Walter C. Bauer

Prediction of early course of breast carcinoma by thymidine labeling.

The thymidine labeling index (TLI) was measured in vitro in 278 primary breast carcinomas. In 227 operable women treated by radical mastectomy, TLIs below the median of 4.55% carried a probability of relapse of 20% at four years, in contrast to 52% for TLIs above the median (P = 0.0001). The probability of relapse was significantly related to the TLI independent of TNM pathologic stage, axillary lymph nodal status alone, estrogen receptor (ER) content, or menopausal status. The abilities of the TLI and nodal status to predict early relapse were equally strong and independent, whereas other variables tested had less or no independent predictive capacity. The predictive value of the ER content depended largely on its relationship to the TLI, and ER was related to the probability of relapse in the below median TLI group only. The TLI can select a subgroup of node‐negative patients with a relapse‐expectancy of approximately 50% at four years.

IRRADIATION OF CARCINOMA OF THE PROSTATE LOCALIZED TO THE PELVIS: ANALYSIS OF TUMOR RESPONSE AND PROGNOSIS

Abstract A group of 195 patients with histologically proven adenocarcinoma of the prostate limited to pelvis were treated with definitive irradiation between 1967 and December 1976. In 42 patients with Stage B adenocarcinoma, the tumor free actuarial five year survival was 80%; for 141 with Stage C it was 56%; there were no long term survivors in 12 patients with Stage D1 (extensive tumor limited to the pelvis, without distant metastasis). The pelvic failure rate was 7% in Stage B, 17% in Stage C and 25% in Stage D1. Histological differentiation of the tumor had no significant impact in survival of patients with Stage B. However, in Stage C, patients with well or moderately differentiated tumor had a five year survival of 70% in contrast to 25% in those with poorly differentiated lesions. In this group of patients 60% of the failures resulted from distant metastasis. In Stage C, 38% of the patients who were treated with doses between 5500 and 6000 rad developed pelvic failures, as opposed to 20% of those treated with a mean dose of 6500 rad and 12% in patients receiving 7000 rad or greater dose. The addition of hormonal therapy, usually castration and diethylstilbestral (DES) (5 mg daily), did not significantly affect the prognosis of patients with Stage B or C. Major complications of therapy occurred in 11% of the patients. The most common problem was urinary incontinence which was observed in 13.3% of 60 patients who had a transurethral resection (TUR) as opposed to 4.4% in 135 patients on whom this procedure was not performed. Less severe complications were noted in 18% of the patients and treated with conservative management. Leg edema developed in three of 14 patients on whom a staging laparotomy was performed (21.4%) in contrast to only three of 181 patients without such a procedure (1.6%). At the present time external irradiation is a viable alternative to radical prostatectomy in the treatment of Stage B and the modality of choice in patients with Stage C adenocarcinoma of prostate. It is important to identify prognostic factors that may optimize the effectiveness of irradiation in the management of this tumor. In order to improve the prognosis of carcinoma of the prostate, effective systemic therapy will be necessary to control micrometastasis in patients with poorly differentiated lesions.

Intravesical Bacillus Calmette-Guerin Therapy for Superficial Bladder Cancer: Effect of Bacillus Calmette-Guerin Viability on Treatment Results

We treated 40 patients with superficial bladder cancer via intravesical bacillus Calmette-Guerin for 1) prophylaxis against tumor recurrence, 2) residual carcinoma or 3) flat carcinoma in situ. A single course of intravesical bacillus Calmette-Guerin therapy was successful in 6 of 11 patients (55 per cent) treated for residual carcinoma and 6 of 12 (50 per cent) treated for carcinoma in situ. Of 17 patients receiving a single course of bacillus Calmette-Guerin for prophylaxis 11 remained free of tumor during short-term followup. A second course of therapy was administered to failures in each treatment category, which resulted in favorable responses in 5 of 6 patients treated for prophylaxis, 2 of 5 treated for residual tumor and 3 of 6 treated for carcinoma in situ. Over-all complete responses were achieved in 16 of 17 patients (94 per cent) treated for prophylaxis, 8 of 11 (73 per cent) for residual carcinoma and 8 of 12 (66 per cent) for carcinoma in situ, with a mean followup from the final treatment of 9.3, 12.3 and 7.9 months, respectively. Favorable results occurred more frequently among patients who exhibited a granulomatous inflammatory response in the bladder and delayed hypersensitivity skin test response to purified protein derivative. Marked variability in viability of bacillus Calmette-Guerin organisms was observed among different lots of bacillus Calmette-Guerin, and a direct relationship was observed between bacillus Calmette-Guerin vaccine viability and therapeutic efficacy. Most patients who failed initial therapy with a low viability lot of bacillus Calmette-Guerin responded favorably to re-treatment with a higher viability lot. The results suggest that the level of viability of each lot of bacillus Calmette-Guerin vaccine should be verified before clinical use.

A proposed classification of breast cancer based on kinetic information derived from a comparison of risk factors in 168 primary operable breast cancers

Flow cytometric DNA analysis was performed on 168 consecutive primary operable breast cancers and the results correlated with thymidine labeling, estrogen receptor (ER) and progesterone receptor values, and various histologic parameters. Seventy‐five cancers (45.0%) were diploid and 93 (55.0%) aneuploid. In 83.9% of aneuploid cancers, the DNA index fell between 1.1 and 2.0. Thirteen cancers were hypertetraploid and three hypodiploid. The percent of S‐phase cancers (SpF) varied from 1.1% to 24.4%, with a mean of 8.0% and a median of 7.1%. The mean SpF of diploid cancers was 5.2%; of aneuploid cancers, 10.3%. There was no significant correlation between SpF or ploidy and tumor size or axillary lymph node status. The thymidine labeling index (TLI) varied from 0.2 to 23.1, with a mean of 7.5 and a median of 6.1. There was good correlation between TLI and SpF (r = 0.892, P = 0.0001). ER‐negative tumors had a significantly higher mean SpF (10.3%) than did ER‐positive tumors (6.7%), but there was no significant correlation between ploidy and receptor positivity or negativity. There was a good correlation between invasive tumor necrosis, poor cytologic differentiation, aneuploidy, and above‐median SpF. Only a fair correlation was observed between mitotic rate and SpF. A classification of invasive breast cancers based on ploidy and SpF is proposed.

Prognostic Value of Purified Protein Derivative Skin Test and Granuloma Formation in Patients Treated with Intravesical Bacillus Calmette-Guerin

We evaluated the prognostic value of purified protein derivative skin test reactivity and a granulomatous response in intravesical bacillus Calmette-Guerin therapy. We treated 62 patients with intravesical bacillus Calmette-Guerin once a week for 6 weeks. Purified protein derivative skin tests were performed before and after therapy. Cold cup bladder biopsies were examined in a blind retrospective manner for the presence of granulomas 6 weeks after completion of therapy. A significant correlation between status free of tumor and the presence of either granulomas or positive purified protein derivative skin tests was observed for the total patient population. Of 25 patients whose purified protein derivative test was converted from negative to positive 19 (77 per cent) remained free of tumor, while only 11 of 32 (34 per cent) whose test did not convert to purified protein derivative positive remained free of tumor (p equals 0.0006, chi-square). Similarly, 28 of 37 patients (77 per cent) who had a granulomatous response remained free of tumor, while only 8 of 25 (32 per cent) without a granulomatous response remained free of tumor (p less than 0.003, chi-square). The correlation was similar for each parameter when the total patient population was subdivided into patients treated for carcinoma in situ, residual tumor or prophylaxis. Calculation of predictive values showed that neither purified protein derivative responsiveness, granuloma formation nor a combination of both provided a highly accurate predictive index of therapeutic response in individual patients. False positive or negative rates, ranging from 23 to 24 per cent and 32 to 39 per cent, respectively, were observed. These results suggest that a link between immunological responsiveness and response to therapy exists but that neither the purified protein derivative skin test nor the granulomatous response exhibits sufficient immunological specificity to serve as accurate prognostic indicators in individual patients.

Practical breast carcinoma cell kinetics: Review and update

SummaryThe S-phase fraction (SPF) measured by flow cytometry of DNA and the thymidine labeling index (TLI) measured autoradiographically indicate the proportion of carcinoma cells currently synthesizing DNA and reflect the rate of proliferation. The TLI and SPF are lognormally distributed. The median TLI performed to maximize precursor uptake is near 5% (5 labeled carcinoma cells per 100), the mean near 7%, and the range from less than 1% to near 40%. Corresponding values for the SPF measured by DNA flow cytometry are slightly higher when appropriate measures are taken to reduce background debris counts and other artefacts. Residual elevation of SPF above TLI may result from S-phase arrested cells. Flow cytometric histograms show that clearly aneuploid cell lines exist in 50–80% of primary breast carcinomas. Aneuploid breast carcinomas have higher mean TLI than diploid breast carcinomas, and therefore proliferate more rapidly. They also more frequently lack estrogen receptor (ER). Carcinomas with minimal nuclear anaplasia, particularly those of tubular, mucinous, infiltrating lobular and adenocystic types have low TLI and SPF, whereas carcinomas with highly anaplastic nuclei, including medullary carcinomas, have high TLI and SPF. TLI and SPF correlate inversely with ER and PgR content, have no relationship to axillary lymph nodal status, and have a weak positive correlation with tumor size and a weak negative correlation with age. High TLI predicts a high risk of early relapse after primary therapy for both node-negative and node-positive carcinomas. Carcinomas that produce brain metastases have particularly high TLI. Current evidence suggests that high SPF and aneuploidy may prove to have prognostic significance like TLI.

Radiation therapy in the definitive treatment of localized carcinoma of the prostate.

A progress report on the treatment of 15 patients with Stage B and 97 patients with Stage C histologically proven adenocarcinoma of the prostate shows that the cumulative absolute 5‐year survival rate is approximately 60% for patients with Stage B and 42% for those with Stage C. Patients received 7000 rads to the prostate, 6000 rads to the external iliac and hypogastric pelvic nodes, and 5000 rads to the common iliac nodes; 22 MeV Betatron photons were used with progressively decreasing AP‐PA fields. The local control rate is 82%. Most of the patients failing have developed distant metastases, particularly those in the poorly differentiated carcinoma group. The morbidity of this treatment is acceptable to physicians and patients; the major complications occurred in approximately 5% of patients, and none of them were fatal. The 5‐year survival rates for patients with well‐ and moderately differentiated tumors are significantly better (50‐65%) than for those with poorly differentiated tumors (15%). There was no significant difference in survival between a group of 41 patients treated with radiation alone compared with 50 patients treated with a combination of irradiation and hormonal therapy. From the data currently available, it seems that definitive radiation therapy should be adequately evaluated in the treatment of patients with carcinoma of the prostate localized to the pelvis, before hormonal therapy is instituted. In addition, the advisability of staging laparotomies must remain uncertain until the information obtained from such procedures can be directly applied to improving survival. In view of the poor prognosis and high propensity for distant dissemination in patients with poorly differentiated carcinoma of the prostate, it is felt that clinical trials are needed to evaluate the potential use of cytotoxic agents combined with pelvic irradiation as a cytoreductive agent.

In vitro determination of tritiated thymidine labeling index (LI). Evaluation of a method utilizing hyperbaric oxygen and observations on the LI of human mammary carcinoma.

A simple method for incubation of tissue specimens with tritiated thymidine under 3 atm oxygen tension gave an in vitro labeling index (LI) that corresponded closely with LIs determined by injection of tritiated thymidine in vivo. The LI of tumors was not affected by storage at room temperature for up to 135 minutes. The mean LI for 39 human mammary carcinomas was 3.8, but the distribution was skewed to the right, and the most frequently observed LIs were between 2 and 3. Larger carcinomas had significantly larger LIs than smaller tumors, which suggests that the larger tumors were faster‐growing at the time of observation than the smaller tumors. The capacity of the larger tumors to maintain a relatively rapid growth rate may account for their large size. The data suggested, but did not prove, that a high LI was associated with more frequent metastasis to axillary lymph nodes.

Squamous carcinoma of the base of the tongue: A clinicopathologic study of 81 cases

Ninety‐one patients were treated for squamous cell carcinoma of the base of the tongue between 1960 and 1974. Eighty‐one of those patients were treated in a consistent manner, either by radiotherapy alone or preoperative radiotherapy plus total en bloc excision with a radical neck dissection. Eighteen patients were treated by radiotherapy alone (1800–7900 rads) to the primary site and bilaterally to the neck. Fifteen of these patients died within five years. Sixty‐three patients were treated with preoperative irradiation (1800–7900 rads) followed by total primary excision with ipsilateral neck dissection. This latter group had a 50% five‐year survival. Death due to uncontrolled tumor occurred within five years, whereas death after five years postinitial therapy was due to unrelated reasons. Unfavorable prognostic features were poor differentiation of the tumor, lack of histologic evidence of radiation‐induced regression of the tumor, and more than three neck lymph node metastases in the initial neck dissection. Cox regression analysis showed that absence of histologic response to therapy was associated with a failure rate 4.05 times higher than that seen in patients whose tumors did respond. Primary tumor size did not affect prognosis as long as the tumor was technically resectable. Primary recurrences occurred in at least 20% of cases regardless of the presence or absence of surgical margin involvement.

Carcinoma of the pyriform sinus: Predictors of TNM relapse and survival

To determine predictors of TNM relapse and survival for 108 patients with epidermoid carcinoma of the pyriform sinus, the histopathologic features of tumor‐related and host‐related characteristics were correlated with primary and/or cervical nodal failure, distant metastases, and actuarial three‐year survival. Patients in this study received preoperative irradiation and pattial laryngopharyngectpmy (PLP) or total laryngopharyngectomy (TLP) with en bloc radical neck dissection. Higher rates of local failure were observed in patients with keratinizing tumors (34 vs. 15%), with tumors having an “infiltrating” tumor‐stromal interface (30 vs. 14%), with positive surgical margins in PLP or TLP specimens (30 vs. 16%), and with extranodal extension of tumor (39 vs. 22%). The development of distant metastases was significantly correlated with nonkeratinizing carcinomas (30 vs 11%, P = 0.02), and was observed more often in patients with positive lymph nodes (17 vs. 7%). Patients with negative surgical margins in PLP or TLP excision (50 vs. 21%, P = 0.01) survived significantly longer.