Delray Schultz

Fifteen-year results of breast-conserving surgery and definitive breast irradiation for the treatment of ductal carcinoma in situ of the breast.

PURPOSE To determine the 15-year outcome for women with ductal carcinoma in situ (DCIS, intraductal carcinoma) of the breast treated with breast-conserving surgery followed by definitive breast irradiation. PATIENTS AND METHODS An analysis was performed of 270 intraductal breast carcinomas in 268 women from 10 institutions in Europe and the United States. In all patients, breast-conserving surgery included complete gross excision of the primary tumor followed by definitive breast irradiation. When performed, pathologic axillary lymph node staging was node-negative (n=86). The median follow-up time was 10.3 years (range, 0.9 to 26.8). RESULTS The 15-year actuarial overall survival rate was 87%, and the 15-year actuarial cause-specific survival rate was 96%. The 15-year actuarial rate of freedom from distant metastases was 96%. There were 45 local recurrences in the treated breast, and the 15-year actuarial rate of local failure was 19%. The median time to local failure was 5.2 years (range, 1.4 to 16.8). A number of clinical and pathologic parameters were evaluated for correlation with local failure, and none were predictive for local failure (all P > or = .15). CONCLUSION The results from the present study demonstrate high rates of overall survival, cause-specific survival, and freedom from distant metastases following the treatment of DCIS of the breast using breast-conserving surgery and definitive breast irradiation. These results support the use of breast-conserving surgery and definitive breast irradiation for the treatment of DCIS of the breast.

A Multivariate Analysis of Clinical and Pathological Factors that Predict for Prostate Specific Antigen Failure after Radical Prostatectomy for Prostate Cancer

A Cox regression multivariate analysis was done to determine the clinical and pathological indicators that predict for prostate specific antigen (PSA) failure in 347 patients who underwent radical prostatectomy for clinically localized prostate cancer between 1989 and 1993. In the patient subgroups (PSA less than 20 ng./ml. and biopsy Gleason sum 5 to 7 or PSA more than 10 to 20 ng./ml. and biopsy Gleason sum 2 to 4) not classifiable into those at high and low risk for postoperative PSA failure using PSA and biopsy Gleason sum, the status of the seminal vesicles and prostatic capsule on endo-rectal coil magnetic resonance imaging (MRI) allowed for this categorization. Specifically, 2-year actuarial PSA failure rates were 84% versus 23% in patients with and without seminal vesicle invasion, respectively, on MRI (p < 0.0001) and 58% versus 21% in those with and without extracapsular extension, respectively (p = 0.0001). In patients with extracapsular extension but without pathological involvement of the seminal vesicle(s) or poorly differentiated tumors (pathological Gleason sum 8 to 10), the 2-year actuarial PSA failure rates were 50% (margin positive), 28% (margin negative with established extracapsular disease) and 9% (margin negative with focal microscopic extracapsular disease). Therefore, endo-rectal coil MRI showing seminal vesicle invasion or extracapsular extension when the PSA level is less than 20 ng./ml. and the biopsy Gleason sum is 5 to 7 or the PSA level is more than 10 but less than 20 ng./ml. and the biopsy Gleason sum is 2 to 4 predicted for PSA failure. In patients with extracapsular extension who had pathological Gleason sum less than 8 disease with uninvolved seminal vesicles, the margin status and extent of extracapsular disease predicted for PSA failure.

Breast recurrence following conservative surgery and radiation: patterns of failure, prognosis, and pathologic findings from mastectomy specimens with implications for treatment

Between 1978 and 1986, 1030 women with clinical Stage I or II breast cancer underwent excisional biopsy, axillary dissection (948 patients), and definitive irradiation. Sixty-five patients developed a recurrence in the treated breast, 9 of which were associated with simultaneous (8) or antecedent (1) distant metastases. Detection was by mammography alone in 29%, physical exam alone in 50%, and both in 21%. The median interval to recurrence was 34 months. Overall, 65% of the recurrences were in the vicinity of the original tumor; however, as the interval to recurrence increased, the percentage of operable recurrences in a separate quadrant increased. For those recurring after 5 years, 54% were in a separate quadrant. Ninety-five percent of the recurrences unassociated with distant metastases were operable and pathology revealed non-invasive cancer only in 10%. Fifty-two patients underwent salvage mastectomy. Thirteen patients had no residual tumor following excisional biopsy at the time of mastectomy. None of the following factors were predictive for no residual tumor: initial age, method of detection, interval to recurrence, location of recurrence, or histology. Local-regional control following mastectomy was 95%. The 5-year actuarial overall and disease-free survivals for salvage mastectomy patients were 84% and 59%, respectively. The only significant prognostic factor for survival was the initial clinical tumor size, which was related to the extent of the recurrence. Based on the inability to identify factors which would predict for a localized recurrence pathologically, we recommend mastectomy as the preferred surgical treatment for an isolated breast recurrence. Adjuvant chemotherapy may be beneficial in patients with an unfavorable prognosis.

Clinical Utility of the Percentage of Positive Prostate Biopsies in Defining Biochemical Outcome After Radical Prostatectomy for Patients With Clinically Localized Prostate Cancer

PURPOSE To determine the clinical utility of the percentage of positive prostate biopsies in predicting prostate-specific antigen (PSA) outcome after radical prostatectomy (RP) for men with PSA-detected or clinically palpable prostate cancer. METHODS A Cox regression multivariable analysis was used to determine whether the percentage of positive prostate biopsies provided clinically relevant information about PSA outcome after RP in 960 men while accounting for the previously established risk groups that are defined according to pretreatment PSA level, biopsy Gleason score, and the 1992 American Joint Committee on Cancer (AJCC) clinical T stage. The findings were then tested using an independent surgical database that included data for 823 men. RESULTS Controlling for the known prognostic factors, the percentage of positive prostate biopsies added clinically significant information (P <.0001) regarding time to PSA failure after RP. Specifically, 80% of the patients in the intermediate-risk group (1992 AJCC T2b, or biopsy Gleason 7 or PSA > 10 ng/mL and </= 20 ng/mL) could be classified into either an 11% or 86% 4-year PSA control cohort using the preoperative prostate biopsy data. These findings were validated in the intermediate-risk patients using an independent surgical data set. CONCLUSION The validated stratification of PSA outcome after RP using the percentage of positive prostate biopsies in intermediate-risk patients is clinically significant. This information can be used to identify men with newly diagnosed and clinically localized prostate cancer who are at high risk for early (</= 2 years) PSA failure and, therefore, may benefit from the use of adjuvant therapy.

Determinants of Prostate Cancer–Specific Survival After Radiation Therapy for Patients With Clinically Localized Prostate Cancer

PURPOSE Identifying pretreatment and posttreatment predictors of time to prostate cancer-specific death (PCSD) after external-beam radiation therapy (RT) was the subject of this study. PATIENTS AND METHODS A Cox regression analysis was used to evaluate the ability of the pretreatment risk group to predict time to PCSD for 381 patients who underwent RT for clinically localized prostate cancer. Posttreatment factors analyzed for the 94 patients who experienced prostate-specific antigen (PSA) failure included the time to PSA failure, the posttreatment PSA doubling time (DT), and the timing of salvage hormonal therapy. RESULTS Despite the median age of 73 years at diagnosis, 45% of patients with high-risk disease were estimated to die from prostate cancer within 10 years after RT compared with 0% (P =.004) and 6% (P =.05) for patients with low- or intermediate-risk disease, respectively. Predictors of time to PCSD after PSA failure included PSA DT (P =.01) and delayed use of hormonal therapy (P <or=.002). Nearly identical estimates of PCSD and all-cause death after PSA failure were noted for patients with a short PSA DT (ie, <or= 12 months). CONCLUSION Prostate cancer was a major cause of death during the first decade after RT for patients with clinically localized but high-risk disease, and the cause of death for patients with a short PSA DT after RT was nearly always prostate cancer. These data provide evidence to propose the hypothesis that a short posttreatment PSA DT may serve as a possible surrogate for PCSD. Prospective validation is needed.

The influence of young age on outcome in early stage breast cancer

PURPOSE To assess the impact of young age on outcome in women with early stage breast cancer undergoing conservative surgery and radiation. METHODS AND MATERIALS Between 1981 and 1991, 980 patients with Stage I and II breast cancer underwent excisional biopsy, axillary dissection, and radiation. The median follow-up was 4.6 years, with a range of 1 month to 11 years. The patients were divided into three groups, based on age at the time of diagnosis: (a) age < or = 35 years--64 patients, (b) age 36-50 years--363 patients, and (c) age > 50 years--553 patients. The comparability of the groups was assessed in terms of clinical factors (tumor size and race), histopathologic factors (histologic subtype, final resection margin, estrogen and progesterone receptor status, pathologic nodal status), and treatment related factors (reexcision, median total dose to the primary, region(s) treated with radiation, and the use of adjuvant systemic chemotherapy and/or tamoxifen). Outcome was evaluated for overall, relapse-free, and cause-specific survival and patterns of first failure (breast, regional nodes, and distant metastasis). RESULTS There were no significant differences among the three groups in terms of race, clinical tumor size, pathology of the primary tumor, pathologic nodal status, final margin of resection, progesterone receptor status, median total dose to the primary tumor, or the regions treated. However, younger women were significantly more likely to have estrogen receptor negative tumors, undergo reexcision, and receive adjuvant systemic chemotherapy without tamoxifen. Younger women were found to have a statistically significantly decreased 8-year actuarial relapse-free survival (53% vs. 67% vs. 74%, p = 0.009), cause-specific survival (73% vs. 84% vs. 90%, p = 0.02), freedom from distant metastasis (76% vs. 75% vs. 83%, p = 0.02), and a significantly increased risk of breast recurrence (24% vs. 14% vs. 12%, p = 0.001), and regional node recurrence (7% vs. 1% vs. 1%, p = 0.0002). The patients were further divided on the basis of their pathologic nodal status. There were no statistically significant differences among the three age groups for axillary node-positive patients for overall survival (75% vs. 80% vs. 74%), relapse-free survival (73% vs. 73% vs. 62%), cause-specific survival (76% vs. 85% vs. 80%), and freedom from distant metastasis (75% vs. 75% vs. 72%), or breast recurrence (0% vs. 9% vs. 6%). The findings were identical when the analysis was restricted to node-positive patients who received chemotherapy. However, for axillary node-negative women, young age was associated with a statistically significant decreased overall survival (71% vs. 83% vs. 92%), relapse-free survival (51% vs. 65% vs. 76%), cause-specific survival (71% vs. 86% vs. 93%), freedom from distant metastasis (77% vs. 76% vs. 88%), and a statistically significant increased risk of breast recurrence (40% vs. 16% vs. 13%), and regional node recurrence (3% vs. 1% vs. 0%). The risk of a breast recurrence in axillary node-negative young women was decreased by the addition of adjuvant systemic chemotherapy but not by the use of reexcision. CONCLUSIONS The present analysis demonstrates that young women with early stage breast cancer do significantly worse when compared to older women in terms of relapse-free survival, cause-specific survival, distant metastasis and breast and regional node recurrence. However, the adverse effect of young age on outcome appears to be limited to the node-negative patients. These findings suggest that node-negative early stage breast cancer in young women is a more aggressive disease, with an increased risk for all patterns of failure and a decreased survival.

Ten year results of conservative surgery and irradiation for stage I and II breast cancer

Between 1977 and 1985, 697 women with clinical Stage I or II invasive breast cancer underwent excisional biopsy, axillary dissection, and definitive irradiation. Reexcision of the primary was performed in 330 and residual tumor was identified in 57% of these patients. Margins of resection were assessed in 50% and 257 had final margins of resection that were negative. Four hundred eighty patients had negative axillary dissections and 217 had histologically positive axillary nodes. Median follow-up was 58 months. The 10-year actuarial survival for the entire group was 83% with an NED survival of 73%. The 10-year actuarial survival was 87% for clinical Stage I and 77% for clinical Stage II patients with an NED survival of 79% and 67%, respectively. Patients with histologically negative axillary nodes had a 10-year overall survival of 86% (NED 78%) compared to 74% (NED 66%) for patients with positive nodes. Sixty-one patients developed a recurrence in the treated breast and in seven of these it was associated with simultaneous distant metastases. The cumulative probability of an isolated breast recurrence was 6% at 5 years and 16% at 10 years. The overall breast recurrence rate (+/- distant metastasis) was 8% at 5 years and 18% at 10 years. Breast recurrence was unrelated to T size, clinical stage, or histologic nodal status. The addition of adjuvant chemotherapy significantly decreased the risk of an isolated breast recurrence both at 5 and 10 years; however, there was no significant impact on the overall risk of a breast recurrence. Complications of treatment included moderate arm edema (5%), symptomatic pneumonitis (less than 1%), rib fraction (1%), pericarditis (0%), and brachial plexopathy (less than 1%). Cosmesis was judged to be good to excellent in 93% of patients in 10 years. These results have been achieved in a series of patients who for the most part have been treated by contemporary standards, that is, pathologic assessment of the axilla in all patients, reexcision in 47%, and adjuvant chemotherapy in 77% of node positive patients. Assessment of resection margins, however, was not performed in all patients (50%) and further follow-up in the group of patients with margin assessment will provide long term information on breast recurrence rate in this group of patients.

The significance of the pathology margins of the tumor excision on the outcome of patients treated with definitive irradiation for early stage breast cancer.

To evaluate the significance of the pathology margins of the tumor excision on the outcome of treatment, an analysis was performed of 697 consecutive women with clinical Stage I or II invasive carcinoma of the breast treated with breast-conserving surgery and definitive irradiation. Complete gross excision of the primary tumor was performed in all cases, and an axillary staging procedure was performed to determine pathologic axillary lymph node status. The 697 patients were divided into four groups based on the final pathology margin from the primary tumor excision or from the re-excision if performed. These four groups were: (a) 257 patients with a negative margin (greater than 2 mm), (b) 57 patients with a positive margin, (c) 37 patients with a close margin (less than or equal to 2 mm), and (d) 346 patients with an unknown margin. The patients with positive final pathology margins were focally positive on microscopic examination. Patients with grossly positive margins or with diffusely positive microscopic margins were treated with conversion to mastectomy. There was a significant difference in the total radiation dose for the four groups (median dose of 6000 vs 6500 vs 6400 vs 6240 cGy, respectively; p less than .0001). There was no significant difference among the four groups for 5-year actuarial overall survival (p = .19), no evidence of disease (NED) survival (p = .95), or relapse-free survival (p = .80). There was no significant difference among the four groups for five year actuarial local or regional control (all p greater than or equal to .29). Subset analyses did not identify any poor outcome subgroups. These results have demonstrated that selected patients with focally positive or close microscopic pathology margins can be adequately treated with definitive breast irradiation. Patient selection and the technical delivery of radiation treatment including a boost may have been important contributing factors to the good outcome in these patients.

A Prognostic Model for Predicting 10-Year Survival in Patients with Primary Melanoma

Malignant melanoma is currently the eighth most common cancer in the United States; 10 years ago, it was the 20th most common. The population-based mortality rate has continued to increase, whereas the case fatality rate has steadily declined to less than 20% [1]. Diagnosis of malignant melanoma earlier than was previously possible is primarily responsible for this improved survival rate. Contributing to earlier recognition of malignant melanoma are the identification of risk markers (such as dysplastic nevi) and improved understanding of clinical characteristics of the biologically early forms [2-4]. Another substantive advance has been the clarification of prognostic factors for patients with primary American Joint Commission on Cancer stage I cutaneous melanoma ( 1.5 mm) and stage II cutaneous melanoma (>1.51 mm); these factors are predominantly pathologic variables that were described by Clark and colleagues [5], Breslow [6], and other investigators [7]. Survival is routinely predicted almost exclusively on the basis of tumor thickness. Although this is an excellent correlate of prognosis, it is imprecise. Death results from thin melanomas, and survival occurs with thick melanomas. Evaluation of other variables improves the ability to predict survival in patients with melanoma. Variables that can be added include the anatomical site of the primary tumor; sex and age of the patient; mitotic rate of the tumor; presence of ulceration, microscopic satellites, or tumor-infiltrating lymphocytes; tumor regression or angiogenesis; and the Clark level of invasion (maximum penetration of the melanoma lesion into levels of the dermis or subcutaneous tissue) [8, 9]. We previously described a multivariable model that predicted 8-year survival of patients with primary melanomas more accurately than did tumor thickness alone [10]. In that model, six variables were found to independently predict survival. These variables (in order of their relative predictive strength) are mitotic rate, presence of tumor-infiltrating lymphocytes, tumor thickness, site of the primary lesion, sex of the patient, and histologic regression of the tumor. Although this model includes powerful predictors of survival, some of the variables used to generate it are not routinely included in standard pathology reports. Therefore, the model cannot be readily generalized for clinical use. To document this, we reviewed 100 randomly selected pathology reports of primary melanomas from community-based hospital pathologists, independent pathology laboratories, and specialized dermatopathology laboratories. Tumor thickness was recorded in 76% of cases; Clark level, in 68%; and histologic subtype, in 64%. However, tumor infiltrating lymphocytes and tumor regression were described in fewer than 20% of cases, and the mitotic rate was reported even less frequently (fewer than 5% of cases). Notably, no pathologists specified pure, invasive, radial-growth-phase melanoma, although such lesions almost never metastasize [10]. Given the limited availability of these histologic variables, we sought to develop a prognostic model based on clinical and pathologic data that are routinely available to the clinician. The model is intended to estimate the chance of survival, within 10 years of definitive therapy, in a patient with primary malignant melanoma. The ability to predict outcome more accurately in these patients could identify patients who are at high risk for recurrence; these patients could then be included in trials of adjuvant therapy. Further trials are becoming increasingly important as effective therapies for post-surgical treatment of melanoma are identified and tested [11-13]. Methods Patients The Pigmented Lesion Group at the University of Pennsylvania prospectively evaluated 624 patients with primary melanoma between 1 September 1972 and 31 December 1979. The pathologic variables were ascertained in an independent study of the primary tumors on two separate occasions by two pathologists who had no knowledge of outcome. Definitive treatment of the primary melanoma consisted of wide re-excision of the primary site to yield negative margins. We excluded 136 cases from analysis. Reasons for exclusion were competing causes of death before 10 years of follow-up with no evidence of melanoma (n = 44), lack of prospective follow-up (n = 22), metastatic disease evident beyond the primary site at presentation (n = 29), inadequate surgical treatment (n = 14), unknown cause of death before 10 years of follow-up (n = 5), occurrence of a high-risk primary tumor after 1979 (n = 2), existence of noncutaneous primary tumors (n = 5), loss to follow-up (n = 10), and unclassified tumor thickness or level (n = 5). Therefore, the final study group consisted of 488 patients who were followed prospectively for at least 10 years. Surviving patients were followed for no more than 20 years. Five patients who died of melanoma after 10 years of follow-up were considered to be 10-year survivors. Our description of what is generally included in melanoma pathology reports was drawn from the last 100 cases submitted for review at the Hospital of the University of Pennsylvania. Forty-three percent of the reports were from community-based hospitals, 17% were from independent pathology laboratories, and 40% were from specialized dermatopathology practices. We did not intend to evaluate current melanoma pathology reporting in nonacademic settings but rather to evaluate which prognostic factors are frequently reported on pathology reports. Validation of the model required a test using patient data that had not been used to generate the model. This sample consisted of 142 patients who had primary melanoma and were identified in an identical manner in 1980 and 1981, with blinded histopathologic assessment of melanoma and 10 years of follow-up data. Clinical and pathologic variables that have been identified as prognostic indicators of survival and that are readily available to the clinician were used to develop the prediction model [7, 9]. Clinical variables included age and sex of the patient and site of the primary lesion. Pathologic variables included histologic subtype, Clark level, and tumor thickness. Tumor thickness was measured from the stratum granulosum epidermidis to the depth of the tumor at its thickest part, according to the method of Breslow [6]. Anatomical site of the primary melanoma was divided into two categories: extremity (upper and lower) and axis. Axial or volar primaries, including melanomas arising on the trunk, head, neck, and palms and soles (volar) and under the nails (subungual), were designated as axis lesions. Lesions on other parts of the body were designated as extremity lesions. Female and male patients were studied. Histologic subtypes of melanoma included superficial spreading melanoma (71%), nodular melanoma (12%), lentigo maligna melanoma (6%), acral-lentiginous melanoma (3%), and other lesions (8%), using standard pathologic criteria. Age at the time of diagnosis was recorded. The Clark level of invasion was determined as described elsewhere [5]. Patient outcome was assigned to two categories: alive at 10 years (with or without evidence of melanoma) or dead from melanoma before 10 years. The 10-year interval was chosen because death from melanoma beyond 10 years is uncommon. We chose to analyze survival as a binary outcome (alive at 10 years compared with dead before 10 years). This method was chosen instead of evaluating the survival time or time to death because our primary objective was to differentiate between patients with high and low probabilities for surviving disease. This differentiation, in turn, can aid patient management and identify candidates for adjuvant therapy trials. Therefore, we were not interested in determining the contribution of prognostic factors that lengthen survival but do not necessarily prevent death. Statistical Analysis We used a univariate logistic regression model to test the six clinical and pathologic variables for their association with death. Patient age and tumor thickness were tested as continuous and nominal variables, and the Clark level was tested as a nominal variable. Tumor site was initially evaluated as a variable falling into one of four categories (trunk, head or neck, subungual or volar location, and extremity) but was subsequently reduced to two categories, axis and extremity. Variables that were statistically significantly associated with survival were retained for testing in a multivariable logistic regression model [14]. A manual stepwise procedure was used to determine the best model. The predicted probability that a patient would survive 10 years was generated using the estimated model variables. The logistic equation is presented as a footnote in Table 1. Table 1. Adjusted Odds Ratios for Independent Predictors of Survival* Figure 1 is a box and whisker plot that shows the distribution of probabilities that were estimated by our model for survival of patients who were alive and those who were dead at 10 years [15]. The boundary lines of the boxes represent the 25th and 75th percentiles of the data; the lines drawn through the interior of the boxes mark the 50th percentiles (the medians). The whiskers are drawn from the edges of each box to the most extreme point a maximum distance of 1.5 times greater and 1.5 times less than the interquartile ranges. Any value more extreme is considered an outlier and is designated by an asterisk. The predictive ability of the four-variable model was compared with that of tumor thickness in two ways. First, receiver-operating characteristic (ROC) curves were calculated [16, 17]. Second, the McNemar test was used to compare the percentages of correct predictions. Goodness of fit was assessed by using the Hosmer-Lemeshow test [14]. Figure 1. Results Overall Of the 488 prospectively followed patients, 108 died of melanoma before 10 years. The median follow-up was 13.

Frequency, sites of relapse, and outcome of regional node failures following conservative surgery and radiation for early breast cancer

Between 1970 and 1986, 990 patients underwent excisional biopsy and radiation for clinical Stage I or II breast cancer. A limited axillary dissection (levels I and II) was performed in 914 of these patients. The median follow-up was 40 months from the initiation of radiation. Thirty-one patients developed a regional node failure as their first site of recurrence either with (12 patients) or without (19 patients) simultaneous distant metastases. The median interval to recurrence was 27 months (range 4-59). The 5-year actuarial rate for an isolated regional node recurrence (without simultaneous distant metastases) was 3%. The most common site for a regional node failure was the axilla (17 patients) followed by the supraclavicular nodes (13 patients). Salvage therapy was effective for an axillary +/- breast failure with 10/14 patients alive with no evidence of disease. Prognosis was related to the site of recurrence as well as the presence or absence of distant metastases. The 5-year actuarial survival from initial treatment for all patients with a regional node failure was 63% with a 3-year actuarial survival of 57% from diagnosis of recurrence. Regional node failure was related to the number of axillary nodes removed at the time of dissection and patient age.