A stochastic numerical model of breast cancer growth that simulates clinical data.

A new stochastic numerical model of breast cancer growth is developed. First, the model suggests that Gompertzian kinetics does apply but that from time to time, in random fashion, there occurs a spontaneous change in the growth rate or rate of decay of growth, such that the overall growth pattern occurs in a stepwise fashion. According to the model, the average time for the tumor burden to increase from one cell to detection is probably in the range of 8 years. Secondly, the model suggests that there is a linear relationship between the number of axillary lymph nodes positive for metastasis at diagnosis and the number of other metastatic sites. This can be described mathematically by the equation S = 0.24 + 0.35N where S is the number of other metastatic sites and N is the number of positive lymph nodes. The model has been verified by simulating three data sets: (a) the survival times of untreated breast cancer patients as described by Bloom et al. [Br. Med. J., 2: 213-221, 1962]; (b) the growth rates of breast cancers immediately prior to diagnosis as described by Heuser and Spratt [Cancer (Phila.), 43: 1888-1894, 1979]; and (c) the disease-free survival time postmastectomy as described by Fisher et al. [Surg. Gynecol. Obstet., 140: 528-534, 1975]. This model could have implications concerning the overall treatment rationale for breast cancer.

Physiological studies of whole-body hyperthermia of dogs.

Whole body hyperthermia to 42 degrees C was induced in five normal beagles, using a humidity- and temperature-controlled chamber. Core temperatures of 41.2-43.0 degrees C were achieved in 50 min and maintained for 60 min. Cardiopulmonary responses included marked tachypnea and tachycardia. Blood gases underwent progressive drops in both PO2 (mean, 117 torr) and PCO2 (mean, 22 torr), suggesting the possibility of the development of a diffusion barrier during heating. Increased anion gaps in the face of respiratory alkalosis indicated that a metabolic acidosis developed in the heated dogs. Transient but significant drops in serum potassium and phosphorus were also observed during hyperthermia. Other physiological data, including serum chemistries, complete blood count, colony-forming units, and urine electrolyte excretion, did not change significantly.

Gastrointestinal cancer. Its geographic distribution and correlation to breast cancer.

Maps of mortality rates in all U.S. counties for cancer of the stomach, colon, and rectum are presented. The maps show a strong geographic dependency indicating that environmental factors are important in the etiology of these cancers. Furthermore, the urban-rural differences which have been noted in the past are not as readily apparent in this study. Evaluation of all cancer sites demonstrates in general that the geographic dependency is highest for organs most exposed to the environment such as the organs along the alimentary canal and lowest for unexposed organs such as prostate, pancreas, and brain. By studying the correlation coefficients between mortality rates for cancer of different organ sites, they were grouped in subsets with high correlations for each pair in the same subset. Cancers of colon, rectum, and breast are shown to be very highly correlated in U.S. data as well as in international data.

Computer simulation of a breast cancer metastasis model.

Recent analysis of relapse data from 1173 untreated early stage breast cancer patients with 16-20 year follow-up shows that frequency of relapse has a double peaked distribution. There is a sharp peak at 18 months, a nadir at 50 months and a broad peak at 60 months. Patients with larger tumors more frequently relapse in the first peak while those with smaller tumors relapse equally in both peaks. No existing theory of tumor growth predicts this effect. To help understand this phenomenon, a model of metastatic growth has been proposed consisting of three distinct phases: a single cell, an avascular growth, and a vascularized lesion. Computer simulation of this model shows that the second relapse peak can be explained by a steady stochastic progression from one phase to the next phase. However, to account for the first relapse peak, a sudden perturbation of the development at the time of surgery is necessary. Model simulations predict that patients who relapse in the second peak would have micrometastases in states of relatively low chemosensitivity when adjuvant therapy is normally administered. The simulation predicts that 15% of T1, 39% of T2, and 51% of T3 staged patients benefit from adjuvant chemotherapy, partially offsetting the advantage of early detection. This suggests that early detection and adjuvant chemotherapy may not be symbiotic strategies. New therapies are needed to benefit patients who would relapse in the second peak.

Prolongation of postoperative disease-free interval and survival in human colorectal cancer by B.C.G. or B.C.G. plus 5-fluorouracil.

83 patients with colorectal carcinoma of the Dukes' C class were randomised to receive postoperative adjuvant therapy with B.C.G. alone or in combination with oral doses of 5-fluorouracil (5-F.U.), and have been followed for up to thirty months. Results were compared with carefully selected historical controls who were treated by surgery alone. A statistically significant prolongation of both disease-free interval and overall survival was observed in 50 patients receiving the combination of B.C.G. and 5-F.U. (P=0.03, P=0.01 respectively) as well as in 33 patients receiving B.C.G. alone (P=0.03, P=0.05 respectively). The efficacy of B.C.G.+5-F.U. was independent of the number of tumour-involved lymph-nodes in the surgical specimen. In contrast, B.C.G. given alone appears to be highly effective among 10 patients with 6 or more positive lymph-nodes (P less than 0.04) and ineffective (as yet) among 23 patients with 5 or less positive lymph-nodes. These results suggest that adjuvant immunotherapy, with or without chemotherapy, can improve the prognosis of surgically treated patients with colorectal carcinoma of the Dukes' C class.

Adjuvant immunotherapy and chemoimmunotherapy in colorectal cancer of the Dukes' C classification. Preliminary clinical results.

Fifty-eight patients with Dukes' C classification of carcinoma of the large bowel were placed on adjuvant immuno- or chemoimmunotherapy with Bacillus calmette guerin (BCG) or combination of 5-fluorouracil (5-FU) plus BCG following primary and definitive surgery, and were followed for up to 21 months. Of twenty-six patients receiving BCG alone by scarification, five have relapsed with 75% of freedom from disease estimated at 15.1 months compared with 10.1 months in a group of carefully selected historical controls who had surgery alone (p = 0.12). The survival of all patients receiving BCG alone has not reached the 75 percentile yet, and the difference from controls is currently estimated at the 18% level. The combination of 5-FU plus BCG (studied in 32 patients) may be superior to BCG alone at this time, in that it appears to more effectively protect against tumor recurrence (75 percentile not yet reached compared to control, (p = 0.08). The survival of patients on 5-FU plus BCG also appears to be improved (p = 0.09). No patients have expired compared to a 75 percentile survival of 16.6 months in the control. Serial determination of plasma CEA was crucial in the clinical follow-up of these patients. Frequent CEA detetminations have led to early detection of clinical relapse. In the elevation of CEA suggests tumor recurrence with a high degree of probability in patients with past history of cancer of the large bowel.