Oncolog, Volume 37, Issue 02, April-June 1992

The primacy of patient welfare Potential doubling time of tumors may be the key to accurate prognosis, appropriate treatment Cognitive deficits in survivors of childhood cancershttps://openworks.mdanderson.org/oncolog/1038/thumbnail.jp

Calculating potential doubling time using monoclonal antibodies specific for two halogenated thymidine analogues

Purpose: A new flow cytometric technique that allows for two incorporated thymidine analogues to be measured simultaneously and independently has been used to improve the accuracy of in vivo cell kinetic estimates, i.e., the length of S-phase (TS) and potential doubling time ( T pot). Methods and Materials: The analogues chlorodeoxyuridine and iododeoxyuridine were injected at different times into mice bearing the mouse mammary tumor MCaK. At different times after labeling, the tumors were harvested and prepared for three color flow cytometric analysis of DNA, chlorodeoxyuridine, and iododeoxyuridine. Control experiments showed that similar estimates of T pot were obtained from each label when administered singly, or as staggered pulses. Comparisons were made between T s and T pot calculated from a single label (single point), from the averaged result of the two labels from the same tumor (two point-ave), and from the simultaneous nonlinear fitting of the measured parameters from the two labels, from the same tumor (two point-fit). These estimates of T s and T pot were then compared to reference values obtained by fitting the pooled measured parameters from all the tumors, that were labeled for different periods of time. Results: While all of the methods resulted in similar mean estimates of T s and T pot that were close to the reference values, the fewest assumptions, and the least variability in the results, were obtained using the two point-fit data. Conclusion: The estimation of T pot using two thymidine analogues is more accurate than that obtained from a single label

Apoptosis and downstaging after preoperative radiotherapy for muscle-invasive bladder cancer

Purpose : To determine the relationship between pretreatment apoptosis levels and clinical-to-pathologic down-staging resulting from properative radiotherapy. Methods and Materials : Between 1960–1983, 338 patients were dispositioned to receive preoperative radiotherapy 4–6 weeks prior to radical cystectomy for muscle-invasive transitional cell carcinoma of the bladder. Of these, adequate hematoxylin and eosin stained tissue sections for morphologic analysis of apoptosis were available in 158 patients. These patients were treated to a median dose of 50 Gy at 2 Gy per fraction. Median follow-up was 90 months. The apoptotic index (AI) was calculated from the ratio of the number of apoptotic cells divided by the total counted and multiplied by 100. A minimum of 500 cells were counted from each patient. Results : The average AI for the whole group ( n = 158) was 2.0 ± 1.3 (±SD), with a median 1.8. The association of AI to clinical stage was significant with AI for the whole averages of 1.8 for Stage T2 ( n = 56), 1.9 for T3a( n = 51), and 2.4 for T3b ( p = 0.038, Kendall Correlation). The relationship of AI to radiotherapy response also was significant with an average of 2.2 for those who were downstaged ( n = 103), 1.9 for those in whom the stage remained unchanged ( n = 20), and 1.7 for those who were upstaged ( n = 35, p =0.054, Kendall Correlation). The other significant correlations with AI were for the factors, grade, mitotic index, number of tumors, and gender. The AI was then categorized into three groups (≤, >1, and ≤3, and >3) to examine the prognostic significance of this parameter. The distributions of patients by clinical stage, grade, mitotic index, number of tumors, radiotherapy response, and the hemoglobin level were significantly associated with AI using this grouping. When the analysis of the distribution of patients by radiation response and AI was segregated by stage, a significant correlation was observed only for those with Stage T3b disease ( p = 0.006); 93% of T3b patients with an AI >3 were downstaged, while in 7% the stage remained unchanged and none were upstaged. The relationship of AI to 5-year actuarial patient outcome was investigated using several end points and although no significant correlations were observed, a trend was seen for improved sirvival when AI was >3 (71% vs. 41%, p = 0.09) for Stage T3b patients. Colnclusion : The AI correlated most strongly with radiotherapy response for patients with clinical stage T3b disease, the o ne subgroup of patients wherein preoperative radiotherapy is likely to be of the most benefit. Further investigation of pretreatment apoptosis levels as a marker of anticancer response is needed, especially for patients treated with chemotherapy and radiotherapy with the goal of bladder preservation

The prognostic significance of DNA ploidy in clinically localized prostate cancer treated with radiation therapy

Purpose : To determine the prognostic significance of deoxyribonucleic acid (DNA) ploidy in comparison to pretreatment prostate specific antigen (PSA) and other prognostic factors for patients with adenocarcinoma of the prostate treated with external beam radiotherapy. Methods and Materials : Paraffin-embedded prostatic adenocarcinoma material was obtained from patients treated from 1987–1991. Sufficient histologic material for flow cytometric DNA content analysis was obtained from 86 patients and adequate histograms were obtained from 76 of these. The DNA histogram profiles were classified as diploid, tetraploid, or aneuploid. Median patient follow-up was 36 months. Results : There were 54 patients with diploid tumors, and 22 with nondiploid tumors (11 tetraploid and 11 aneuploid). Since the disease outcome for tetraploid and aneuploid tumors was the same, these were pooled (nondiploid tumors). The distribution of diploidy and nondiploidy correlated with pretreatment PSA ( p < 0.0005) and grade ( p = 0.055), but not with stage, pretreatment prostatic acid phosphatase, transurethral resection, pretreatment serum testosterone, or age. In actuarial univariate analyses, DNA ploidy was a significant predictor of outcome for local failure, distant metastases, any clinical relapse, rising PSA, and rising PSA and/or relapse. Ploidy was not a significant predictor of overall survival, although there were only six deaths. Diploidy predicted for improved outcome, for example, 34.6% incidence of a rising PSA and/or relapse at 4 years compared to 76.9% with nondiploidy ( p < 0.0001). An actuarial univariate analysis of other potential prognostic factors using the composite endpoint of rising PSA and/or relapse also revealed pretreatment PSA, grade, pretreatment prostatic acid phosphatase, stage, and serum testosterone to be significant predictors of outcome. In Cox proportional hazards analysis, pretreatment PSA, DNA ploidy, and grade were the only independent prognostic factors for disease outcome using the composite endpoint. Conclusion : DNA ploidy is an independent predictor of outcome in patients with Stages T,-T3 prostate cancer treated with definitive external beam radiotherapy

The significance of DNA‐ploidy and S‐phase fraction in node‐positive (stage D1) prostate cancer treated with androgen ablation

BACKGROUND The prognostic significance of primary tumor DNA‐ploidy and S‐phase fraction (SPF) was evaluated in patients treated with androgen ablation for regionally localized node‐positive prostate cancer. METHODS All patients were diagnosed with lymph node involvement by pelvic lymphadenectomy between 1984 and 1992 and were treated only with androgen ablation. Median follow‐up was 45 months. Adequate material for DNA/nuclear protein flow cytometric analysis was available in 33 patients. RESULTS The tumors were classified as diploid in 11, near‐diploid in 4, tetraploid in 10, and aneuploid in 8 cases. Grouping the patients by nonaneuploidy (diploid and near‐diploid and tetraploid) and aneuploidy revealed actuarial 4‐year disease progression rates of 14 and 48% (log‐rank, P = 0.04), and overall survival rates of 100 and 61% (P= 0.008); however, biochemical progression (rising prostate‐specific antigen profile) rates were similar at around 70%. In contrast, SPF was not significantly related to any of the endpoints tested. Several other potential prognostic factors were examined and none correlated significantly with disease progression or survival. CONCLUSIONS The biochemical progression rates for patients with nonaneuploid and aneuploid tumors were comparable and high, while the disease progression rates were higher and survival rates lower for those with aneuploid tumors. These data indicate that the lead time from biochemical to disease progression and death was shorter with aneuploidy. That these relationships were observed in such a small patient population attest to the strength of DNA‐ploidy as a prognostic factor in this cohort. Prostate 31:21–28, 1997. © 1997 Wiley‐Liss, Inc

Supraadditive apoptotic response of R3327-G rat prostate tumors to androgen ablation and radiation

Purpose : Androgen ablation is often combined with radiation in the treatment of patients with prostate cancer, yet, the optimal sequencing and the mechanisms governing the interaction are not understood. The objectives were to determine if cell killing via apoptosis is enhanced when the combined treatment is administered and to defined the relationship of changes in this form of cell killing to tumor volume growth delay. Methods and Materials : Dunning R3327-G rat prostate tumors, grown inthe flanks of Copenhagen rats, were used at a volume of approximately 1 cc. Androgen ablation was initiated by castration, and androgen restoration was achived with 0.5 cm silastic tube implants containing testosterone. 60Co was used for irradiation. The terminal deoxynucleotidyl transferase (TUNEL) histochemical assay was used to quantify apoptosis. Results : Tumors from intact and castrate unirradiated control rats had average apoptotic indices (percent of apoptotic cells) of 0.4 and 1.0%, respectively. The apoptotic index varied only slightly over time (3 h to 28 days) after castration (range 0.75-1.43%). Irradiation of intact rats to 7 Gy resulted in a peak apoptotic response at 6 h of 2.3%. A supradditive apoptotic response was seen when castration was initiated 3 days prior to 7 Gy radiation, with peak levels of about 10.1%. When the radiation was administered at increasing times beyond 3 dats after castration, the apoptotic response gradually diminished and was back to levels seenin intact rats by 28 days after castration. Tumor volume growth delay studies were consistent with, but not conclusive proof of, a supraadditive effect when the combination was used. Discussion : A supraaddtive apoptotic response was seen when androgen ablation and radiation were used to treat androgen sensitive R3327-G rat prostate tumors. This supraadditive effect was dependent on the timing of the two treatments. Further studies are required to more fully define the optimal timing and administration of androgen ablation and radiation

Relationship of Ki‐67 labeling index to DNA‐ploidy, S‐phase fraction, and outcome in prostate cancer treated with radiotherapy

BACKGROUND Our purpose was to evaluate the relationship of Ki‐67 labeling index (Ki67‐LI) to deoxyribonucleic acid (DNA) ploidy, S phase fraction (SPF), other clinical prognostic factors, and clinical outcome for patients with prostate cancer treated by external beam radiotherapy. METHODS Tissue was retrieved from 42 patients who underwent transurethral resection of the prostate before treatment with external beam radiotherapy between 1987–1993. DNA histogram profiles were classified as diploid (diploid + near‐diploid) and nondiploid (tetraploid + aneuploid). Immunohistochemical staining of Ki‐67 by the MIB‐1 monoclonal antibody was used to calculate Ki67‐LI. Median patient follow‐up was 62 months. Treatment failure was defined as two consecutive rises in serum prostate‐specific antigen (PSA) or clinical evidence of disease recurrence. RESULTS The mean and median Ki67‐LIs were 3.1 and 2.4, respectively (range, 0–12.4). Mean Ki67‐LI values were significantly associated with higher stage, Gleason score, and pretreatment PSA. Nondiploid tumors had significantly higher Ki67‐LIs, as did patients who failed radiotherapy over the follow‐up period. SPF was not significantly correlated with Ki67‐LI. As a categorical variable, the most significant relationships were seen when Ki67‐LI was subdivided into thirds around the median (Ki67‐LI ≤1.5%, Ki67‐LI >1.5–3.5%, and Ki67‐LI >3.5%). This trichotomous variable correlated significantly with pretreatment PSA (P = 0.0008), tumor stage (P = 0.016), Gleason score (P = 0.024), and treatment failure (P = 0.0015), but not with DNA‐ploidy (P = 0.15). In actuarial univariate analyses, Ki67‐LI appeared to be a more significant predictor of patient outcome (P = 0.003) than DNA‐ploidy (P = 0.035). CONCLUSIONS The Ki67‐LI correlated with known prognostic factors such as pretreatment PSA, tumor stage, and Gleason score, and was also weakly related to DNA‐ploidy. In comparison to DNA‐ploidy, Ki67 LI seems to be a better correlate of treatment outcome. Prostate 41:166–172, 1999. © 1999 Wiley‐Liss, Inc