K.L. Martz

The influence of treatment time on outcome for squamous cell cancer of the uterine cervix treated with radiation: A patterns-of-care study

PURPOSE To analyze the effect of total treatment time on infield pelvic control and survival for squamous cell carcinoma of the uterine cervix using the combined 1973 and 1978 Patterns of Care (PCS) data base. METHODS AND MATERIALS Eight hundred thirty-seven evaluable patients were analyzed for the effect of total treatment time on outcome. The Kaplan-Meier method was used to estimate time-to-outcome annual rates. Comparisons of time to failure were performed with the log rank test. Multivariate analysis was performed using the Cox regression analysis. RESULTS A highly significant decrease in survival (p = .0001) and pelvic control (p = .0001) was demonstrated as the total treatment time was increased from < 6, 6 to 7.9, 8 to 9.9, and 10+ weeks. Stage III accounted for the majority of the adverse effect from the prolongation of total treatment time. Multivariate analysis of total treatment time in addition to previously reported significant pretreatment and treatment factors from the PCS data base revealed three independent factors for infield recurrence, namely Stage I versus II versus III (p = .0001), total treatment time < 6 versus 6 to 7.9 versus 8 to 9.9 versus 10+ weeks (p = .003), and age > 50 versus < or = 50 years (p = .01). When the analysis was performed by stage to evaluate the effect of overall treatment time with respect to the extent of pelvic disease as defined by PCS, total treatment time continued to be an independent prognosticator for infield pelvic control (p = .01) and survival (p = .02) for Stage III but not Stages I and II. CONCLUSION This study demonstrates a significant adverse effect on survival and pelvic control with prolongation of the total radiation treatment time for Stage III squamous cell cancer of the uterine cervix in multivariate analysis. In the future design of clinical trials, limitations on total treatment time should be rigorously controlled, and the effect of variations in this important factor by altered fractionation schemes should be studied.

The effect of dose on local control of prostate cancer.

Three patterns of care outcome surveys in prostate cancer totalling 1516 patients had been combined and analyzed for the effect of dose on infield recurrence. There are significant dose effects observed in the overall data (1516 patients, p = .003), Stage B cancers (725 patients, p = .004) and Stage C cancers (624 patients, p = .059). No dose effect was observed for Stage A cancers (168 patients, p = .217) within the dose range observed (5500 cGy to greater than 7000 cGy). For patients with Stage B cancer one may conclude that dose between 6000 cGy and 6999 cGy is appropriate. Patients treated to less than 6000 cGy show a highly significant increase in local failure. Patients treated to greater than 7000 cGy do not show a demonstrable improvement in local control, but do show an increase in complications. Patients with Stage C cancer appear to require dose that is equal or greater than 7000 cGy to obtain the best local control, and the potential increased morbidity of these high doses appears to be justified in this stage of the disease. Patients who have been given hormonal therapy more than 1 month prior to radiation therapy show an increase in local failure rate for all stages of cancer. This is presumed to be the selection of poor risk patients for adjuvant hormonal treatment or by referring non-responding hormone treated patients for radiation therapy. Histologic grade exerts a major influence on local failure for patients with Stage C disease (p = less than .001), identifying an important stratification point for prospective clinical trials and a sub-group for which it is important to develop strategies for improving local control. The policy of treating all stages of prostate cancer with the same dose is not supported by these data.

A ten year follow-up of 682 patients treated for prostate cancer with radiation therapy in the United States

This report extends the follow-up of patients studied in the Patterns of Care Survey of Prostate Cancer treated in the United States between 1973 and 1975 from a maximum of 5 years to a maximum of 10 years. Survival for 60 Stage A patients was the same as expected for their age distribution (83% at 5 years and 62% at 10 years). Survival for 312 Stage B patients was 73% at 5 years and 46% at 10 years and for 296 Stage C patients was 58% at 5 years and 38% at 10 years. Infield recurrence was determined by clinical means, at 5 years 97% of Stage A patients, 86% of Stage B patients, and 74% of Stage C patients were free of local recurrence. At 10 years 97% of Stage A patients, 74% of Stage B patients, and 69% of Stage C patients remained free of local recurrence. Patients with Stage B and C cancer who developed their first failure infield show a long-term survivorship after recurrence of 40% and 20% respectively. This is in contrast to Stage B and C patients who develop a first recurrence at a metastatic site where the rate of progress to death was slower in Stage B patients than for those with Stage C disease (mean survival 32 months versus 19 months), but eventually all are dead by 7 years after recurrence. Complications were infrequent, actuarial analysis shows 93% of patients free of serious complications at 5 years and 89% free at 10 years. There were 14 patients (2%) whose complications required surgical correction and 2 of the 682 patients died of complications.

Tumor and treatment factors improving outcome in stage III-B cervix cancer

This report reviews 271 patients with Stage III-B squamous cell cancer of the uterine cervix from three national surveys conducted by the Patterns of Care Study. A progressive increase in local control and survival is seen among the three surveys which parallels a progressive increase in paracentral (point A) dose and use of intracavitary treatment. Multivariate analysis reveals extent of pelvic disease (unilateral sidewall vs. bilateral sidewall vs. lower 1/3 vagina) and use of intracavitary treatment to be the only significant tumor and treatment factors associated with local control and survival. With aggressive radiotherapy, local control rates exceeding 65% and survival of 50% at 4 years can be anticipated at the expense of a small increase in complications.

Influence of age, prior abdominal surgery, fraction size, and dose on complications after radiation therapy for squamous cell cancer of the uterine cervix. A patterns of care study

The 1973 and 1978 national surveys conducted by the Patterns of Care Study (PCS) for squamous cell cancer of the uterine cervix were combined to analyze factors associated with complications after radiation therapy (RT). Overall, 1558 patients were reviewed, with a median follow‐up of 43 months. Major complications (defined as necessitating hospitalization for management) were seen in 152 of 1558 (9.8%) patients, with a 5‐year actuarial rate of 14%. A number of pretreatment and treatment factors were analyzed with respect to complications. In univariate analysis, significant pretreatment and treatment factors associated with an increase in complications included young age, prior laparotomy for staging, history of prior abdominal surgery, increasing stage, use of external RT, high fraction size, cesium source, and high para‐central (PCS point A) and lateral (PCS point P) doses. Multivariate analysis showed a history of prior abdominal surgery, paracentral dose greater than 7500 cGy, use of cesium, daily fraction size greater than 200 cGy, and age younger than 40 years to be associated independently with complications. A detailed analysis of the type of and time to complications is presented. The knowledge and skillful management of these pretreatment and treatment factors may improve the therapeutic ratio for RT, which is the most active curative modality against cervical cancer.

Prognostic factors in carcinoma of the prostate— analysis of rtog study 75-06

A total of 566 evaluable patients were accessioned to a phase III RTOG study of extended field irradiation in carcinoma of the prostate from 1976 to 1983. Eligible patients were those with locally advanced disease, either clinical Stage C or clinical Stage A2 or B with pelvic lymph node involvement. The treatment consisted of irradiation of the regional lymphatics followed by a boost to the prostate. The data have been analyzed extensively to identify variables of potential prognostic significance. The assessed factors include tumor size, clinical stage, the degree of histological differentiation, nodal status, serum acid phosphatase status, hormonal management status, age, and race. These factors have been assessed as to their interdependence and correlation with the clinical course (study endpoints) using univariate analyses and Coxs Regression model. Significant interdependence of tumor size and Gleason score and tumor size and acid phosphatase was identified. The population receiving hormonal management either prior to or during radiotherapy had a significantly higher proportion of high grade tumors. Correlation of the assessed variables and the study endpoints (local control, incidence of distant metastases, NED survival, survival) singled out the degree of histological differentiation as the most powerful prognostic factor for all the endpoints. Age proved a useful predictor of local control (younger patients failed at a significantly higher rate), as did tumor size. Elevation of serum acid phosphatase correlated well with the incidence of metastatic disease but was not a useful predictor of survival. Tumor size and hormonal management status correlated well with the incidence of metastatic disease but only when analyzed separately from other factors. Their prognostic value was absent when Cox regression analysis was applied. Nodal status did not correlate well with any of the study endpoints, indicating then that in patients with clinical Stage C disease, treated with definitive radiotherapy to the prostate and regional lymphatics, this parameter may have limited prognostic usefulness. Although patients who received concomitant hormonal management had a significantly higher proportion of high grade lesions, their clinical course fared favorably in comparison with the population not receiving concomitant hormonal management. This may indicate a beneficial effect of adjuvant hormonal treatment which needs to be tested in a prospective study.

Correlation of radiotherapeutic parameters and treatment related morbidity in carcinoma of the prostate--analysis of RTOG study 75-06.

Treatment related morbidity, recorded in patients entered onto a RTOG phase III study (testing the value of periaortic irradiation in locally advanced carcinoma of the prostate), has been correlated with radiotherapeutic parameters to identify and quantify the relationship with treatment volumes, doses, and techniques. Between 1976 and 1983 a total of 526 analyzable cases were entered onto the study. The study design entailed randomization to either pelvic irradiation followed by a prostate boost or pelvic and periaortic irradiation followed by a prostate boost. Periaortic irradiation was not associated with a significantly increased incidence of bowel injuries manifested by diarrhea. No correlation between the total dose to the regional lymphatics (ranging from 4400 to 5100 cGy) and the incidence of bowel and bladder injuries could be established. Doses to the prostate in excess of 7000 cGy have not resulted in a significantly increased incidence of bladder injuries, but have been associated with a significant increase in the incidence of bowel injuries manifested by diarrhea. The techniques of pelvic irradiation did not seem to significantly influence the incidence of bowel or bladder complications. The technique of delivery of the prostatic boost did seem to influence the incidence of bowel injuries. This refers to the lateral boost technique and the perineal boost technique which have been associated with a higher incidence of diarrhea. All of the conclusions based on this analysis are applicable only to treatment volumes and dose ranges used in this study and to conventional fractionation of 180 to 200 cGy per day.

Results of re-excisional biopsy of the primary tumor in preparation for definitive irradiation of patients with early stage breast cancer

From December 1977 through November 1984, 251 patients underwent a re-excisional biopsy procedure in preparation for definitive radiation therapy because of uncertainty in the extent of the initial biopsy procedure. Analysis of the cases was limited to patients with AJC Clinical Stages I or II breast cancer and whose initial biopsy procedure demonstrated invasive carcinoma. Sixty-three percent (158/251) of the 251 re-excisions were positive for residual tumor, and 37% (93/251) did not show any residual tumor. Of the positive re-excisions, 85% (134/158) revealed an invasive component of tumor; 15% (24/158) revealed only non-invasive disease. For patients whose initial biopsy was described as incisional only, 97% (64/66) had residual tumor; 51% (94/185) of patients with an initial excisional biopsy had residual tumor. Because of the extremely high rate of positive re-excision in patients with an initial incisional biopsy, these cases were excluded from the remainder of the analysis. When the pathologic margin of the initial biopsy specimen was described as positive, 60% (15/25) had residual tumor on re-excision and 49% (79/160) when the pathology margin was unknown. Of the clinical T1 lesions, 45% (57/126) had positive re-excision, and of the clinical T2 lesions, 63% (37/59) were positive. When a post-biopsy mammogram (i.e. following initial biopsy procedure but before re-excision) showed residual microcalcifications, 86% (12/14) had residual tumor found in the re-excision specimen. Based on these findings, indications for re-excisional biopsy of the primary tumor are: initial incisional biopsy, positive or unknown pathologic margin on an initial excisional biopsy specimen, or residual microcalcifications on post-biopsy mammogram. When inked margins were negative on pathological examination of an initial excisional biopsy specimen, re-excision of the primary tumor bed was not recommended. These results suggest that a re-excisional biopsy procedure may be an important component of the overall treatment approach to assure removal of all tumor, and should continue to be used when indicated prior to definitive irradiation of the breast for early stage breast cancer.

DEFINITIVE IRRADIATION FOR EARLY STAGE BREAST CANCER: THE UNIVERSITY OF PENNSYLVANIA EXPERIENCE

From 1977 to 1984, 552 breast cancers in 548 women were treated with definitive irradiation following breast-conserving surgery at the Hospital of the University of Pennsylvania and the Fox Chase Cancer Center. All patients had invasive carcinoma and were AJC clinical Stage I or II. Pathologic axillary lymph node staging was known for all cases. The 5-year actuarial survival for the entire group was 93% with an NED survival of 81%. The 5-year survival for clinical Stage I and II patients was 97 and 87%, respectively, with a corresponding NED survival of 87 and 73%, respectively. For pathologic Stage I and II patients, the corresponding survival figures were 97 and 89%, respectively, with NED survival rates of 86 and 76%, respectively. The overall 5-year actuarial local failure rate was 6%, and the rate of local only as the first failure was 3%. The overall local-regional failure rate was 13% with a local-regional only first failure rate of 8%. These results compare favorably with other reported series and contribute a substantial number of patients to the increasing experience with definitive irradiation following breast-conserving procedures. The relatively low incidence of breast recurrence may be related to the emphasis on integrating the surgical, pathologic, and radiotherapeutic aspects of treatments, as well as the emergence of a re-excision policy for patients at high risk to have residual tumor.

Patterns and sites of failure in cervix cancer treated in the U.S.A. in 1978.

Abstract Patterns of Care Study (PCS) conducted the second survey of carcinoma of the cervix in 1978. The data of this survey are derived from 565 patient questionnaires completed from 120 randomly selected facilities. Through these surveys PCS has set out to establish a profile of the practice of radiation therapy in the United States as well as determine the survival, local control rates, patterns of recurrence, complications, and relationship of these events with dose. This study deals with the patterns and sites of failure and relationship with dose to the paracentral and lateral points previously defined. The breakdown of patients according to the stage was as follows: Stage I = 203, Stage Il = 243, Stage III = 115, undetermined = 4. Twenty-three percent of the patients failed within the field of irradiation, whereas 9% failed outside of the irradiated field. The infield failure rate increased as a function of stage from 9% in Stage I to 23% in Stage II and 48% in Stage 111. Distant metastasis was the first site of failure in 4% of patients with Stage 1, 7% for Stage 11, 9% for Stage III, and 6% for the entire group. The cervix and vagina were the first site of recurrence in 20% of the patients. The cervical/vaginal recurrence rate increased as a function of stage from 7% in Stage I to 21% in Stage II, and 37% in Stage Ill. An analysis of the cervical /vaginal recurrences as a function of the average total dose to the paracentral points showed a decreased recurrence rate as a function of dose within the range of 8500 cGy. The disease-free survival was lower for the patients in the 8500 cGy, was better than that of the lower dose group, but there was no difference between these two higher dose groups. Based on the data of this survey, the highest local control rate and disease-free survival are achieved with a total average dose of 7500–8500 cGy to the paracentral points. From the data of this study, no recommendation can be made regarding the optimum dose to the lateral points with respect to parametrial/sidewal recurrences and/or survival.