Left anterior descending artery avoidance in patients receiving breast irradiation.

PURPOSE: Dose to the left anterior descending artery (LAD) may be significant in patients receiving left-sided irradiation for breast cancer. We investigated if prospective contouring and avoidance of the LAD during treatment planning were associated with lower LAD dose. METHODS AND MATERIALS: We reviewed dosimetric plans for 323 patients who received left whole breast or chest wall irradiation with or without internal mammary node (IMLN) coverage between 1/2014 and 1/2019 at a single institution. The LAD was contoured prospectively for 155 cases, and techniques were utilized to minimize LAD dose. Dose-volume-histograms from these patients were compared to those of 168 patients for whom the LAD was contoured retrospectively after treatment completion. EQD2 was calculated to account for fractionation differences. RESULTS: Compared to cases where the LAD was contoured retrospectively (n = 126), prospective LAD contouring (n = 124) was associated with lower unadjusted median max and mean LAD doses for 250 patients receiving whole-breast irradiation (WBI) without IMLN coverage: 8.5 Gy vs 5.2 Gy (p < 0.0001) and 3.6 Gy vs 2.7 Gy (p < 0.0001), respectively. EQD2 median max and mean LAD doses were also lower with prospective LAD contouring: 5.2 Gy vs 3.0 Gy (p < 0.0001) and 1.9 Gy vs 1.5 Gy (p < 0.0001), respectively. Compared to cases where the LAD was contoured retrospectively (n = 42), prospective LAD contouring (n = 31) was associated with lower max LAD doses for 73 patients with IMLN coverage: 20.4 Gy vs 14.3 Gy (p = 0.042). There was a nonsignificant reduction in median mean LAD dose: 6.2 Gy vs 6.1 Gy (p = 0.33). LAD doses were reduced while maintaining IMLN coverage (mean V90%Rx >90%). CONCLUSIONS: Prospective contouring and avoidance of the LAD were associated with lower max and mean LAD doses in patients receiving WBI and with lower max LAD doses in patients receiving IMLN treatment. Further reduction in LAD dose may require stricter optimization weighting or compromise in IMLN coverage.

Omission of Axillary Lymph Node Dissection is Associated with Inferior Survival in Breast Cancer Patients with Residual N1 Nodal Disease Following Neoadjuvant Chemotherapy.

BACKGROUND: The appropriateness of substituting sentinel lymph node dissection (SLND) and regional nodal irradiation (RNI) for axillary lymph node dissection (ALND) in patients with residual lymph node (LN) disease following neoadjuvant chemotherapy (NAC) is unknown. We used the National Cancer Database (NCDB) to compare survival following SLND and ALND in breast cancer patients with residual LN disease. METHODS: We analyzed NCDB patients, treated between 2006 and 2014, with cT1-3, cN1, cM0 breast cancer and residual disease in 1-3 axillary LNs (ypN1) following NAC. Patients were grouped into those who received SLND (defined as removal of ≤ 4 LNs) and RNI, or ALND and RNI. Patients were matched for all patient, tumor, and treatment characteristics. RESULTS: We identified 1313 eligible patients in the ALND group and 304 patients in the SLND group. For the matched cohorts, SLND was associated with significantly lower survival in both univariate and doubly robust multivariable analyses (MVA) (HR 1.7, 95% CI 1.3-2.2, P < 0.001 for MVA), with estimated 5-year OS of 71%, compared with 77% in the ALND group (P = 0.01). Exploratory subgroup analyses showed that SLND was comparable with ALND in patients with luminal A or B tumors with a single metastatic LN (HR 1.03, 95% CI 0.59-1.8, (P = 0.91). CONCLUSIONS: Our analysis suggests that, while an ALND may not be needed for patients with limited residual nodal burden and biologically favorable tumors, SLND should not be routinely substituted for ALND in patients with ypN1 disease following NAC until its efficacy is confirmed by prospective trials.

Sequencing of Adjuvant Chemoradiation for Advanced Stage Endometrial Cancer: Outcomes and Toxicity Profiles.

OBJECTIVES: Radiation is frequently added to chemotherapy for adjuvant treatment of advanced stage endometrial cancer. Multiple adjuvant therapy sequencing options exist, and little data is available to compare these. We compared outcomes and toxicities after "sandwich" chemoradiation (chemotherapy, then radiation, then chemotherapy) and nonsandwich sequences (chemotherapy then radiation, radiation then chemotherapy, or concurrent chemoradiation). MATERIALS AND METHODS: We recorded baseline characteristics, adjuvant treatment details, clinical outcomes, and toxicities for stage III to IVA patients who underwent surgical staging followed by both adjuvant chemotherapy and radiation therapy at our institution. Effects of adjuvant treatment order (sandwich or nonsandwich) on these outcomes were analyzed. Toxicities were graded according to CTCAE v4.0. RESULTS: We identified 107 patients with a median follow-up of 3.2 years. Five-year local, regional, and distant recurrence were 7%, 15%, and 33%; disease-free and overall survival were 61% and 68%, respectively. Outcomes did not differ by sequence group. The overall rate of acute toxicity did not differ by sequence group. The overall rate of chronic toxicity was significantly lower for sandwich patients (P<0.001), as were overall rates of chronic genitourinary (P=0.048) and gynecologic (P<0.001) toxicities. There were no grade 4 or 5 acute or chronic toxicities. CONCLUSIONS: Advanced stage endometrial cancer is an aggressive disease and adjuvant chemotherapy and radiation therapy are indicated. Clinical outcomes were similar amongst the different sequences; however, sandwich therapy led to less chronic toxicity, offering an opportunity for improved quality of life in survivorship.

Post-mastectomy radiotherapy is associated with improved overall survival in T3N0 patients who do not receive chemotherapy.

BACKGROUND AND PURPOSE: There is limited retrospective evidence addressing the utility of post-mastectomy radiotherapy (PMRT) in patients with T3N0 breast cancer. We performed a retrospective analysis of the National Cancer Database (NCDB) comparing overall survival (OS) in T3N0 patients treated with mastectomy alone (MTX) or with PMRT. MATERIALS AND METHODS: We performed a matched-cohort analysis of NCDB breast cancer patients with pT3N0 disease who did not receive NAC, or cT3N0 patients who received NAC treated between 2006 and 2014. Patients were matched for all available baseline characteristics using propensity scores with inverse probability of treatment weighting (IPTW) with stabilized weights. RESULTS: We identified 13,901 eligible patients. In the pT3N0 cohort, median follow-up was 47 months for the MTX group and 50 months for the PMRT group. In the cT3N0 cohort, median follow-up was 44 months for the MTX group and 46 months for the PMRT group. OS was higher in pT3N0 patients treated with PMRT compared to MTX: 7-year OS of 74% vs. 65% (P < 0.001). Doubly robust multivariable analysis showed an association between PMRT and improved OS (HR 0.78, 95% CI 0.68-0.89, P < 0.001). There was no benefit to PMRT in patients who received adjuvant chemotherapy (AC). In the NAC cohort, PMRT did not change OS, with 7-year OS of 78% with MTX and 79% with PMRT. There was a trend of improved OS with PMRT in patients with residual disease in the breast and lymph nodes (HR 0.70, 95% CI 0.46-1.07). CONCLUSION: PMRT improves OS in patients with pT3N0 disease, but the benefit appears limited to those who do not receive AC. PMRT does not improve OS in patients with cT3N0 disease who receive NAC, but there might be a benefit in patients with a poor response to chemotherapy. However, longer follow-up may be needed to make a definitive conclusion about the benefit of PMRT in patients who receive chemotherapy.

Mapping of Metastatic Level I Axillary Lymph Nodes in Patients with Newly Diagnosed Breast Cancer.

PURPOSE: We examined the distribution of pretreatment nodal metastases to the level I axilla (Ax-L1) to assess the appropriateness of current breast atlases and provide guidelines in relationship to easily identifiable anatomic landmarks for accurate delineation of this lymph node (LN) basin. METHODS AND MATERIALS: Patients with newly diagnosed breast cancer and biopsy-proven metastatic Ax-L1 LNs were identified. We related the location of each LN to its most adjacent rib and its distance from the bottom of the humeral head, axillary vessels, and a line connecting the anterior aspects of the pectoralis and latissimus dorsi muscles (P-L line). LNs were mapped onto a representative planning computed tomography scan, and their distribution was used to validate the current Radiation Therapy Oncology Group, European Society for Radiotherapy and Oncology, and Radiotherapy Comparative Effectiveness breast atlases. Furthermore, we examined metastases to a subregion encompassing the superolateral Ax-L1, irradiation of which correlates highly with lymphedema. RESULTS: We identified 106 eligible patients with 107 biopsied LNs. All LNs fell between the second and fifth ribs (mean, 3.8 ± 0.56). Mean distance from the inferior aspect of the humeral head was 4.3 ± 1.6 cm (range, 0.3-8.4). Mean distance from the inferior aspect of the axillary vessels was 2.9 ± 1.5 cm (range, -0.6 to 5.4). Mean distance from the P-L line was 0.01 ± 1.9 cm (range, -2.2 to 2.4); negative and positive values denote medial or lateral to the P-L line. A Radiation Therapy Oncology Group-compliant Ax-L1 consensus contour, created from contours by 4 attending breast radiation oncologists, partially or fully missed 45% of mapped LNs. European Society for Radiotherapy and Oncology- and Radiotherapy Comparative Effectiveness-compliant Ax-L1 similarly missed 46% and 34% of mapped LNs, respectively. LNs were most frequently missed in the lateral direction. The superolateral Ax-L1 encompassed 9.3% of the mapped LNs. CONCLUSIONS: A significant percentage of at-risk Ax-L1 tissue falls outside current contouring atlases. We propose expansion of the recommended Ax-L1 borders, most notably in the lateral direction.

Breast conserving therapy is associated with improved overall survival compared to mastectomy in early-stage, lymph node-negative breast cancer.

BACKGROUND AND PURPOSE: Recent retrospective studies suggest improved overall survival (OS) with breast conserving therapy (BCT), including breast conserving surgery and adjuvant whole breast radiotherapy, compared to mastectomy in the modern era. The patient subset most likely to benefit from BCT remains unclear, and the role of Oncotype DX Recurrence Score (RS) in this context is unknown. We compared BCT to mastectomy in early-stage, node-negative breast cancer. We further explored outcomes after stratification by RS and age. MATERIALS AND METHODS: We performed a matched-cohort analysis of National Cancer Database (NCDB) patients with pT1-2, pN0, cM0 breast cancer treated between 2006 and 2014 with BCT or mastectomy. Patients were matched for all available baseline characteristics using propensity scores with inverse probability of treatment weighting (IPTW) with stabilized weights. RESULTS: We identified 144,263 eligible patients treated with BCT and 87,379 patients treated with mastectomy. After IPTW-matching, OS was higher with BCT compared to mastectomy: 5-year OS of 94.4% vs. 91.8% (P < 0.001) and 7-year OS of 90% vs. 85.2% (P < 0.001). Doubly robust multivariable analysis showed an association between BCT and improved OS (HR 0.66, 95% CI, 0.64-0.69, P < 0.001). In a subset analysis, BCT was associated with improved OS in patients with RS >25, but not patients with RS ≤25. When stratified by age, only patients >50 years had improved OS with BCT. CONCLUSION: BCT is associated with improved OS compared to mastectomy in women with early-stage, node-negative breast cancer. The improvement in OS with BCT appears to be most pronounced in patients with high RS and >50 years of age. Prospective validation of these findings is required.

The Cost-Effectiveness and Value Proposition of Brachytherapy.

Brachytherapy is an effective treatment modality for a wide range of malignancies. However, brachytherapy utilization for both prostate and gynecologic malignancies has significantly declined over the last 20 years in favor of external beam radiation techniques. The cause of this decline is multifactorial, with logistical challenges, lower reimbursement, and inadequate training contributing to the preference of many radiation oncologists to more frequently recommend external beam radiation therapy. While the authors recognize the application of brachytherapy to a wider range of disease presentations among which include breast, skin, head and neck, and connective tissue cancers, in this review, we will review the analyses supporting brachytherapy as a cost-effective component of the management in patients with prostate, cervix, and endometrial cancer.

Histopathological Findings After Reirradiation Compared to First Irradiation of Spinal Bone Metastases With Stereotactic Body Radiotherapy: A Cohort Study.

BACKGROUND: Stereotactic body radiotherapy (SBRT) of the spine provides superior tumor control, but vertebral compression fractures are increased and the pathophysiological process underneath is not well understood. Data on histopathological changes, particularly after salvage SBRT (sSBRT) following conventional irradiation, are scarce. OBJECTIVE: To investigate surgical specimens after sSBRT and primary SBRT (pSBRT) regarding histopathological changes. METHODS: We assessed 704 patients treated with spine SBRT 2006 to 2012. Thirty patients underwent salvage surgery; 23 histopathological reports were available. Clinical and histopathological findings were analyzed for sSBRT (69.6%) and pSBRT (30.4%). RESULTS: Mean time to surgery after sSBRT/pSBRT was 8.3/10.3 mo (P = .64). Reason for surgery included pain (sSBRT/pSBRT: 12.5%/71.4%, P = .25), fractures (sSBRT/pSBRT: 37.5%/28.6%, P = .68), and neurological symptoms (sSBRT/pSBRT: 68.8%/42.9%, P = .24). Radiological tumor progression after sSBRT/pSBRT was seen in 71.4%/42.9% (P = .2). Most specimens displayed viable/proliferative tumor (sSBRT/pSBRT: 62.5%/71.4%, P = .68 and 56.3%/57.1%, P = .97). Few specimens showed soft tissue necrosis (sSBRT/pSBRT: 20%/28.6%, P = .66), osteonecrosis (sSBRT/pSBRT: 14.3%/16.7%, P = .89), or bone marrow fibrosis (sSBRT/pSBRT: 42.9%/33.3%, P = .69). Tumor bed necrosis was more common after sSBRT (81.3%/42.9%, P = .066). Radiological tumor progression correlated with viable/proliferative tumor (P = .03/P = .006) and tumor bed necrosis (P = .03). Fractures were increased with bone marrow fibrosis (P = .07), but not with osteonecrosis (P = .53) or soft tissue necrosis (P = .19). Neurological symptoms were common with radiological tumor progression (P = .07), but not with fractures (P = .18). CONCLUSION: For both, sSBRT and pSBRT, histopathological changes were similar. Neurological symptoms were attributable to tumor progression and pathological fractures were not associated with osteonecrosis or tumor progression.

Seven-Year Outcomes Following Accelerated Partial Breast Irradiation Stratified by ASTRO Consensus Groupings.

OBJECTIVES: Limited long-term data exist regarding outcomes for patients treated with accelerated partial breast irradiation (APBI), particularly, when stratified by American Society for Radiation Oncology (ASTRO) Consensus Statement (CS) risk groups. The purpose of this analysis is to present 5- and 7-year outcomes following APBI based on CS groupings. MATERIALS AND METHODS: A total of 690 patients with early-stage breast cancer underwent APBI from 1993 to 2012, receiving interstitial brachytherapy (n=195), balloon-based brachytherapy (n=290), or 3-dimensional conformal radiotherapy (n=205) at a single institution. Patients were stratified into suitable, cautionary, and unsuitable groups with 5-year outcomes analyzed. Seven-year outcomes were analyzed for a subset with follow-up of ≥2 years (n=625). RESULTS: Median follow-up was 6.7 years (range, 0.1 to 20.1 y). Patients assigned to cautionary and unsuitable categories were more likely to have high-grade tumors (21% to 25% vs. 9%, P=0.001), receive chemotherapy (15% to 38% vs. 6%, P<0.001), and have close/positive margins (9% to 11% vs. 0%, P<0.001). There was no difference in ipsilateral breast tumor recurrence at 5 or 7 years: 2.2%, 1.2%, 2.8% at 5 years (P=0.57), and 2.2%, 1.9%, 4.6% at 7 years (P=0.58) in the suitable, cautionary, and unsuitable groups, respectively. As compared with the suitable group, increased rates of distant metastases were noted for the unsuitable and cautionary groups at 5 years (P=0.04). CONCLUSIONS: No differences in rates of ipsilateral breast tumor recurrence were seen at 5 or 7 years when stratified by ASTRO CS groupings. Modest increases in distant recurrence were noted in the cautionary and unsuitable groups. These findings suggest that the ASTRO CS groupings stratify more for systemic recurrence and may not appropriately select patients for whole versus partial breast irradiation.

Brachytherapy-based Accelerated Partial Breast Irradiation Provides Equivalent 10-Year Outcomes to Whole Breast Irradiation: A Matched-Pair Analysis.

INTRODUCTION: Although whole breast irradiation (WBI) represents the standard radiotherapy technique in breast conserving therapy, accelerated partial breast irradiation (APBI) has emerged as an option to reduce treatment duration with comparable clinical outcomes. The purpose of this analysis is to present long-term clinical outcomes between WBI and APBI. METHODS: A total of 3009 patients were treated with breast conserving therapy at a single institution between 1980 and 2012. Among them, 2528 patients received WBI and 481 received APBI (interstitial or balloon based). A matched-pair analysis was performed with patients matched by age (±3 years), stage (T-stage vs. T1 vs. T2), and estrogen receptor status (+/-). All patients had a minimum of 12 months follow-up. A total of 274 matches (ratio 1:1) were made. RESULTS: No differences between groups were noted with respect to clinicopathologic features; WBI patients demonstrated a trend for slightly larger tumors (1.3 vs. 1.1 cm, P=0.06). At 10 years, no differences were noted with respect to rates of ipsilateral breast tumor recurrence (4% vs. 4%, P=0.11), regional recurrence (1% vs. 1%, P=0.20), contralateral breast failure (9% vs. 3%, P=0.06), or distant metastases (3% vs. 6%, P=0.47) for WBI and APBI, respectively. In addition, 10-year disease-free survival (93% vs. 91%, P=0.10) and overall survival (83% vs. 75%, P=0.34) were similar. Long-term cosmesis was good to excellent in 94% of WBI patients versus 95% of APBI patients (P=0.78). CONCLUSIONS: At 10 years, no differences in recurrence or survival were found between patients undergoing WBI or brachytherapy-based APBI.

Comparison of chronic toxicities between brachytherapy-based accelerated partial breast irradiation and whole breast irradiation using intensity modulated radiotherapy.

PURPOSE: Brachytherapy-based APBI (bAPBI) shortens treatment duration and limits dose to normal tissue. While studies have demonstrated similar local control when comparing bAPBI and whole breast irradiation using intensity modulated radiotherapy (WBI-IMRT), comparison of late side effects is limited. Here, we report chronic toxicity profiles associated with these two treatment modalities. METHODS: 1034 patients with early stage breast cancer were treated at a single institution; 489 received standard-fractionation WBI-IMRT between 2000 and 2013 and 545 received bAPBI (interstitial 40%, applicator-based 60%) between 1993 and 2013. Chronic toxicity was evaluated ≥6 months utilizing CTCAE version 3.0; cosmesis was evaluated using the Harvard scale. RESULTS: Median follow-up was 4.6 years (range 0.1-13.4) for WBI-IMRT versus 6.7 years (range 0.1-20.1) for bAPBI (p < 0.001). Compared to WBI-IMRT, bAPBI was associated with higher rates of ≥grade 2 seroma formation (14.4% vs 2.9%, p < 0.001), telangiectasia (12.3% vs 2.1%, p = 0.002) and symptomatic fat necrosis (10.2% vs 3.6%, p < 0.001). Lower rates of hyperpigmentation were observed (5.8% vs 14.5%; p = 0.001). Infection rates were similar (3.3% vs 1.3%, p = 0.07). There was no difference between rates of fair (6.1% vs. 4.1%, p = 0.30) or poor (0.2% vs. 0.5%, p = NS) cosmesis. Mastectomy rates for local recurrence (3.1% for WBI-IMRT and 1.2% for bAPBI, p = 0.06), or for other reasons (0.8% and 0.6%, p = 0.60) were similar between groups. CONCLUSION: With 5-year follow-up, WBI-IMRT and bAPBI are associated with similar, acceptable rates of toxicity. These data further support the utilization of bAPBI as a modality to deliver adjuvant radiation in a safe and efficacious manner.

Combination therapy improves prostate cancer survival for patients with potentially lethal prostate cancer: The impact of Gleason pattern 5.

PURPOSE: To investigate the impact of Gleason pattern 5 (GP5) prostate cancer after either external beam radiotherapy (EBRT) or the combination of EBRT with low-dose rate brachytherapy boost (combo). METHODS AND MATERIALS: Between 1998 and 2008, 467 patients with National Comprehensive Cancer Network high-risk prostate cancer were treated with EBRT (n = 326) or combo (low-dose rate to 90-108 Gy using I-125 followed by EBRT) (n = 141). Freedom from biochemical failure, freedom from metastasis (FFM), cancer-specific survival (CSS), and overall survival were evaluated. RESULTS: Combo patients were younger (66 vs. 72 years, p < 0.001) and had fewer comorbidities (Charlson comorbidity index 3.7 vs. 4.4, p < 0.001). EBRT patients had higher tumor stages (T3-4: 30% vs. 21%, p = 0.03) and lower Gleason scores (8-10: 61% vs. 75%, p = 0.01). Androgen deprivation therapy use was similar between cohorts (85% vs. 87%, p = 0.5), but EBRT patients had longer androgen deprivation therapy use (median 14 vs. 12 months, p = 0.05). GP5 predicted worse FFM (p < 0.001, hazard ratio [HR] 3.3, 95% confidence interval [CI]1.8-6.2]) and CSS (p < 0.001, HR 5.9, 95% CI 2.7-12.9) for the EBRT group, but not for the combo group (p = 0.86, HR 0.48, 95% CI 0.1-2.4 for metastasis and p = 0.5, HR 1.6, 95% CI 0.33-8.0 for CSS). In those with GP5 (n = 143), combo was associated with improved outcomes in all endpoints. On univariate analysis, 5-year outcomes for combo vs. EBRT were as follows: freedom from biochemical failure 89% vs. 65%, FFM 89% vs. 67%, CSS 93% vs. 78%, and overall survival 88% vs. 67% (p < 0.05 for all). CONCLUSION: Combo was associated with improved outcomes for men with GP5 prostate cancer. This highlights the importance of local therapy, especially in patients with the highest pathologic grade disease.

Twenty-year outcomes after breast-conserving surgery and definitive radiotherapy for mammographically detected ductal carcinoma in situ.

BACKGROUND: Management of mammographically detected ductal carcinoma in situ (DCIS) at a single institution was reviewed to determine long-term clinical outcomes after treatment with breast-conserving therapy (BCT). METHODS: Data from all patient-cases with DCIS who received BCT between 1980 and 1993 were reviewed. Patient demographics and pathologic factors were analyzed for their effect on outcomes, including ipsilateral breast tumor recurrence (IBTR) and survival. BCT included breast-conserving surgery followed by external-beam radiotherapy to the whole breast, with 86 % of patients receiving a lumpectomy cavity boost. The median dose to the whole breast was 50 Gy and 60.4 Gy to the lumpectomy cavity. RESULTS: A total of 129 cases were evaluated; the median follow-up was 19.3 years. Twenty-one patients developed an ipsilateral breast tumor recurrence (IBTR), 76.2 % of which were invasive (n = 16). Fourteen recurrences (66 %) were within the same breast quadrant (true recurrence), while an additional 7 cases developed an IBTR elsewhere in the breast. True recurrences were more prevalent in women <45 years of age (20 %/24 % vs. 5.1 %/8 %) at 10 and 20 years (p = 0.02). The 5-, 10-, 15-, and 20-year actuarial rates of IBTR for this cohort were 8.7, 10.4, 12.1, and 16.3 % (IBTR), while overall survival at 5, 10, and 20 years was 97.6, 96.8, and 96.8 %, respectively. CONCLUSIONS: Mammographically detected DCIS remains a clinically distinct subset of noninvasive breast cancer. With 20 year follow-up, local control and overall survival are excellent after BCT.