Carl F. Dmuchowski

THE CORRELATION BETWEEN THE ASTRO CONSENSUS PANEL DEFINITION OF BIOCHEMICAL FAILURE AND CLINICAL OUTCOME FOR PATIENTS WITH PROSTATE CANCER TREATED WITH EXTERNAL BEAM IRRADIATION

PURPOSE We reviewed our institutions experience treating patients with external beam irradiation (RT) to determine if the ASTRO Consensus Panel definition of biochemical failure (BF) following radiation therapy correlates with clinical distant metastases free survival (DMFS), disease-free survival (DFS), cause-specific survival (CSS), and local control (LC). METHODS AND MATERIALS Between 1/1/87 and 12/31/92, 568 patients with clinically localized prostate cancer received external beam irradiation (RT) using localized prostate fields at William Beaumont Hospital (median total dose 66.6 Gy; range: 60-70.4 Gy). Biochemical failure was defined as three consecutive increases in post-treatment prostate specific antigen (PSA) after achieving a nadir. Biochemical failure was recorded as the time midway between the nadir and the first rising PSA. Five-year actuarial rates of clinical DMFS, DFS, CSS, and LC were calculated for patients who were biochemically controlled (BC) versus those who failed biochemically. Median follow-up was 56 months (range: 24-118 months). RESULTS Five-year actuarial rates of DMFS, DFS, CSS, and LC were significantly greater in patients who were biochemically controlled versus those who were not (p < 0.001). In patients who were BC, the 5-year actuarial rates of DMFS, DFS, CSS, and LC were 99%, 99%, 98%, and 99% respectively. For patients who failed biochemically, the 5-year actuarial rates of DMFS, DFS, CSS, and LC were 74%, 64%, 89%, and 86% respectively. When stratifying by pretreatment PSA, Gleason score, and T stage these differences remained significant for DMFS, DFS, and CSS. The Cox proportional hazards model demonstrated that BC was the single most important predictor of clinical outcome for DMFS, DFS, CSS, and LC. Pretreatment PSA and Gleason score were also independent predictors of outcome for DMFS and DFS. CONCLUSIONS The ASTRO Consensus Panel definition of BF following radiation therapy correlates well with clinical DMFS, DFS, and CSS. These findings suggest that the Consensus Panel definition may be a surrogate for clinical progression and survival and should be considered a valid endpoint for separating successful versus unsuccessful treatment. Additional studies with longer follow-up will be needed to corroborate these findings.

The role of regional nodal irradiation in the management of patients with early-stage breast cancer treated with breast-conserving therapy

PURPOSE To determine the incidence of regional nodal failure (RNF) and indications for regional nodal irradiation (RNI) in patients with Stage I and II breast cancer treated with breast-conserving therapy (BCT). METHODS AND MATERIALS Four hundred fifty-six patients with Stage I/II breast cancer were treated with BCT at William Beaumont Hospital. All patients underwent excisional biopsy and 288 (63%) were reexcised. A Level I/II ipsilateral axillary lymph node dissection was performed on 431 patients (95%). Pathologically involved nodes were found in 106 (23%) cases (69 with one to three nodes and 37 with > or = four nodes involved). All patients received whole breast irradiation (median dose 50 Gy) and 415 (91%) were boosted to the tumor bed (median total dose 60.4 Gy). Three hundred and sixty (79%) patients received breast alone irradiation and 96 (21%) also received RNI. The median axilla/supraclavicular fossa dose was 50 Gy. RESULTS With a median follow-up of 83 months, 15 patients developed a RNF for a 5- and 8-year actuarial rate of 3 and 4%, respectively. The 5- and 8-year actuarial rates of axillary failure (AF) were 0.7 and 1.0%, respectively. The incidence of RNF or AF was not affected by the use of RNI in N0 or N1 patients with one to three positive nodes. Only in patients with four or more positive nodes was there a trend towards improved regional control with RNI (p = 0.09). However, patient numbers were extremely small, and this improvement was limited to a reduction in the rate of failure in the supraclavicular fossa (SCF) (20 vs. 0%, p = 0.04). Multiple clinical, pathologic, and treatment related factors were analyzed for an association with AF. On univariate analysis, AF was associated with the number of lymph nodes excised (p < 0.0001) estrogen receptor status (p = 0.0016), and pathologic node status (p = 0.0021). CONCLUSIONS Regional nodal failure as the first site of failure is uncommon in patients with early-stage breast cancer treated with BCT with < or = three positive lymph nodes and appears unaffected by RNI. For patients with four or more positive lymph nodes, a trend towards improved RNF was noted with RNI, primarily in the SCF. However, patient numbers were extremely small in all subsets analyzed. Additional studies are needed to further define the need for RNI in these patients and help determine other factors associated with RNF.

Assessing the variability of outcome for patients treated with localized prostate irradiation using different definitions of biochemical control

PURPOSE Biochemical control using serial posttreatment serum prostate specific antigen (PSA) levels is being increasingly used to assess treatment efficacy for localized prostate cancer. However, no standardized definition of biochemical control has been established. We reviewed our experience treating patients with localized prostate cancer and applied three different commonly used definitions of biochemical control to determine if differences in therapeutic outcome would be observed. METHODS AND MATERIALS Between January 1987 and December 1991, 480 patients with clinically localized prostate cancer received external beam irradiation (RT) using localized prostate fields at William Beaumont Hospital. The median dose to the prostate was 66.6 Gy (range 58-70.4) using a four-field or arc technique. Pretreatment and posttreatment serum PSA levels were recorded. Over 86% (414 of 480) of patients had a pretreatment PSA level available. Three different definitions of biochemical control were used: (a) PSA nadir < 1 ng/ml within 1 year of treatment completion. After achieving nadir, if two consecutive increases of PSA were noted, the patient was scored a failure at the time of the first increase; (b) PSA nadir < 1.5 ng/ml within 1 year of treatment completion. After achieving nadir, if two consecutive increases of PSA were noted, the patient was scored a failure at the time of the first increase; (c) Posttreatment PSA nadir < 4 ng/ml without a time limit. Once the nadir was achieved, if it did not rise above normal the patient was considered to be biochemically controlled. Clinical local control was defined as no palpable prostate nodularity beyond 18 months, no new prostate nodularity, or a negative prostate biopsy. RESULTS Median follow-up was 48 months (range 3-112). Pretreatment PSA values were correlated with treatment outcome using the three definitions of biochemical control as well as clinical local control. Pretreatment PSA values were stratified into five groups (Group 1: PSA < 4; Group 2: PSA 4-10; Group 3: PSA 10-15; Group 4: PSA 15-20; and Group 5: PSA > 20), and 5-year actuarial rates of biochemical control were calculated using the three biochemical control and one clinical local control definitions. For Group 1, 5-year actuarial rates of biochemical control were 84%, 90%, 91%, and 96% for Definitions 1-3 and clinical local control, respectively. For Group 2, 5-year actuarial control rates were 45%, 54%, 74%, and 92% for the four definitions, respectively. For Group 3, 5-year actuarial control rates were 26%, 31%, 63%, and 100% for the four definitions, respectively. For Group 4, 5-year actuarial control rates were 24%, 24%, 50%, and 100% for the four definitions, respectively. Finally, for Group 5, 5-year actuarial control rates were 5%, 14%, 15%, and 89% for the four definitions, respectively. Depending on the definition used, statistically significant differences overall in outcome rates were observed. Differences between all four definitions for all pairwise comparisons ranged from 5 to 53% (p < 0.001). CONCLUSION When different definitions of biochemical control are used in assessing treatment outcome, significantly different rates of success are noted. Until a standardized definition of biochemical control is adopted, differences in treatment outcome cannot be meaningfully compared.

Excellent functional outcome in patients with squamous cell carcinoma of the base of tongue treated with external irradiation and interstitial iodine 125 boost

Local control, functional outcome, and complications in patients with carcinoma of the base of tongue (BOT) were analyzed to assess the impact of interstitial implant boost with I‐125 seeds.

Long term results with breast‐conserving therapy for patients with early stage breast carcinoma in a community hospital setting

Prospective randomized trials and retrospective reviews from academic centers have documented the success of breast‐conserving therapy (BCT) for patients with early stage breast carcinoma. The authors retrospectively reviewed the outcome of BCT for early stage breast carcinoma to determine the success of BCT at the study institution, a 1000‐bed community hospital.

Ductal carcinoma in situ detected in the mammographic era: An analysis of clinical, pathologic, and treatment-related factors affecting outcome with breast-conserving therapy

PURPOSE We reviewed our institutions experience treating predominantly mammographically detected ductal carcinoma in situ (DCIS) with breast-conserving therapy (BCT) to determine if any clinical, pathologic, or treatment-related factors affected outcome. METHODS AND MATERIALS From January 2, 1980 to January 6, 1992, 107 breasts in 105 patients were treated with BCT at William Beaumont Hospital, Royal Oak, MI. All patients underwent at least an excisional biopsy and 70 patients (65%) were reexcised. All patients received whole-breast irradiation to a median dose of 50.4 Gy (range 43.1 to 56.0 Gy). Ninety-nine patients (93%) received a supplemental boost to the tumor bed for a median total dose of 60.4 Gy (range 59.1 to 71.8 Gy) using either photons (2 patients), electrons (69 patients), or an interstitial implant (28 patients). RESULTS With a median follow-up of 78 months, 10 patients have failed in the treated breast for a 5- and 10-year actuarial local control rate of 91.2 and 89.8%, respectively. Thirteen percent of the population have been followed for 10 years or more. Three recurrences were pure DCIS, and seven were invasive. All patients were salvaged with mastectomy. Nine patients remain without evidence of disease a median of 30.6 months after surgery. One patient failed distantly 36 months after local recurrence for an ultimate cause specific survival of 99%. Potential clinical (age, mammographic findings, method of detection, etc.), pathologic (nuclear grade, margins, etc.), and treatment-related factors (dose, boost technique, reexcision status, etc.) affecting outcome were analyzed. No variable was found to be associated with an ipsilateral breast tumor recurrence. However, when only recurrences that occurred within or immediately adjacent to the lumpectomy cavity were analyzed, both margin status and the extent of cancerization of lobules (COL) near the surgical margin were associated with the development of a local recurrence. CONCLUSIONS Patients treated with BCT for predominantly mammographically detected DCIS achieve excellent rates of local control and overall survival. Both margin status and the extent of COL near the surgical margin appear to be associated with recurrences within or immediately adjacent to the lumpectomy cavity. These data suggest that careful attention to the completeness of surgical resection of DCIS is an important determinant of outcome.

LONG-TERM OUTCOME WITH INTERSTITIAL BRACHYTHERAPY IN THE MANAGEMENT OF PATIENTS WITH EARLY-STAGE BREAST CANCER TREATED WITH BREAST-CONSERVING THERAPY

PURPOSE We reviewed our institutions experience with interstitial implant boosts to determine their long-term impact on local control and cosmetic results. METHODS AND MATERIALS Between January 1, 1980 and December 31, 1987, 390 women with 400 cases of Stage I and II breast cancer were managed with breast-conserving therapy (BCT) at William Beaumont Hospital. All patients were treated with an excisional biopsy and 253 (63%) underwent reexcision. Radiation consisted of 45-50 Gy external beam irradiation to the whole breast followed by a boost to the tumor bed to at least 60 Gy using either electrons [108], photons [15], or an interstitial implant [277] with either 192Ir [190] or 125I [87]. Long-term local control and cosmetic outcome were assessed and contrasted between patients boosted with either interstitial implants, electrons, or photons. RESULTS With a median follow-up of 81 months, 25 patients have recurred in the treated breast for a 5- and 8-year actuarial rate of local recurrence of 4 and 8%, respectively. There were no statistically significant differences in the 5- or 8-year actuarial rates of local recurrence using either electrons, photons, or an interstitial implant. Greater than 90% of patients obtained a good or excellent cosmetic result, and no statistically significant differences in cosmetic outcome were seen whether electrons, photons, or implants were used. CONCLUSIONS We conclude that patients with Stage I and II breast cancer undergoing BCT and judged to be candidates for boosts can be effectively managed with LDR interstitial brachytherapy. Long-term local control and cosmetic outcome are excellent and similar to patients boosted with either electrons or photons.

An analysis of clinical and treatment related prognostic factors on outcome using biochemical control as an end-point in patients with prostate cancer treated with external beam irradiation

PURPOSE We reviewed our institutions experience in treating patients with clinically localized prostate cancer with external beam irradiation (RT) to determine if previously analyzed clinical and treatment related prognostic factors affected outcome when biochemical control was used as an end-point to evaluate results. MATERIALS AND METHODS Between 1 January 1987 and 31 December 1991, 470 patients with clinically localized prostate cancer were treated with external beam RT using localized prostate fields at William Beaumont Hospital. Biochemical control was defined as PSA nadir < or =1.5 ng/ml within 1 year of treatment. After achieving nadir, if two consecutive increases of PSA were noted, the patient was scored a failure at the time of the first increase. Prognostic factors, including the total number of days in treatment, the method of diagnosis, a history of any pretreatment transurethral resection of the prostate (TURP) and the type of boost were analyzed. RESULTS Median follow-up was 48 months. No statistically significant difference in rates of biochemical control were noted for treatment time, overall time (date of biopsy to completion of RT), history of any pretreatment TURP, history of diagnosis by TURP, or boost techniques. Patients diagnosed by TURP had a significant improvement in the overall rate of biochemical control (P < 0.03) compared to transrectal/transperineal biopsy. The 5-year actuarial rates were 58 versus 39%, respectively. This improvement was not evident when pretreatment PSA, T stage, or Gleason score were controlled for. On multivariate analysis, no variable was associated with outcome. When analysis was limited to a more favorable group of patients (T1/T2 tumors, pretreatment PSA < or =20 ng/ml and Gleason score <7), none of these variables were significantly predictive of biochemical control when controlling for pretreatment PSA, T stage and Gleason score. CONCLUSIONS No significant effect of treatment time, overall time, pretreatment TURP, or boost technique was noted on outcome in patients treated with conventional external beam irradiation when biochemical control was used as the end-point to evaluate results.

Impact of clinical, pathologic, and treatment-related factors on outcome in patients with locally advanced breast cancer treated with multimodality therapy.

The authors reviewed the experience at their institution treating patients with locally advanced breast cancer using multimodality therapy to identify clinical, pathologic, and treatment-related factors affecting outcome. One hundred patients with locally advanced breast cancer were treated with definitive therapy at William Beaumont Hospital. Three patients had stage IIB disease, 45 patients had stage IIIA disease, and 52 patients had IIIB disease. Thirteen patients had inflammatory breast carcinoma. Seventy-four patients (74%) received trimodality therapy consisting of systemic therapy, radiation therapy, and surgery. Systemic therapy was delivered to 90 patients. Eighty-three patients (83%) received adjuvant radiation therapy. Eighty-five patients underwent mastectomy (85%). Multiple clinical, pathologic, and treatment-related factors were analyzed for their impact on outcome. The median follow-up was 47 months. Overall, the 5-year actuarial rates of local control, disease-free survival, overall survival, and cause-specific survival were 81%, 43%, 53%, and 55%, respectively. The 5-year actuarial cause-specific survival rates for patients with inflammatory breast carcinoma, stage IIIA disease, and stage IIIB disease were 25%, 55%, and 53%, respectively. On multivariate analysis, local control was improved with radiation therapy (p = 0.008) and the absence of inflammatory breast carcinoma (p = 0.008). Disease-free survival was improved with the addition of radiation therapy (p = 0.001) and with less than four positive lymph nodes (p = 0.003). Distant metastasis-free survival was improved in patients without inflammatory breast carcinoma (p = 0.0249) and with less than four involved lymph nodes (p = 0.0135). Cause-specific survival and overall survival were adversely affected by the presence of inflammatory breast carcinoma (p = 0.0135 and p = 0.0325, respectively) or four or more involved lymph nodes (p = 0.0082 and p = 0.012, respectively). Radiation therapy appears to be a critical component in the overall treatment of patients with locally advanced breast cancer by improving the rates of local control and disease-free survival. Other adverse factors for survival include four or more positive lymph nodes and inflammatory breast carcinoma.

Impact of the mode of detection on outcome in breast cancer patients treated with breast-conserving therapy.

The impact of the mode of detection on outcome in patients with early stage breast cancer treated with breast-conserving therapy (BCT) was reviewed. Between January 1980 and December 1987, 400 cases of stage I and II breast cancer were treated with BCT. All patients underwent an excisional biopsy, external beam irradiation (RT) to the whole breast (45-50 Gy), and a boost to 60 Gy to the tumor bed. One hundred twenty-four cases (31%) were mammographically detected, whereas 276 (69%) were clinically detected. Median follow-up was 9.2 years. Patients whose cancers were detected by mammography more frequently had smaller tumors (90% T1 vs. 62%, p < 0.0001), lower overall disease stage (78% stage I vs. 47%, p < 0.0001), were older at diagnosis (78% >50 years vs. 54%, p < 0.001), less frequently received chemotherapy (8% vs. 21%, p = 0.001), and had an improved disease-free survival (DFS) (80% vs. 70%, p = 0.014), overall survival (OS) (82% vs. 70%, p = 0.005), and cause-specific survival (CSS) (88% vs. 77%, p = 0.003) at 10 years. However, controlling for tumor size, nodal status, and age, no statistically significant differences in the 5- and 10-year actuarial rates of local recurrence (LR), DFS, CSS, or OS were seen based on the mode of detection. Initial mode of detection was the strongest predictor of outcome after a LR. The 3-year DFS rate after LR was significantly better in initially mammographically detected versus clinically detected cases (100% vs. 61%, p = 0.011). Patients with mammographically detected breast cancer generally have smaller tumors and lower overall disease stage at presentation. However, the mode of detection does not independently appear to affect the success of BCT in these patients.