Citations

PurposeTo examine the value of surgical resection combined with preoperative external beam radiation therapy and intraoperative radiation therapy (Surg‐RT) for retroperitoneal sarcoma (RPS).MethodsReview of 63 consecutive patients with RPS from 1996 to 2011.ResultsThirty‐seven patients (59%) underwent Surg‐RT and 26 (41%) had surgery alone. 51% of tumors were high grade and 36% of patients had locally recurrent disease. Final margin status was: R0 73%, R1 16%, R2 6%, and unknown 5%. Of those with R0 resections, 67% received Surg‐RT. Median follow‐up was 45 months. The 5‐year local control rate was 89% for Surg‐RT patients and 46% for surgery alone patients (P = 0.03). On multivariate analysis, Surg‐RT was the only variable associated with a lower risk of LR (HR 0.19; CI 0.05–0.69, P = 0.003). The actuarial 5‐year OS was 60% for patients receiving either Surg‐RT or surgery alone.ConclusionsThe combination of pre‐operative radiation, surgical resection, and intraoperative radiation produces excellent local disease control for RPS. Combination therapy was associated with improved local control but not with overall survival. J. Surg. Oncol. 2014 109:798–803. © 2014 Wiley Periodicals, Inc.

Purpose Indications for sentinel lymph node biopsy (SLNB) for thin melanoma are continually evolving. We present a large multi-institutional study to determine factors predictive of sentinel lymph node (SLN) metastasis in thin melanoma. Patients and Methods Retrospective review of the Sentinel Lymph Node Working Group database from 1994 to 2012 identified 1,250 patients who had an SLNB and thin melanomas (≤ 1 mm). Clinicopathologic characteristics were correlated with SLN status and outcome. Results SLN metastases were detected in 65 (5.2%) of 1,250 patients. On univariable analysis, rates of Breslow thickness ≥ 0.75 mm, Clark level ≥ IV, ulceration, and absence of regression differed significantly between positive and negative SLN groups (all P < .05). These four variables and mitotic rate were used in multivariable analysis, which demonstrated that Breslow thickness ≥ 0.75 mm (P = .03), Clark level ≥ IV (P = .05), and ulceration (P = .01) significantly predicted SLN metastasis with 6.3%, 7.0%, and 11.6% of the patients with these respective characteristics having SLN disease. Melanomas < 0.75 mm had positive SLN rates of < 5% regardless of Clark level and ulceration status. Median follow-up was 2.6 years. Melanoma-specific survival was significantly worse for patients with positive versus negative SLNs (P = .001). Conclusion Breslow thickness ≥ 0.75 mm, Clark level ≥ IV, and ulceration significantly predict SLN disease in thin melanoma. Most SLN metastases (86.2%) occur in melanomas ≥ 0.75 mm, with 6.3% of these patients having SLN disease, whereas in melanomas < 0.75 mm, SLN metastasis rates are < 5%. By using a 5% metastasis risk threshold, SLNB is indicated for melanomas ≥ 0.75 mm, but further study is needed to define indications for SLNB in melanomas < 0.75 mm.

BACKGROUNDData suggest that weight, and specifically body mass index (BMI), plays a role in breast cancer development and outcome. The authors hypothesized that there would be a correlation between BMI and clinical outcome in patients with early stage, human epidermal receptor 2 (HER2)‐positive breast cancer enrolled in the N9831 adjuvant trial.METHODSPatients were grouped according to baseline BMI as follows: normal (BMI <25 kg/m2), overweight (BMI ≥25 kg/m2 and <30 kg/m2), and obese (BMI ≥30 kg/m2). Disease‐free survival (DFS) was estimated using the Kaplan‐Meier method. Comparisons between treatment arms A, B, and C (chemotherapy with or without trastuzumab) were performed using a stratified Cox proportional hazards model.RESULTSAnalysis was completed on 3017 eligible patients. Obese patients were more likely to be older and postmenopausal (P < .0001 for both), to have larger tumors (P = .002), and to have positive lymph nodes (P = .004). In the pooled analysis cohort, differences in DFS among the BMI groups were statistically significant (5‐year DFS rate: 82.5%, 78.6%, and 78.5% for normal weight, overweight, and obese women, respectively; log‐rank P = .02). The adjusted hazard ratio comparing the DFS of overweight women with the DFS of normal women was 1.30 (95% confidence interval, 1.06‐1.61); and, comparing the DFS of obese women with the DFS normal women, the adjusted hazard ratio was 1.31 (95% confidence interval, 1.07‐1.59). There were no statistically significant differences in DFS by weight group for women within any trial arm.CONCLUSIONSPatients with early stage, HER2‐positive breast cancer and normal BMI had a better 5‐year DFS compared with overweight and obese women. The current results indicated that adjuvant trastuzumab improves clinical outcome regardless of BMI. Cancer 2013;119:2447‐2454. © 2013 American Cancer Society.

Breast cancer is the most common malignancy among women in the United States with the second highest incidence of cancer-related death following lung cancer. The decision-making process regarding adjuvant therapy is a time intensive dialogue between the patient and her oncologist. There are multiple tools that help individualize the treatment options for a patient. Population-based analysis with Adjuvant! Online and genomic profiling with Oncotype DX are two commonly used tools in patients with early stage, node-negative breast cancer. This case report illustrates a situation in which the population-based prognostic and predictive information differed dramatically from that obtained from genomic profiling and affected the patient’s decision. In light of this case, we discuss the benefits and limitations of these tools.

Purpose Symptoms and complications of metastatic colorectal cancer (mCRC) differ by metastatic sites. There is a paucity of prospective survival data for patients with peritoneal carcinomatosis colorectal cancer (pcCRC). We characterized outcomes of patients with pcCRC enrolled onto two prospective randomized trials of chemotherapy and contrasted that with other manifestations of mCRC (non-pcCRC). Methods A total of 2,095 patients enrolled onto two prospective randomized trials were evaluated for overall survival (OS) and progression-free survival (PFS). A Cox proportional hazard model was used to assess the adjusted associations. Results The characteristics of the pcCRC group (n = 364) were similar to those of the non-pcCRC patients in median age (63 v 61 years, P = .23), sex (57% males v 61%, P = .23), and performance status (Eastern Cooperative Oncology Group performance status 0 or 1 94% v 96%, P = .06), but differed in frequency of liver (63% v 82%, P < .001) and lung metastases (27% v 34%, P = .01). Median OS (12.7 v 17.6 months, hazard ratio [HR] = 1.3; 95% CI, 1.2 to 1.5; P < .001) and PFS (5.8 v 7.2 months, HR = 1.2; 95% CI, 1.1 to 1.3; P = .001) were shorter for pcCRC versus non-pcCRC. The unfavorable prognostic influence of pcCRC remained after adjusting for age, PS, liver metastases, and other factors (OS: HR = 1.3, P < .001; PFS: HR = 1.1, P = .02). Infusional fluorouracil, leucovorin, and oxaliplatin was superior to irinotecan, leucovorin, and fluorouracil as a first-line treatment among pcCRC (HR for OS = 0.62, P = .005) and non-pcCRC patients (HR = 0.66, P < .001). Conclusion pcCRC is associated with a significantly shorter OS and PFS as compared with other manifestations of mCRC. Future trials for mCRC should consider stratifying on the basis of pcCRC status.

Abstract Background: Trastuzumab (H) improves disease-free survival (DFS) in patients (pts) with HER2 positive breast cancer (BR Ca) when used with adjuvant chemotherapy. We herein compare the rates of local regional recurrence (LRR) in pts randomized to adjuvant chemotherapy with or without adjuvant H. Methods: The phase 3 randomized trial NCCTG N9831 enrolled 3505 pts with high risk HER2 positive Br Ca to evaluate the effect of adjuvant H on DFS. Pts were randomized to either doxorubicin (A) and cyclophosphamide (C) followed by paclitaxel (T); or AC→TH→H. RT was given concurrently with H after ACT chemotherapy. Pts analyzed underwent lumpectomy (L) + radiotherapy (RT), mastectomy (M) alone, or M+RT. All pts underwent sentinel lymph node biopsy alone and/or axillary dissection. 2816 pts were eligible for competing risk analysis of LRR as a first event (competing risks were distant recurrence, contralateral Br Ca, second primary cancer, or death). Median follow-up is 5.3 years. Results: Primary breast therapy included L+RT 1062 (38%), M 711 (25%), and M+RT 1043 (37%). Axillary dissection was performed in 90% of pts but less frequently with L+RT (83%) compared to M (88%) or M+RT (98%), chi-sq P&lt;0.001. Stage at presentation was I 41%, II 51%, and III 8% with a significant greater proportion of higher stage pts undergoing M+RT, chi-sq P&lt;0.001. Overall the 5-year LRR rate was 4.1% (95% CI 3.5-4.9%) and similar among the treatment groups: L+RT 4.7% (95% CI 3.6-6.1%), M 3.5% (95% CI 2.4-5.1%), and M+RT 2.3% (95% CI 1.6-3.4%). Among pts with a LRR, 66% were local recurrence only, 11% were local-regional, and 23% were regional only. In the L+RT patients with a LRR, the corresponding rates were 74%, 7%, and 19%, respectively. In the M patients with a LRR, the corresponding rates were 40%, 23%, and 37%, respectively. In the M+RT patients with LRR, the rates were 79%, 4%, and 17%, respectively. H is associated with a non-statistically significant reduction in the risk of LRR for pts who receive L+RT or M+RT (Table 1). No such trend was seen in the M alone group but the number of events was low. Table 1. LRR According to Local and Adjuvant Treatment Groups Conclusion: The LRR as the first reported site of failure was low with a median 5. 3 year follow-up. Adjuvant H was associated with a trend of lower LRR in the pts treated with L + RT or M+RT. This observation suggests an additive effect of RT and H on LRR that warrants further investigation. The small number of local-regional events in this one randomized trial supports further investigation of LRR across other adjuvant trastuzumab trials. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-13-02.

Abstract It has long been known that immune suppression is induced by the presence of a tumor, resulting in compromised T cell and dendritic cell (DC) functionality. What is not well understood is how soon the immune system recovers normal functionality following surgical removal of tumors and adjuvant therapy. This timing is of critical importance, as the effectiveness of therapeutic immune strategies relies on optimal presentation of antigens and activation of T cells. Blood from breast cancer patients was collected prior to surgery and at 3 and 6 months post adjuvant therapy. Patients were treated with surgery (breast conservation or mastectomy) and chemotherapy (CT) (n=22) or surgery without chemotherapy (n=38). Most patients had radiation therapy (RT). Blood from 22 healthy woman of similar age served as controls. T cell functionality (TCF) was determined following stimulation with plate-bound anti-CD3 (1 µg/ml) and anti-CD28 (0.5 µg/ml) and proliferation was measured by 3H-thymidine uptake. DC functionality (DCF) was determined by ability to present allo-antigens in a mixed lymphocyte reaction. Values for the normal samples determined the normal ranges (NR). Responses were grouped into 4 categories based on their status at 6 months: Group 1 - remained in NR; Group 2 - climbed into NR; Group 3 - remained below NR; Group 4 - fell below NR. Analysis of immunosuppression will be based on lymphocyte subsets, cytokine, COX-2, and PGE2 metabolite levels.T Cell Proliferation AllWith CTNo CT N=60N=22N=38Group 120%14%24%Group 223%23%24%Group 338%41%37%Group 418%23%16% DC Function AllWith CTNo CT N=58N=20N=38Group 143%35%47%Group 219%25%16%Group 317%15%18%Group 421%25%18% Forty-three percent of patients had normal levels (Groups 1 and 2) for TCF and 62% for DCF by 6 months post adjuvant therapy, suggesting that breast cancer patients are potentially amenable to vaccine therapy. 28% of patients had both TCF and DCF in NR; 50% had either TCF or DCF in NR; and 22% had neither in NR. The percentage of patients who had TCF in NR by adjuvant therapy was: 35% CT+RT (6/17); 33% CT (1/3); 52% (17/33) RT; and 20% (1/5) neither. The percentage of patients who had DCF in NR by adjuvant therapy was: 67% (10/15) CT+RT; 33% (1/3) CT; 67% (22/33) RT; and 40% (2/5) neither. Proper understanding of the effects of tumor, chemotherapy and radiation therapy on immune function, especially the effects on T cells and DCs, may enable us to identify the appropriate patients in whom to study immunotherapy approaches in women with early breast cancer and to examine strategies to counteract cancer-related defects in immune function. (supported by P50CA116201) Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4131.

Abstract Abstract #5110 Background: It has been demonstrated that certain chemotherapeutic drugs such as taxanes increases cyclooxygenase-2 (COX-2) levels. Upregulation of COX-2 may be a resistance mechanism of the tumor, or a method to modulate toxic effects of the agent. COX-2 is associated with less differentiated and more aggressive breast cancers, and the expression may be a prognostic indicator of disease. Studies defining the “true” impact of therapy on COX-2 activity are lacking. Hypothesis: Chemotherapy increases COX-2 function in patients with invasive breast cancer. This leads to increased PGE2, VEGF, and downregulation of immune responses. Objective: Patients with stage II or III breast cancer were enrolled in a phase II preoperative chemotherapy trial of docetaxel and carboplatin administered every two weeks (4 cycles). We evaluated circulating PGE2, VEGF, and immune cell phenotype at diagnosis and after chemotherapy. Results: Fifty seven patients were enrolled in the study and 32 were analyzed in the lab, most of them being infiltrating ductal carcinoma. Four had complete response, 20 had partial response, and 8 were non-responders. Due to low numbers of patients analyzed, statistical significance was not achieved in most instances. Nevertheless, intriguing data has been generated that warrants further investigation. VEGF/PGE2 versus clinical response to chemotherapy: 86% of the patients in whom VEGF levels decrease post chemotherapy were responders compared to 60% in which VEGF remained unchanged or increased slightly. Responders had decreased VEGF levels on average, while the non-responders increased. Interestingly, even with low sample size, if both VEGF and PGE2 levels increase post treatment the response rate to chemotherapy is significantly lower (55% versus 88% if both VEGF and PGE2 decrease post treatment, p=0.05). Thus, both VEGF and PGE2 are critical factors in determining response rate. Whether COX-2 activity is driving both factors or whether VEGF is independently regulated is yet to be determined. Clinical Response versus Dendritic cell (DCs) / T-cell data: Data revealed highly important trends that warrant future investigation. Patients with increased B7H4 (an immunosuppressive molecule expressed on tolerizing DCs) were non-responders while patients with decreased B7H4 were responders. In contrast, responders had increased levels of CD80 and CD86 (co-stimulatory molecules expressed on activating DCs). VEGF/PGE2 Change versus Dendritic/T-cell data: When VEGF increased post treatment, B7H4 and FoxP3 (T regulatory cells) increased, while CD80, CD86, and CD8 decreased. The association between VEGF and immune cells post chemotherapy treatment is the first indication that VEGF may regulate immune cell function possibly independent of COX-2 activity. These data suggest that anti-VEGF therapy (which may include COX-2 inhibitor) may not only augment responses to chemotherapy but may also augment immune responses post chemotherapy. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5110.