How to organize a multidisciplinary clinic for the management of breast cancer.

It is the opinion of this essayist that the advantages to the patient and the clinician of a multidisciplinary clinic far outweight the modest loss of autonomy and the need for commitment of additional time in order to make such a clinic function effectively. It is hoped that the success of this issue of the Surgical Clinics of North America and the serious application of the principles outlined in it will encourage the creation of many such successful clinics.

Overview. Current status of clinical trials.

The five areas outlined in this discussion represent a large proportion of the current environment for clinical trials. They identify significant obstacles to the advancement of knowledge in clinical oncology. There is no single or overriding solution to the health care system and its problems with funding and access or to the antiintellectual mood of our times. Continuous efforts to improve science are needed now more than ever. Adequate accession to trials is an ongoing issue. These problems are compounded by the ethical issues created by today's opportunities. The etiquette of territoriality is no less daunting. Each of these affects the environment in which trials are conducted, and each deserves the serious attention of all of us. Some suggestions for action have been made. The need for resolution is obvious.

Analysis with antiidiotype antibody of a patient with chronic lymphocytic leukemia and a large cell lymphoma (Richter's syndrome).

A murine monoclonal antibody made against an idiotypic determinant (Id) of surface IgM/IgD lambda molecules on chronic lymphocytic leukemia (CLL) cells of a 71-year-old woman was used for clonal analysis by two-color immunofluorescence. The anti-Id antibody identified IgM+/IgD+/lambda+ B cells as the predominant cell type of her CLL clone. In addition, substantial proportions of the IgG and IgA B cells and most of the IgM plasma cells in her bone marrow and blood were Id+. Six years after diagnosis, the patient died of respiratory failure due to infiltration of lungs by malignant cells. Autopsy revealed a dramatic change in the tumor cell morphology. The lungs, hilar nodes, and liver were infiltrated by a diffuse large cell lymphoma admixed with the leukemic cells. By immunohistologic staining these anaplastic lymphoma cells were IgM+/IgD-/lambda+ B cells expressing the same Id noted earlier on the CLL cells. The immunoglobulin gene rearrangement pattern on Southern blot analysis was also the same in leukemic blood cells and in the tissues involved by the lymphoma. Thus, the combination of antiidiotype and immunoglobulin gene analyses in this patient with Richter's syndrome revealed that a CLL clone, seemingly "frozen" in differentiation, was actually undergoing isotype switching, differentiation into plasma cells, and evolution into a rapidly growing and fetal lymphoma.

Tumor burden, chemotherapy, and cell kill in osteosarcoma model.

The complex relationships among tumor cell burden, dose and schedule of chemotherapy, and efficacy were investigated in a murine osteosarcoma model in which an easily measured marker provided an accurate, dynamic estimate of host tumor cell burden. Cytoxan (200 mg/kg) produced a 93.2-99.997% tumor cell kill in animals with a pretreatment tumor burden of 0.6-3% body weight. In animals with a pretreatment tumor burden of 5.1-10.24% body weight, however, the same dose of cytoxan produced less than 1 order of magnitude tumor cell kill (31-71%). A schedule utilizing three doses q12 days in animals with a moderate burden of tumor (up to 5% body weight) produced a cell kill of six or more orders of magnitude with some cures, an event which was more frequent with added immunostimulation. A schedule utilizing two doses q20 days in animals with a larger body burden (5-10% of body weight) was essentially ineffective. These results suggest that a small initial body burden (low stage) and an aggressive schedule of treatment are necessary for optimum results in cancer treatment. Small delays in initiation of treatment and prolonged intervals between doses can convert an effective drug to an ineffective one without the need to invoke biochemical mechanisms of resistance.

Loss of high-energy phosphate following hyperthermia demonstrated by in vivo 31P-nuclear magnetic resonance spectroscopy.

We have used in vivo 31P-nuclear magnetic resonance spectroscopy to study the changes in high-energy phosphates following hyperthermia. Immediately after heating, there is a fall in adenosine triphosphate and apparent intracellular pH and an increase in inorganic phosphate. Following sublethal heating (40 degrees for 15 min), these changes were partial, and they resolved over the subsequent 45 hr. With tumors given severe hyperthermia (47 degrees for 15 min), there was complete disappearance of adenosine triphosphate, with no recovery by 24 hr posttreatment. Qualitatively similar effects were seen after heating of normal leg muscle. The degree of fall of the adenosine triphosphate/inorganic phosphate concentration ratio was directly proportional to the heat dose and to thermal cell kill. 31P-Nuclear magnetic resonance spectroscopy may be useful in thermal dosimetry and treatment evaluation following hyperthermia.

Hormonal therapy of gynecologic cancers.

Progestins produce objective responses in about 30% of unselected patients with metastatic adenocarcinoma of the uterus. Selection of patients for treatment based on the presence of progesterone receptors may increase the probability of a response. There is little evidence to support a role of hormones as adjuvants in the primary management of poor-risk patients or in combination with chemotherapy. Antiestrogens may have a role as secondary agents in adenocarcinoma of the uterus, and progestins may have a role as secondary agents in ovarian cancer.

Acute myelogenous leukemia as a second malignant neoplasm following the successful treatment of advanced Hodgkin's disease.

Of 209 Hodgkin's disease patients treated at least 6 months with a five-drug combination of induction chemotherapy and having a complete remission, four patients developed acute myelogenous leukemia (AML) as a second malignant neoplasm. The overall relative risk for development of AML is 185.0 (P less than 0.05) and the mean time to occurrence of AML is 5.3 years (median, 5.25 years). When examining patient subgroups, the highest relative risk noted was 338.5 (P less than 0.05) for that group of patients receiving an additional 6 months of postinduction MOPP (nitrogen mustard, vincristine, procarbazine, and prednisone). Patients receiving only 6 months of induction BVCPP (BCNU, vinblastine, cyclophosphamide, procarbazine, and prednisone) had a relative risk of 166.2 (P less than 0.05). These data results are consistent with previous reports that patients treated for Hodgkin's disease are at high risk for development of AML. However, to date, no patients in this series have developed second malignancies other than AML.

The impact of surgical quality control in multi-institutional group trials involving adjuvant cancer treatments.

Quality control involving surgical treatment in multi-institutional cancer trials is important because the results of postoperative adjuvant therapy might be obscured by inadequate surgery or pathologic examination of the specimen. In 1975, the Southeastern Cancer Study Group (SEG) initiated a randomized clinical trial of adjuvant immunotherapy (Corynebacterium parvum vs. bacillus Calmette-Guerin) in melanoma patients with nodal metastases. During the course of reviewing the results several years later, 20 of 136 patients (15%) entered into this study were judged as surgically ineligible. The reasons were: 1) biopsy of a metastatic node only without any subsequent regional lymph node dissection (12 patients), 2) partial lymph node dissection (six patients), or 3) too few nodes surgically removed or pathologically identified in the specimen (six patients). All 20 patients were entered into the study by medical oncologists. Thirteen of these 20 surgically ineligible patients have relapsed so far; many were taken off the study as "immunotherapy failures," when, in fact, they were surgical failures. Compared to the 116 surgically eligible patients, the 20 ineligible patients had a shorter median survival (4 months vs. 25 months) and a lower 1-year disease-free survival rate (36% vs. 62%, p = 0.01). The two groups were balanced equally with respect to prognostic factors. Because of these findings, minimum surgical and pathologic guidelines were established for each adjuvant therapy protocol in the SEG. Surgical quality control was reviewed by a surgeon in each institution prior to randomization and again by a surgical investigator centrally. Pathologic criteria were also defined more precisely. The problems with surgically ineligible patients have since been virtually eliminated. Quality control measures for surgical patients entered into cooperative group trials is an essential part of the protocol design and data review. In order to evaluate properly the impact of adjuvant therapy, each clinical trial must comprise a uniform group of surgically treated patients.

Hyperthermia with implanted electrodes: in vitro and in vivo correlations.

Hyperthermia as a treatment for cancer has elicited much recent interest. However, major difficulties persist both in the technology for heating deep-seated tumors, and in thermal dosimetry. We have investigated a heating technique for deep-seated neoplasms that employs an internal implanted electrode and an external electrode to apply radiofrequency current to a tumor mass. The internal electrode consists of an array of stainless steel needles or wires which define a Faraday cage within the tumor, while the external electrode consists of a variety of electrical conductors at the skin surface. Phantom measurements have closely reproduced calculated temperature distributions. The temperature profiles within the volume enclosed by the internal electrode show relatively homogenous heating. Temperature measurements in a rat tumor model have demonstrated that significant heating within such an internal electrode array is easily obtained. The heating may extend some centimeters outside the electrode. Using a dog model we have shown that with such a treatment technique the temperature profiles obtained are reproducible both spatially and temporally. A case report of a clinical application is presented. A 5 cm bronchogenic carcinoma was easily heated without significant heating of the surrounding normal lung, and without apparent toxicity. Such a technique may be applicable to a variety of operable but unresectable neoplasms. The reproducibility and relative homogeneity of heating suggest possible usefulness in combined modality trials.

Tumor proliferation and chemotherapy in immunosuppressed mice.

The influences on host immunosuppression by treatment with cyclophosphamide (200 mg/kg), steroid (prednisolone, 12.0 mg/kg for seven doses or 235 mg/kg for one dose), and adult thymectomy on tumor growth were compared. Treatment with cyclophosphamide 24 hr prior to MOPC 104E tumor transplantation produced the greatest facilitation of tumor growth. The role of prednisolone in rendering the MOPC 104E cells more vulnerable to conventional chemotherapy was also investigated. The combination of prednisolone with melphalan added measurably to the cytotoxicity of the treatment and increased the percentage of disease-free survivors. The observed effects of prednisolone might have been due to the increase in the cycling of myeloma cells directly, or the drug may have facilitated growth of the myeloma by blocking host expansion of T-cell immunity. Alterations of the host by adult thymectomy and immunosuppression with cyclophosphamide or prednisolone led to growth facilitation of myeloma. The limited studies reported here point out the usefulness of facilitation of tumor growth to accomplish increased neoplastic cell kill and increased percentage of disease-free survivors.

A multifactorial analysis of melanoma. IV. Prognostic factors in 200 melanoma patients with distant metastases (stage III).

A multifactorial analysis of 200 cutaneous melanoma patients with distant metastasis (stage III) was performed on 13 clinical and pathological factors using the Cox regression analysis. There were only three dominant prognostic variables that independently predicted the patient's clinical course: (1) number of metastatic sites (1 vs. 2 vs. greater than or equal to 3, p less than 0.00001), (2) remission duration (less than 12 mo vs. greater than or equal to 12 mo, p = 0.0186), and (3) the location of the metastases (visceral vs. nonvisceral vs. combined, p = 0.0192). Factors that were not significant in the multifactorial analysis included the patients' age and sex, the site of the primary melanoma, the sequence of metastases, and all histopathological features of the primary melanoma (thickness, level of invasion, ulceration, growth pattern, pigmentation, and lymphocyte infiltration). For a single metastatic site, the 1-yr survival rate was 36%, while it was only 13% for 2 sites, and 0% for greater than or equal to 3 sites (p less than 0.00001). The 1-yr survival for patients was 40% for nonvisceral sites (skin, subcutaneous, distant lymph nodes) compared to only 11% for visceral metastases and 8% for combined sites (p less than 0.00001). Pulmonary metastases were associated with a significantly higher survival rate than metastatic melanoma in any other visceral site. The most common first site of distant metastases (either alone or in combination) was skin (38%), lung (36%), liver (20%), and brain (20%). The skin, subcutaneous and distant lymph node group was the first site of metastases in 59% of patients. This finding emphasizes the importance of careful physical exams in routine metastatic evaluations. Only a minority (25%) of stage I patients progressed to stage III disease after a median interval of 2.8 years. In contrast, the majority (75%) of melanoma patients with nodal metastases (stage II) progressed to stage III disease after a median duration of only 11 mo. Of the patients who eventually developed stage III disease, 95% of those who initially presented with stage II disease progressed within 3 yr, while stage I patients who progressed to stage III did not reach a 95% cumulative incidence until 8 yr.

In vivo 31P NMR study of the metabolism of murine mammary 16/C adenocarcinoma and its response to chemotherapy, x-radiation, and hyperthermia.

(31)P NMR spectroscopy with surface coils has been used to monitor, in vivo, the phosphate metabolism of subcutaneously implanted mammary 16/C adenocarcinoma in C3H/He mice. This model tumor was studied during untreated tumor growth and after treatment with adriamycin, hyperthermia, and x-radiation. The mammary 16/C tumor exhibited a Gompertzian growth pattern. Levels of high-energy phosphate metabolites-phosphocreatine and ATP-decreased with increases in tumor mass. There was a concomitant increase in the level of P(i) and a decrease in the apparent pH of the tumor. These spectral changes appear to reflect changes in tumor vascularization that accompany tumor growth, the tumor becoming progressively more hypoxic. Partial response of this tumor to chemotherapy with adriamycin was reflected in a small but measurable increase in the phosphocreatine resonance, a decrease in P(i), and a return of the intra-tumor pH to neutral. Hyperthermia resulted in progressive conversion of the (31)P NMR spectrum to that of a dead tumor (high levels of P(i), small levels of residual sugar phosphates and pyridine dinucleotides, and acidic pH). X-irradiation (14.0 Gy) led to disappearance of the phosphocreatine peak within 15 min of treatment. Subsequently, this resonance grew back beyond its pretreatment level. As the tumor receded, its spectrum reflected the characteristics of aerobically metabolizing tissue (high levels of phosphocreatine and ATP and low levels of P(i) and sugar phosphates).