et al: Since studies in other . Melanoma antigens on cultured melanoma cell lines detected by xeno and alloantibody. have shown the potential beneficial Proc Am Assoc Cancer Res 16: 311, 1976 FISHER B, CARBONE P, EcoNoMou SG, Ct al: effects of adjuvant chemotherapy after 20. 1-phenylalanine mustard (L-PAM) in the mansurgical removal of all visible tumour agement of primary breast cancer. A report of early findings. N Engi I Med 292: 117, the next step would be to use both Coams EP, HOLLAND JF, WANG JJ, et al: chemotherapy and immunotherapy. 21. 1975 Amputation and adriamycin in primary osteoDTIC is a good drug in this respect sarcoma. N Engi I Med 291: 998, 1974 JAFFE N, FanI E TRAGGIs D, et al: Adjuvant because it produces a substantial pro- 22. methotrexate and citrovorum factor treatment of osteogenic sarcoma. Ibid. p 998 portion of complete remissions, even
36 CMA JOURNAL/JULY 9, 1977/VOL. 117
Twenty-nine patients referred consecutively to a cancer clinic because of recurrent metastatic malignant melanoma were given 5 mg of Connaught Laboratories bacillus Calmette-Guerin (BCG) by multiple cutaneous puncture at weekly and later at monthly intervals. Eight were also treated with autologous tumour vaccine and three with intralesional BCG. This group was compared with a retrospective control group of 54 patients treated with surgery and radiotherapy alone after recurrence. Prognostic features such as site of primary and of first metastasis, disease-free interval, age and sex were similar in the two groups. However, the median survival from the time of first recurrence was 12 months in the control group but 21 months in the BCG-treated group. The major improvement was in patients with disease limited to the regional lymph nodes: the median survival was 16 months in the control group but over 32 months in the BCG-treated group. Autologous tumour vaccine appeared to have no effect on survival. Serial testing of immunocompetence did not offer any prognostic advantage, although the results of some tests correlated well with extent of disease. Vingt-neuf patients vus consecutivement en consultation dans une clinique From the Hamilton clinic of the Ontario Cancer Treatment and Research Foundation, and McMaster University, Hamilton Presented in part to the American Association for Cancer Research, May 1975 Reprint requests to: Dr. P.B. McCulloch, Hamilton clinic. Ontario Cancer Treatment and Research Foundation, 711 Concession St., Hamilton, Ont. L8V 1C3
d'oncologie pour un m6lanome maim dissemin6 en rechute ont re.u 5 mg de bacille Calmette-Guerin (BCG) des Laboratoires Connaught par ponction percutan6e multiple, hebdomadairement au debut, puis a Intervalle d'un mols par Ia suite. Huit patients ont aussi ete traites a l'aide d'un vaccin antitumoral autologue et trois ont re.u des injections de BCG dans les l6sions. Ce groupe a et6 compare de fa9on r6trospective a un groupe temoin compos6 de 54 patients traites par chirurgie et radiotherapie seules apres recidive. Les elements de pronostic tels que le foyer de Ia lesion primaire et de Ia premiere metastase, l'intervalle de remission, l'Age et le sexe etalent semblabies chez les deux groupes. Toutefois, Ia survie mediane a partir de Ia premiere r6cidive a 6t6 de 12 mois chez le groupe temoin mais de 21 mois chez le groupe traite au BCG. La principale amelioration a touch6 les patients dont Ia maladie se limitait aux ganglions lymphatiques regionaux: Ia survie m6diane a 6t6 de 16 mois pour le groupe t6moin par rapport a 32 mois pour le groupe BCG. Le vaccin antitumoral autologue semble n 'avoir eu aucun effet sur Ia survie. Des epreuves s6riees du statut immunitaire ne semblent avoir offert aucun avantage diagnostique, bien que les resultats de quelques tests aient montre une bonne corr6lation avec l'6tendue de Ia maladie.
Immunologic stimulation may be of benefit in human cancer.1 Bacillus Calmette-Gu6rin (BCG) is the most commonly used immunotherapeutic agent in treating human and animal malig-
nant disease.1 It has shown promise in studies of malignant melanoma,34 acute myelogenous leukemia6'7 and lung cancer.8 Several studies have also demonstrated that intralesional injections of BCG into cutaneous melanoma deposits often produce regression of injected lesions and occasionally of distant noninjected lesions.2 Administration of autologous or allogeneic tumour cells, modified in various ways, has also been shown to be of benefit in human malignant disease.9'10 Two American groups have published controlled studies purporting to show benefit from BCG immunotherapy on rates of recurrence and survival in recurrent malignant melanoma. The Houston group3 presented a preliminary report of a study of 16 patients with disease limited to regional lymph nodes, 5 of whom benefited greatly from treatment with the Tice strain of BCG; however, the minimum follow-up was only 1 year, and various strains and doses of BCG were used. The treatment was also moderately toxic in that most patients had a fever, with a temperature of up to 38.8 0C, lasting 24 to 48 hours after the injection. The Los Angeles group has published reports of two studies in similar patients with regional lymph node metastases. In the first study4 67 such patients were treated and compared with 34 controls not selected at random. No clinical data were presented for the controls. The minimum follow-up was less than 6 months, and the median follow-up, less than 16 months. In the second study5 84 such patients were treated with BCG, but once again the minimum follow-up was less than 16 months and the median follow-up, about 20 months. The 42 controls in
CMA JOURNAL/JULY 9, 1977/VOL. 117 33
a
controlled
manner,
with
a
Table I-Criteria for staging of malignant melanoma* Stage
Criterion Primary melanoma only; no metastases II Local recurrence within 3 cm of primary Ill Regional metastases more than 3 cm from primary Intradermal ("in transit" metasA tases) B Regional lymph nodes AB Intradermal and regional lymph nodes IV Distant hematogenous metastases *System of the University of Texas M.D. Anderson Hospital and Tumor Institute at Houston.
Table Il-Details of two groups of patients with malignant melanoma Treatment group; no. (and %) of patients Immunotherapy (n = 29) Control (n = 54)
Datum Site of primary Head and neck Limb Trunk Eye Unknown Site of first metastasis Skin Lymph nodes Lung Other viscera
4 (14) 10 (34) 13 (45) 1(3) 1 (3)
8 (15) 22 (41) 17 (31) 6(11) 1 (2)
5 18 2 4
9 (17) 33 (61) 1 (2) 11(20)
Clinical Ill III III IV
2 (7)1 18(62) 1-69% 0 (0) j 9 (31)
5 (9)1 30(56) 1-70% 3 (5) J 16 (30)
stage at time of first metastasis A B AB
(17) (62) (7) (14)
Time interval between appearance of primary and metastasis Syr Mean (mo) Median (mo) Sex distribution Males Females
4 (14) 18(62) 3(10) 4(14) 24 18
10 (18) 23(43) 16(30) 5 (9) 20 26
15 (52) 14 (48)
21(39) 33 (61)
Mean age at time of first appearance of metastasis (yr)
46
47
Gross residual tumour present after surgical treatment of first recurrence
17 (59)
23 (43)
BCG-treated group and 12 months for the control group (Fig. 1). This difference is significant at the 5% level by the chi-square method of Mantel.14 Survival was prolonged from the time of diagnosis of the primary by 10 months in the BCG-treated group over the controls, and the 5-year survival from the time of diagnosis of the primary was 45% in the BCG-treated group as opposed to 26% in the control group. There was no improvement in survival for patients with stage IV disease at the time of the first recurrence (median survival, approximately 4 months). However, the median survival from the time of first recurrence for controls with stage III disease (Fig. 2) was 16 months. For immunotherapy patients with stage III disease the median survival has not yet been reached at 32 months. The difference between these survival curves is also significant at the 5% level. Eleven of the immunotherapy patients were treated with the chemotherapeutic agent 5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide (DTIC) in single doses of 850 mg/in2 intravenously every 4 weeks for two doses.15 Three patients responded with measurable regressions lasting 2, 7 and 10 months. When these responders were excluded, the survival curve for the remaining 26 matched the survival curve in Fig. 1. Thus, although the chemotherapy produced objective and subjective remissions it did not influence the prolongation of survival of the whole group. In addition to BCG, eight of the patients received autologous tumour vaccine containing 10. irradiated cells treated with Vibrio cholerae neuramin100
idase (Behringwerke), 5 units per 1O cells, for 30 minutes at 37 0C. The cells were then washed and resuspended in 0.2 ml of Hanks' buffered saline solution containing 0.05 mg of live BCG vaccine and injected subcutaneously in two sites. Survival in these patients was not altered and the curves closely matched that of the overall group in Fig. 1. In three of the immunotherapy patients 0.1 to 0.5 mg of the same BCG was injected intralesionally on several occasions, resulting in inflammation and regression of the injected lesions in all three. In one patient uninjected lesions also became inflamed and regressed, and biopsy of the residual pigmented areas revealed only pigmentladen macrophages. The dose of BCG given to all 29 patients (5 mg) produced only local inflammation, with no systemic toxicity. One patient had transient episodes of fever after 10 months of therapy, but died 4 months later with disseminated malignant melanoma and no evidence of mycobacterial infection at auLopsy. Discussion The prognosis for survival in recurrent malignant melanoma is bleak; most series show a long-term survival of 10 to 15% and apparent cure only if all recurrent disease is completely resected. The median survival from time of primary diagnosis in our control group was 24 and 42 months, respectively, for men and women; these figures are almost identical to those of the group at M.D. Anderson Institute in Houston1' (23 and 44 months), de-
0--c 30G treated(29)
.
100
spite the use of various chemotherapeutic regimens in the latter group that were not used in our control group. Our finding of a beneficial effect of BCG immunotherapy in patients with recurrent malignant melanoma supports the previous observations of the Houston group3 and the Los Angeles group.4'5 This benefit seems to be limited to patients without distant metastases. The very poor prognosis of patients with metastases is usually not improved by immunotherapy; however, within this group we and others4 have found that some patients with abdominal, pulmonary and even central nervous system masses have a prolonged survival following surgery and chemoimmunotherapy. The most striking improvement was in patients with disease limited to the regional lymph nodes (stage III). In these patients, even when complete resection was not possible, a significant survival advantage appears to have been conferred by immunotherapy when this group is compared with our control group and with other control groups in the literature. This improved survival seems to be attributable to nonspecific immune stimulation plus reduction of tumour mass by repeated surgery. Specific immune stimulation with an autologous tumour vaccine did not appear to provide additional benefits. Chemotherapy with DTIC, while relieving symptoms and producing objective regression of disease, did not affect overall survival when this treatment was restricted to patients with gross symptomatic disease. A recent study by Pinsky and colleagues17 of the Memorial Sloan-Ket-
20
.ontrol (54) 90
90 .
80
4,
24
80
O.0.0 . 23
70
70
21
0 7o
Survival
60
Oh
0246
12
18
%
60
Survival
. 17
24
30
36
months from recurrence FIG. 1-Survival curves for 83 patIents with malignant melanoma. Numbers beside curves represent numbers of patients at risk of recurrence. Difference between curves significant at 5% leveL
0246
12
18
24
30
36
months from recurrence FIG. 2-Survival curves for 58 patIents with stage III disease. Numbers beside curves represent numbers of patients at risk of recurrence. Difference between curves significant at 5% level.
CMA JOURNAL/JULY 9, 1977/VOL. 117 35
The Royal College of Physicians
and Surgeons of Canada
Examinations The examinations of the Royal College are held in September of each year. Candidates wishing to sit for the examinations should note the following: 1. Every candidate for admission to the examinations must submit an application for assessment of training. 2. Candidates in training in Canada should apply for preliminary assessment of training at least one year before the date on which they expect to sit for the examinations, that Is to say not later than September 1st of the preceding year. Candidates who have had training outside of Canada should submit their initial application for assessment at lesst eighteen months before they expect to sit for the examinations, that is by March 1st of the preceding year. Only candidates whose assessment of credentials Is complete will be accepted to sit for the examinations. 3. Candidates who desire to sit for an examination, having complied with the above requirement of preliminary assessment of training, must notify the College in writing of their intent before February 1st of the year of the examination. Upon receipt of this notice of intent, the evaluation of the candidate's performance during training will be added to the previously completed assessment of credentials. Each candidate will then receive notification as to eligibility together with an application formfor admission. to the examination which he will complete and return. 4. The following documents may be obtained from the College office: (a) Application forms for assessment oftraining. (b) General Information booklet on training requirements and examinations. (c) Specific requirements for training and regulations relating to the examinations of each specialty. Requests should indicate the specialty or specialties of Interest to the applicant. (d) Listing of specialty training programmes in Canada accreditedby the College. 5. Address all enquiries to: Division of Training and Evaluation ROYAL COLLEGE OF PHYSICIANS AND SURGEONS OF CANADA 74 Stanley Avenue Ottawa, Ontario KIM 1P4 Tel.: (613) 746-8177
tering Cancer Center, New York, failed in established disease, and its immunoto confirm a beneficial effect of BCG suppressive potential is relatively low. in patients with stage III disease. These Controlled randomized studies are unauthors reported a median survival of der way in Canada to assess the role 32 months from the time of first recur- of chemoimmunotherapy with DTIC rence for both controls and BCG- and Connaught Laboratories BCG in treated patients; in contrast, the me- early (stages I, II and III) malignant dian survival for our controls was 16 melanoma. months, which is similar to that reWe thank Dr. Charles Dunnett for the ported by the Houston group,16 and statistical Dr. Silvio Landi of the median survival for BCG-treated Connaught analysis, Laboratories for supplying the patients has not been reached at 32 BCG, the nurses of the immunotherapy months. There are a number of major ciinic of the Hamilton clinic for their differences between the study of Piasky unfailing enthusiasm, Mrs. Sharon D'Anand associates and ours that may ac- gelo and Mrs. Cheryl lacobucci for typing count for the differences. Their pa- the manuscript, and the Ontario Cancer tients all received prophylactic lymph- Treatment and Research Foundation for adenectomy as primary treatment, so supplying the funds. recurrence would have been diagnosed References earlier and the survival time after re1. BAKER MA, TAUB RN: Immunotherapy of currence increased in their control human cancer. Prog Allergy 17: 227. 1973 group as compared with ours. The fail- 2. BAST RC JR, ZBAR B, BoRsos T, et al: BCG and cancer. N Engi I Med 290: 1458, 1974 ure of BCG to prolong survival in their 3. GUTrERMAN JU, MCBRIDE C, Faassascn EJ. Ct at: Active immunotherapy with B.C.G. for patients may be due to the fact that a recurrent malignant melanoma. Lancea' 1: different strain of BCG (Tice) was used 1208, 1973 MORTON DL, EILBER FR, HOLMES EC, et al: in a lower dose than in the studies of 4. BCG immunotherapy of malignant melanoma: summary of a seven-year experience. Ann the Los Angeles group4'5 and the study Surg 180: 635, 1974 of Gutterman and colleagues.6 BCG 5. ESLBER FR, MORTON DL, HOLMES EC, et al: Adjuvant immunotherapy with BCG in treatvaccination in the limbs draining the ment of regional-lymph-node metastases from malignant melanoma. N Engi I Med 294: 237. afeas of lymph node resection was 1976 omitted in the study of Pinsky and as- 6. GUlTERMAN JU, HERSH EM, RODRIGUEZ V. et at: Chemoimmunotherapy of adult acute sociates, whereas all four limbs were leukaemia. Prolongation of remission in myeloblastic leukaemia with B.C.G. Lancet 2: treated by us and by the Houston and 1974 Los Angeles groups. Finally, none of 7. 1405, VOGLER WR, CHAN YK: Prolonging remission myeloblastic in leukaemia by Tice-strain bacilthe patients of Pinsky and associates lus Calmette-Gu6rin. Lancet 2: 128, 1974 MS. MAyER C, KAUSEL 11W: had residual disease, compared with 8. MCKNEALLY Regional immunotherapy of lung cancer with 25% of our patients. It is conceivable intrapleural B.C.G. Lancet 1: 377, 1976 9. Pows its R: Immunotherapy for acute myethat a small amount of tumour antigen logenous leukemia using irradiated and Unirradiated leukemia cells. Cancer 34 (suppl may be necessary for optimal benefit 4): 1558, 1974 from nonspecific immunotherapy. 10. Bstxitss JG, HOLLAND .75, YAms 3W. et al: Chemotherapy of acute myelocytic leukemia Studies of tumour-specific and nonwith neuraminidase treated allogeneic leukemic cells. Proc Am Assoc Cancer Res 16: specific immunologic function were 121, 1975 carried out in patients receiving BCG 11. Luca JK, MCBRIDE CN, FRIE E In: Melanoma, in Cancer Medicine, HOLLAND JF, immunotherapy.18 Data on nonspecific FREt E III (eds), Philadelphia, Lea & Febiger, 1973, p 1823 immune competence showed that with 12. MACKIE RM, CARFRAE DC, COCHRAN AJ: increasing severity of disease there was Assessment of prognosis in patients with malignant Lancet 2: 455, 1972 a significant decrease in circulating 13. FAIRORIEVE melanoma. J: Selective criteria for surgical removal of the endocrine glands in advanced lymphocyte counts and in vitro rebreast cancer. Surg Gynecol Obstee 120: 371, sponses to suboptimal concentrations 1965 MANTEL N: Evaluation of survival data and of phytohemagglutinin. BCG therapy, 14. two new rank order statistics arising in its consideration. Cancer Chemother Rep 50: however, produced no significant 163, 1966 change in the degree of nonspecific 15. COWAN DH, BEROSAGEL DE: Intermittent treatment of metastatic malignant melanoma immunoreactivity in these patients. In with high dose 5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide. Cancer Chemother another study1' we found that patients Rep 55: 1971 with stage IV disease demonstrated a 16. EINHORN 175, LH, BURGESS MA, VALLEJOS C, et Prognostic al: correlations and response lower level of reactivity in indirect imto treatment in advanced metastatic malignant Cancer Res 34: 1995, 1974 munofluorescent tests for antibody 17. melanoma. PINsKY CM, HIRSHAUT Y, WANESO 113, et al: Randomized trial of BCG (percutaneous adagainst the membrane of cultured melaministration). A surgical .uvant immunonoma cells than patients with more limtherapy for patients with melanoma, stage II. Ann NY Acad Sd 277: 187, ited disease. The effect of BCG im- 18. Lul VK, KARPucHAs J, Dit.tT1976PB, et al: munotherapy on this feature has not Cellular immunocompetence in melanoma: effect of extent of disease and immunotheryet been evaluated. apy. Br I Cancer 32: 323, 1975 19. DENT PB, LsAo 5K, MCCULLOCH PB, et al: Since studies in other . Melanoma antigens on cultured melanoma cell lines detected by xeno and alloantibody. have shown the potential beneficial Proc Am Assoc Cancer Res 16: 311, 1976 FISHER B, CARBONE P, EcoNoMou SG, Ct al: effects of adjuvant chemotherapy after 20. 1-phenylalanine mustard (L-PAM) in the mansurgical removal of all visible tumour agement of primary breast cancer. A report of early findings. N Engi I Med 292: 117, the next step would be to use both Coams EP, HOLLAND JF, WANG JJ, et al: chemotherapy and immunotherapy. 21. 1975 Amputation and adriamycin in primary osteoDTIC is a good drug in this respect sarcoma. N Engi I Med 291: 998, 1974 JAFFE N, FanI E TRAGGIs D, et al: Adjuvant because it produces a substantial pro- 22. methotrexate and citrovorum factor treatment of osteogenic sarcoma. Ibid. p 998 portion of complete remissions, even
36 CMA JOURNAL/JULY 9, 1977/VOL. 117
