Elyn Riedel

Prevalence of Lymphedema in Women With Breast Cancer 5 Years After Sentinel Lymph Node Biopsy or Axillary Dissection: Objective Measurements

PURPOSE Sentinel lymph node biopsy was adopted for the staging of the axilla with the assumption that it would reduce the risk of lymphedema in women with breast cancer. The aim of this study was to determine the long-term prevalence of lymphedema after SLN biopsy (SLNB) alone and after SLNB followed by axillary lymph node dissection (SLNB/ALND). PATIENTS AND METHODS At median follow-up of 5 years, lymphedema was assessed in 936 women with clinically node-negative breast cancer who underwent SLNB alone or SLNB/ALND. Standardized ipsilateral and contralateral measurements at baseline and follow-up were used to determine change in ipsilateral upper extremity circumference and to control for baseline asymmetry and weight change. Associations between lymphedema and potential risk factors were examined. RESULTS Of the 936 women, 600 women (64%) underwent SLNB alone and 336 women (36%) underwent SLNB/ALND. Patients having SLNB alone were older than those having SLNB/ALND (56 v 52 years; P < .0001). Baseline body mass index (BMI) was similar in both groups. Arm circumference measurements documented lymphedema in 5% of SLNB alone patients, compared with 16% of SLNB/ALND patients (P < .0001). Risk factors associated with measured lymphedema were greater body weight (P < .0001), higher BMI (P < .0001), and infection (P < .0001) or injury (P = .02) in the ipsilateral arm since surgery. CONCLUSION When compared with SLNB/ALND, SLNB alone results in a significantly lower rate of lymphedema 5 years postoperatively. However, even after SLNB alone, there remains a clinically relevant risk of lymphedema. Higher body weight, infection, and injury are significant risk factors for developing lymphedema.

Frequency and Distinctive Spectrum of KRAS Mutations in Never Smokers with Lung Adenocarcinoma

Purpose:KRAS mutations are found in ∼25% of lung adenocarcinomas in Western countries and, as a group, have been strongly associated with cigarette smoking. These mutations are predictive of poor prognosis in resected disease as well as resistance to treatment with erlotinib or gefitinib. Experimental Design: We determined the frequency and type of KRAS codon 12 and 13 mutations and characterized their association with cigarette smoking history in patients with lung adenocarcinomas. Results:KRAS mutational analysis was done on 482 lung adenocarcinomas, 81 (17%) of which were obtained from patients who had never smoked cigarettes. KRAS mutations were found in 15% (12 of 81; 95% confidence intervals, 8-24%) of tumors from never smokers. Similarly, 22% (69 of 316; 95% confidence intervals, 17-27%) of tumors from former smokers, and 25% (21 of 85; 95% confidence intervals, 16-35%) of tumors from current smokers had KRAS mutations. The frequency of KRAS mutation was not associated with age, gender, or smoking history. The number of pack years of cigarette smoking did not predict an increased likelihood of KRAS mutations. Never smokers were significantly more likely than former or current smokers to have a transition mutation (G→A) rather than the transversion mutations known to be smoking-related (G→T or G→C; P < 0.0001). Conclusions: Based on our data, KRAS mutations are not rare among never smokers with lung adenocarcinoma and such patients have a distinct KRAS mutation profile. The etiologic and biological heterogeneity of KRAS mutant lung adenocarcinomas is worthy of further study.

Histologic subtype and margin of resection predict pattern of recurrence and survival for retroperitoneal liposarcoma.

Objective The aim of this study was to determine the pattern of recurrence and prognostic significance of histologic subtype in a large series of patients with primary retroperitoneal liposarcoma. Summary Background Data Classification of liposarcoma into subtypes, based on morphologic features and cytogenetic aberrations, is now widely accepted. Previous studies have shown that high histologic grade and incomplete gross resection are the most important prognostic factors for survival in patients with retroperitoneal sarcoma and suggest that patients with liposarcoma have a 3-fold higher risk of local recurrence compared with other histologies. Methods A prospective database was used to identify 177 patients with primary retroperitoneal liposarcoma treated between July 1982 and June 2002. Histology at primary presentation was reviewed by a sarcoma pathologist and subtyped into 4 distinct groups according to strict criteria. The influence of clinicopathological factors on local recurrence, distant recurrence, and disease-specific survival was analyzed. Results Of 177 patients with primary retroperitoneal liposarcoma operated on for curative intent, 99 (56%) presented with well-differentiated, 65 (37%) with dedifferentiated, 9 (5%) with myxoid, and 4 (2%) with round cell morphology. The tumor burden was determined by the sum of the maximum tumor diameters. The median tumor burden was 26 cm (5–139). Median follow-up time for 92 (52%) surviving patients was 37 (mean, 0.5–192) months. Multivariate analysis showed that dedifferentiated liposarcoma subtype was associated with a 6-fold increased risk of death compared with well-differentiated histology (P < 0.0001). In addition to histologic subtype, incomplete resection (P < 0.0001), contiguous organ resection (excluding nephrectomy; P = 0.05), and age (P = 0.03) were important independent prognostic factors for survival in retroperitoneal liposarcoma. Retroperitoneal dedifferentiated liposarcoma was associated with an 83% local recurrence rate and 30% distant recurrence rate at 3 years. Conclusions The histologic subtype and margin of resection are prognostic for survival in primary retroperitoneal liposarcoma. Dedifferentiated histologic subtype and the need for contiguous organ resection (excluding nephrectomy) was associated with an increase risk of local and distant recurrence. Nephrectomy may be needed to achieve complete resection, but has no measurable influence on disease specific survival.

Long-term outcome of low-grade oligodendroglioma and mixed glioma

Background: Low-grade oligodendrogliomas and mixed gliomas can be indolent and remain unchanged for years. Optimal timing and effectiveness of initial treatment is uncertain and therapy can be associated with toxicity. Methods: Retrospective review of patients diagnosed between 1979 and 1997 with low-grade oligodendroglioma or mixed glioma. Time to progression, survival, prognostic factors, and treatment toxicities were evaluated. Results: A total of 106 patients (77 oligodendroglioma, 29 mixed glioma) were identified; median age was 36.7 years. Initial presenting symptoms were seizures in 76 (72%) and headache in 11 (10%); tumor was diagnosed as an incidental finding in five patients. Tumor progression was diagnosed in 72 patients (68%). Overall median time to progression (MTTP) was 5.0 years (range 0.5 to 14.2). Median overall survival (OS) was 16.7 years. No prognostic factors reached statistical significance. MTTP and OS were not significantly affected by treatment. Of 62 patients who received radiation therapy, 9 (15%) developed radiation necrosis and 13 developed radiation therapy–related cognitive changes, requiring ventriculoperitoneal shunting in six. Significant myelosuppression was seen in 35 of 76 (46%) patients treated with chemotherapy. Conclusions: Low-grade oligodendroglioma and mixed glioma have a long median overall survival. There were no apparent differences in either immediate versus deferred treatment or choice of initial therapy on disease-free or overall survival. Chemotherapy was associated with significant acute toxicity in almost one half of patients; radiation therapy produced late neurotoxicity in one third, justifying deferred treatment until clinically necessary.

Predicting Complications following Expander/Implant Breast Reconstruction : An Outcomes Analysis Based on Preoperative Clinical Risk

Background: Complications following postmastectomy reconstruction can cause significant morbidity. The compound effect of individual risk factors on the development of complications following expander/implant reconstruction has not, however, been well delineated. This study evaluated the impact of clinical risk factors to predict complications following postmastectomy expander/implant reconstruction. Methods: From 2003 through 2004, 1170 expander/implant reconstructions were performed at a single center. A prospectively maintained database was reviewed. Variables including age, smoking status, body mass index, history of diabetes, hypertension, chemotherapy and/or radiation, as well as timing and laterality of reconstruction were evaluated. The primary endpoint was the development of a complication; the secondary endpoint was failure of reconstruction. Results: Over the 2 year study period, 1170 expander/implant reconstructions were performed in 884 patients. The odds of developing complications was 2.2 times greater in smokers (p < 0.001) and 2.5 times greater in women over 65 (p = 0.008). Patients who were obese were at nearly two times the odds of having complications (p = 0.02), as were patients with hypertension (p = 0.02). Similarly, the odds of reconstructive failure were five times greater in smokers (p < 0.001). Age was not a significant predictor of reconstructive failure (p = 0.09); yet, failure was nearly seven times greater in obese patients (p < 0.001), and four more times likely in those who were hypertensive (p = 0.005). Conclusions: Smoking, obesity, hypertension, and age over 65 were independent risk factors for perioperative complications following expander/implant breast reconstruction. Smoking, obesity, and hypertension were similarly associated with reconstructive failure. This information can be used to evaluate overall procedural risks and individualize reconstructive options.

Phase II Study of Doxorubicin and Bevacizumab for Patients With Metastatic Soft-Tissue Sarcomas

PURPOSE To evaluate the antitumor activity and tolerability of bevacizumab and doxorubicin in patients with metastatic soft-tissue sarcoma (STS). PATIENTS AND METHODS Patients may have had up to one nonanthracycline line of therapy. Seventeen patients with metastatic STS were treated with doxorubicin at 75 mg/m2 intravenous (IV) push followed by bevacizumab 15 mg/kg IV every 3 weeks. Dexrazoxane was started for total doxorubicin dose exceeding 300 mg/m2. RESULTS A total of 85 cycles of doxorubicin/bevacizumab were administered, median four cycles (range, one to 11), with three patients receiving one to four cycles of bevacizumab maintenance after reaching 600 mg/m2 doxorubicin. All 17 patients were assessable for response. Two partial responses (12%, 95% CI = 1% to 36%) were observed, lasting seven and 12 cycles of therapy. Eleven patients (65%) had stable disease for four cycles or more. Six patients developed cardiac toxicity grade 2 or greater, with four patients grade 2 (cumulative doxorubicin 75, 150, 300, 300 mg/m2, respectively), one grade 3 (total doxorubicin 591 mg/m2), and one grade 4 (total doxorubicin 420 mg/m2). One patient with extensive lung disease died of recurrent bilateral pneumothoraces, possibly treatment-related. CONCLUSION The 12% response rate for these patients was no greater than that observed for single-agent doxorubicin. However, the 65% of patients with stable disease lasting four cycles or longer suggests further study is warranted in STSs. The observed cardiac toxicity, despite close monitoring and standard use of dexrazoxane, obliges a change in the dose and/or schedule in future studies of this combination.

cT3N0 Rectal Cancer: Potential Overtreatment With Preoperative Chemoradiotherapy Is Warranted

PURPOSE Although combined-modality therapy (CMT) is the preferred treatment for T3 and/or lymph node (LN)-positive rectal cancer, the German rectal cancer study published in 2004 demonstrated that 18% of patients deemed suitable for preoperative CMT by endorectal ultrasound (ERUS) may be overstaged. Because data also suggest that LN-negative rectal cancer after total mesorectal excision may not require radiotherapy, it is reasonable to consider omitting radiotherapy for the cT3N0 subset. We therefore determined the accuracy of pre-CMT ERUS or magnetic resonance imaging (MRI) staging, to explore the validity of a nonpreoperative CMT approach for cT3N0 disease. PATIENTS AND METHODS One hundred eighty-eight ERUS-/MRI-staged T3N0 rectal cancer patients received preoperative CMT (fluorouracil based and 45-50.4 Gy) followed by radical resection. Rates of pathologic complete response (pCR) and mesorectal LN involvement were determined. RESULTS Tumors were located a median of 5 cm from the anal verge. Sphincter-preserving surgery was performed in 143 patients (76%). Overall pCR was 20%, and 41 patients (22%) had pathologically positive mesorectal LNs. The incidence of positive LNs significantly increased with T stage: ypT0, 3%; ypT1, 7%; ypT2, 20%; ypT3-4, 36% (P = .001). CONCLUSION The accuracy of preoperative ERUS/MRI for staging mid to distal cT3N0 rectal cancer is limited because 22% of patients have undetected mesorectal LN involvement despite CMT. Therefore, ERUS-/MRI-staged T3N0 rectal cancer patients should continue to receive preoperative CMT. Although 18% may be overstaged and therefore overtreated, our data suggest that an even larger number would be understaged and require postoperative CMT, which is associated with significantly inferior local control, higher toxicity, and worse functional outcome.

Adequacy of 1-cm Distal Margin After Restorative Rectal Cancer Resection With Sharp Mesorectal Excision and Preoperative Combined-Modality Therapy

Background: Preoperative combined-modality therapy (CMT) for rectal cancer allows a sphincter-sparing procedure in some individuals who would otherwise require an abdominoperineal resection. To further define the subset of rectal cancer patients suitable for this approach, we determined the adequacy of a distal margin of ≤1 cm in patients with locally advanced rectal cancer requiring preoperative CMT.Methods: Ninety-four consecutive patients, status post curative low anterior resection for rectal cancer after preoperative CMT, were identified from the prospective Colorectal Service Database. Distal margin length, tumor grade, tumor-node-metastasis stage, presence of lymphovascular and perineural invasion, and tumor distance from the anal verge were examined for their effect on recurrence and survival. Median follow-up was 44 months.Results: Distal margin length ranged from .1 to 9.5 cm (median, 2.0 cm) and did not correlate with local recurrence (hazard ratio, 1.1; P = .34) or recurrence-free survival (hazard ratio, 1.1; P = .29) by univariate analysis. Kaplan-Meier estimates of recurrence-free survival and local recurrence at 3 years for the ≤1 cm versus >1 cm and the ≤2 cm versus >2 cm groups were not significantly different. Groups were well matched for other clinicopathologic variables.Conclusions: Our data suggest that for patients with locally advanced rectal cancer undergoing resection and preoperative CMT, distal margins ≤1 cm do not seem to compromise oncological outcome.

Chemotherapy Is Associated With Improved Survival in Adult Patients With Primary Extremity Synovial Sarcoma

Purpose:To determine if ifosfamide-based chemotherapy (IF) offers a survival benefit to adult patients with primary extremity synovial sarcoma. Patients and Methods:Prospectively collected patient data from 2 institutions was used to identify all adult patients (≥16 years) with ≥5 cm, deep, primary, extremity, synovial sarcoma that underwent surgical treatment of cure from 1990 to 2002. A total of 101 patients were identified and the median follow-up for survivors was 58 months. Clinical, pathologic, and treatment variables were analyzed for disease-specific survival (DSS), distant recurrence-free survival (DRFS), and local recurrence-free survival (LRFS). Results:Sixty-eight (67%) patients were treated with IF and 33 (33%) patients received no chemotherapy (NoC) for the primary tumor. The characteristics of the IF-treated patients [median tumor size = 7.2 cm; monophasic n = 46 (68%)] were similar to NoC patients [median tumor size = 7 cm; monophasic n = 23 (70%)]. The 4-year DSS of the IF-treated patients was 88% compared with 67% for the NoC patients (P = 0.01). Smaller size (HR = 0.3 per 5-cm decrease, P < 0.0001) and treatment with IF (HR = 0.3 compared with NoC, P = 0.007) were independently associated with an improved DSS. Treatment with IF was independently associated with an improved DRFS (HR = 0.4, P = 0.03) but not associated with an improved LRFS (P = 0.39). Conclusion:Ifosfamide-based chemotherapy was associated with an improved DSS in adult patients with high-risk, primary, extremity, synovial sarcoma and should be considered in the treatment of such patients.

Prevalence of Lymphedema in Women With Breast Cancer 5 Years After Sentinel Lymph Node Biopsy or Axillary Dissection: Patient Perceptions and Precautionary Behaviors

PURPOSE Sentinel lymph node (SLN) biopsy was adopted for the staging of the axilla with the assumption that it would reduce the risk of lymphedema in women with breast cancer. This study was undertaken to examine patient perceptions of lymphedema and use of precautionary behaviors several years after axillary surgery. PATIENTS AND METHODS Nine hundred thirty-six women who underwent SLN biopsy (SLNB) alone or SLNB followed by axillary lymph node dissection (SLNB/ALND) between June 1, 1999, and May 30, 2003, were evaluated at a median of 5 years after surgery. Patient-perceived lymphedema and avoidant behaviors were assessed through interview and administered a validated instrument, and compared with arm measurements. RESULTS Current arm swelling was reported in 3% of patients who received SLNB alone versus 27% of patients who received SLNB/ALND (P < .0001), as compared with 5% and 16%, respectively, with measured lymphedema. Only 41% of patients reporting arm swelling had measured lymphedema, and 5% of patients reporting no arm swelling had measured lymphedema. Risk factors associated with reported arm swelling were greater body weight (P < .0001), higher body mass index (P < .0001), infection (P < .0001), and injury (P = .007) in the ipsilateral arm since surgery. Patients followed more precautions if they had measured or perceived lymphedema. CONCLUSION Body weight, infection, and injury are significant risk factors for perceiving lymphedema. There is significant discordance between the presence of measured and patient-perceived lymphedema. When compared to SLNB/ALND, SLNB-alone results in a significantly lower rate of patient-perceived arm swelling 5 years postoperatively, and is perceived by fewer women than are measured to have it.