BCG immunotherapy in stage I melanoma patients

Summary Previously, we have provided evidence for a positive correlation between HLA-DR expression in primary melanoma and early metastasis [3, 4]. In the present study we investigated whether this relationship was modified by adjuvant BCG immunotherapy. The study comprised 107 patients with a stage I high-risk melanoma; 44 patients had been treated with BCG, whereas the remaining patients had not received any adjuvant therapy. There was no difference in disease-free survival between BCG-treated and untreated patients. Disease-free survival was significantly shorter in patients with high expression of HLA-DR antigens in the primary tumor.Subgrouping BCG-treated and control patients according to HLA-DR phenotype of the melanoma revealed a prolongation of disease-free survival in the subgroup of BCG-treated patients with no or low expression of HLA-DR antigens in the primary melanoma. BCG therapy apparently did not influence prognosis of patients with high expression of HLA-DR antigens in the tumor.     

Immunotherapy of breast cancer,malignant melanoma,and acute leukemia with BCG: Prolongation of disease free interval and survival

Summary Results of immunotherapy with BCG in patients with malignant melanoma, breast cancer, and acute leukemia are described. The first study demonstrated that high doses of living BCG organisms (6×10⁸ viable units) delivered by scarification in the upper arms and legs prolonged the disease-free interval and survival of 52 malignant melanoma patients with regional lymph node metastases compared to 218 comparable surgical control patients. Patients with trunk and extremity, but not head and neck melanoma, benefited from BCG, suggesting the importance of the delivery of BCG into the tumor-involved lymphatics.The second study evaluated the therapeutic efficacy of living BCG organisms by scarification in a group of adult acute leukemia patients after the cessation of chemotherapy. Thirty-seven patients had been in remission on intermittent chemotherapy for 12–24 months. Following late intensive consolidation chemotherapy, 7 consecutive patients received no further therapy and then 30 consecutive patients received BCG. Patients maintained on BCG have had a prolonged disease-free interval compared to those given on no further therapy (P=0.07) or compared to a group of similar patients maintained on chemotherapy alone (P=0.001). Similarly, the survival has been improved for patients maintained on BCG compared to those left unmaintained (P=0.009), or those maintained on chemotherapy (P=0.001).The principles of intermittent chemotherapy combined with BCG immunotherapy, first developed in patients with disseminated melanoma and acute myelogenous leukemia, have been confirmed in a series of patients with disseminated breast cancer. Forty-five patients treated with a combination of 5-FU, adriamycin, and cyclophosphamide (FAC) plus BCG by scarification showed prolongation of remission as well as survival compared to a comparable group of 44 patients treated with FAC chemotherapy without immunotherapy. Thus, 23/44 patients treated with FAC have died (median=14 months) compared to only 5/45 patients on FAC-BCG (median=12⁺ months), P=0.005. The limitations of BCG immunotherapy as well as speculations for future developments of immunotherapy are discussed.This work was supported by Contract No1-CB 33888 from the National Institutes of Health, Public Health Service, Bethesda, Maryland 20014. Drs. Gutterman and Mavligit are the recipients of Career Development Awards (Ca 71007-02 and CA 00130-01, respectively) from the National Institutes of Health, Education, and Welfare, Bethesda, Maryland 20014.     

Prognostic factors for recurrence and survival in axillary node-negative breast cancer

The question of which node-negative breast cancer patients should be treated with adjuvant systemic therapy is a debatable topic. Our approach in San Antonio is to examine the risk profile for an individual patient and attempt to classify the patient into a good risk group or a high risk group in terms of disease recurrence. Features such as small tumor size (less than 2 cm), diploid tumors with low proliferative rate, and nuclear grade I, all indicate a good prognosis with a disease-free survival of approx. 90% at 5 yr. Examination of the cost vs benefits in this category of patients suggest that routine treatment with systemic adjuvant therapy is not appropriate.     

Present status of BCG immunotherapy of malignant melanoma

Summary BCG systemic adjuvant immunotherapy may be effective for improving both the recurrence and survival rates in patients with regional metastases from malignant melanoma. Clinical trials show that many of the principles derived from the study of animal tumor systems are applicable to human cancer in that immunotherapy is most effective for a small residual number of tumor cells. BCG treatment fulfills many of the ideal criteria for adjuvant treatment following surgery when disease burden is lowest. It is relatively nontoxic; it is effective for disseminated melanoma; it has systemic activity in the adjuvant treatment of subclinical metastases. However, until clinical trials are complete, BCG adjuvant therapy must be considered investigational.Supported by USPHS grants CA05252, CA12582, and NIH 0732001 CB43852.     

BCG immunotherapy for recurrent malignant melanoma

Summary A study was made of immunologic parameters obtained from patients with stage IIIB malignant melanoma who were treated with BCG. Patients with the longest disease-free interval and survival times were those who had small initial skin test reactions and developed larger reactions during the course of BCG treatment. Of these patients, those with less than five involved nodes had the longest disease-free interval and survival times. Patients who had increases in skin test reactivity generally showed these increases by the first visit after initiation of BCG therapy.     

Adjuvant BCG immunotherapy for malignant melanoma.

A total of 199 patients with stage I malignant melanoma at Clark''s level 3 to 5 of invasion were entered into a prospectively controlled randomized clinical trial that attempted to assess the value of local and systemic immunotherapy with BCG (bacille Calmette-Guérin) after surgery. The patients were randomly assigned, with stratification by Clark''s level, to receive either routine follow-up or immunotherapy with BCG, administered intradermally with a Heaf gun around the site of wide excision and then given orally for 2 years. Intradermal administration of BCG was repeated after 1 year''s oral therapy with BCG. Of the 99 patients in the treatment group 66 had Clark''s level 3, 28 had level 4, and 5 had level 5 invasion. Of the 100 patients in the control group, 61 had level 3, 36 had level 4, and 3 had level 5 invasion. Other prognostic factors, such as sex, depth of invasion, histologic features, site of disease and type of surgery, were evenly distributed. There were 57 recurrences of the melanoma, 24 in the treatment group and 33 in the control group. However, this trend was not statistically significant (p = 0.194). The suggestion that BCG may reduce the likelihood of local/regional recurrence has not been confirmed with longer follow-up. There were 13 such recurrences in the BCG group, compared with 21 in the control group; the proportions of patients in each group who had such a recurrence were not significantly different. Of the 199 patients 41 died, 24 in the control group and 17 in the treatment group; again, this difference was not significant. While there may be minor activity in selected patients, there appeared to be no benefit from this form of adjuvant BCG therapy in patients with malignant melanoma.     

Immunotherapy for superficial bladder cancer

The treatment of superficial bladder cancer requires adjuvant therapies besides transurethral resection because of a high recurrence rate after this standard treatment alone. Current adjuvant therapies involve intravesical chemotherapy for patients at low and intermediate risk for recurrence and progression, and intravesical bacillus Calmette-Guérin for patients at intermediate and high risk. However, these adjuvant therapies fail in a significant number of patients, dictating the need for new and improved adjuvant treatment modalities for superficial bladder cancer. Immunotherapy aiming at the modulation of the immune system of the patient is a promising alternative adjuvant. This review discusses the current status of the clinical development of various immunotherapy approaches for superficial bladder cancer, including passive immunotherapy, immune stimulants, immunogene therapy and cancer vaccination.     

BCG-Mediated Bladder Cancer Immunotherapy: Identifying Determinants of Treatment Response Using a Calibrated Mathematical Model

Intravesical Bacillus Calmette Guérin (BCG) immunotherapy is considered the standard of care for treatment of non-muscle invasive bladder cancer; however the treatment parameters were established empirically. In order to evaluate potential optimization of clinical parameters of BCG induction therapy, we constructed and queried a new mathematical model. Specifically, we assessed the impact of (1) duration between resection and the first instillation; (2) BCG dose; (3) indwelling time; and (4) treatment interval of induction therapy – using cure rate as the primary endpoint. Based on available clinical and in vitro experimental data, we constructed and parameterized a stochastic mathematical model describing the interactions between BCG, the immune system, the bladder mucosa and tumor cells. The primary endpoint of the model was the probability of tumor extinction following BCG induction therapy in patients with high risk for tumor recurrence. We theoretically demonstrate that extending the duration between the resection and the first BCG instillation negatively influences treatment outcome. Simulations of higher BCG doses and longer indwelling times both improved the probability of tumor extinction. A remarkable finding was that an inter-instillation interval two times longer than the seven-day interval used in the current standard of care would substantially improve treatment outcome. We provide insight into relevant clinical questions using a novel mathematical model of BCG immunotherapy. Our model predicts an altered regimen that may decrease side effects of treatment while improving response to therapy.     

Cytokine gene polymorphisms are associated with risk of urinary bladder cancer and recurrence after BCG immunotherapy

The association of interleukin-1β (IL-1B) -511C?>?T and IL-1 receptor antagonist (IL-1RN) VNTR, transforming growth factor-β (TGF-B1) +28C?>?T and interferon-γ (IFN-G)?+?874T>A polymorphisms with bladder cancer (CaB) susceptibility and risk of recurrence in Bacillus Calmette–Guérin (BCG)-treated patients was analyzed in 287 controls and 213 CaB patients (73 BCG treated). Increased risk was observed with the IL-1RN*2 allele (odds ratio (OR) 5.01) and the IFN-G +874 A allele (OR 1.78). TGF-B TT and IFN-G +874 A carriers were associated with reduced (hazard ratio (HR) 0.37) and enhanced (HR 2.24) risk of recurrence after BCG immunotherapy, respectively. The study suggests that cytokine gene variants may modulate CaB susceptibility and risk of recurrence after BCG immunotherapy.     

Recurrent malignant melanoma: effect of adjuvant immunotherapy on survival.

Twenty-nine patients referred consecutively to a cancer clinic because of recurrent metastatic malignant melanoma were given 5 mg of Connaught Laboratories bacillus Calmette-Guérin (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 correleated well with extent of disease.     

Adjuvant specific immunotherapy of resectable squamous cell lung carcinoma analysis at the eighth year

From June 1976 to June 1981, 86 patients with resectable (Stage I and II) squamous cell lung carcinoma were entered into a randomized controlled study with three arms: Control Group - no treatment postoperatively. Specific Immunotherapy Group - three monthly doses of 500 micrograms of tumor associated antigen (TAA) emulsified with complete Freund's adjuvant (CFA). Nonspecific Immunotherapy Group - three monthly doses of CFA emulsified in saline. All the patients in the study received skin tests with PPD (5TU) and 100 micrograms of the same TAA used for the immunotherapy at 1, 4, 6, 9, and 12 months postoperatively. Patients in both immunotherapy groups showed a tendency for a better disease-free interval and overall survival compared to those of the control, but these interval and beneficial therapeutic effects were statistically significant only in the Group III patients who had no hilar lymph node metastasis (T1N0 and T2N0). Although Group III was originally designated as a nonspecific immunotherapy group, retrospectively, it should be called a lowdose specific immunotherapy group because these patients actually received a total of 500 micrograms of TAA (as skin tests) and three doses of CFA at separate sites.     

Association of polymorphisms in oxidative stress genes with clinical outcomes for bladder cancer treated with Bacillus Calmette-Guérin

Genetic polymorphisms in oxidative stress pathway genes may contribute to carcinogenesis, disease recurrence, treatment response, and clinical outcomes. We applied a pathway-based approach to determine the effects of multiple single nucleotide polymorphisms (SNPs) within this pathway on clinical outcomes in non-muscle-invasive bladder cancer (NMIBC) patients treated with Bacillus Calmette-Guérin (BCG). We genotyped 276 SNPs in 38 genes and evaluated their associations with clinical outcomes in 421 NMIBC patients. Twenty-eight SNPs were associated with recurrence in the BCG-treated group (P<0.05). Six SNPs, including five in NEIL2 gene from the overall and BCG group remained significantly associated with recurrence after multiple comparison adjustments (q<0.1). Cumulative unfavorable genotype analysis showed that the risk of recurrence increased with increasing number of unfavorable genotypes. In the analysis of risk factors associated with progression to disease, rs3890995 in UNG, remained significant after adjustment for multiple comparison (q<0.1). These results support the hypothesis that genetic variations in host oxidative stress genes in NMIBC patients may affect response to therapy with BCG.     

Immunologic function during adjuvant BCG immunotherapy for malignant melanoma: Induction of anergy

Summary Serial tests of immunological function were performed on 28 patients participating in a randomized controlled clinical trial of adjuvant Tice-stain BCG immunotherapy administered by tine technique for malignant melanoma. Cryopreserved lymphocyte samples obtained prior to study entry and at 3 and 6 months there-after were tested by mixed lymphocyte culture (MLC), cell-mediated lympholysis (CML), antibody-dependent cell-mediated cytotoxicity (K cell), and natural killing (NK cell) assays, the last two assays being performed with the Chang cell line. Delayed-type hypersensitivity (DTH) skin tests to recall antigens were performed at the same intervals.At entry to the study in vitro lymphocyte reactivity of patients was similar to that of normal controls, and most (75%) of the patients reacted to at least one recall antigen. Serial lymphocyte reactivity measured by the in vitro tests was not different in the BCG and control groups, but BCG treatment was associated with a marked, statistically significant (P<0.01) reduction in DTH skin test reactivity. BCG therapy was not shown to delay recurrence of the disease.     

The need for immune evaluation prior to thymosin-containing chemoimmunotherapy for melanoma

Summary In an attempt improve the response to BCG or BCG + DTIC therapy in Stage IIIB melanoma patients, we added thymosin treatment with repeated doses of 4 mg/m² or 40 mg/m². Twenty-eight patients were clinically and immunologically evaluable. Pretreatment immunological evaluation consisted of determination of delayed-type hypersensitivity to recall antigens, enumeration of E-rosettes in blood, and measurement of blood lymphocyte response to phytohemmagglutinin (PHA) and concanavalin A (Con-A). The disease-free interval was correlated with thymosin dose and parameters of immunocompetence. Immunocompetent melanoma patients treated with a high thymosin dose and BCG relapsed earlier than those treated with a low thymosin dose and BCG. Thus, 72% of the melanoma patients who had a PHA SI50 and were treated with 4 mg thymosin/m², were disease-free at 9 months, compared with only 31% of those treated with 40 mg/m² (P=0.02). When the dermatophytin delayed hypersensitivity response (>10 mm induration) was used as a parameter of immunocompetence, 86% of the patients treated with 4 mg/m², were disease-free at 9 months, as against 28% of patients treated with 40 mg thymosin/m² (P=0.07). None of the immunoincompetent patients on high thymosin dose relapsed (0/3). The results suggest that while a high thymosin dose (40 mg/m²) may be detrimental to immunocompetent patients, it may have a beneficial effect in immunoincompetent patients. A low thymosin dose is probably not detrimental to immunocompetent melanoma patients in this study. Monitoring of the immune status prior to and during the use of thymosin in cancer immunotherapy is mandatory.This paper was presented at the Thirteenth Annual Meeting of the American Society for Clinical Oncology, Denver, 1977     

BCG in the immunotherapy of malignant lymphomas

Summary The effectiveness of a nonspecific immunostimulation in related human or animal diseases incited us to do a study of nonspecific immunotherapy by BCG in Hodgkin's disease, and then in other malignant lymphomas. Seventy patients, each one fulfilling at least 2 criteria of poor prognosis, were initially put in complete remission by a combination of radio-chemotherapy, followed by a reinforcing chemotherapy. These patients were then randomized into two groups. The first group received no further treatment; the second received BCG in weekly cutaneous scarifications. Eight patients were excluded from the study. The rate of relapses is significantly lower in the treated group. The results are discussed. Other therapeutic studies are necessary to fix the indications and modalities of this immunotherapy.Communication to the Medical Oncology Society, Nice, December 7, 1976     

Equine sarcoid: BCG immunotherapy compared to cryosurgery in a prospective randomised clinical trial

Summary A total of 30 horses with single or multiple sarcoid tumors of the skin were randomly divided into three treatment groups: (i) cryosurgical treatment, (ii) intralesional immunotherapy with a live BCG vaccine, (iii) intralesional immunotherapy with a BCG cell wall preparation. Complete tumour regression was obtained in all 10 crysurgically treated horses, in 6 of 10 live BCG treated horses, and in 7 of 10 BCG cell wall treated horses. One live BCG and 2 BCG cell wall treated horses showed partial tumour regression of more than 50% of the tumour area. Eleven horses with sarcoid tumours were not eligible for random allocation in the trial because unfavourable site or size of the tumour precluded cryosurgical treatment. These animals were treated with BCG cell wall vaccine except for 1 animal, which was treated with live BCG. In 4 cases this treatment was combined with cytoreductive surgery of the tumour. In this prognostically unfavourable group 8 animals showed complete tumour regression and 3 animals did not respond.Regression after BCG immunotherapy appeared to correlate with size (larger tumours worse response) and localization of the sarcoid (less favourable results in the limb), and increase in peripheral blood leucocytes after the first injection. Horses with a positive delayed type hypersensitivity reaction to PPD before the start of treatment showed a tendency to more favourable prognosis than PPD negative horses. No correlation was present between regression and single or multiple presence of sarcoids, increase in body temperature after injection of BCG and the formation of specific antibodies to BCG. None of the cured animals have shown tumour recurrence 3 to 40 months following treatment.Animals were maintained under the guidelines prescribed by the Faculty of Veterinary Medicine, State University Utrecht, The NetherlandsGrant recipient of the Koningin Wilhelmina Fonds (Netherlands Cancer Foundation)     

Evaluation of adjuvant chemotherapy in patients with colorectal cancer in Primorsko-Goranska and Istarska County--a twenty years retrospective study

Colorectal cancer is the second most common malignant disease in developed countries, with about one million new cases worldwide every year, accompanied with high mortality rate. We examined the survival rate and recurrence (occurrence of distant metastases and/or local recurrence) of patients with colorectal cancer in Primorsko-Goranska and Istarska County who received adjuvant chemotherapy, compared to those who did not in the period since 1980. until 1999. This study involves 483 patients with colorectal cancer stages II and III of Primorsko-Goranska and Istarska County, which were underwent curative resections of colorectal cancer at the Clinical Hospital Centre Rijeka, and then treated with chemotherapy (288) or without Chemotherapy (195). We analyzed the five year survival rate and the recurrence of malignant disease in the adjuvant treatment group in comparison with not treated group with chemotherapy, depending on the stage of disease, degree of histological differentiation, patient age and location of cancer (colon or rectum). After follow-up of 60 months died 44.79% (129/288) of patients who received chemotherapy and 53.33% (104/195) of patients who did not receive chemotherapy. The relative risk of death (from any cause) in chemotherapy-treated group versus the group without chemotherapy was 0.82 (p < 0.008). Recurrence of malignant disease in the chemotherapy group was 38.54% (111/288), and in the group without chemotherapy was 46.15% (90/195). The relative risk of recurrence of malignant disease in the chemotherapy group versus the group without chemotherapy was 0.78 (p < 0.001). There was no difference in treatment efficacy regard to the localization of the tumor, but there were differences in efficiency with respect to disease stage, grade and age. Chemotherapy with 5-fluorouracil and leukovorin ameliorate the survival and reduces recurrence and distant metastases in patients with colorectal cancer stages II and III.     

Postoperative radiotherapy and late mortality: evidence from the Cancer Research Campaign trial for early breast cancer.

OBJECTIVE--To identify any excess mortality caused by adjuvant radiotherapy for early breast cancer. DESIGN--Prospective randomised clinical trial. Two thousand subjects needed for study to have a 90% chance of detecting a difference in survival rate of 7% with 95% significance. Patients were followed up until June 1988, giving follow up of 158-216 months. SETTING--A multicentre trial mainly drawing patients from centres in the United Kingdom. PATIENTS--2800 Women presenting with clinical stage I or II carcinoma of the breast from June 1970 to April 1975. INTERVENTIONS--One group of women (n = 1376) had simple mastectomy followed by immediate postoperative radiotherapy (1320 to 1510 rets). The remaining women (n = 1424) had simple mastectomy with subsequent careful observation of the axilla, radiotherapy being delayed until there was obvious progression or recurrence of disease locally. END POINT--Increased mortality in patients treated with radiotherapy from causes other than breast cancer. MEASUREMENTS AND MAIN RESULTS--Survival was measured from time of first treatment to death or last follow up. Deaths from any cause and from specified causes were counted as events. Comparison over the whole follow up showed a slight excess mortality in the group treated with radiotherapy (relative risk 1.04; 95% confidence interval 0.94 to 1.15). The relative risk of death from breast cancer was 0.97 (0.87 to 1.08) but that of death from other causes was 1.37 (1.09 to 1.72), the increase mainly being in women who had had tumours of the left breast (1.61 (1.17 to 2.24)) and had been treated with orthovoltage (1.85 (1.27 to 2.71)). Analysis of causes of death after five years showed a relative risk of 2.11 (1.25 to 3.59) for new malignancies and of 1.65 (1.05 to 2.58) for cardiac disease, the increase in cardiac mortality being most pronounced in patients who had had tumours of the left breast and whose treatment had included orthovoltage radiation (relative risk 2.67 (1.28 to 5.55)). CONCLUSIONS--Adjuvant radiotherapy after simple mastectomy for early breast cancer produces a small excess late mortality from other cancers and cardiac disease. The risk has to be balanced against the higher risk of local recurrence when immediate postoperative radiotherapy is not given. The balance has to be assessed for each patient, and for many patients radiotherapy will still be desirable in the initial treatment of their early breast cancer.     

A controlled trial of BCG immunotherapy in bronchogenic carcinoma treated by surgical resection

Summary Ninety-two patients with bronchogenic carcinoma who were treated by surgical resection of the tumour were subsequently given immunotherapy with BCG (Glaxo). The study was strictly randomised into three groups. Twenty-nine patients received multipuncture BCG (50–250×10⁶ viable units) and 26 patients intradermal BCG (0.4–0.9×10⁶ viable units) treatment being given at 1, 2, 5, 9, 13 and 26 weeks after operation and every 26 weeks thereafter. Thirty-seven control patients did not receive BCG. The patients have been observed for 15–33 months. There was no significant difference in survival between the control group and the two immunotherapy groups or between the two immunotherapy groups. The tumour cell type and presence of mediastinal nodes significantly influenced overall survival but not the response to BCG immunotherapy. The possible reasons for the failure of BCG to prolong survival in this study are discussed.     

Controlled trial of active immunotherapy in management of stage IIB malignant melanoma.

The prognosis for patients who undergo surgery for stage IIB malignant melanoma is poor. Animal studies have suggested that BCG and tumour cell vaccines given together may provide effective immunotherapy. To assess the effectiveness of this treatment 15 patients with stage IIB malignant melanoma who had their tumour excised were studied. Seven were treated conservatively, and eight were vaccinated with BCG and autologous irradiated cells. Three vaccinated patients suffered widespread recurrence within three months. All four vaccinated patients who suffered a recurrence within the first year died, while none of the three controls with recurrent disease died. In view of this alarming trend the trial was stopped after a year. BCG and the tumour cells may have enhanced the tumour growth, although there was no apparent reason for this. The results of uncontrolled or unrandomised trials that have suggested that this treatment is beneficial should be treated with scepticism.