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1.  The importance of complete excision in the prevention of local recurrence of ductal carcinoma in situ. 
British Journal of Cancer  1998;77(1):110-114.
Mastectomy probably represents over-treatment for the majority of women with screen detected ductal carcinoma in situ (DCIS) and breast-conserving surgery is now widely advocated. In this study, biopsy cavity shavings were used to ensure complete excision in 129 women undergoing breast-conserving surgery for screen detected DCIS. A margin was considered clear if DCIS was > 1 mm from any margin of excision and shavings were clear. Patients with involved margins (DCIS at resection margin) underwent re-excision, irrespective of shaving status. After re-excision, 101 women (78%) had clear margins and 28 (22%) close margins (DCIS < or = 1 mm from resection margin). Cavity shavings were histologically clear of DCIS in all cases. Ipsilateral DCIS recurrence occurred in 12 (9.3%) patients. Two recurrences also contained invasive carcinoma. The median time to diagnosis was 14 months and all recurrences occurred at the site of the previous biopsy. Seven recurrences were detected at the first annual mammogram, four at the second and one at the third. Ipsilateral recurrence was related to margin status; only 2 out of 101 (2%) patients with clear margins recurred, compared with 10 out of 28 (36%) patients with close margins. Local recurrence and close margin status both correlated with a high modified Van Nuys prognostic index score. Our results indicate that local relapse represents residual DCIS rather than true recurrence in the majority of cases. Cavity shavings have proved ineffective in ensuring complete excision. We now ensure a minimum 10 mm margin of excision around all screen-detected DCIS lesions.
PMCID: PMC2151263  PMID: 9459154
2.  Ultrasound-guided breast-sparing surgery to improve cosmetic outcomes and quality of life. A prospective multicentre randomised controlled clinical trial comparing ultrasound-guided surgery to traditional palpation-guided surgery (COBALT trial) 
BMC Surgery  2011;11:8.
Background
Breast-conserving surgery for breast cancer was developed as a method to preserve healthy breast tissue, thereby improving cosmetic outcomes. Thus far, the primary aim of breast-conserving surgery has been the achievement of tumour-free resection margins and prevention of local recurrence, whereas the cosmetic outcome has been considered less important. Large studies have reported poor cosmetic outcomes in 20-40% of patients after breast-conserving surgery, with the volume of the resected breast tissue being the major determinant. There is clear evidence for the efficacy of ultrasonography in the resection of nonpalpable tumours. Surgical resection of palpable breast cancer is performed with guidance by intra-operative palpation. These palpation-guided excisions often result in an unnecessarily wide resection of adjacent healthy breast tissue, while the rate of tumour-involved resection margins is still high. It is hypothesised that the use of intra-operative ultrasonography in the excision of palpable breast cancer will improve the ability to spare healthy breast tissue while maintaining or even improving the oncological margin status. The aim of this study is to compare ultrasound-guided surgery for palpable tumours with the standard palpation-guided surgery in terms of the extent of healthy breast tissue resection, the percentage of tumour-free margins, cosmetic outcomes and quality of life.
Methods/design
In this prospective multicentre randomised controlled clinical trial, 120 women who have been diagnosed with palpable early-stage (T1-2N0-1) primary invasive breast cancer and deemed suitable for breast-conserving surgery will be randomised between ultrasound-guided surgery and palpation-guided surgery. With this sample size, an expected 20% reduction of resected breast tissue and an 18% difference in tumour-free margins can be detected with a power of 80%. Secondary endpoints include cosmetic outcomes and quality of life. The rationale, study design and planned analyses are described.
Conclusion
The COBALT trial is a prospective, multicentre, randomised controlled study to assess the efficacy of ultrasound-guided breast-conserving surgery in patients with palpable early-stage primary invasive breast cancer in terms of the sparing of breast tissue, oncological margin status, cosmetic outcomes and quality of life.
Trial Registration Number
Netherlands Trial Register (NTR): NTR2579
doi:10.1186/1471-2482-11-8
PMCID: PMC3069937  PMID: 21410949
3.  Neoadjuvant-intensified treatment for rectal cancer: Time to change? 
AIM: To investigate whether neoadjuvant-intensified radiochemotherapy improved overall and disease-free survival in patients with locally advanced rectal cancer.
METHODS: Between January 2007 and December 2011, 80 patients with histologically confirmed rectal adenocarcinoma were enrolled. Tumors were clinically classified as either T3 or T4 and by the N stage based on the presence or absence of positive regional lymph nodes. Patients received intensified combined modality treatment, consisting of neoadjuvant radiation therapy (50.4-54.0 Gy) and infusional chemotherapy (oxaliplatin 50 mg/m2) on the first day of each week, plus five daily continuous infusions of fluorouracil (200 mg/m2 per die) from the first day of radiation therapy until radiotherapy completion. Patients received five or six cycles of oxaliplatin based on performance status, clinical lymph node involvement, and potential risk of a non-sphincter-conserving surgical procedure. Surgery was planned 7 to 9 wk after the end of radiochemotherapy treatment; adjuvant chemotherapy treatment was left to the oncologist’s discretion and was recommended in patients with positive lymph nodes. After treatment, all patients were monitored every three months for the first year and every six months for the subsequent years.
RESULTS: Of the 80 patients enrolled, 75 patients completed the programmed neoadjuvant radiochemotherapy treatment. All patients received the radiotherapy prescribed total dose; five patients suspended chemotherapy indefinitely because of chemotherapy-related toxicity. At least five cycles of oxaliplatin were administered to 73 patients. Treatment was well tolerated with high compliance and a good level of toxicity. Most of the acute toxic effects observed were classified as grades 1-2. Proctitis grade 2 was the most common symptom (63.75%) and the earliest manifestation of acute toxicity. Acute toxicity grades 3-4 was reported in 30% of patients and grade 3 or 4 diarrhoea reported in just three patients (3.75%). Seventy-seven patients underwent surgery; low anterior resection was performed in 52 patients, Miles’ surgery in 11 patients and total mesorectal excision in nine patients. Fifty patients showed tumor downsizing ≥ 50% pathological downstaging in 88.00% of tumors. Out of 75 patients surviving surgery, 67 patients (89.33%) had some form of downstaging after preoperative treatment. A pathological complete response was achieved in 23.75% of patients and a nearly pathologic complete response (stage ypT1ypN0) in six patients. An involvement of the radial margin was never present. During surgery, intra-abdominal metastases were found in only one patient (1.25%). Initially, 45 patients required an abdominoperineal resection due to a tumor distal margin ≤ 5 cm from the anal verge. Of these patients, only seven of them underwent Miles’ surgery and sphincter preservation was guaranteed in 84.50% of patients in this subgroup. Fourteen patients received postoperative chemotherapy. In the full analysis of enrolled cohort, eight of the 80 patients died, with seven deaths related to rectal cancer and one to unrelated causes. Local recurrences were observed in seven patients (8.75%) and distant metastases in 17 cases (21.25%). The five-year rate of overall survival rate was 90.91%. Using a median follow-up time of 28.5 mo, the cumulative incidence of local recurrences was 8.75%, and the overall survival and disease-free survival rates were 90.00% and 70.00%, respectively.
CONCLUSION: The results of this study suggest oxaliplatin chemotherapy has a beneficial effect on overall survival, likely due to an increase in local tumor control.
doi:10.3748/wjg.v19.i20.3052
PMCID: PMC3662944  PMID: 23716984
Rectal cancer; Neoadjuvant treatment; Intensified radiochemotherapy; Oxaliplatin; Fluorouracil
4.  Intraoperative Ultrasound Guidance Is Associated with Clear Lumpectomy Margins for Breast Cancer: A Systematic Review and Meta-Analysis 
PLoS ONE  2013;8(9):e74028.
Purpose
Margin status is one of the most important predictors of local recurrence after breast conserving surgery (BCS). Intraoperative ultrasound guidance (IOUS) has the potential to improve surgical accuracy for breast cancer. The purpose of the present meta-analysis was to determine the efficacy of IOUS in breast cancer surgery and to compare the margin status to that of the more traditional Guide wire localization (GWL) or palpation-guidance.
Methods
We searched the database of PubMed for prospective and retrospective studies about the impact of IOUS on margin status of breast cancer, and a meta-analysis was conducted.
Results
Of the 13 studies included, 8 were eligible for the impact of IOUS on margin status of non-palpable breast cancers, 4 were eligible for palpable breast cancers, and 1 was for both non-palpable and palpable breast cancers. The rate of negative margins of breast cancers in IOUS group was significantly higher than that in control group without IOUS (risk ratio (RR)  = 1.37, 95% confidence interval (CI)  = 1.18–1.59 from 7 prospective studies, odds ratio (OR)  = 2.75, 95% CI  = 1.66–4.55 from 4 retrospective studies). For non-palpable breast cancers, IOUS-guidance enabled a significantly higher rate of negative margins than that of GWL-guidance (RR  = 1.26, 95% CI  = 1.09–1.46 from 6 prospective studies; OR  = 1.45, 95% CI  = 0.86–2.43 from 2 retrospective studies). For palpable breast cancers, relative to control group without IOUS, the RR for IOUS associated negative margins was 2.36 (95% CI  = 1.26–4.43) from 2 prospective studies, the OR was 2.71 (95% CI  = 1.25–5.87) from 2 retrospective studies.
Conclusion
This study strongly suggests that IOUS is an accurate method for localization of non-palpable and palpable breast cancers. It is an efficient method of obtaining high proportion of negative margins and optimum resection volumes in patients undergoing BCS.
doi:10.1371/journal.pone.0074028
PMCID: PMC3779206  PMID: 24073200
5.  Network Meta-analysis of Margin Threshold for Women With Ductal Carcinoma In Situ 
Background
Negative margins are associated with reduced risk of ipsilateral breast tumor recurrence (IBTR) for women with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery (BCS). However, there is no consensus about the best minimum margin width.
Methods
We searched the PubMed database for studies of DCIS published in English between January 1970 and July 2010 and examined the relationship between IBTR and margin status after BCS for DCIS. Women with DCIS were stratified into two groups, BCS with or without radiotherapy. We used frequentist and Bayesian approaches to estimate the odds ratios (OR) of IBTR for groups with negative margins and positive margins. We further examined specific margin thresholds using mixed treatment comparisons and meta-regression techniques. All statistical tests were two-sided.
Results
We identified 21 studies published in 24 articles. A total of 1066 IBTR events occurred in 7564 patients, including BCS alone (565 IBTR events in 3098 patients) and BCS with radiotherapy (501 IBTR events in 4466 patients). Compared with positive margins, negative margins were associated with reduced risk of IBTR in patients with radiotherapy (OR = 0.46, 95% credible interval [CrI] = 0.35 to 0.59), and in patients without radiotherapy (OR = 0.34, 95% CrI = 0.24 to 0.47). Compared with patients with positive margins, the risk of IBTR for patients with negative margins was smaller (negative margin >0 mm, OR = 0.45, 95% CrI = 0.38 to 0.53; >2 mm, OR = 0.38, 95% CrI = 0.28 to 0.51; >5 mm, OR = 0.55, 95% CrI = 0.15 to 1.30; and >10 mm, OR = 0.17, 95% CrI = 0.12 to 0.24). Compared with a negative margin greater than 2 mm, a negative margin of at least 10 mm was associated with a lower risk of IBTR (OR = 0.46, 95% CrI = 0.29 to 0.69). We found a probability of .96 that a negative margin threshold greater than 10 mm is the best option compared with other margin thresholds.
Conclusions
Negative surgical margins should be obtained for DCIS patients after BCS regardless of radiotherapy. Within cosmetic constraint, surgeons should attempt to achieve negative margins as wide as possible in their first attempt. More studies are needed to understand whether margin thresholds greater than 10 mm are warranted.
doi:10.1093/jnci/djs142
PMCID: PMC3916966  PMID: 22440677
6.  Standardized and reproducible methodology for the comprehensive and systematic assessment of surgical resection margins during breast-conserving surgery for invasive breast cancer 
BMC Cancer  2009;9:254.
Background
The primary goal of breast-conserving surgery (BCS) is to completely excise the tumor and achieve "adequate" or "negative" surgical resection margins while maintaining an acceptable level of postoperative cosmetic outcome. Nevertheless, precise determination of the adequacy of BCS has long been debated. In this regard, the aim of the current paper was to describe a standardized and reproducible methodology for comprehensive and systematic assessment of surgical resection margins during BCS.
Methods
Retrospective analysis of 204 BCS procedures performed for invasive breast cancer from August 2003 to June 2007, in which patients underwent a standard BCS resection and systematic sampling of nine standardized re-resection margins (superior, superior-medial, superior-lateral, medial, lateral, inferior, inferior-medial, inferior-lateral, and deep-posterior). Multiple variables (including patient, tumor, specimen, and follow-up variables) were evaluated.
Results
6.4% (13/204) of patients had positive BCS specimen margins (defined as tumor at inked edge of BCS specimen) and 4.4% (9/204) of patients had close margins (defined as tumor within 1 mm or less of inked edge but not at inked edge of BCS specimen). 11.8% (24/204) of patients had at least one re-resection margin containing additional disease, independent of the status of the BCS specimen margins. 7.1% (13/182) of patients with negative BCS specimen margins (defined as no tumor cells seen within 1 mm or less of inked edge of BCS specimen) had at least one re-resection margin containing additional disease. Thus, 54.2% (13/24) of patients with additional disease in a re-resection margin would not have been recognized by a standard BCS procedure alone (P < 0.001). The nine standardized resection margins represented only 26.8% of the volume of the BCS specimen and 32.6% of the surface area of the BCS specimen.
Conclusion
Our methodology accurately assesses the adequacy of surgical resection margins for determination of which individuals may need further resection to the affected breast in order to minimize the potential risk of local recurrence while attempting to limit the volume of additional breast tissue excised, as well as to determine which individuals are not realistically amendable to BCS and instead need a completion mastectomy to successfully remove multifocal disease.
doi:10.1186/1471-2407-9-254
PMCID: PMC2724549  PMID: 19635166
7.  The Effect of Simultaneous Peripheral Excision in Breast Conservation upon Margin Status 
Annals of surgical oncology  2010;17(11):2933-2939.
Background
Negative margins in breast conservation therapy (BCT) decrease local recurrence risk. Excision may be performed via two techniques: either as a single lumpectomy specimen or as a central segment with simultaneously resected peripheral segments (PSs). There is little data directly comparing these methods for their effect on margin status.
Methods
A retrospective review of all patients undergoing BCT for invasive breast cancer was conducted to evaluate and compare the two techniques. Presentation, pathologic characteristics, surgical technique, specimen volume, and final margin status were recorded.
Results
Among 259 cancers in 257 women, 33 had positive margins. A single segment was removed in 69 patients, while 190 patients had 1-6 PSs simultaneously removed. By univariate analysis, smaller tumor size (p=0.017) and greater numbers of segments removed (p=0.01) lowered the risk of positive margins. In a multivariate model, smaller tumor size (p=0.0024), lack of EIC (p=0.049), and greater numbers of segments removed (p=0.0061) lowered the risk of margin positivity. Despite this last predictor, the total resected specimen volume did not increase with the number of PSs removed (p=0.4). There was no residual tumor in 49.2% of PSs despite a compromised primary segment margin.
Conclusions
Smaller tumor size, lack of EIC and greater numbers of simultaneous PSs excised decrease the likelihood of positive margins, despite a lack of correlation between segment numbers and excised volume. These findings suggest that excision of simultaneous PSs may assist in achieving negative margins, in part, due to avoidance of pathologic artifact.
doi:10.1245/s10434-010-1123-z
PMCID: PMC2941710  PMID: 20549566
8.  A Randomized Prospective Study of Lumpectomy Margin Assessment with Use of MarginProbe in Patients with Nonpalpable Breast Malignancies 
Annals of Surgical Oncology  2014;21(5):1589-1595.
Background
The presence of tumor cells at the margins of breast lumpectomy specimens is associated with an increased risk of ipsilateral tumor recurrence. Twenty to 30 % of patients undergoing breast-conserving surgery require second procedures to achieve negative margins. This study evaluated the adjunctive use of the MarginProbe device (Dune Medical Devices Ltd, Caesarea, Israel) in providing real-time intraoperative assessment of lumpectomy margins.
Methods
This multicenter randomized trial enrolled patients with nonpalpable breast malignancies. The study evaluated MarginProbe use in addition to standard intraoperative methods for margin assessment. After specimen removal and inspection, patients were randomized to device or control arms. In the device arm, MarginProbe was used to examine the main lumpectomy specimens and direct additional excision of positive margins. Intraoperative imaging was used in both arms; no intraoperative pathology assessment was permitted.
Results
In total, 596 patients were enrolled. False-negative rates were 24.8 and 66.1 % and false-positive rates were 53.6 and 16.6 % in the device and control arms, respectively. All positive margins on positive main specimens were resected in 62 % (101 of 163) of cases in the device arm, versus 22 % (33 of 147) in the control arm (p < 0.001). A total of 19.8 % (59 of 298) of patients in the device arm underwent a reexcision procedure compared with 25.8 % (77 of 298) in the control arm (6 % absolute, 23 % relative reduction). The difference in tissue volume removed was not significant.
Conclusions
Adjunctive use of the MarginProbe device during breast-conserving surgery improved surgeons’ ability to identify and resect positive lumpectomy margins in the absence of intraoperative pathology assessment, reducing the number of patients requiring reexcision. MarginProbe may aid performance of breast-conserving surgery by reducing the burden of reexcision procedures for patients and the health care system.
doi:10.1245/s10434-014-3602-0
PMCID: PMC3975090  PMID: 24595800
9.  Positive Margins Rates Following Breast-Conserving Surgery for Stage I–III Breast Cancer: Palpable versus Non-Palpable Tumors 
The Journal of surgical research  2012;177(1):109-115.
Background
Margin status is a significant risk factor for local recurrence. We sought to examine whether the method of tumor localization predicted the margin status and the need for re-excision for both non-palpable and palpable breast cancer.
Methods
We identified 358 consecutive breast cancer patients who were treated with breast-conserving therapy (BCT) from 1999–2006. Data included patient and tumor characteristics, method of localization (needle versus palpation), and pathologic outcomes. Descriptive statistics were utilized for data summary and data were compared using Chi-square.
Results
Of 358 patients undergoing BCT, 234 (65%) underwent needle localization for a non-palpable tumor and 124 (35%) underwent a palpation-guided procedure. Patients undergoing palpation-guided procedures were younger and had larger tumors at a more advanced pathologic stage of disease than those undergoing needle localization procedures (p<0.05 for each). Patient race, tumor grade, presence of lymphovascular invasion, biomarker profile, and nodal status were not significantly different between the two groups (p>0.05). Overall, 137 (38%) patients had one or more positive margins; 90 of 234 (38%) who had a needle localization procedure and 47 of 124 (38%) who had a palpation-guided procedure (p>0.05). The number of margins affected did not differ significantly between the two groups.
Conclusion
Although patients with palpable breast cancer had larger tumors than those with non-palpable breast cancer, the incidence and number of positive margins was similar to those who had needle localization for non-palpable tumors. Improved methods of localization are needed to reduce the rate of positive margins and the need for re-excision.
doi:10.1016/j.jss.2012.03.045
PMCID: PMC3924771  PMID: 22516344
Breast Cancer; Margin Status; Needle Localization
10.  Multiple Margin Positivity of Frozen Section Is an Independent Risk Factor for Local Recurrence in Breast-Conserving Surgery 
Journal of Breast Cancer  2012;15(4):420-426.
Purpose
Breast-conserving surgery (BCS) with radiotherapy has become a standard treatment for early stage breast cancer, since the installation of NSABP B-06. One of the serious problems in BCS is that of local recurrence. There are many risk factors for local recurrence, such as large tumor size, multiple tumors, axillary lymph node involvement, young age, high nuclear grade, and so on. The aim of this study is to identify patients with a higher risk of local recurrence of breast cancer.
Methods
Between January 2002 and December 2006, 447 patients with breast cancer, and who had undergone BCS with immediate breast reconstruction, were enrolled in the study. The follow-up period was 5 years from the time of operation and we analyzed local recurrence, disease-free survival (DFS), and overall survival (OS). The analysis included various clinicopathological factors such as age, chemotherapy, radiotherapy, hormone therapy, pathologic characteristics, and margin status. Statistical analysis was performed with log-rank test and Kaplan-Meier method. The p-value <0.05 was considered statistically significant.
Results
The mean follow-up period was 88 months and local recurrence of breast cancer occurred only in 16 cases (3.6%). The actual 5-year DFS, and OS rates were 90.6% and 93.3%, respectively. For the local recurrence of breast cancer, positive margin status, multiple margin positivity, conversed margin cases, T/N stages showed statistical significance in univariate analysis. However, only multiple margin positivity was identified as an independent risk factor for local recurrence in multivariate analysis.
Conclusion
When the multiple margin positivity is diagnosed on intraoperative frozen biopsy, surgeons should consider a much wider excision of the breast and a more aggressive management.
doi:10.4048/jbc.2012.15.4.420
PMCID: PMC3542850  PMID: 23346171
Breast neoplasms; Local neoplasm recurrence; Segmental mastectomy
11.  Breast cancer (non-metastatic) 
Clinical Evidence  2011;2011:0102.
Introduction
Breast cancer affects at least 1 in 10 women in the UK, but most present with primary operable disease, which has an 80% 5-year survival rate overall.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions after breast-conserving surgery for ductal carcinoma in situ? What are the effects of treatments for primary operable breast cancer? What are the effects of interventions in locally advanced breast cancer (stage 3B)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 83 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding chemotherapy (cyclophosphamide/methotrexate/fluorouracil and/or anthracycline and/or taxane-based regimens), or hormonal treatment to radiotherapy; adjuvant treatments (aromatase inhibitors, adjuvant anthracycline regimens, tamoxifen); axillary clearance; axillary dissection plus sentinel node dissection; axillary radiotherapy; axillary sampling; combined chemotherapy plus tamoxifen; chemotherapy plus monoclonal antibody (trastuzumab); extensive surgery; high-dose chemotherapy; hormonal treatment; less extensive mastectomy; less than whole-breast radiotherapy plus breast-conserving surgery; multimodal treatment; ovarian ablation; primary chemotherapy; prolonged adjuvant combination chemotherapy; radiotherapy (after breast-conserving surgery, after mastectomy, plus tamoxifen after breast-conserving surgery, to the internal mammary chain, and to the ipsilateral supraclavicular fossa, and total nodal radiotherapy); sentinel node biopsy; and standard chemotherapy regimens.
Key Points
Breast cancer affects at least 1 in 10 women in the UK, but most present with primary operable disease, which has an 80% 5-year survival rate overall.
In women with ductal carcinoma in situ (DCIS), radiotherapy reduces local recurrence and invasive carcinoma after breast-conserving surgery. The role of tamoxifen added to radiotherapy for DCIS remains unclear because of conflicting results.
In women with primary operable breast cancer, survival may be increased by full surgical excision, tamoxifen, chemotherapy, radiotherapy, ovarian ablation, or trastuzumab (in women who over-express HER2/neu oncogene). Incomplete excision may increase the risk of local recurrence, but less-extensive mastectomy that excises all local disease is as effective as radical mastectomy at prolonging survival, with better cosmetic results. Axillary clearance (removal of all axillary lymph nodes) achieves local disease control, but has not been shown to increase survival, and can cause arm lymphoedema. Sentinel lymph node biopsy or 4-node sampling may adequately stage the axilla with less morbidity compared with axillary clearance. Adjuvant tamoxifen reduces the risk of recurrence and death in women with oestrogen-positive tumours. Primary chemotherapy may facilitate successful breast-conserving surgery instead of mastectomy. Adjuvant combination chemotherapy improves survival compared with no chemotherapy, with greatest benefit likely with anthracycline-based regimens at standard doses for 4 to 6 months.Radiotherapy decreases recurrence and mortality after breast-conserving surgery. Post-mastectomy radiotherapy for women who are node-positive or at high risk of recurrence decreases recurrence and mortality. Adjuvant aromatase inhibitors improve disease-free survival compared with tamoxifen, but their effect on overall survival is unclear. Adjuvant taxane-based regimens may improve disease-free survival over standard anthracycline-based therapy.
In women with locally advanced breast cancer, radiotherapy may be as effective as surgery or tamoxifen at increasing survival and local disease control. Adding tamoxifen or ovarian ablation to radiotherapy increases survival compared with radiotherapy alone, but adding chemotherapy may not reduce recurrence or mortality compared with radiotherapy alone.We don't know if chemotherapy alone improves survival in women with locally advanced breast cancer as we found few trials.
PMCID: PMC3217212  PMID: 21718560
12.  Optimizing Surgical Margins in Breast Conservation 
Adequate surgical margins in breast-conserving surgery for breast cancer have traditionally been viewed as a predictor of local recurrence rates. There is still no consensus on what constitutes an adequate surgical margin, however it is clear that there is a trade-off between widely clear margins and acceptable cosmesis. Preoperative approaches to plan extent of resection with appropriate margins (in the setting of surgery first as well as after neoadjuvant chemotherapy,) include mammography, US, and MRI. Improvements have been made in preoperative lesion localization strategies for surgery, as well as intraoperative specimen assessment, in order to ensure complete removal of imaging findings and facilitate margin clearance. Intraoperative strategies to accurately assess tumor and cavity margins include cavity shave techniques, as well as novel technologies for margin probes. Ablative techniques, including radiofrequency ablation as well as intraoperative radiation, may be used to extend tumor-free margins without resecting additional tissue. Oncoplastic techniques allow for wider resections while maintaining cosmesis and have acceptable local recurrence rates, however often involve surgery on the contralateral breast. As systemic therapy for breast cancer continues to improve, it is unclear what the importance of surgical margins on local control rates will be in the future.
doi:10.1155/2012/585670
PMCID: PMC3523540  PMID: 23304479
13.  Breast cancer (non-metastatic) 
Clinical Evidence  2007;2007:0102.
Introduction
Breast cancer affects at least 1 in 10 women in the UK, but most present with primary operable disease, which has an 80% 5-year survival rate overall.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions after breast-conserving surgery for ductal carcinoma in situ? What are the effects of treatments for primary operable breast cancer? What are the effects of interventions in locally advanced breast cancer (stage IIIB)? We searched: Medline, Embase, The Cochrane Library and other important databases up to February 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 79 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding chemotherapy (cyclophosphamide/methotrexate/ fluorouracil and/or anthracycline and/or taxane-based regimens), or hormonal treatment to radiotherapy; adjuvant treatments (aromatase inhibitors, adjuvant anthracycline regimens, tamoxifen); axillary clearance; axillary dissection plus sentinel node dissection; axillary radiotherapy; axillary sampling; combined chemotherapy plus tamoxifen; chemotherapy plus monoclonal antibody (trastuzumab); extensive surgery; high-dose chemotherapy; hormonal treatment; less extensive mastectomy; less than whole breast radiotherapy plus breast conserving surgery; multimodal treatment; ovarian ablation; primary chemotherapy; prolonged adjuvant combination chemotherapy; radiotherapy (after breast-conserving surgery, after mastectomy, plus tamoxifen after breast-conserving surgery, to the internal mammary chain, and to the ipsilateral supraclavicular fossa, and total nodal radiotherapy); sentinel node biopsy; and standard chemotherapy regimens.
Key Points
Breast cancer affects at least 1 in 10 women in the UK, but most present with primary operable disease, which has an 80% 5-year survival rate overall.
In women with ductal carcinoma in situ, radiotherapy reduces local recurrence and invasive carcinoma after breast-conserving surgery, but may not improve survival.
In women with primary operable breast cancer, survival may be increased by full surgical excision, tamoxifen, chemotherapy, radiotherapy, ovarian ablation or trastuzumab (in women who overexpress HER2/neu oncogene). Incomplete excision may increase the risk of local recurrence, but less-extensive mastectomy that excises all local disease is as effective as radical mastectomy at prolonging survival, with better cosmetic results. Axillary clearance (removal of all axillary lymph nodes) achieves local disease control, but has not been shown to increase survival, and can cause arm lymphoedema. Sentinel lymph node biopsy or 4-node sampling may adequately stage the axilla with less morbidity compared with axillary clearance. Adjuvant tamoxifen reduces the risk of recurrence and death in women with oestrogen-positive tumours, but adverse effects begin to outweigh benefit after 5 years of treatment. Primary chemotherapy may facilitate successful breast-conserving surgery instead of mastectomy. Adjuvant combination chemotherapy improves survival compared with no chemotherapy, with greatest benefit likely with anthracycline-based regimens at standard doses for 4-6 months.Radiotherapy decreases recurrence and mortality after breast-conserving surgery. Post-mastectomy radiotherapy for women who are node-positive or at high risk of recurrence decreases recurrence and mortality, but may increase mortality in node-negative women. Adjuvant aromatase inhibitors improve disease-free survival compared with tamoxifen, but their effect on overall survival is unclear.Adjuvant taxoid regimens may improve disease-free survival over standard anthracycline-based therapy.
In women with locally advanced breast cancer, radiotherapy may be as effective as surgery or tamoxifen at increasing survival and local disease control. Adding tamoxifen or ovarian ablation to radiotherapy increases survival compared with radiotherapy alone, but adding chemotherapy may not reduce recurrence or mortality compared with radiotherapy alone.Chemotherapy alone, while widely used, does not improve survival in women with locally advanced breast cancer.
PMCID: PMC2943780  PMID: 19450345
14.  Clinical importance and surgical decision-making regarding proximal resection margin for gastric cancer 
Because of the intramural spread of gastric cancer, a sufficient length of a resection margin has to be attained to ensure complete excision of the tumor. There has been debate on an adequate length of proximal resection margin (PRM) and its related issues. Thus, the objective of this article is to review several studies on PRM and to summarize the current evidence on the subject. Although there is some discrepancy in the recommended values for PRM between authors, a PRM of more than 2-3 cm for early gastric cancer and 5-6 cm for advanced gastric cancer is thought to be acceptable. Once the margin is confirmed to be clear, however, the length of PRM measured in postoperative pathologic examination does not affect the patient’s survival, even when it is shorter than the recommended values. Hence, the recommendations for PRM length should be applied only to intraoperative decision-making to prevent positive margins on the final pathology. Given that a negative resection margin is the ultimate goal of determining an adequate PRM, development and improvement of reliable methods to confirm a negative resection margin intraoperatively would minimize the extent of surgery and offer a better quality of life to more patients. In the same context, special attention has to be paid to patients who have advanced stage or diffuse-type gastric cancer, because they are more likely to have a positive margin. Therefore, a wider excision with intraoperative frozen section (IFS) examination of the resection margin is necessary. Despite all the attempts to avoid positive margins, there is still a certain rate of positive-margin cases. Since the negative impact of a positive margin on prognosis is mostly obvious in low N stage patients, aggressive further management, such as extensive re-operation, is required for these patients. In conclusion, every possible preoperative and intraoperative evaluation should be thoroughly carried out to identify in advance the patients with a high risk of having positive margins; these patients need careful management with a wider excision or an IFS examination to confirm a negative margin during surgery.
doi:10.4251/wjgo.v5.i1.4
PMCID: PMC3671068  PMID: 23738049
Resection margin; Proximal resection margin; Negative resection margin; Positive resection margin; Gastrectomy; Gastric cancer
15.  Study of circumferential resection margin in patients with middle and lower rectal carcinoma 
AIM: To clarify the relationship between circumferential resection margin status and local and distant recurrence as well as survival of patients with middle and lower rectal carcinoma. The relationship between circumferential resection margin status and clinicopathologic characteristics of middle and lower rectal carcinoma was also evaluated.
METHODS: Cancer specimens from 56 patients with middle and lower rectal carcinoma who received total mesorectal excision at the Department of General Surgery of Guangdong Provincial People’s Hospital were studied. A large slice technique was used to detect mesorectal metastasis and evaluate circumferential resection margin status.
RESULTS: Local recurrence occurred in 12.5% (7 of 56 cases) of patients with middle and lower rectal carcinoma. Distant recurrence occurred in 25% (14 of 56 cases) of patients with middle and lower rectal carcinoma. Twelve patients (21.4%) had positive circumferential resection margin. Local recurrence rate of patients with positive circumferential resection margin was 33.3% (4/12), whereas it was 6.8% (3/44) in those with negative circumferential resection margin (P = 0.014). Distant recurrence was observed in 50% (6/12) of patients with positive circumferential resection margin; conversely, it was 18.2% (8/44) in those with negative circumferential resection margin (P = 0.024). Kaplan-Meier survival analysis showed significant improvements in median survival (32.2 ± 4.1 mo, 95% CI: 24.1-40.4 mo vs 23.0 ± 3.5 mo, 95% CI: 16.2-29.8 mo) for circumferential resection margin-negative patients over circumferential resection margin-positive patients (log-rank, P < 0.05). 37% T3 tumors examined were positive for circumferential resection margin, while only 0% T1 tumors and 8.7% T2 tumors were examined as circumferential resection margin. The difference between these three groups was statistically significant (P = 0.021). In 18 cancer specimens with tumor diameter ≥ 5 cm 7 (38.9%) were detected as positive circumferential resection margin, while in 38 cancer specimens with a tumor diameter of < 5 cm only 5 (13.2%) were positive for circumferential resection margin (P = 0.028).
CONCLUSION: Our findings indicate that circumferential resection margin involvement is significantly associated with depth of tumor invasion and tumor diameter. The circumferential resection margin status is an important predictor of local and distant recurrence as well as survival of patients with middle and lower rectal carcinoma.
doi:10.3748/wjg.v13.i24.3380
PMCID: PMC4172721  PMID: 17659680
Middle and lower rectal carcinoma; Circumferential resection margin; Prognosis
16.  Factors Associated with Re-excision after Breast-Conserving Surgery for Early-Stage Breast Cancer 
Journal of Breast Cancer  2012;15(4):412-419.
Purpose
Re-excisions after breast-conserving surgery (BCS) for breast cancer cause delays in the adjuvant treatment, increased morbidity, and leads to poor aesthetic results. Thus, efforts to reduce the re-excision rate are essential. This study aimed to conclusively determine the re-excision rate and the factors associated with re-excision after BCS.
Methods
We retrospectively reviewed the medical records and pathological reports of 711 cases that underwent BCS for early-stage breast cancer. Univariate and multivariate analyses were performed.
Results
Of the 711 cases of BCS, 71 (10.0%) required re-excision. Patients in the re-excision group were younger than those in the no re-excision group. Non-palpable lesions, the presence of non-mass-like enhancement at magnetic resonance imaging, multifocality, the presence of a ductal carcinoma in situ (DCIS) component, and an infiltrative tumor border were also significantly associated with re-excision. Multivariate analysis indicated that younger age, non-palpable lesions, multifocal lesions, and the presence of a DCIS component were factors which were independently associated with re-excision. Tumors located in the lower inner quadrant had a relatively high involved resection margin rate as well as a narrow resection margin width, especially at the superior and medial margins. Lateral margins showed a tendency toward a wider resection margin width.
Conclusion
At our institution, the rate of re-excision was low despite the lack of an intraoperative frozen section. Patients with non-palpable or multifocal tumors, a DCIS component, or those who were younger than 50 years were more likely to require re-excision after BCS. These factors should be considered when planning surgical management of early-stage breast cancer. Positive resection margin rates and margin widths differed on a directional basis based on tumor location, and these differences were considerable.
doi:10.4048/jbc.2012.15.4.412
PMCID: PMC3542849  PMID: 23346170
Breast neoplasms; Safety of margin; Segmental mastectomy
17.  The influence of the treatment response on the impact of resection margin status after preoperative chemoradiotherapy in locally advanced rectal cancer 
BMC Cancer  2013;13:576.
Background
Circumferential resection margin (CRM) and distal resection margin (DRM) have different impact on clinical outcomes after preoperative chemoradiotherapy (CRT) followed by surgery. Effect and adequate length of resection margin as well as impact of treatment response after preoperative CRT was evaluated.
Methods
Total of 403 patients with rectal cancer underwent preoperative CRT followed by total mesorectal excision between January 2004 and December 2010. After applying the criterion of margin less than 0.5 cm for CRM or less than 1 cm for DRM, 151 cases with locally advanced rectal cancer were included as a study cohort. All patients underwent conventionally fractionated radiation with radiation dose over 50 Gy and concurrent chemotherapy with 5-fluorouracil or capecitabine. Postoperative chemotherapy was administered to 142 patients (94.0%). Median follow-up duration was 43.1 months.
Results
The 5-year overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS) rates, and locoregional control rates (LRC) were 84.5%, 72.8%, 74.2%, and 86.3%, respectively. CRM of 1.5 mm and DRM of 7 mm were cutting points showing maximal difference in a maximally selected rank method. In univariate analysis, CRM of 1.5 mm was significantly related with worse clinical outcomes, whereas DRM of 7 mm was not. In multivariate analysis, CRM of 1.5 mm, and ypN were prognosticators for all studied endpoints. However, CRM was not a significant prognostic factor for good responders, defined as patients with near total regression or T down-staging, which was found in 16.5% and 40.5% among studied patients, respectively. In contrast, poor responders demonstrated a significant difference according to the CRM status for all studied end-points.
Conclusions
Close CRM, defined as 1.5 mm, was a significant prognosticator, but the impact was only prominent for poor responders in subgroup analysis. Postoperative treatment strategy may be individualized based on this finding. However, findings from this study need to be validated with larger cohort.
doi:10.1186/1471-2407-13-576
PMCID: PMC3938897  PMID: 24304825
Rectal cancer; Preoperative chemoradiotherapy; Resection margin; Treatment response
18.  Obtaining Adequate Surgical Margins in Breast-Conserving Therapy for Patients with Early-Stage Breast Cancer: Current Modalities and Future Directions 
Annals of Surgical Oncology  2009;16(10):2717-2730.
Inadequate surgical margins represent a high risk for adverse clinical outcome in breast-conserving therapy (BCT) for early-stage breast cancer. The majority of studies report positive resection margins in 20% to 40% of the patients who underwent BCT. This may result in an increased local recurrence (LR) rate or additional surgery and, consequently, adverse affects on cosmesis, psychological distress, and health costs. In the literature, various risk factors are reported to be associated with positive margin status after lumpectomy, which may allow the surgeon to distinguish those patients with a higher a priori risk for re-excision. However, most risk factors are related to tumor biology and patient characteristics, which cannot be modified as such. Therefore, efforts to reduce the number of positive margins should focus on optimizing the surgical procedure itself, because the surgeon lacks real-time intraoperative information on the presence of positive resection margins during breast-conserving surgery. This review presents the status of pre- and intraoperative modalities currently used in BCT. Furthermore, innovative intraoperative approaches, such as positron emission tomography, radioguided occult lesion localization, and near-infrared fluorescence optical imaging, are addressed, which have to prove their potential value in improving surgical outcome and reducing the need for re-excision in BCT.
doi:10.1245/s10434-009-0609-z
PMCID: PMC2749177  PMID: 19609829
19.  The significance of the Van Nuys prognostic index in the management of ductal carcinoma in situ 
Background
Debate regarding the benefit of radiotherapy after local excision of ductal carcinoma in situ (DCIS) continues. The Van Nuys Prognostic Index (VNPI) is thought to be a useful aid in deciding which patients are at increased risk of local recurrence and who may benefit from adjuvant radiotherapy (RT). Recently published interim data from the Sloane project has showed that the VNPI score did significantly affect the chances of getting planned radiotherapy in the UK, suggesting that British clinicians may already be using this scoring system to assist in decision making. This paper independently assesses the prognostic validity of the VNPI in a British population.
Patients and methods
A retrospective review was conducted of all patients (n = 215) who underwent breast conserving surgery for DCIS at a single institution between 1997 – 2006. No patients included in the study received additional radiotherapy or hormonal treatment. Kaplan Meier survival curves were calculated, to determine disease free survival, for the total sample and a series of univariate analyses were performed to examine the value of various prognostic factors including the VNPI. The log-rank test was used to determine statistical significance of differential survival rates. Multivariate Cox regression analysis was performed to analyze the significance of the individual components of the VNPI. All analyses were conducted using SPSS software, version 14.5.
Results
The mean follow-up period was 53 months (range 12–97, SD19.9). Ninety five tumours were high grade (44%) and 84 tumours exhibited comedo necrosis (39%). The closest mean initial excision margin was 2.4 mm (range 0–22 mm, standard deviation 2.8) and a total of 72 tumours (33%) underwent further re-excision. The observed and the actuarial 8 year disease-free survival rates in this study were 91% and 83% respectively. The VNPI score and the presence of comedo necrosis were the only statistically significant prognostic indicators (P < 0.05).
Conclusion
This follow-up study of 215 patients with DCIS treated with local excision and observation alone is one of the largest series in which rates of recurrence are unaffected by radiation therapy, hormone manipulation or chemotherapy. It has afforded us the opportunity to assess the prognostic impact of patient and tumour characteristics free of any potentially confounding treatment related influences. The results suggest that the VNPI can be used to identify a subset of patients who are at risk of local recurrence and who may potentially benefit from RT.
doi:10.1186/1477-7819-6-61
PMCID: PMC2459183  PMID: 18564426
20.  Effect of the plane of surgery achieved on local recurrence in patients with operable rectal cancer: a prospective study using data from the MRC CR07 and NCIC-CTG CO16 randomised clinical trial 
Lancet  2009;373(9666):821-828.
Summary
Background
Local recurrence rates in operable rectal cancer are improved by radiotherapy (with or without chemotherapy) and surgical techniques such as total mesorectal excision. However, the contributions of surgery and radiotherapy to outcomes are unclear. We assessed the effect of the involvement of the circumferential resection margin and the plane of surgery achieved.
Methods
In this prospective study, the plane of surgery achieved and the involvement of the circumferential resection margin were assessed by local pathologists, using a standard pathological protocol in 1156 patients with operable rectal cancer from the CR07 and NCIC-CTG CO16 trial, which compared short-course (5 days) preoperative radiotherapy and selective postoperative chemoradiotherapy, between March, 1998, and August, 2005. All analyses were by intention to treat. This trial is registered, number ISRCTN 28785842.
Findings
128 patients (11%) had involvement of the circumferential resection margin, and the plane of surgery achieved was classified as good (mesorectal) in 604 (52%), intermediate (intramesorectal) in 398 (34%), and poor (muscularis propria plane) in 154 (13%). We found that both a negative circumferential resection margin and a superior plane of surgery achieved were associated with low local recurrence rates. Hazard ratio (HR) was 0·32 (95% CI 0·16–0·63, p=0·0011) with 3-year local recurrence rates of 6% (5–8%) and 17% (10–26%) for patients who were negative and positive for circumferential resection margin, respectively. For plane of surgery achieved, HRs for mesorectal and intramesorectal groups compared with the muscularis propria group were 0·32 (0·16–0·64) and 0·48 (0·25–0·93), respectively. At 3 years, the estimated local recurrence rates were 4% (3–6%) for mesorectal, 7% (5–11%) for intramesorectal, and 13% (8–21%) for muscularis propria groups. The benefit of short-course preoperative radiotherapy did not differ in the three plane of surgery groups (p=0·30 for trend). Patients in the short-course preoperative radiotherapy group who had a resection in the mesorectal plane had a 3-year local recurrence rate of only 1%.
Interpretation
In rectal cancer, the plane of surgery achieved is an important prognostic factor for local recurrence. Short-course preoperative radiotherapy reduced the rate of local recurrence for all three plane of surgery groups, almost abolishing local recurrence in short-course preoperative radiotherapy patients who had a resection in the mesorectal plane. The plane of surgery achieved should therefore be assessed and reported routinely.
Funding
Medical Research Council (UK) and the National Cancer Institute of Canada.
doi:10.1016/S0140-6736(09)60485-2
PMCID: PMC2668948  PMID: 19269520
21.  Cervical cancer 
Clinical Evidence  2011;2011:0818.
Introduction
Worldwide, cervical cancer is the third most common cancer in women. In the UK, incidence fell after the introduction of the cervical screening programme, to the current level of approximately 2334 women in 2008, with a mortality to incidence ratio of 0.33. Survival ranges from almost 100% 5-year disease-free survival for treated stage Ia disease to 5–15% in stage IV disease. Survival is also influenced by tumour bulk, age, and comorbid conditions.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent cervical cancer? What are the effects of interventions to manage early-stage cervical cancer? What are the effects of interventions to manage bulky early-stage cervical cancer? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 14 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: human papillomavirus (HPV) vaccine for preventing cervical cancer; conisation of the cervix for microinvasive carcinoma (stage Ia1), conisation of the cervix plus lymphadenectomy (stage Ia2 and low-volume, good prognostic factor stage Ib), radical trachelectomy for low-volume stage Ib disease, neoadjuvant chemotherapy, radiotherapy, chemoradiotherapy, or different types of hysterectomy versus each other for treating early-stage and bulky early-stage cervical cancer.
Key Points
Worldwide, cervical cancer is the third most common cancer in women. In the UK, incidence fell after the introduction of the cervical screening programme to the current level of approximately 2334 women in 2008, with a mortality to incidence ratio of 0.33.About 80% of tumours are squamous type, and staging is based on the FIGO classification.Survival ranges from almost 100% 5-year disease-free survival for treated stage Ia disease to 5–15% in stage IV disease. Survival is also influenced by tumour bulk, age, and comorbid conditions.Development of cervical cancer is strongly associated with HPV infection, acquired mainly by sexual intercourse.The peak prevalence of HPV infection is 20–40% in women aged 20 to 30 years, but in 80% of cases the infection resolves within 12 to 18 months.Other risk factors for cervical cancer include early onset of sexual activity, multiple sexual partners, long-term use of oral contraceptives, tobacco smoking, low socioeconomic status, and immunosuppressive therapy.
Vaccination against HPV is effective in preventing certain types of oncogenic HPV infection, and at reducing rates of cervical intraepithelial neoplasia, but there has been insufficient long-term follow-up to assess effects on cervical cancer rates.
Conisation with adequate excision margins is considered effective for microinvasive carcinoma (stage Ia1), and can preserve fertility, unlike simple hysterectomy; however, it has been associated with an increased risk of preterm delivery and low birth weight. Conisation is often performed for stage Ia1 disease, but evidence for its benefit is from observational studies only.
We don’t know how conisation of the cervix with pelvic lymphadenectomy and simple or radical hysterectomy compare with each other for stage Ia2 and low volume stage 1b cervical cancer, as we found no RCTs.
We don’t know how simple hysterectomy plus lymphadenectomy and radical hysterectomy plus lymphadenectomy compare with each other, in early cervical cancer, as we found no RCT evidence.
Limited observational evidence shows that radical trachelectomy plus lymphadenectomy results in similar disease-free survival as radical hysterectomy in women with early-stage cervical cancer; however, we found no RCTs. Radical trachelectomy plus lymphadenectomy can preserve fertility.
Limited RCT evidence shows that radiotherapy is as effective as surgery in early-stage disease. Overall and disease-free survival are similar after radiotherapy or radical hysterectomy plus lymphadenectomy, but radiotherapy is less likely to cause severe adverse effects.
Chemoradiotherapy improves survival compared with radiotherapy in women with bulky early-stage cervical cancer. Combined chemoradiotherapy improves overall and progression-free survival when used either before or after hysterectomy, but is associated with more haematological and gastrointestinal toxicity compared with radiotherapy alone.
The benefits of neoadjuvant chemotherapy plus surgery compared with radiotherapy alone are unknown.
PMCID: PMC3217784  PMID: 21791123
22.  Multimodality treatment of locally advanced soft-tissue sarcomas of the extremities 
Background
Adjuvant radiotherapy (RTE) still has a fundamental role as a post-operative treatment of locally advanced soft tissues sarcomas of the extremities. Moreover the employment of combined modalities in locally advanced soft tissues sarcomas of the extremities allow to maximize the chance of local cure even in difficult presentation cases, and possibly improve survival, especially in high-risk disease patients. In patients with sarcomas of the extremities in which definitive surgery has not been radical (with positive or “close” margins) radiotherapy can improve the results in terms of Disease Free Survival (DFS) and, together with chemotherapy, of Overall Survival (OS). We recommend radiotherapy in case of deep tumor location, inadequate surgical margins and grade 3 tumour; for positive or “marginal (or close)” excision (that means inadequate surgery) or in selected patients with a bad prognosis, we believe that a multidisciplinary approach can be preferable.
Introduction
Adjuvant radiotherapy (RTE) still has a fundamental role as a post-operative treatment. In patients with sarcomas of the extremities in whom definitive surgery has been or not radical (positive or “close” margins), radiotherapy with chemotherapy can improve the results in terms of Disease Free Survival (DFS) and Overall Survival (OS), while RTE alone seems to improve local control.
Materials and methods
From 1/2000 to 12/2005 we treated 34 patients affected by locally advanced sarcomas of the upper or lower extremities with radiotherapy (doses ranging from 54 to 66 Gy) and chemotherapy in 18/34 with an adjuvant scheme that consisted in Epirubicine (120 mg/m2) plus Ifosfamide (7000–9000 mg/m2).
Results
Disease Free Survival (DFS) and the Overall Survival (OS) rates were 76% and 82%, respectively. Eighteen patients developed one or more long-term side effects. Most of these complications were mild: all patients experienced only erithema, edema, local sclerosis or moderate pain.
Conclusion
Radiotherapy has an important role as a post-operative treatment also when surgery was non-radical. It improves local control more in patients with high-grade sarcomas of the extremity with positive or close margins. It is still difficult to assess the role of adjuvant chemotherapy.
doi:10.1016/j.rpor.2010.08.006
PMCID: PMC3863139  PMID: 24376937
Radiotherapy; Chemotherapy; Sarcomas of extremities
23.  Anemia and long-term outcome in adjuvant and neoadjuvant radiochemotherapy of stage II and III rectal adenocarcinoma: The Freiburg experience (1989-2002) 
AIM: To evaluate the long-term outcome of standard 5-FU based adjuvant or neoadjuvant radiochemotherapy and to identify the predictive factors, especially anemia before and after radiotherapy as well as hemoglobin increase or decrease during radiotherapy.
METHODS: Two hundred and eighty-six patients with Union International Contre Cancer (UICC) stage II and III rectal adenocarcinomas, who underwent resection by conventional surgical techniques (low anterior or abdominoperineal resection), received either postoperative (n = 233) or preoperative (n = 53) radiochemotherapy from January 1989 until July 2002. Overall survival (OAS), cancer-specific survival (CSS), disease-free survival (DFS), local-relapse-free (LRS) and distant-relapse-free survival (DRS) were evaluated using Kaplan-Meier, Log-rank test and Cox’s proportional hazards as statistical methods. Multivariate analysis was used to identify prognostic factors. Median follow-up time was 8 years.
RESULTS: Anemia before radiochemotherapy was an independent prognostic factor for improved DFS (risk ratio 0.76, P = 0.04) as well as stage, grading, R status (free radial margins), type of surgery, carcinoembryonic antigen (CEA) levels, and gender. The univariate analysis revealed that anemia was associated with impaired LRS (better local control) but with improved DFS. In contrast, hemoglobin decrease during radiotherapy was an independent risk factor for DFS (risk ratio 1.97, P = 0.04). During radiotherapy, only 30.8% of R0-resected patients suffered from hemoglobin decrease compared to 55.6% if R1/2 resection was performed (P = 0.04). The 5-year OAS, CSS, DFS, LRS and DRS were 47.0%, 60.0%, 41.4%, 67.2%, and 84.3%, respectively. Significant differences between preoperative and postoperative radiochemotherapy were not found.
CONCLUSION : Anemia before radiochemotherapy and hemoglobin decrease during radiotherapy have no predictive value for the outcome of rectal cancer. Stage, grading, R status (free radial margins), type of surgery, CEA levels, and gender have predictive value for the outcome of rectal cancer.
doi:10.3748/wjg.v12.i12.1849
PMCID: PMC4087509  PMID: 16609990
Rectal cancer; Adjuvant radiotherapy; Adjuvant radiochemotherapy; Anemia; Prognostic factor
24.  The management of extra-abdominal desmoid tumours 
International Orthopaedics  2004;28(4):252-256.
We performed a retrospective analysis of 35 cases of desmoid tumours (aggressive fibromatoses) that underwent treatment at our institutions between 1987 and 2002. The purpose was to evaluate the rate of local recurrence of desmoid tumours treated with surgical excision, to assess the impact of surgical margins on local recurrence and to define the role of radiotherapy in the treatment. Nine patients experienced a recurrence at an average of 16 months after initial treatment. Seven of the 15 patients with a less-than-wide margin had a local recurrence. Comparatively, only two of the 20 patients with a wide margin had a local recurrence. Thirty-three of the 35 patients were disease free at the last follow-up. We recommend wide excision with clear margins whenever possible. Marginal resections are appropriate when wide excision would severely compromise the function of the limb. Surgical resections and selective supplementation of adjuvant radiotherapy give excellent control rates.
doi:10.1007/s00264-004-0571-0
PMCID: PMC3456932  PMID: 15168085
25.  Successful management of elderly breast cancer patients treated without radiotherapy 
Background
Breast cancer in the elderly may follow a less aggressive course. There are data suggesting that radiotherapy (RT) following breast conserving surgery (BCS) for invasive carcinoma may not be necessary in some elderly patients. The addition of RT to surgery might constitute an imposition to such patients due to age-related factors. The aim of this study was to assess the efficacy of BCS without adjuvant RT in this group of patients.
Patients and methods
A retrospective review of 92 elderly (median age 75 years; range: 70 – 87 years) patients (analysed as 93 'patients' due to one patient having bilateral cancers) managed in a dedicated breast clinic and who underwent BCS for invasive carcinoma was carried out. Eighty-three patients did not receive postoperative RT to the breast (no-RT group) whereas the remaining 10 had RT (RT-group).
Results
The median age in this group was 75 (range 70 – 87) years. The mean tumour size was 18 mm with a median follow-up of 37 (range 6 – 142) months. In the no RT group, adjuvant endocrine therapy with tamoxifen was given to 40/53 patients. No patients in the oestrogen receptor (ER) negative group received tamoxifen. The local recurrence (LR) rate in this group was 8.4% (2.4% per year, n = 7/83), with median time to LR of 17 months. In this no-RT group LR was correlated to ER status (2/53 ER+, 5/26ER-, p = 0.024) and margins of excision (n = 1/54 >5 mm, 2/17 1–5 mm, 4/12 <1 mm, p = 0.001). Within the ER positive group the LR rate was 0.92% per annum (0.62% per annum in patients treated with adjuvant tamoxifen, regardless of margin status). Breast cancer specific survival was correlated to histological grade (p < 0.05) and ER status (p < 0.05).
Conclusion
It would appear that omission of RT following successful BCS in elderly patients with ER positive tumours receiving adjuvant tamoxifen may be acceptable. The LR rate as shown in this retrospective study is highly comparable to that of younger patients treated by conventional therapy. This concept is now being evaluated prospectively following a change in treatment practice.
doi:10.1186/1477-7819-5-62
PMCID: PMC1892555  PMID: 17543132

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