Treatment patterns for ductal carcinoma in situ with close or positive mastectomy margins.

BACKGROUND: Mastectomy remains an effective treatment for ductal carcinoma in situ (DCIS) but whether further therapy is warranted for close or positive margins is controversial. We aim to characterize the treatment practices of DCIS throughout the United States in patients who undergo mastectomy with close or positive margins to better understand the use of postmastectomy radiation therapy (PMRT). MATERIALS AND METHODS: Using the 2004-2013 National Cancer Database, we identified all female patients with a diagnosis of DCIS who underwent mastectomy. Distributional characteristics were summarized for overall and margin-stratified samples. Characteristic differences were assessed by region and receipt of radiation. Chi-square and independent sample t-tests were used to assess differences for categorical and continuous variables, respectively. RESULTS: In 21,591 patients who met inclusion criteria, 470 patients with close/positive margins were identified. Sixteen percent of patients with close/positive margins received PMRT compared to 1.5% with negative margins (P < 0.01). There was no difference in PMRT and patient race, insurance status, treatment facility, or endocrine therapy. Patients with close/positive margins who received PMRT were more likely to be in an urban setting from the Midwest (24.6%) and Northeast (21.8%) compared to the West (11.0%) and South (10.7%) (P < 0.01). CONCLUSIONS: Use of PMRT for DCIS following mastectomy with close/positive margins differs across the country. Regional variations in treatment patterns reinforce a need to determine whether PMRT improves survival to establish treatment guidelines.

Basal Cell Skin Cancer, Version 1.2016, NCCN Clinical Practice Guidelines in Oncology.

Basal cell carcinoma (BCC) of the skin is the most common cancer, with a higher incidence than all other malignancies combined. Although it is rare to metastasize, patients with multiple or frequently recurring BCC can suffer substantial comorbidity and be difficult to manage. Assessment of risk is a key element of management needed to inform treatment selection. The overall management of BCC primarily consists of surgical approaches, with radiation therapy as an alternate or adjuvant option. Many superficial therapies for BCC have been explored and continue to be developed, including topicals, cryosurgery, and photodynamic therapy. Two hedgehog pathway inhibitors were recently approved by the FDA for systemic treatment of advanced and metastatic BCC, and others are in development. The NCCN Guidelines for Basal Cell Skin Cancer, published in full herein, include recommendations for selecting among the various surgical approaches based on patient-, lesion-, and disease-specific factors, as well as guidance on when to use radiation therapy, superficial therapies, and hedgehog pathway inhibitors.

Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Melanoma focuses on adjuvant therapy and treatment of in-transit disease, because substantial changes were made to the recommendations for the 2016 update. Depending on the stage of the disease, options for adjuvant therapy now include biochemotherapy and high-dose ipilimumab. Treatment options for in-transit disease now include intralesional injection with talimogene laherparepvec (T-VEC), a new immunotherapy. These additions prompted re-assessment of the data supporting older recommended treatment options for adjuvant therapy and in-transit disease, resulting in extensive revisions to the supporting discussion sections.

NCCN Guidelines Insights: Melanoma, Version 3.2016.

The NCCN Guidelines for Melanoma have been significantly revised over the past few years in response to emerging data on a number of novel agents and treatment regimens. These NCCN Guidelines Insights summarize the data and rationale supporting extensive changes to the recommendations for systemic therapy in patients with metastatic or unresectable melanoma.

Melanoma, version 4.2014.

The NCCN Guidelines for Melanoma provide multidisciplinary recommendations for the management of patients with melanoma. These NCCN Guidelines Insights highlight notable recent updates. Dabrafenib and trametinib, either as monotherapy (category 1) or combination therapy, have been added as systemic options for patients with unresectable metastatic melanoma harboring BRAF V600 mutations. Controversy continues regarding the value of adjuvant radiation for patients at high risk of nodal relapse. This is reflected in the category 2B designation to consider adjuvant radiation following lymphadenectomy for stage III melanoma with clinically positive nodes or recurrent disease.

Merkel cell carcinoma, version 1.2014.

Merkel cell carcinoma is a rare, aggressive cutaneous tumor that combines the local recurrence rates of infiltrative nonmelanoma skin cancer with the regional and distant metastatic rates of thick melanoma. The NCCN Guidelines for Merkel Cell Carcinoma provide recommendations on the diagnosis and management of this aggressive disease based on clinical evidence and expert consensus. This version includes revisions regarding the use of PET/CT imaging and the addition of a new section on the principles of pathology to provide guidance on the analysis, interpretation, and reporting of pathology results.

Dermatofibrosarcoma protuberans, version 1.2014.

Dermatofibrosarcoma protuberans (DFSP) is an uncommon soft tissue tumor characterized by a relatively high risk of local recurrence and low risk of metastasis. The NCCN Guidelines for DFSP provide multidisciplinary recommendations on the management of patients with this rare disease. These NCCN Guidelines Insights highlight the addition of the Principles of Pathology section, which provides recommendations on the pathologic assessment of DFSP. Because DFSP can mimic other lesions, immunohistochemical studies are often required to establish diagnosis. Cytogenetic testing for the characteristic translocation t(17;22)(q22;q13) can also be valuable in the differential diagnosis of DFSP with other histologically similar tumors.

What is a clear margin in breast conserving cancer surgery?

OPINION STATEMENT: Team work is the key to successful breast conservation therapy. Patient education and the informed consent process should include a discussion about the importance of margin status. Specimen management is critically important to obtain the highest quality information about margins. Operating technique should avoid trauma to or disruption of the specimen surface. The specimen should be oriented for the pathologist using standard techniques including sutures, clips, or colored inks. Specimen radiography is mandatory to confirm complete resection of the target tissues and can be used to direct additional margin resections during the initial procedure. With a well-designed and oriented specimen, the pathologist can give an accurate description of the margin distance for both the invasive and in situ components of the cancer. In most cases, decision-making about margins will be straightforward. Positive margins should be re-excised or the treatment is converted to mastectomy. Clear margins (>5 mm) require no further surgical therapy. "Close" margins (1-4 mm) will remain a point of controversy because of conflicting reports from clinical series. At UAB, decision for re-excision is made on a case-by-case basis. Routinely 2 mm is considered adequate, however, volume of disease and intraductal component are important considerations when making recommendations.

Diversity of stage III melanoma in the era of sentinel lymph node biopsy.

BACKGROUND: Sentinel lymph node (SLN) biopsy for melanoma often detects minimal nodal tumor burden. Although all node-positive patients are considered stage III, there is controversy regarding the necessity of adjuvant therapy for all patients with tumor-positive SLN. METHODS: Post hoc analysis was performed of a prospective multi-institutional study of patients with melanoma ≥ 1.0 mm Breslow thickness. All patients underwent SLN biopsy; completion lymphadenectomy was performed for patients with SLN metastasis. Kaplan-Meier analysis of disease-free survival (DFS) and overall survival (OS) was performed. Univariate and multivariate Cox regression analyses were performed. Classification and regression tree (CART) analysis also was performed. RESULTS: A total of 509 patients with tumor-positive SLN were evaluated. Independent risk factors for worse OS included thickness, age, gender, presence of ulceration, and tumor-positive non-SLN (nodal metastasis found on completion lymphadenectomy). As the number of tumor-positive SLN and the total number of tumor-positive nodes (SLN and non-SLN) increased, DFS and OS worsened on Kaplan-Meier analysis. On CART analysis, the 5-year OS rates ranged from 84.9% (women with thickness < 2.1 mm, age < 59 years, no ulceration, and tumor-negative non-SLN) to 14.3% (men with thickness ≥ 2.1 mm, age ≥ 59 years, ulceration present, and tumor-positive non-SLN). Six distinct subgroups were identified with 5-year OS in excess of 70%. CONCLUSIONS: Stage III melanoma in the era of SLN is associated with a very wide range of prognosis. CART analysis of prognostic factors allows discrimination of low-risk subgroups for which adjuvant therapy may not be warranted.

Melanoma, version 2.2013: featured updates to the NCCN guidelines.

The NCCN Guidelines for Melanoma provide multidisciplinary recommendations on the clinical management of patients with melanoma. This NCCN Guidelines Insights report highlights notable recent updates. Foremost of these is the exciting addition of the novel agents ipilimumab and vemurafenib for treatment of advanced melanoma. The NCCN panel also included imatinib as a treatment for KIT-mutated tumors and pegylated interferon alfa-2b as an option for adjuvant therapy. Also important are revisions to the initial stratification of early-stage lesions based on the risk of sentinel lymph node metastases, and revised recommendations on the use of sentinel lymph node biopsy for low-risk groups. Finally, the NCCN panel reached clinical consensus on clarifying the role of imaging in the workup of patients with melanoma.

Ulceration as a predictive marker for response to adjuvant interferon therapy in melanoma.

OBJECTIVE: This analysis was performed to investigate the hypothesis that ulceration predicts improved response to adjuvant interferon (IFN) therapy. SUMMARY BACKGROUND DATA: Several studies have demonstrated that adjuvant therapy for high-risk melanoma patients with IFN alfa-2b improves disease-free survival (DFS), although the impact on overall survival (OS) is controversial. Recent data have suggested that IFN therapy may preferentially benefit patients with ulcerated primary melanomas. METHODS: Post hoc analysis was performed by a prospective multi-institutional randomized study of observation versus adjuvant IFN therapy for melanoma. All patients underwent sentinel lymph node biopsy; completion lymphadenectomy was performed for patients with sentinel lymph node metastasis. Patients were stratified by Breslow thickness, ulceration, and nodal status. Kaplan-Meier analysis of DFS and OS was performed and included univariate and multivariate analyses. RESULTS: A total of 1769 patients were analyzed (1311 without ulceration, 458 with ulceration) with a median follow-up of 71 months. Ulceration was associated with significantly worse DFS and OS in both node-negative and node-positive patients. Kaplan-Meier analysis of node-negative and node-positive patients by ulceration status revealed that the only significant impact of interferon was improved DFS in the ulcerated node-positive patients (P = 0.0169). IFN therapy had no significant impact on OS regardless of ulceration status, however. On multivariate analysis, IFN treatment was a significant independent predictor of DFS among ulcerated patients (odds ratio, 0.51; 95% confidence interval, 0.30-0.83; P = 0.0053), but not among patients without ulceration. CONCLUSIONS: These data support the conclusion that ulceration is a predictive marker for response to adjuvant IFN therapy. Future studies to evaluate specifically the differential effect of IFN on patients with ulcerated melanomas may allow us to focus this therapy on patients most likely to benefit from it.

Factors associated with false-negative sentinel lymph node biopsy in melanoma patients.

INTRODUCTION: Some melanoma patients who undergo sentinel lymph node (SLN) biopsy will have false-negative (FN) results. We sought to determine the factors and outcomes associated with FN SLN biopsy. METHODS: Analysis was performed of a prospective multi-institutional study that included patients with melanoma of thickness > 1.0 mm who underwent SLN biopsy. FN results were defined as the proportion of node-positive patients who had a tumor-negative sentinel node biopsy. Kaplan-Meier survival analysis and univariate and multivariate analyses were performed. RESULTS: This analysis included 2,451 patients with median follow-up of 61 months. FN, true-positive (TP), and true-negative (TN) SLN results were found in 59 (10.8%), 486 (19.8%), and 1,906 (77.8%) patients, respectively. On univariate analysis comparing the FN with TP groups, respectively, the following factors were significantly different: age (52.6 vs. 47.6 years, p = 0.004), thickness (mean 2.1 vs. 3.1 mm, p = 0.003), lymphovascular invasion (LVI; 3.7 vs. 13.7%, p = 0.037), and local/in-transit recurrence (LITR; 32.2 vs. 12.4%, p < 0.0001); these factors remained significant on multivariate analysis. Overall 5-year survival was greater in the TN group (86.7%) compared with the TP (62.3%) and FN (51.3%) groups (p < 0.0001); however, there was no significant difference in overall survival comparing the TP and FN groups (p = 0.32). CONCLUSIONS: This is the largest study to evaluate FN SLN results in melanoma, with a FN rate of 10.8%. FN results are associated with greater patient age, lower mean thickness, less frequent LVI, and greater risk of LITR. However, survival of patients with FN SLN is not statistically worse than that of patients with TP SLN.

Molecular detection of micrometastatic breast cancer in histopathology-negative axillary lymph nodes fails to predict breast cancer recurrence: a final analysis of a prospective multi-institutional cohort study.

BACKGROUND: To address the clinical relevance of molecular detection of occult breast cancer in sentinel lymph nodes and nonsentinel axillary lymph nodes (ALN), we initiated the Minimally Invasive Molecular Staging of Breast Cancer (MIMS) trial, a multi-institutional prospective cohort study. This trial represents the first prospective cohort study in which a multimarker, real-time reverse transcription polymerase chain reaction (RT-PCR) analysis was applied to the detection of breast cancer micrometastases in ALN. MATERIALS AND METHODS: Sentinel and/or nonsentinel ALN from 501 breast cancer subjects with T1-T3 primary tumors were analyzed by standard histopathology and multimarker, real-time RT-PCR analysis. Seven breast cancer-associated genes (mam, mamB, PIP, CK19, muc1, PSE, and CEA) known to be overexpressed in metastatic breast cancer compared with control lymph nodes were used. Follow-up data were collected for 5 years. RESULTS: Of the 501 breast cancer subjects enrolled, 348 were node negative and completed the 5-year follow-up. Of these patients (n = 94), 27% demonstrated evidence of molecular overexpression. The 5-year relapse-free survival rate was 95.4% (95% confidence interval [95% CI], 92.4-97.2%). No single gene or combination of study genes was predictive of recurrence. CONCLUSIONS: The genes in this study panel failed to be predictive of clinical relapse. This may be a function of several factors: the low event rate at 5 years, the particular gene set, the methodology used for detection/analysis or that our original hypothesis was wrong and that the presence of positive marker signal by real-time RT-PCR is not associated with a worsened clinical outcome.

Second primary melanomas: incidence and outcome.

The objective of this study was to determine the incidence of multiple primary melanomas (MPM) and other cancers types among patients with melanoma. Factors associated with development of MPM were assessed in a post hoc analysis of the database from a multi-institutional prospective randomized trial of patients with melanoma aged 18 to 70 years with Breslow thickness 1 mm or greater. Disease-free survival (DFS) and overall survival (OS) were evaluated by Kaplan-Meier analysis. Forty-eight (1.9%) of 2506 patients with melanoma developed additional primary melanomas. Median follow-up was 66 months. Except in one patient, the subsequent melanomas were thinner (median, 0.32 mm vs. 1.50 mm; P < 0.0001). Compared with patients without MPM, patients with MPM were more likely to be older (median age, 54.5 vs. 51.0 years; P = 0.048), to have superficially spreading melanomas (SSM) (P = 0.025), to have negative sentinel lymph nodes (P = 0.021), or to lack lymphovascular invasion (LVI) (P = 0.008) with the initial tumor. On multivariate analysis, age (P = 0.028), LVI (P = 0.010), and SSM subtype of the original melanoma (P = 0.024) were associated with MPM. Patients with MPM and patients with single primary melanoma had similar DFS (5-year DFS 88.7 vs. 81.3%, P = 0.380), but patients with MPM had better OS (5-year OS 95.3 vs. 80.0%, P = 0.005). Nonmelanoma malignancies occurred in 152 patients (6.1%). Ongoing surveillance of patients with melanoma is important given that a significant number will develop additional melanoma and nonmelanoma tumors. With close follow-up, second primary melanomas are usually detected at an early stage.

Final Results of the Sunbelt Melanoma Trial: A Multi-Institutional Prospective Randomized Phase III Study Evaluating the Role of Adjuvant High-Dose Interferon Alfa-2b and Completion Lymph Node Dissection for Patients Staged by Sentinel Lymph Node Biopsy.

PURPOSE: The Sunbelt Melanoma Trial is a prospective randomized trial evaluating the role of high-dose interferon alfa-2b therapy (HDI) or completion lymph node dissection (CLND) for patients with melanoma staged by sentinel lymph node (SLN) biopsy. PATIENTS AND METHODS: Patients were eligible if they were age 18 to 70 years with primary cutaneous melanoma ≥ 1.0 mm Breslow thickness and underwent SLN biopsy. In Protocol A, patients with a single tumor-positive lymph node after SLN biopsy underwent CLND and were randomly assigned to observation versus HDI. In Protocol B, patients with tumor-negative SLN by standard histopathology and immunohistochemistry underwent molecular staging by reverse transcriptase polymerase chain reaction (RT-PCR). Patients positive by RT-PCR were randomly assigned to observation versus CLND versus CLND+HDI. Primary end points were disease-free survival (DFS) and overall survival (OS). RESULTS: In the Protocol A intention-to-treat analysis, there were no significant differences in DFS (hazard ratio, 0.82; P = .45) or OS (hazard ratio, 1.10; P = .68) for patients randomly assigned to HDI versus observation. In the Protocol B intention-to-treat analysis, there were no significant differences in overall DFS (P = .069) or OS (P = .77) across the three randomized treatment arms. Similarly, efficacy analysis (excluding patients who did not receive the assigned treatment) did not demonstrate significant differences in DFS or OS in Protocol A or Protocol B. Median follow-up time was 71 months. CONCLUSION: No survival benefit for adjuvant HDI in patients with a single positive SLN was found. Among patients with tumor-negative SLN by conventional pathology but with melanoma detected in the SLN by RT-PCR, there was no OS benefit for CLND or CLND+HDI.

Laparoscopic adrenalectomy and splenectomy are safe and reduce hospital stay and charges.

The proposed benefits of laparoscopy for certain surgical procedures have been decreased post-operative pain and hospital stay balanced against the proposed deficits of increased costs. We have reviewed our data to evaluate factors associated with patient, procedure, and hospital charges for patients undergoing open versus laparoscopic adrenalectomy and splenectomy during the same time period. Eighty-seven patients underwent adrenalectomy (n = 47) or splenectomy (n = 40) from October 30, 1995 to June 6, 2001 and were retrospectively reviewed. Patient and operative factors were analyzed by intent to treat; the major endpoints were operating room (OR) time in minutes, blood loss in cm3, length of hospital stay in days, and charges broken down by anesthesia/operation [OR/recovery room (RR)] and total charges in dollars x 1000. Comparisons of means were analyzed by unpaired t test; data are presented as mean +/- SEM, and significance is defined as P < 0.05. Median age of the group was 47 years (range 20-77). Forty-five patients underwent a laparoscopic approach of which two were converted to open (4%) as compared with 42 undergoing an open operation; one patient from each group was excluded from outcome analyses because of prolonged hospitalization (>3 weeks). Operative mortality of the whole group was one per cent. There were no differences between the groups with respect to age, gender, or comorbidity. The laparoscopic group had significantly longer operative times and OR/RR charges. However, the length of hospital stay and the total charges for the patient undergoing a laparoscopic approach were significantly less (P < 0.05). We conclude that a laparoscopic approach for adrenalectomy or splenectomy can be accomplished in approximately 95 per cent of patients selected for this procedure. Despite prolonged OR time and increased OR/RR charges the laparoscopic procedures resulted in significantly decreased length of hospital stay and overall patient charges. Laparoscopy is a safe and cost-effective approach and should be strongly considered in patients requiring adrenalectomy or splenectomy.

Results of long-term follow-up for transanal excision for rectal cancer.

Low anterior resection and abdominoperineal resection are the surgical techniques used most frequently in the treatment of rectal cancer. It is our hypothesis that selected patients with early T stage, well or moderate grade of differentiation, and small tumor size are good candidates for transanal excision in terms of minimal morbidity, low recurrence rate, and sphincter preservation. From January 1993 until August 2001 30 patients underwent transanal excision; three patients were excluded because they had histology other than adenocarcinoma. Factors analyzed included those related to the patient [age (years), gender, race, body mass index, and anal tone], tumor [size (cm), distance from the anal verge (cm), differentiation, and American Joint Committee on Cancer stage], and additional treatment. Median follow-up of the group was 40.7 months (range 0.6-99) and the primary end points were local and distant recurrence. Data are presented as mean (range). The median age of the group was 58.9 years (range 27-94); 52 per cent were female and 48 per cent were male. The mean body mass index was 25.9 (range 22.7-36.7). Preoperatively 81, 11, and 4 per cent of the patients had stage I, II, and III/IV cancer, respectively. Preoperative size of the tumor was 2.0 cm (1-3 cm), and distance from the anal verge was 5.0 cm (3-15 cm). Blood loss was 50 cm3 (5-200 cm3), and there were no operative complications. Tumor differentiation levels were well (37%) and moderate (63%). All patients had negative margins. Additional treatment consisted of radiation therapy in seven patients (six postoperative and one preoperative). Chemotherapy was given to seven patients (six postoperative and one preoperative). The local recurrence rate was 7.4 per cent (two patients), and 3.7 per cent recurred distantly (one patient). Transanal excision of low rectal cancer in selected patients is an acceptable alternative to formal resection. Important selection criteria include early T stage, well or moderate differentiation, relatively small tumor size, and negative microscopic margins. The roles of radiation and chemotherapy remain controversial.