Frank C. Sparks

BCG Immunotherapy of Malignant Melanoma: Summary of a Seven-year Experience

Over the past 7 years, 151 patients with malignant melanoma have been treated with BCG immunotherapy alone or as an adjunct to surgical therapy. Direct injection of metastatic melanoma lesions limited to skin resulted in 90% regression of injected lesions and 17% regression of uninjected lesions in immunocompetent patients. Approximately 25% of these patients remained free of disease for 1 to 6 years. Direct injections of BCG into nodules of patients with subcutaneous or visceral metastases resulted in a lower incidence of local control and no long term survivors. Attempts to improve the results of immunotherapy in these patients by palliative surgical resection of large metastatic lesions to lower tumor burden followed by BCG immunotherapy significantly improved the results although many patients still developed recurrent disease. Early results of a clinical trial combining BCG immunotherapy with regional lymphadenectomy in patients with melanoma metastatic to lymph nodes have been encouraging and promising. Further controlled clinical trials are necessary to elucidate the role of BCG in immunotherapy. However, since BCG is but one of a number of potential immunologic adjuvants, even more effective immunotherapy will be possible as further knowledge of the interactions of cellular and humoral immunity is acquired.

Complications of BCG Immunotherapy in Patients with Cancer

Abstract Eighty-two patients with solid neoplasms were treated with BCG. BCG was well tolerated when given intradermally and alone by the multiple-puncture tine technic (24 patients) or with a tumor-cell vaccine (34 patients). Intratumor injection of BCG was associated with frequent complications, including marked malaise and an influenza-like syndrome in 16 of 25 patients, a temperature of 40°C or higher in 12, reversible hepatic dysfunction in six, and jaundice in three patients. Antituberculous chemotherapy with isoniazid promptly alleviated symptoms in seven patients so treated. BCG administration appears to be well tolerated with the multiple-puncture technic, but the intra-tumor injection of BCG may be associated with more serious side effects. (N Engl J Med 289:827–830, 1973)

Adjuvant chemotherapy for breast carcinoma: Psychosocial implications

Fifty women receiving adjuvant chemotherapy after surgery for Stage II breast carcinoma were interviewed in an effort to describe the psychosocial effect of the treatment. Perceptions of emotional distress and behaviorial disruption were rated in five areas, yielding a rating of overall level of disruption and distress. Results showed that all women experienced adverse changes while receiving adjuvant treatments. Of the 50 women, 88% described a decrease in activities related to the effects of adjuvant chemotherapy; 54% reported an increased financial burden; and 41% claimed that their family and/or sexual life had been adversely affected. Despite these adverse changes, 74% of these patients “would definitely” recommend the treatment to friends in a similar situation. Results from this preliminary study may provide useful information to potential participants in adjuvant trials and to the physicians who conduct such trials.

Hazards and Complications of BCG Immunotherapy

The hazards and complications of BCG immunotherapy, as well as the potential for enhanced tumor growth, make it imperative that the clinician know the clinical setting in which BCG can offer therapeutic benefit. This would include the intratumor injection of localized intradermal tumor deposits of melanoma and breast cancer, chemoimmunotherapy with BCG to prolong remission in acute myelogenous leukemia, and possibly the use of BCG as an adjuvant to control minimal residual disease. Aside from these situations, it is advisable to treat patients only on clearly defined experimental protocols.

Quality of life for breast cancer patients receiving adjuvant chemotherapy.

Many stage II breast cancer patients receive some form of adjuvant chemotherapy. Although research reports differ about the degree to which such treatments affect recurrence in postmenopausal women, physicians have found that adjuvant chemotherapy significantly delays recurrence of disease in premenopausal women(1-4). Despite the benefical effects that these treatment programs appear to have on the health of some of the participants, the potential psychological and physical stresses they create for the women involved may be great. With many patients as potential recipients of adjuvant chemotherapy, nurses and physicians need to know the impact of prophylactic chemotherapy on the quality of life for these patients. Data regarding common reactions may be essential in answering accurately the many questions that patients and their families may pose. Many patients have identified nurses as the persons they feel most comfortable with when they seek answers to their questions(5). A recent study reported that explanations about chemotherapy given by a nurse in addition to a physician were better understood by breast cancer patients than explanations given by a physician alone(6). To provide a picture of how women respond to adjuvant chemotherapy, we interviewed 50 women during the course of treatment with cyclophosphamide, methotrexate, and fluorouracil(7). Not surprisingly, we found that the degree and type of psychosocial impact reported varied greatly, but some generalizations can be drawn.

Delayed cutaneous hypersensitivity and peripheral lymphocyte counts in patients with advanced cancer.

One hundred eighty‐three patients with advanced solid neoplasms were tested for their ability to react to four common skin test antigens (tuberculin PPD, streptokinase‐streptodornase, mumps, and Monilia) and their ability to develop delayed cutaneous hypersensitivity (DCH) to 2, 4 dinitrochlorobenzene (DNCB). All patients were followed for at least 6 months or until death. Histologic tumor types studied were: melanoma (65), sarcoma (28), squamous cell carcinoma (23), and adenocarcinoma (67). The rate of progression of disease within 6 months of testing was lower in patients who had a positive response to a challenging dose of 50 μg of DNCB. Reactivity to recall antigens had no prognostic value except in patients with adenocarcinomas. Among patients with adenocarcinoma, those who reacted strongly to DNCB and one or more skin test antigens had the best prognosis, while those who were nonreactive to all had the worst prognosis (progression rate: 18% vs. 78%). Peripheral lymphocyte counts were related to the results of DCH to DNCB and skin tests. The presence or absence of lymphocytopenia (count less than 1000/mm3) had prognostic value in patients who had positive skin test(s). In such patients, the disease progression rate was much higher in patients who were anergic to DNCB and who were lymphocytopenic (90% vs. 40%). These data suggest that DCH to DNCB, recall antigens, and peripheral lymphocyte counts are useful immunologic measurements in patients with advanced cancer. Although the prognostic value of each individual test is relatively limited, the predictive worth can be increased when multiple tests are employed. Pertinent findings reported in the literature are reviewed.

A prospective study of parotid metastases from head and neck cancer

Abstract A prospective study of eighty-eight patients with cutaneous head and neck cancer was undertaken to define patients at high risk for parotid lymph node metastases. Over a three year period, twenty-one patients with highly malignant primary melanoma or squamous carcinoma of the eyelid, frontal, temporal, posterior cheek, or anterior ear skin underwent either initial wide primary excision and superficial parotidectomy with radical neck dissection (16 patients) or secondary parotidectomy after initial treatment elsewhere (5 patients). Of these twenty-one patients, eleven (52 per cent) had parotid lymph node metastases, seven (33 per cent) had metastases limited to the parotid nodes, and four (19 per cent) had both parotid and cervical node metastases. Eighteen of the twenty-one presented with clinically uninvolved parotid nodes, and eight of these (45 per cent) developed parotid metastases during the course of their disease. Five patients manifested parotid metastases within one year when superficial parotidectomy was not performed at initial node dissection. All patients who manifested clinically involved parotid nodes had proved metastases and all patients with cervical node metastases also had parotid metastases. On the basis of these data, patients with potentially metastatic primary head and neck cancers of the eyelid, frontal, temporal, posterior cheek, and anterior ear skin are at high risk for parotid node metastases and should undergo ipsilateral, wide primary excision and superficial parotidectomy with in-continuity radical neck dissection for adequate disease staging and treatment.

Hepatic artery ligation and 5-fluorouracil infusion for metastatic colon carcinoma and primary hepatoma.

Nine patients with extensive bilateral hepatic metastases of colorectal cancer were treated with hepatic artery ligation and continuous infusion of 5-fluorouracil (5-FU). Silastic catheters were inserted into the hepatic artery at laparotomy, and continuous perfusion was effected by a Sigmamotor pump. There was no operative mortality or morbidity, and drug toxicity was acceptable. Dosage averaged 10 mg/kg/day and average time of infusion was sixty-three days. Liver function returned to preoperative values within two weeks in all patients, and four patients had improvement of preoperative liver function for three to six months after perfusion. Two patients had palpable regressions that lasted five months or more, and one patient had a slight palpable regression for two months. Five who are dead had a mean survival of 10.4 months after therapy, with a median survival of 11.5 months. Eight of the nine patients had significant clinical improvement following treatment. Seven patients with irresectable primary liver carcinoma were treated with continuous 5-FU infusion. A Silastic catheter was placed at laparotomy into the hepatic artery via the gastroduodenal artery. Ligation of the hepatic artery was not performed. There was no operative mortality or morbidity. Dosage averaged 10 mg/kg/day and the average time of infusion was 140 days. Significant clinical improvement was noted in six of the seven patients although this did not correlate with improvement of hepatic function. All six responding patients are still living (mean survival, 14 months). Prolongation of life with hepatic artery infusion of 5-FU has been significantly better than with any previously reported chemotherapy for this disease.

Multimodality cancer therapy in man: A pilot study of adriamycin by arterial infusion

Adriamycin was given by an infra‐arterial route as part of a planned program of combined modality therapy in 10 patients with regionally advanced neoplasms. Doses ranged from 45–107 mg/m2 given as a continuous infusion over 1.5–3.0 days. Adriamycin was followed by radiation therapy and/or radical surgical excision of the tumor in most cases, making long‐term evaluation of response difficult. However, 4 of 7 evaluable patients had prompt partial responses prior to subsequent treatment. We conclude that adriamycin can be administered by the intra‐arterial route and that it may be useful as part of a program of combined modality therapy in selected patients. Cancer 33:1485–1490, 1974.

Present status of BCG immunotherapy of malignant melanoma

SummaryBCG 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.