Dosimetric feasibility and acute toxicity in a prospective trial of ultrashort-course accelerated partial breast irradiation (APBI) using a multi-lumen balloon brachytherapy device.

BACKGROUND: Shorter courses of APBI, including single-fraction intraoperative therapy, are under active investigation. We designed a prospective trial to identify and address the potential radiobiological and logistical shortcomings of single-fraction APBI. METHODS: We designed a single-arm, multi-institutional, prospective phase II trial that sequentially treats 3 cohorts of women (each n = 30) with 3 progressively hypofractionated schedules. Eligible women were age ≥50 years with unifocal invasive or in situ tumors ≤3.0 cm, excised with negative margins, and with negative lymph nodes and positive hormone receptors. We defined strict dosimetric criteria for appropriateness. RESULTS: A total of 30 patients were enrolled at the 7 Gy × 4 fractions dose-level and followed for 6 months. The median skin dose as a percent of prescription dose (PD) was 84 % (40-100), and the median rib dose was 71 % (16-119). Also, 95 % of the PTV_eval received a median of 95 % of PD (range 85-103). The V150 (range 14-48 cc) and V200 (range 0-29 cc) criteria were met in all cases. One breast infection occurred and was treated; 2 cases of symptomatic fat necrosis and 2 cases of symptomatic seromas occurred. CONCLUSION: Short-course APBI is dosimetrically feasible using the Contura MLB and appears to be tolerable in terms of acute toxicities. Our approach is based on well-defined radiobiological parameters and allows for an abbreviated course of treatment that is guided by full pathological review and the ability to objectively achieve and validate acceptable dosimetric criteria in each case. We have opened enrollment to the next schedule of 8.25 Gy for 3 fractions.

Defining a dose-response relationship with radiotherapy for prostate cancer: is more really better?

PURPOSE: Data were reviewed addressing the association between radiation therapy (RT) dose and treatment outcome for localized prostate cancer to help clarify the existence of a potential dose-response relationship. METHODS AND MATERIALS: Articles were identified through the MEDLINE database, CancerLit database, and reference lists of relevant articles. Studies were categorized into four groups based upon the endpoint analyzed, including biochemical control (BC), local control (LC), pathologic control (PC), and cause-specific survival (CSS). The impact of increasing RT dose with each endpoint was recorded. RESULTS: Twenty-two trials involving a total of 11,297 patients were identified. Of the 11 trials addressing the association of RT dose with LC, 9 showed statistically significant improvements. Of the 12 trials that reported BC with RT dose, all showed statistically significant improvements. Two out of 4 studies analyzing PC with increasing dose showed a positive correlation. Finally, 3 out of 9 studies addressing RT dose with CSS showed statistically significant improvements. Despite inconclusive results, patients with poor risk features (e.g., prostate-specific antigen [PSA] > or = 10, Gleason score [GS] > or = 7, or tumor stage > or = T2b) were most likely to benefit from increasing dose with respect to each endpoint. However, the optimal RT dose and the magnitude of benefit of dose escalation could not be identified. CONCLUSIONS: Although RT dose appears to correlate with various measures of treatment outcome, objective, high-quality data addressing this critical issue are still lacking. At the present time, the absolute improvement in outcome due to dose escalation, the subset of patients benefitting most, and the optimal dose remain to be defined.

Clinicopathologic implications of E-cadherin reactivity in patients with lobular carcinoma in situ of the breast.

BACKGROUND: The current study addressed two questions pertaining to lobular carcinoma in situ (LCIS) of the breast. First, does the risk of a subsequent carcinoma decrease over time after an LCIS biopsy and second, what is the clinical significance of E-cadherin-reactive LCIS? METHODS: Eighty-two consecutive patients with a biopsy containing LCIS only, no prior history of breast carcinoma, and follow-up information available for the period 1955-1976 were reviewed. No patients underwent a mastectomy for LCIS. Four hundred eighty-six sections were stained with E-cadherin. E-cadherin reactivity was correlated with clinicopathologic features of the LCIS and subsequent tumors. The mean number of blocks stained per case was 5.9. The mean follow-up period was 21.6 years. RESULTS: Sixteen patients (19.5%) developed 21 subsequent invasive carcinomas (9 ipsilateral, 2 contralateral, and 5 bilateral carcinomas). The 10-year and 20-year actuarial rates of developing subsequent carcinoma were 7.8% and 15.4%, respectively. Six of the 21 carcinomas (29%) developed after 20 years. Nine LCIS cases (10.9%) had focal E-cadherin reactivity. When compared with patients with nonreactive LCIS, patients with E-cadherin-reactive LCIS more frequently developed a subsequent ipsilateral carcinoma that had a ductal component (55.5% vs. 12.3%; P < 0.01). The subsequent carcinomas also developed after significantly shorter time periods (mean of 7.6 years vs. 19.6 years; P < 0.01). CONCLUSIONS: LCIS appears to confer a persistent, increased risk of subsequent breast carcinoma that does not appear to decrease over time. E-cadherin reactivity appears to identify a subset of LCIS patients with risk factors for subsequent carcinoma similar to those of patients with low-grade intraductal carcinoma.

Mammographically detected ductal carcinoma in situ of the breast treated with breast-conserving surgery and definitive breast irradiation: long-term outcome and prognostic significance of patient age and margin status.

PURPOSE: This study was performed to determine the long-term outcome for women with mammographically detected ductal carcinoma in situ (DCIS; intraductal carcinoma) of the breast treated with breast-conserving surgery followed by definitive breast irradiation. METHODS AND MATERIALS: An analysis was performed of 422 mammographically detected intraductal breast carcinomas in 418 women from 11 institutions in North America and Europe. All patients were treated with breast-conserving surgery followed by definitive breast irradiation. The median follow-up time was 9.4 years (mean, 9.4 years; range, 0.1-19.8 years). RESULTS: The 15-year overall survival rate was 92%, and the 15-year cause-specific survival rate was 98%. The 15-year rate of freedom from distant metastases was 94%. There were 48 local failures in the treated breast, and the 15-year rate of any local failure was 16%. The median time to local failure was 5.0 years (mean, 5.7 years; range, 1.0-15.2 years). Patient age at the time of treatment and final pathology margin status from the primary tumor excision were both significantly associated with local failure. The 10-year rate of local failure was 31% for patient age < or = 39 years, 13% for age 40-49 years, 8% for age 50-59 years, and 6% for age > or = 60 years (p = 0.0001). The 10-year rate of local failure was 24% when the margins of resection were positive, 9% when the margins of resection were negative, 7% when the margins of resection were close, and 12% when the margins of resection were unknown (p = 0.030). Patient age < or = 39 years and positive margins of resection were both independently associated with an increased risk of local failure (p = 0.0006 and p = 0.023, respectively) in the multivariable Cox regression model. CONCLUSIONS: The 15-year results from the present study demonstrated high rates of overall survival, cause-specific survival, and freedom from distant metastases following the treatment of mammographically detected ductal carcinoma in situ of the breast using breast-conserving surgery and definitive breast irradiation. Younger age and positive margins of resection were both independently associated with an increased risk of local failure. The 15-year results in the present study serve as an important benchmark for comparison with other treatment modalities. These results support the use of breast-conserving surgery and definitive breast irradiation for the treatment of appropriately selected patients with mammographically detected ductal carcinoma in situ of the breast.

The use of high-dose-rate brachytherapy alone after lumpectomy in patients with early-stage breast cancer treated with breast-conserving therapy.

PURPOSE: We present the preliminary results of our in-house protocol using outpatient high-dose-rate (HDR) brachytherapy as the sole radiation modality following lumpectomy in patients with early-stage breast cancer. METHODS AND MATERIALS: Thirty-seven patients with 38 Stage I-II breast cancers received radiation to the lumpectomy cavity alone using an HDR interstitial implant with (192)Ir. A minimum dose of 32 Gy was delivered on an outpatient basis in 8 fractions of 4 Gy to the lumpectomy cavity plus a 1- to 2-cm margin over consecutive 4 days. RESULTS: Median follow-up is 31 months. There has been one ipsilateral breast recurrence for a crude failure rate of 2.6% and no regional or distant failures. Wound healing was not impaired in patients undergoing an open-cavity implant. Three minor breast infections occurred, and all resolved with oral antibiotics. The cosmetic outcome was good to excellent in all patients. CONCLUSION: In selected patients with early-stage breast cancer, treatment of the lumpectomy cavity alone with outpatient HDR brachytherapy is both technically feasible and well tolerated. Early results are encouraging, however, longer follow-up is necessary before equivalence to standard whole-breast irradiation can be established and to determine the most optimal radiation therapy technique to be employed.

Accelerated treatment of breast cancer.

PURPOSE: Radiation therapy (RT) restricted to the tumor bed, by means of an interstitial implant, and lasting 4 to 5 days after lumpectomy was prospectively evaluated in early-stage breast cancer patients treated with breast-conserving therapy (BCT). The goals of the study were to determine whether treatment time can be reduced and whether elective treatment of the entire breast is necessary. MATERIALS AND METHODS: Between January 1993 and January 2000, 174 cases of early-stage breast cancer were managed with lumpectomy followed by RT restricted to the tumor bed using an interstitial implant. Each brachytherapy patient was matched with one external-beam RT (ERT) patient derived from a reference group of 1,388 patients treated with standard BCT. Patients were matched for age, tumor size, histology, margins of excision, absence of an extensive intraductal component, nodal status, estrogen receptor status, and tamoxifen use. Median follow-up for both the ERT and brachytherapy groups was 36 months. RESULTS: No statistically significant differences were noted in the 5-year actuarial rates of ipsilateral breast treatment failure or locoregional failure between ERT and brachytherapy patients (1% v 0%, P =.31 and 2% v 1%, P =.63, respectively). In addition, there were no statistically significant differences noted in rates of distant metastasis (6% v 3%, P =.24), disease-free survival (87% v 91%, P =.55), overall survival (90% v 93%, P =.66), or cause-specific survival (97% v 99%, P =.28). CONCLUSION: Accelerated treatment of breast cancer using an interstitial implant to deliver radiation to the tumor bed alone over 4 to 5 days seems to produce 5-year results equivalent to those achieved with conventional ERT. Extended follow-up will be required to determine the long-term efficacy of this treatment approach.

Relationship between excision volume, margin status, and tumor size with the development of local recurrence in patients with ductal carcinoma-in-situ treated with breast-conserving therapy.

BACKGROUND AND OBJECTIVES: We reviewed our institution's experience treating patients with ductal carcinoma-in-situ (DCIS) with breast-conserving therapy (BCT) to help define the interrelationship between excision volume, margin status, and tumor size with local recurrence. METHODS: From January 1980 to December 1993, 146 patients received BCT for DCIS. All patients underwent excisional biopsy and 95 cases (64%) underwent re-excision. Each patient received whole breast radiation to a median dose of 45 Gy. An additional 139 cases (94%) received a supplemental boost to the tumor bed (median total dose 60.4 Gy). The median follow-up is 7.2 years. RESULTS: Seventeen patients developed an ipsilateral breast failure for a 5- and 10-year actuarial rate of 10.2 and 12.4%, respectively. On multivariate analysis, patient age, margin status, the number of slides containing DCIS, the number of DCIS/cancerization of lobules (COL) foci near (< 5 mm) the margin, and a smaller volume of excision (< 60 cm(3)) were all independently associated with outcome. Although the local recurrence rate generally decreased as margin distance increased, these differences did not achieve statistical significance unless the volume of excision was taken into consideration. CONCLUSIONS: These findings suggest that the success of BCT is directly related to the degree of surgical removal of DCIS and that margin status alone may be suboptimal in defining excision adequacy.

Brachytherapy in the treatment of breast cancer.

Whole-breast external-beam radiation therapy (EBRT) involves a 6-week course of fractionated treatments. In contrast, brachytherapy can be completed in a 4- to 5-day treatment course. Because of this shortened time frame, there has been interest in breast brachytherapy as a sole modality after lumpectomy. The American Brachytherapy Society (ABS) has issued guidelines specifically for the use of brachytherapy in breast carcinoma. In these guidelines, the ABS addresses important areas of controversy related to the indications, execution, and evaluation of breast implants when utilized in the following settings: as the sole treatment modality following lumpectomy, as an alternative to a 6-week course of EBRT following lumpectomy, as a boost following whole-breast irradiation, and for the treatment of local recurrences following breast-conservation treatment. The ABS recommends a precise definition and meticulous delineation of the clinical target volume. In addition, the Society recommends the routine use of dose-volume histograms and a dose-homogeneity index as tools to ensure reproducible brachytherapy and to allow interinstitutional comparisons. Brachytherapy as a sole modality is currently considered investigational and should be performed in the context of a controlled clinical trial. Practitioners and cooperative groups are encouraged to use these guidelines to formulate treatment and dose-reporting policies, but responsibility for medical decisions ultimately rests with the treating radiation oncologist.

Impact of boost technique on outcome in early-stage breast cancer patients treated with breast-conserving therapy.

We reviewed our institution's experience treating early-stage breast cancer patients with breast-conserving therapy (BCT) to determine the impact of boost technique on outcome. A total of 552 patients with stage I and II breast cancer were managed with BCT. All patients were treated with a partial mastectomy and radiation therapy (RT). RT consisted of 45 Gy to 50 Gy external beam irradiation to the whole breast followed by a boost to the tumor bed using either electrons (232 patients), photons (15 patients), or an interstitial implant (316 patients). Local control and cosmetic outcome was compared among three patient groups based on the type of boost used. Forty-one patients had a recurrence of cancer in the treated breast for 5-, 10-, and 13-year actuarial local recurrence rates of 2.8%, 7.5%, and 11.2%, respectively. There were no significant differences in the local recurrence rates or cosmetic outcome using electrons, photons, or an interstitial implant. On multivariate analysis, only young age and margin status were associated with local recurrence. Stage I and II breast cancer patients undergoing BCT can be effectively managed with electron, photon, or interstitial implant boost techniques. Long-term local control and cosmetic outcome are excellent regardless of which boost technique is used.

Salvage treatment for local recurrence after breast-conserving surgery and radiation as initial treatment for mammographically detected ductal carcinoma in situ of the breast.

BACKGROUND: The purpose of the current study is to evaluate the outcome of salvage treatment for local recurrence after breast-conserving surgery and radiation as initial treatment for mammographically detected ductal carcinoma in situ (DCIS; intraductal carcinoma) of the breast. METHODS: An analysis was performed of 42 patients with local only first failure (n = 41) or local-regional only first failure (n = 1) after breast-conserving surgery and radiation treatment had been given for DCIS of the breast. Surgical treatment at the time of local recurrence included mastectomy (n = 37; 88%) or excision (n = 5; 12%). Adjuvant systemic therapy at the time of local recurrence was chemotherapy (n = 3; 7%), tamoxifen (n = 8; 19%), both (n = 1; 2%), none (n = 29; 69%), or unknown (n = 1; 2%). The median interval from the time of initial treatment to local recurrence was 4.8 years (range = 1.0-15.2 yrs). The median follow-up after salvage treatment was 4.5 years (range = 0.2-12.8 yrs). RESULTS: At the time of the local recurrence, 22 patients (52%) had invasive ductal carcinoma, 18 patients (43%) had DCIS, 1 patient (2%) had invasive lobular carcinoma, and 1 patient (2%) had angiosarcoma. After salvage treatment, the rate of overall survival and the rate of cause specific survival for all 42 patients were 92% at both 5- and 8-years after treatment. The rate of freedom from distant metastases was 89% at 5 and 8 years. Favorable prognostic factors after salvage treatment were DCIS as the histology of the local recurrence and mammography only as the method of detection of the local recurrence. CONCLUSIONS: The results of salvage treatment in the current study demonstrated that local recurrences were salvaged with high rates of survival and freedom from distant metastases. These results support the use of breast-conserving surgery and radiation for initial management of DCIS of the breast.

Complications and patient satisfaction following expander/implant breast reconstruction with and without radiotherapy.

PURPOSE: To compare the rates of complications and patient satisfaction among breast cancer patients treated with mastectomy and tissue expander/implant reconstruction with and without radiotherapy. METHODS AND MATERIALS: As part of the Michigan Breast Reconstruction Outcome Study (MBROS), breast cancer patients undergoing mastectomy with reconstruction were prospectively evaluated with respect to complications, general patient satisfaction with reconstruction, and esthetic satisfaction. Included in this study was a cohort of women who underwent breast reconstruction using an expander/implant (E/I). A subset of these patients also received radiotherapy (RT). At 1 and 2 years postoperatively, a survey was administered which included 7 items assessing both general satisfaction with their reconstruction and esthetic satisfaction. Complication data were also obtained at the same time points using hospital chart review. Radiotherapy patients identified in the University of Michigan Radiation Oncology database that underwent expander/implant reconstruction but not enrolled in the MBROS study were also added to the analysis. RESULTS: Eighty-one patients underwent mastectomy and E/I reconstruction. Nineteen patients received RT and 62 underwent reconstruction without RT. The median dose delivered to the reconstructed breast/chest wall, including boost, was 60.4 Gy (range, 50.0-66.0 Gy) in 1.8- to 2.0-Gy fractions. With a median follow-up of 31 months from the date of surgery, complications occurred in 68% (13/19) of the RT patients compared to 31% (19/62) in the no RT group (p = 0.006). Twelve of 81 patients (15%) had a breast reconstruction failure. Reconstruction failure was significantly associated with experiencing a complication (p = 0.0001) and the use of radiotherapy (p = 0.005). The observed reconstruction failure rates were 37% (7/19) and 8% (5/62) for patients treated with and without radiotherapy, respectively. Tamoxifen was associated with a borderline risk of complications (p = 0.07) and a significant risk of reconstruction failure (p = 0.01). Sixty-six patients of the study group completed the satisfaction survey; 15 patients did not. To offset potential bias for patients not completing the survey, we analyzed satisfaction data assuming "dissatisfaction" scores for surveys not completed. In the analysis of patients with unilateral E/I placement, reconstruction failure was significantly associated with a lower general satisfaction (p = 0.03). Ten percent of patients experiencing a reconstruction failure were generally satisfied compared to 23% who completed E/I reconstruction. In addition, tamoxifen use was associated with a significantly decreased esthetic satisfaction (p = 0.03). Radiotherapy was not associated with significantly decreased general or esthetic satisfaction. CONCLUSION: Irradiated patients had a higher rate of expander/implant reconstruction failure and complications than nonirradiated patients. Despite these differences, our pilot data suggest that both general satisfaction and patient esthetic satisfaction were not significantly different following radiotherapy compared to patients who did not receive RT. Although statistical power was limited in the present study and larger patient numbers are needed to validate these results, this study suggests comparable patient assessment of cosmetic outcome with or without radiotherapy in women who successfully complete expander/implant reconstruction.

Intensity modulation to improve dose uniformity with tangential breast radiotherapy: initial clinical experience.

PURPOSE: We present a new technique to improve dose uniformity and potentially reduce acute toxicity with tangential whole-breast radiotherapy (RT) using intensity-modulated radiation therapy (IMRT). The technique of multiple static multileaf collimator (sMLC) segments was used to facilitate IMRT. METHODS AND MATERIALS: Ten patients with early-stage breast cancer underwent treatment planning for whole-breast RT using a new method of IMRT. The three-dimensional (3D) dose distribution was first calculated for equally weighted, open tangential fields (i.e., no blocks, no wedges). Dose calculation was corrected for density effects with the pencil-beam superposition algorithm. Separate MLC segments were constructed to conform to the beam's-eye-view projections of the 3D isodose surfaces in 5% increments, ranging from the 120% to 100% isodose surface. Medial and lateral MLC segments that conformed to the lung tissue in the fields were added to reduce transmission. Using the beam-weight optimization utility of the 3D treatment planning system, the sMLC segment weights were then determined to deliver the most uniform dose to 100 reference points that were uniformly distributed throughout the breast. The accuracy of the dose calculation and resultant IMRT delivery was verified with film dosimetry performed on an anthropomorphic phantom. For each patient, the dosimetric uniformity within the breast tissue was evaluated for IMRT and two other treatment techniques. The first technique modeled conventional practice where wedges were derived manually without consideration of inhomogeneity effects (or density correction). A recalculation was performed with density correction to represent the actual dose delivered. In the second technique, the wedges were optimized using the same beam-weight optimization utility as the IMRT plan and included density correction. All dose calculations were based on the pencil-beam superposition algorithm. RESULTS: For the sMLC technique, treatment planning required approximately 60 min. Treatment delivery (including patient setup) required approximately 8-10 min. Film dosimetry measurements performed on an anthropomorphic phantom generally agreed with calculations to within +/- 3%. Compared to the wedge techniques, IMRT with sMLC segments resulted in smaller "hot spots" and a lower maximum dose, while maintaining similar coverage of the treatment volume. A median of only 0.1% of the treatment volume received > or = 110% of the prescribed dose when using IMRT versus 10% with standard wedges. A total of 6-8 segments were required with the majority of the dose delivered via the open segments. The addition of the lung-block segments to IMRT was of significant benefit for patients with a greater proportion of lung parenchyma within the irradiated volume. Since August 1999, 32 patients have been treated in the clinic with the IMRT technique. No patient experienced RTOG grade III or greater acute skin toxicity. CONCLUSION: The use of intensity modulation with an sMLC technique for tangential breast RT is an efficient and effective method for achieving uniform dose throughout the breast. It is dosimetrically superior to the treatment techniques that employ only wedges. Preliminary findings reveal minimal or no acute skin reactions for patients with various breast sizes.

Matched-pair analysis of conformal high-dose-rate brachytherapy boost versus external-beam radiation therapy alone for locally advanced prostate cancer.

PURPOSE: We performed a matched-pair analysis to compare our institution's experience in treating locally advanced prostate cancer with external-beam radiation therapy (EBRT) alone to EBRT in combination with conformal interstitial high-dose-rate (HDR) brachytherapy boosts (EBRT + HDR). MATERIALS AND METHODS: From 1991 to 1998, 161 patients with locally advanced prostate cancer were prospectively treated with EBRT + HDR at William Beaumont Hospital, Royal Oak, Michigan. Patients with any of the following characteristics were eligible for study entry: pretreatment prostate-specific antigen (PSA) level of >/= 10.0 ng/mL, Gleason score >/= 7, or clinical stage T2b to T3c. Pelvic EBRT (46.0 Gy) was supplemented with three (1991 through 1995) or two (1995 through 1998) ultrasound-guided transperineal interstitial iridium-192 HDR implants. The brachytherapy dose was escalated from 5.50 to 10.50 Gy per implant. Each of the 161 EBRT + HDR patients was randomly matched with a unique EBRT-alone patient. Patients were matched according to PSA level, Gleason score, T stage, and follow-up duration. The median PSA follow-up was 2.5 years for both EBRT + HDR and EBRT alone. RESULTS: EBRT + HDR patients demonstrated significantly lower PSA nadir levels (median, 0.4 ng/mL) compared with those receiving EBRT alone (median, 1.1 ng/mL). The 5-year biochemical control rates for EBRT + HDR versus EBRT-alone patients were 67% versus 44%, respectively (P <.001). On multivariate analyses, pretreatment PSA, Gleason score, T stage, and the use of EBRT alone were significantly associated with biochemical failure. Those patients in both treatment groups who experienced biochemical failure had a lower 5-year cause-specific survival rate than patients who were biochemically controlled (84% v 100%; P <.001). CONCLUSION: Locally advanced prostate cancer patients treated with EBRT + HDR demonstrate improved biochemical control compared with those who are treated with conventional doses of EBRT alone.

Differences in the pathologic features of ductal carcinoma in situ of the breast based on patient age.

BACKGROUND: Young patient age at diagnosis has been reported as a risk factor for recurrence in patients with ductal carcinoma in situ (DCIS) of the breast treated with breast-conserving therapy (BCT). The authors examined pathologic features of DCIS in three different age groups of patients to identify differences that might explain why young patient age at the time of diagnosis is a risk factor for recurrence. METHODS: Excised specimens from 177 breasts of 172 patients with DCIS treated with BCT were studied. All slides from all specimens were reviewed. Patients were divided into 3 age groups: those age < 45 years, those ages 45-59 years, and those age >/= 60 years. The histologic features that were quantified included most common and highest nuclear grades, DCIS architectural pattern, amount of central necrosis (quartiles), calcifications, amount of DCIS, and number of terminal duct lobular units (TDLUs) with cancerization of lobules (COL) within 0.42 cm of the margin, margin status, and size and volume of excision specimens. RESULTS: Patients age < 45 years at the time of diagnosis more frequently had higher nuclear grade DCIS (highest nuclear Grade 3: 69%, 60%, and 39%; P = 0.003), respectively and central necrosis (72%, 62%, and 44%; P = 0. 01), respectively. Although not statistically significant, younger patients tended to have comedo subtype DCIS more often (31%, 23%, and 19%; P = 0.35), respectively. Younger patients also more often had smaller initial biopsy specimen maximum dimensions (4.3 cm, 5.2 cm, and 5.7 cm; P = 0.004), respectively, with close or positive margins (89%, 61%, and 64%; P = 0.03), and more TDLUs with COL in the 0.42-cm rim of tissue adjacent to the margin (5.2, 3.6, and 1.9; P = 0.23), respectively. No other features including the amount of DCIS when classified as > 50% or > 75% of ducts, calcifications within DCIS ducts, pattern of DCIS involvement, number of slides examined, number of slides with DCIS, and mean number of DCIS ducts near the margin were found to occur more frequently in younger patients. CONCLUSIONS: Younger patients with DCIS may have an increased risk of local recurrence when treated with BCT due to smaller initial excision volumes, a greater proportion of high nuclear grade DCIS, and central necrosis.

The correlation of serial prostate specific antigen measurements with clinical outcome after external beam radiation therapy of patients for prostate carcinoma.

BACKGROUND: The authors analyzed retrospectively their institution's experience in treating patients with localized prostate carcinoma with external beam radiation therapy (EBRT) to determine the correlation of various biochemical failure (BF) definitions with clinical failure and cause specific survival (CSS). METHODS: Between January 1987 and December 1997, 1,094 patients with clinical T1-T3N0M0 prostate carcinoma were treated with definitive EBRT alone at William Beaumont Hospital, Royal Oak, Michigan. All patients received EBRT alone (no adjuvant hormones) to a median total prostate dose of 66.6 grays (Gy) (range, 59.4-70.4 Gy). Multiple BF definitions were tested for their correlation with clinical failure and cause specific death (CSD = 1-CSS). All BF definitions were tested for sensitivity, specificity, and accuracy of predicting subsequent clinical failure and CSD. Positive and negative predictive values were calculated in the form of 10-year actuarial clinical failure and CSD rates. Analyses were performed on all 1,094 patients as well as for those 727 patients who had at least 5 post-RT prostate specific antigen (PSA) level measurements and who did not receive hormonal therapy for post-RT PSA elevations. The median PSA follow-up was 4.0 years for the entire population and 4.5 years for those 727 patients included in the second analysis. RESULTS: In the entire population, 167 patients (15%) experienced clinical failure corresponding to 5- and 10-year actuarial rates of 16% and 34%, respectively. The correlation of various BF definitions with outcome was calculated in those 727 patients who did not receive hormonal therapy. For these patients, BF (as defined by the American Society for Therapeutic Radiology and Oncology Consensus Panel) yielded a 73% sensitivity, 76% specificity, and 75% overall accuracy for predicting clinical failure and a 74% sensitivity, 69% specificity, and 69% overall accuracy for predicting CSD. The 10-year clinical failure rate for those 251 patients demonstrating 3 consecutive PSA rises (BF) was 64% versus 14% for those patients who did not meet these criteria (biochemically controlled [BC]). As expected, definitions requiring only two rises were more sensitive but less specific in predicting clinical failure than those definitions requiring three or four rises. Because there were dramatically more clinically controlled patients (85%) than clinical failures (15%), the overall accuracy for each definition more closely approximated its specificity. The definitions classifying BF as a postnadir increase of > or = 3 or > or = 4 ng/mL above the nadir yielded the highest accuracies of 87% and 88%, respectively. In addition, these definitions also appeared to provide the greatest separation in clinical failure rates between BC and BF patients, an absolute difference of 77% and 76%, respectively. CONCLUSIONS: The correlation between BF and clinical failure and CSD varies markedly depending on the BF definition used. Definitions incorporating a fixed baseline (the nadir level) and the postnadir PSA profile may have better correlation with clinical failure than definitions using the nadir only or a specific number of consecutive rises in which a variable baseline "resets" after a PSA decrease.

Interim report of image-guided conformal high-dose-rate brachytherapy for patients with unfavorable prostate cancer: the William Beaumont phase II dose-escalating trial.

PURPOSE: We analyzed our institution's experience treating patients with unfavorable prostate cancer in a prospective Phase II dose-escalating trial of external beam radiation therapy (EBRT) integrated with conformal high-dose-rate (HDR) brachytherapy boosts. This interim report discusses treatment outcome and prognostic factors using this treatment approach. METHODS AND MATERIALS: From November 1991 through February 1998, 142 patients with unfavorable prostate cancer were prospectively treated in a dose-escalating trial with pelvic EBRT in combination with outpatient HDR brachytherapy at William Beaumont Hospital. Patients with any of the following characteristics were eligible: pretreatment prostate-specific antigen (PSA) >/= 10.0 ng/ml, Gleason score >/= 7, or clinical stage T2b or higher. All patients received pelvic EBRT to a median total dose of 46.0 Gy. Pelvic EBRT was integrated with ultrasound-guided transperineal conformal interstitial iridium-192 HDR implants. From 1991 to 1995, 58 patients underwent three conformal interstitial HDR implants during the first, second, and third weeks of pelvic EBRT. After October 1995, 84 patients received two interstitial implants during the first and third weeks of pelvic EBRT. The dose delivered via interstitial brachytherapy was escalated from 5.50 Gy to 6.50 Gy for each implant in those patients receiving three implants, and subsequently, from 8.25 Gy to 9.50 Gy per fraction in those patients receiving two implants. To improve implant quality and reduce operator dependency, an on-line, image-guided interactive dose optimization program was utilized during each HDR implant. No patient received hormonal therapy unless treatment failure was documented. The median follow-up was 2.1 years (range: 0.2-7.2 years). Biochemical failure was defined according to the American Society for Therapeutic Radiology and Oncology Consensus Panel definition. RESULTS: The pretreatment PSA level was >/= 10.0 ng/ml in 51% of patients. The biopsy Gleason score was >/= 7 in 58% of cases, and 75% of cases were clinical stage T2b or higher. Despite the high frequency of these poor prognostic factors, the actuarial biochemical control rate was 89% at 2 years and 63% at 5 years. On multivariate analysis, a higher pretreatment PSA level, higher Gleason score, higher PSA nadir level, and shorter time to nadir were associated with biochemical failure. In the entire population, 14 patients (10%) experienced clinical failure at a median interval of 1.7 years (range: 0.2-4.5 years) after completing RT. The 5-year actuarial clinical failure rate was 22%. The 5-year actuarial rates of local failure and distant metastasis were 16% and 14%, respectively. For all patients, the 5-year disease-free survival, overall survival, and cause-specific survival rates were 89%, 95%, and 96%, respectively. The 5-year actuarial rate of RTOG Grade 3 late complications was 9% with no patient experiencing Grade 4 or 5 acute or late toxicity. CONCLUSION: Pelvic EBRT in combination with image-guided conformal HDR brachytherapy boosts appears to be an effective treatment for patients with unfavorable prostate cancer with minimal associated morbidity. Our dose-escalating trial will continue.

Use of conformal high-dose rate brachytherapy for management of patients with prostate cancer: optimizing dose escalation.

PURPOSE: We reviewed our institution's experience treating patients with locally advanced prostate cancer using high-dose rate (HDR) conformal brachytherapy. Treatment technique, interim results, and toxicity are reviewed. MATERIALS AND METHODS: From November 1991 to May 1998, 161 patients with locally advanced prostate cancer were treated on a dose escalation trial of external-beam radiation therapy (EBRT) combined with HDR conformal brachytherapy boosts. Patients with any of the following characteristics were acceptable for enrollment: pretreatment prostate-specific antigen (PSA) > or =10 ng/mL, Gleason score > or =7, or clinical stage T2b or higher. All patients received pelvic EBRT to a median dose of 46 Gy. Transperineal ultrasound-guided temporary HDR brachytherapy implant boosts were performed in the first, second, and third week of EBRT. Seventy-two patients were boosted with three implants (boost dose 5.50 to 6.50 Gy), and 89 patients received two implants (boost dose 8.25 to 10.50 Gy). All implants were placed using interactive real-time dosimetry. Biochemical failure was calculated using the American Society for Therapeutic Radiology and Oncology Consensus Panel definition. Median follow-up was 2.8 years (range 0.3-7.2). RESULTS: The 2- and 5-year actuarial biochemical control rates were 86% and 67%, respectively. The 5-year actuarial biochemical control rates for patients with a pretreatment PSA < or =3.9, 4.0-9.9, 10.0-19.9, and > or =20.0 ng/mL were 80%, 87%, 56%, and 54%, respectively. Factors associated with biochemical failure on multivariate analysis included the pretreatment PSA, Gleason score, PSA nadir, and time to PSA nadir. A total of 6 patients (4%) developed grade 3 late toxicity consisting of urethral stricture (5 patients) or incontinence (1 patient). Forty- four patients (27%) developed impotence after radiation therapy. CONCLUSIONS: Conformal HDR brachytherapy boosts appear to offer a safe, reproducible, and effective method of dose escalation in patients with locally advanced prostate cancer treated with RT. Interim results with this technology reveal biochemical control rates paralleling those achieved with three-dimensional conformal EBRT and other forms of treatment.

Mammographically detected ductal carcinoma in situ treated with conservative surgery with or without radiation therapy: patterns of failure and 10-year results.

OBJECTIVE: The authors reviewed their institution's experience treating mammographically detected ductal carcinoma in situ (DCIS) of the breast with breast-conserving therapy (BCT) to determine 10-year rates of local control and survival, patterns of failure, and factors associated with outcome. SUMMARY BACKGROUND DATA: From January 1980 to December 1993, 177 breasts in 172 patients were treated with BCT for mammographically detected DCIS of the breast at William Beaumont Hospital, Royal Oak, Michigan. METHODS: All patients underwent an excisional biopsy, and 65% were reexcised. Thirty-one breasts (18%) were treated with excision alone, whereas 146 breasts (82%) received postoperative radiation therapy (RT). All patients undergoing RT received whole-breast irradiation to a median dose of 50.0 Gy. One hundred thirty-six (93%) received a boost to the tumor bed for a median total dose of 60.4 Gy. Median follow-up was 5.9 years for the lumpectomy alone group and 7.2 years for the lumpectomy + RT group. RESULTS: In the entire population, 15 patients had an ipsilateral breast recurrence. The 5- and 10-year actuarial rates of ipsilateral breast recurrence were 7.8% and 7.8% for lumpectomy alone and 8.0% and 9.2% for lumpectomy + RT, respectively. Eleven of the 15 recurrences developed within or immediately adjacent to the lumpectomy cavity and were designated as true recurrences or marginal misses (TMM). Four recurred elsewhere in the breast. Eleven of the 15 recurrences were invasive, whereas 4 were pure DCIS. Only one patient died of disease, yielding 5- and 10-year actuarial cause-specific survival rates of 100% and 99.2%, respectively. Eleven patients were diagnosed with subsequent contralateral breast cancer, yielding 5- and 10-year actuarial rates of 5.1% and 8.3%, respectively. Clinical, pathologic, and treatment-related factors were analyzed for an association with ipsilateral breast failure or TR/MM. No factors were significantly associated with ipsilateral breast failure. In the entire population, the omission of RT and younger age at diagnosis were significantly associated with TR/MM. Patients younger than 45 years at diagnosis had a significantly higher rate of TR/MM in both the lumpectomy + RT and lumpectomy alone groups. None of the 37 patients who received a postexcisional mammogram had an ipsilateral breast failure versus 15 in the patients who did not receive a postexcisional mammogram. CONCLUSIONS: Patients diagnosed with mammographically detected DCIS of the breast appear to have excellent 100-year rates of local control and overall survival when treated with BCT. These results suggest that the use of RT reduces the risk of local recurrence and that patients diagnosed at a younger age have a higher rate of local recurrence with or without the use of postoperative RT.

Improving the dosimetric coverage of interstitial high-dose-rate breast implants.

PURPOSE/OBJECTIVE: We performed a retrospective computed tomography (CT)-based three-dimensional (3D) dose-volume analysis of high-dose-rate (HDR) interstitial breast implants to evaluate the adequacy of lumpectomy cavity coverage, and then designed a simple, reproducible algorithm for dwell-time adjustment to correct for underdosage of the lumpectomy cavity. METHODS AND MATERIALS: Since March 1993, brachytherapy has been used as the sole radiation modality after lumpectomy in selected protocol patients with early-stage breast cancer treated with breast-conserving therapy. In this protocol, all patients received 32 Gy in 8 fractions of 4 Gy over 4 days. Eleven patients treated with HDR brachytherapy who underwent CT scanning after implant placement were included in this analysis. For each patient, the postimplant CT dataset was transferred to a 3D treatment planning system, and the relevant tissue volumes were outlined on each axial slice. The implant dataset, including the dwell positions and dwell times, were imported into the 3D planning system and then registered to the visible implant template in the CT dataset. The calculated dose distribution was analyzed with respect to defined volumes via dose-volume histograms. Due to the variability of lumpectomy cavity coverage discovered in this 3D quality assurance analysis, dwell times at selected positions were adjusted in an attempt to improve dosimetric coverage of the lumpectomy cavity. Using implant data from 5 cases, a dwell-time adjustment algorithm was designed and was then tested on 11 cases. In this algorithm, a point P was identified using axial CT images, which was representative of the underdosed region within the cavity. The distance (d) from point P to the nearest dwell position was measured. A number of dwell positions (N) nearest to point P were selected for dwell time adjustment. The algorithm was tested by increasing the dwell times of a variable number of positions (N = 1, 3, 5, 7, 10, and 20) by a weighting factor (alpha), where alpha = f(d) and alpha > 1, and subsequently performing 3D dose-volume analysis to evaluate the improvement in lumpectomy cavity coverage. RESULTS: Before adjustment in the 11 implants, the median proportion of the lumpectomy cavity and target volume that received at least the prescription dose was 85% and 68%, respectively. After dwell-time adjustment, lumpectomy cavity coverage was significantly improved in all 11 cases. The median distance from point P to the nearest dwell position (d) was 1.4 cm (range 0.9-1.9). The median volume of the lumpectomy cavity receiving 32 Gy increased from 85.3% in the actual implant to 97.0% (range 74-100%) by increasing the dwell time of a single dwell position by a median factor (alpha) of 12.2 according to the above algorithm. With N = 3, the median proportion of the cavity volume receiving 32 Gy was improved to 97.5% (range 77-100%), with a median alpha of 5.7. Further improvement in lumpectomy cavity coverage was relatively small by increasing additional dwell times. In addition, with N = 20, the median absolute volume of breast tissue receiving 150% of the prescription dose was 70.3 cm3 compared to 26.3 cm3 in the actual implant; whereas with N = 1 or N = 3, this median volume was only 35.9 and 42.0 cm3, respectively. CONCLUSION: Lumpectomy cavity coverage sometimes appears suboptimal with interstitial HDR breast brachytherapy using our current technique. A simple dwell-time increase at only 1-3 dwell positions can compensate for some underdosage without creating significant regions of overdosage. Using simple methodology, a single reference point representing the underdosed region can be utilized for initial selection of the dwell positions to be increased.

Impact of young age on outcome in patients with ductal carcinoma-in-situ treated with breast-conserving therapy.

PURPOSE: We reviewed our institution's experience treating patients with ductal carcinoma-in-situ (DCIS) with breast-conserving therapy (BCT) to determine the impact of patient age on outcome. PATIENTS AND METHODS: From 1980 to 1993, 146 patients were treated with BCT for DCIS. All patients underwent excisional biopsy, and 64% underwent re-excision. All patients received whole-breast irradiation to a median dose of 45 Gy. Ninety-four percent of patients received a boost to the tumor bed, for a median total dose of 60.4 Gy. All slides on every patient were reviewed by one pathologist. The median follow-up period was 7.2 years. RESULTS: Seventeen patients developed an ipsilateral local recurrence, for 5- and 10-year actuarial rates of 10.2% and 12.4%, respectively. The 10-year rate of ipsilateral failure was 26.1% in patients younger than 45 years of age versus 8.6% in older patients (P =.03). On multivariate analysis, young age was independently associated with recurrence of the index lesion (true recurrence/marginal miss ¿TR/MM failures), regardless of how it was analyzed (eg, < 45 years of age or as a continuous variable). In addition, young patients had a dramatically higher 10-year rate of invasive TR/MM failures (19.9% v 3.2%). In a separate multivariate analysis for the development of invasive TR/MM failures, only patient age and predominant nuclear grade were independently associated with recurrence. The relationship between excision volume and outcome was analyzed in the 95 patients who underwent re-excision. The 5-year actuarial rate of TR/MM failure was significantly worse only in young patients with smaller (< 40 mL) re-excision volumes (33.3% v 9.1%; P =.02). In a separate multivariate analysis of only these 95 patients (25 of whom were < 45 years of age), the volume of re-excision had the strongest association with outcome (P =.05). Patient age was no longer associated with local recurrence. CONCLUSION: These findings suggest that young patients with DCIS have a significantly greater risk of local recurrence after BCT that is independent of other previously defined risk factors. Our data also suggest that the extent of resection may in part be related to the less optimal results that are observed in these patients.