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• Breast cancer is a growing global health care issue in older women
• The incidence of breast cancer has risen steadily in most European countries between 1990 and 2002:
  • In women aged 70 years or older
• In several clinical trials, low-risk patients have been identified in whom the effect of postoperative whole-breast irradiation is modest:
  • Although these studies have been done mainly in younger patient populations:
    • However, in older patients, the biology of breast cancer might be less aggressive:
      • In view of the increased proportion of hormone receptor-positive tumors in this age group
• Postoperative whole-breast radiotherapy remains the standard of care:
  • For most patients treated by breast-conserving surgery, irrespective of age and other risk factors:
    • However, little evidence exists for the role of postoperative radiotherapy in older patients after breast-conserving surgery and adjuvant endocrine treatment:
      • Because many trials, historically, excluded patients older than age 70 years
• Extrapolation of the results of trials in younger patients to older patients might not be valid:
  • Particularly because of the competing risks of comorbidities in older patients
• Data for the effect of age on local recurrence after breast-conserving surgery have been conflicting:
  • In some trials, ipsilateral breast tumor recurrence falls with increasing age or no effect is seen:
    • However, patients older than 65 years (and particularly those older than 75 years) were not well represented in any of these trials
    • Since tamoxifen with or without adjuvant radiotherapy reduces the risk of tumor recurrence:
      • The investigators of the PRIME II trial designed a randomized controlled trial in a group of older, low-risk, node-negative women with invasive breast cancer after breast-conserving surgery and adjuvant endocrine treatment to assess the effect omission of whole-breast irradiation has on local control
• Methods:
  • Participants:
    • They performed a phase 3 randomized controlled trial at 76 specialist cancer centres and district or regional hospitals in four countries (the UK, Greece, Australia, and Serbia)
    • They recruited women aged 65 years or older with breast cancer who had undergone breast-conserving surgery and pathological axillary staging (ipsilateral four-node lower axillary node sample, sentinel node biopsy, or axillary node clearance)
    • Eligibility criteria were:
      • T1 to T2 (up to 3 cm, longest dimension); N0; M0; hormone receptor-positive (estrogen receptor, progesterone receptor, or both); clear excision margins (≥ 1 mm); no axillary involvement on histological examination (pN0); and receiving adjuvant hormone treatment (we permitted neoadjuvant hormonal treatment)
    • Staging investigations included full blood count, liver function tests, and chest radiography
    • They required re-excision margins to be 1 mm or greater, but we did not request the actual final measurement because this value can be difficult for the pathologist to estimate
    • All patients had to be fit for treatment and follow-up (as assessed by the participating centre) and able and willing to give informed consent
    • They did not request details of specific performance status nor formal documentation of comorbidities
    • Patients’ tumors could have grade 3 histological features or lymphovascular invasion, but not both
    • They excluded patients if they were younger than 65 years at the time pathological results were issued or if they had a history of previous in-situ or invasive breast cancer of either breast
    • We also excluded women with current or previous malignant disease within the past 5 years, other than non-melanomatous skin cancer or carcinoma in situ of the cervix
    • We did not record HER2 status in these patients because this marker was not routinely assessed at the start of the trial
    • The PRIME II study protocol received UK national ethics (MREC) approval on Sept 24, 2001
    • All patients gave written informed consent before randomization
    • Follow-up is ongoing and will end at the 10-year anniversary of the last randomized patient
  • Randomization and masking:
    • We randomly allocated patients to either whole-breast radiotherapy or no radiotherapy in a 1:1 ratio using a computerized randomization service
    • Randomization was by block permutation, stratified by center, with a block size of four
    • Once a patient had provided informed consent, a research nurse familiar with the trial contacted the central independent randomization service (Information Services Division Scotland, Edinburgh, UK) by telephone; a trial identifier was generated and treatment was assigned
    • The assignment was confirmed by a fax sent to both the registering center and the trial manager
    • They could not mask participants to the treatment being given
    • However, no evidence was present in the trial identifier to indicate to which treatment the patient had been allocated; therefore, during follow-up and data analysis, researchers were unaware of patients’ allocation unless they specifically looked for it
  • Procedures:
    • The total radiotherapy dose, number of fractions, and overall treatment time was administered according to local practice in every center:
      • However, we provided a guideline for dose fractionation of 40 to 50 Gy(2.66–2.00 Gy per fraction in 15 to 25 fractions) over 3 to 5 weeks at megavoltage irradiation to the breast
    • They permitted a breast boost with electrons of 10 to 15 Gy at appropriate energy or an iridium implant (eg, 20 Gy to 85% reference isodose)
    • Guidelines on radiotherapy included some form of immobilization, a planned target volume of the whole breast (margin of 1 cm), and all patients being simulated to establish the volume of lung irradiated (maximum lung thickness no greater than 3 cm)
    • They specified that the peripheral lymphatic system was not to be irradiated
    • They stated that a minimum of one transverse outline, taken at the central axis of the tangential fields, was to be taken
    • All fields were to be treated with megavoltage irradiation, with wedged fields so that dose homogeneity did not vary by more than 10%
    • They indicated that doses were to be prescribed to the reference point at or close to the center of the target volume (ICRU-50)
    • For the boost volume, they specified the tumor bed with lateral margins of 2 cm and a deep margin extending down to the underlying muscle
  • They indicated tamoxifen (20 mg daily for 5 years) as the standard adjuvant endocrine treatment, but we allowed other forms of adjuvant and neoadjuvant endocrine treatment
  • Follow-up was for 10 years and consisted of annual clinic visits, examination and mammography for at least 5 years, and, beyond this time, either a clinic visit or a phone call to the patients’ primary health care doctor to ascertain their health status, in addition to follow-up mammography
  • Outcomes:
    • The primary endpoint was ipsilateral breast tumor recurrence
    • Secondary endpoints were:
      • Regional recurrence, contralateral breast cancer, distant metastases, disease-free survival, and overall survival
    • They defined ipsilateral breast tumor recurrence as any cancer in the scar, the adjacent area in the same breast, or in a different quadrant of the same breast
    • They defined regional recurrence as disease in the ipsilateral axillary or supra- clavicular lymph nodes
    • The endpoints were not centrally assessed but based on local investigator review
• Results:
  • Between April 16, 2003, and Dec 22, 2009, 1326 patients were randomly allocated to either:
    • No radiotherapy (n=668) or whole-breast radiotherapy (n=658)
  • Of these, 39 did not receive radiotherapy after randomization and five received radiotherapy when they had been randomly allocated to the no radiotherapy group
  • Another three patients did not begin endocrine treatment after randomization or stopped taking it shortly after starting
  • 1263 patients were recruited from the UK, 22 were from Greece, 16 were from Australia, and 25 were from Serbia
  • Patients’ median age was 70 years (IQR 67–74)
  • Fewer than 10% of patients had tumors with poor estrogen receptor status
  • 91 (16%) of 584 patients for whom radiotherapy treatment data were available received a tumor bed boost after whole-breast radiotherapy
  • At median follow-up of 5 years (IQR 3·84–6·05):
    • Actuarial ipsilateral breast tumor recurrence was 1.3% (95% C1 0·2–2·3) in women allocated whole-breast radiotherapy and 4.1% (2.4–5.7) in those assigned no radiotherapy (log-rank p=0·0002)
    • The hazard ratio for ipsilateral breast tumor recurrence in patients allocated to no radiotherapy was 5.19 (95% CI 1·99–13·52; p=0·0007; full data, not truncated at 5 years)
    • The absolute risk reduction in ipsilateral breast tumor recurrence at 5 years was 2.9% (95% CI 1·1–4·8)
    • The number needed to treat was calculated to be 31.8 (95% CI 27·4–55·0), which equates to an adjusted absolute risk reduction of 3.1% (95% CI 1·8–3·6) by the Altman and Andersen methodology
    • 26 (4%) patients assigned to no radiotherapy and five (1%) women allocated to whole-breast radiotherapy had local recurrences
    • Of the 26 local recurrences in the no radiotherapy group:
      • 18 women had a local recurrence only
      • Six had both local and regional recurrence
      • Two had a local recurrence with distant spread
    • In the radiotherapy group:
      • Four patients had local recurrence only
      • One had local and regional recurrence
    • They did a multivariate Cox proportional hazards analysis of local recurrence according to known risk factors for local recurrence, including:
      • Pathological tumor size, margin status, tumor grade, age, presence of lymphovascular invasion, estrogen receptor status, and use of radiotherapy
    • Progesterone receptor status was excluded from analyses because roughly 30% of data were missing in each treatment group
    • The only factor that predicted local recurrence was:
      • Omission of radiotherapy (hazard ratio 4·87, 95% CI 1·86–12·74; p=0·0013), although poor estrogen receptor status and grade 3 tumors were of borderline significance (p=0·06):
        • However, very few women had either of these factors (36 [3%] patients had grade 3 tumors and 120 [9%] had poor estrogen receptor status)
    • Overall survival at 5 years was identical in the two treatment groups (93.9%, 95% CI 91.8–96·0; p=0·34)
    • At 5 years, no differences between treatment groups were noted:
      • In regional recurrences, distant metastases, contralateral breast cancers, or new cancers
    • Breast cancer-free survival at 5 years was 94.5% (95% CI 92·5–96·5) in women allocated to no radiotherapy and 97.6% (96·2–99·0) in those assigned to whole-breast radiotherapy:
      • The difference was attributable mainly to ipsilateral breast tumor recurrence
    • Only 12 (13%) of 89 deaths recorded by the time of analysis were due to breast cancer, eight (16%) of 49 women assigned to no radiotherapy and four (10%) of 40 allocated to whole-breast radiotherapy
    • In a hypothesis-generating unplanned subgroup analysis of local recurrence by estrogen receptor score:
      • Local recurrence at 5 years for women in the rich estrogen receptor subgroup was lower than in the whole population:
        • For patients assigned no radiotherapy, 20 (3%) of 593 patients had a local recurrence compared with five (<1%) of 601 women allocated whole-breast radiotherapy:
          • 5-year ipsilateral breast tumor recurrence was 3.3% [95% CI 1·7–4·8] and 1.2% [0·1–2·2], respectively; p=0·002
        • In women with poor estrogen receptor status, six (9%) of 65 women allocated no radiotherapy had local recurrence compared with none of 55 women allocated to whole-breast radiotherapy (ipsilateral breast tumor recurrence at 5 years was 10.3% [95% CI 2·5–18·2] and 0%, respectively; p=0·026); however, the number of patients in this analysis is small
• Conclusion
  • Postoperative whole-breast radiotherapy achieved a significant but relatively small reduction in local breast recurrence at 5 years in a population of low-risk older patients with early breast cancer after breast-conserving surgery and adjuvant endocrine treatment
  • The only other trial in which omission of radiotherapy was investigated in a low-risk population was the CALGB 9343 trial,17,18 in which a similar 3% reduction in local recurrence at 5 years was noted with addition of radiotherapy
  • Our findings add to existing evidence of the safety of omitting radiotherapy after breast-conserving surgery in older patients, in whom the benefits of adjuvant radiotherapy have been controversial, and they might encourage clinicians to consider omission of radiotherapy in all or selected older women with low-risk breast cancer after breast-conserving surgery depending on the weight they and the patient give to local recurrence

#Arrangoiz #BreastSurgeon #CancerSurgeon #SurgicalOncologist #BreastCancer #CASO #CenterforAdvancedSurgicalOncology

• SCC is a non-melanoma skin cancer:
  • That arises from keratinocytes of the epidermis
  • It accounts for one fifth of all skin cancers:
    • Is more lethal than basal cell carcinoma:
      • As difficult-to-treat metastatic disease:
        • Can occur in up to 5% of patients
• Management of SCC, like basal cell carcinoma:
  • Consists of adequate local control:
    • Several characteristics have been identified to stratify lesions at high risk for recurrence:
      • These include:
        • Tumor size greater than 2 cm
        • Ulcerated
        • Location on the:
          • Lips / nose / forehead / chin and neck (H areas of the face)
        • Ill-defined borders
        • Previous radiation
        • Chronic scar
        • Immunosuppression
        • Recurrent tumors
        • Poor differentiation
        • Deep Clark level invasion
  • Presence of risk factors directs local therapy:
    • As lesions with no risk factors can be safely excised with 4 mm to 6 mm margins
  • With one or more risk factors:
    • Larger margins should be obtained, and 1-cm margins are recommended, if possible (given local tissue constraints)
  • The use of SLN biopsy for high-risk SCC has been reported in several small, single institutional reports:
    • However, its impact on patient outcomes has not been well defined
• A highly successful alternative to standard surgical excision is Mohs micrographic surgery, performed by experienced dermatopathologists:
  • This involves serial resections of the tumor with real-time mapping and complete peripheral and deep pathologic evaluation to direct immediate further resection:
    • It has the lowest recurrence rates when compared to curettage / electrodessication, standard surgical excision, and radio therapy
• Surgical excision with grossly negative margins, with immediate primary closure is inappropriate:
  • As the tumor’s size alone is a negative risk factor precluding smaller (4- to 6-mm) margins
• References:
  • Brodland DG, Zitelli JA. Surgical margins for excision of primary cutaneous squamous cell carcinoma. J Am Acad Dermatol. 1992; 27:241-248.
  • National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Basal cell and squamous cell cancers. Available at: http://www.nccn.org.
  • Renzi C, Caggiati A, Mannooranparampil TJ, et al. Sentinel lymph node biopsy for high risk cutaneous squamous cell carcinoma: case series and review of the literature. Eur J Surg Oncol. 2007;33:364-369.
  • Rowe DE, Carroll RJ, Day CL Jr. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lips: implications for treatment modality selection.J Am Acad Dermatol.1992;26:976-990.

• MCC:
  • Also known as primary small-cell carcinoma of the skin and anaplastic carcinoma of the skin:
    • Is a rare, aggressive cutaneous malignancy
• Risk factors for MCC include:
  • Immunosuppression:
    • Human immunodeficiency virus (HIV) infection
    • Cancer
    • Organ transplant
  • Chemotherapy
  • Radiation
  • Arsenic
  • Sun exposure
• Approximately 80% of Merkel cell tumors:
  • Harbor a polyoma virus:
    • But its role in pathogenesis remains unclear
• The cornerstone of management for MCC is:
  • Wide local excision with a margin of 1 to 2 cm
  • Nodal staging in clinically node-negative patients:
    • Is a subject of controversy:
      • About one third of the patients with MCC will have a positive SLN:
        • SLN biopsy does not appear to have an impact on survival but does improve local control
      • On the basis of the current evidence, National Comprehensive Cancer Network guidelines:
        • Recommend routine SLN biopsy for clinically node-negative MCC
• MCC is an extremely radiosensitive tumor:
  • A recent randomized study for stage 1 Merkel cell carcinoma:
    • Showed significant reduction on regional recurrence with radiation
  • A retrospective Surveillance, Epidemiology, and End Results (SEER) database study:
    • Demonstrated an improvement in survival for patients who received adjuvant radiation:
      • This effect was more pronounced in the 2 cm tumors
    • Recommendations for adjuvant radiation after appropriate surgical resection are still unclear:
      • However, adjuvant radiation therapy to the primary tumor site should be considered for:
        • Larger ( greater than 1 cm) tumors with adverse features such as:
          • Perineural invasion and lymphovascular invasion
      • In high-risk cases that omit a SLN biopsy:
        • Radiation to nodal basin is recommended
    • Regional lymph node dissection and / or nodal irradiation is recommended for patients with nodal metastases;
      • However, for resectable lesions there is no role for neoadjuvant radiation therapy
• References:
  • Gupta SG, Wang LC, Peñas PF, Gellenthin M, Lee SJ, Nghiem P. Sentinel lymph node biopsy for evaluation and treatment of patients with Merkel cell carcinoma: The Dana-Farber experience and meta-analysis of the literature. Arch Dermatol. 2006;142:685-690.
  • Jouary T, Leyral C, Dreno B, et al. Adjuvant prophylactic regional radiotherapy versus observation in stage I Merkel cell carcinoma: A multicentric prospective randomized study. Ann Oncol. 2012;23:1074-1080.
  • Mehrany K, Otley CC, Weenig RH, Phillips PK, Roenigk RK, Nguyen TH. A meta-analysis of the prognostic significance of sentinel lymph node status in Merkel cell carcinoma. Dermatol Surg. 2002; 28:113-117.Mojica P, Smith D, Ellenhorn JD. Adjuvant radiation therapy is associated with improved survival in Merkel cell carcinoma of the skin. J Clin Oncol. 2007;25:1043-1047.

• Radiation therapy (RT) after breast-conserving surgery (BCS):
  • Decreases the risk of ipsilateral breast recurrence (IBTR)
• Several studies have suggested that there exists a favorable subgroup of patients:
  • In whom irradiation may not provide meaningful overall benefit, including but not limited to:
    • Older women with smaller estrogen receptor (ER)–positive cancers treated with anti-hormonal therapy
• To test this hypothesis, the Cancer and Leukemia Group B (CALGB) initiated CALGB 9343
  • A randomized trial comparing the efficacy of:
    • Tamoxifen alone (Tam) with tamoxifen plus RT (TamRT) in older women with ER-positive, clinical stage I breast cancer
• When reported in 2004 (median follow-up, 5 years):
  • The 5-year incidence of IBTR or regional nodal recurrence was:
    • 4% for patients receiving Tam
    • 1% for those receiving TamRT
  • There was no difference in:
    • Survival
    • Time to distant metastasis
    • Ultimate breast-preservation rate
  • Examining Medicare data through 2007, Soulis et al found:
    • That CALGB 9343 report:
      • Had little impact, with the use of irradiation:
        • Only slightly diminishing in this population:
          • Because it was possible that with longer-term follow-up the results of the CALGB 9343 trial might not persist:
            • The CALGB 9343 trial performed a longterm analysis to address these concerns
• The methods of the CALGB 9343 trial study have been previously described:
  • CALGB 9343 was designed in cooperation with the Eastern Cooperative Oncology Group (ECOG) and Radiation Therapy Oncology Group (RTOG)
  • Local institutional review boards reviewed and approved the study in compliance with the Declaration of Helsinki
  • Written informed consent was obtained from all patients.
  • An independent data and safety monitoring committee provided oversight
  • The CALGB Statistical Center managed data collection, and data quality was ensured by the study chairperson and statistical center review
  • CALGB statisticians performed the statistical analyses
  • The CALGB quality-assurance program has been previously described
  • Patient Selection:
    • Women age 70 years or older with clinical stage I, ER-positive breast cancer and no history of cancer other than in situ cervical or non melanoma skin cancer within 5 years were eligible
    • Initial eligibility criteria included breast cancers up to 4 cm regardless of estrogen receptor status, but this was reduced in August 1996 to equal or less 2 cm (T1) with ER-positive or indeterminate receptor status
    • Patients were required to have clinically negative axillae
  • Treatment:
    • At entry, patients were randomly assigned (1:1 ratio) to receive Tam or TamRT
    • Random assignment was stratified by age (less 75 years vs equal or greater than 75 years) and axillary dissection (yes vs no)
    • Patients were observed every 4 months for 5 years and yearly thereafter
    • This study did not rigorously capture tamoxifen discontinuation
    • Local therapy:
      • All women underwent lumpectomy with a clear margin (absence of tumor at the inked margin)
      • Axillary node dissection was allowed but not encouraged
      • RT included tangential fields to the entire breast followed by an electron boost to the lumpectomy site
    • Tamoxifen:
      • All women received 20 mg of tamoxifen per day for 5 years:
        • Initiated either during or after irradiation
      • Adjuvant hormonal treatment beyond 5 years was discretionary
  • Study End Points:
    • The primary study end points were time to locoregional recurrence, frequency of mastectomy for recurrence, breast cancer–specific survival, time to distant metastasis, and overall survival (OS)
    • IBTR was defined as any cancer in the ipsilateral breast
    • Regional recurrence was defined as any recurrence in the ipsilateral supraclavicular, infraclavicular, or axillary nodes
    • Secondary end points were:
      • Cosmetic results, as judged by physician and patient, and adverse effects such as breast pain and skin changes
  • Actuarial Survival:
    • The expected proportion of women in this study who would be alive at each year after random assignment was found assuming the women were randomly sampled from women of the same age in the general population
    • They used the 2001 period life table of the US Social Security Administration (approximate middle of follow-up for this study)
    • They compared actual survival proportion and its confidence limits over time after random assignment of women in the study with their actuarial survival distribution
• Results:
  • The study was initiated by the CALGB (July 1994) and by the RTOG and ECOG (December 1996)
  • Enrollment ended in February 1999 with 647 women:
    • CALGB, 307; ECOG, 112; and RTOG, 228 women
    • Eleven patients (2%) never began protocol treatment
    • Statistical analyses used a modified intent-to-treat approach that included all 636 patients who began protocol treatment:
      • 317 with TamRT and 319 with Tam
    • Before the eligibility change, 10 patients with ER-negative tumors and 13 patients with tumors greater than 2 cm were entered
    • Baseline characteristics of the women were similar in the two groups
    • As of January 2011, median follow-up was 12.6 years (maximum, 16.5 years)
    • Of the 636 treated patients:
      • 335 (53%) survived at least 10 years:
        • 227 of whom remain in active follow-up
    • Because the observed treatment effect was similar when assessed by both log-rank and multivariate methods, they quote the P values from only the log-rank test
    • Time to Locoregional Recurrence:
      • As compared with the Tam group:
        • The TamRT group experienced a significantly longer time to locoregional recurrence (observed HR, 0.18; 95% CI, 0.07 to 0.42; P < .001)
      • At 10 years:
        • 90% of patients in the Tam group (95% CI, 85% to 93%) compared with 98% in the TamRT group (95% CI, 96% to 99%):
          • Were free from locoregional recurrence
        • Thirty-two women in the Tam group experienced locoregional recurrence:
          • Of these, 20 had only IBTR
          • Six, IBTR with distant metastasis
          • Five, only axillary recurrence
          • One, both IBTR and axillary recurrence
        • Six women in the TamRT group experienced locoregional recurrence:
          • All six were IBTRs
      • At 10 years:
        • 91% in the Tam group (95% CI, 87% to 94%) compared with 98% in the TamRT group (95% CI, 96% to 99%) were free from local (IBTR) recurrence
        • There were no axillary recurrences among the 244 women who underwent initial axillary dissection
        • Among those who did not undergo axillary dissection:
          • There were no axillary recurrences in the TamRT group
          • There were six of 200 in the Tam group
    • Treatment of IBTR:
      • Six patients receiving TamRT and 27 receiving Tam had in-breast recurrences (IBTRs):
        • Of these, four (TamRT) and 10 (Tam) underwent mastectomy
        • One patient in the TamRT arm underwent lumpectomy without RT
        • 13 in the Tam arm underwent lumpectomy (four without RT, eight with RT, and one unknown RT)
    • Time to Mastectomy:
      • Time to mastectomy did not differ significantly between the two treatment groups (observed HR, 0.50; 95% CI, 0.17 to 1.48; P 􏰅 .17)
      • The 10-year probability of not undergoing mastectomy was 98% (95% CI, 96% to 99%) in the TamRT group and 96% (95% CI, 93% to 98%) in the Tam group
    • Time to Distant Metastasis:
      • Time to distant metastasis did not differ significantly between the two treatment groups (P < .50;); distant relapse occurred in 21 patients in the TamRT group (13 have died as a result of breast cancer) and 16 in the Tam group (eight have died as a result of breast cancer)
      • The 10-year probability of freedom from distant metastasis was 95%
    • Survival:
      • Of the 636 women in the trial, there were 334 deaths:
        • 166 in the TamRT arm and 168 in the Tam arm (HR, 0.95; 95% CI, 0.77 to 1.18)
        • The respective 10-year estimates of OS were:
          • 67% (95% CI, 62% to 72%) and 66% (95% CI, 61% to 71%)
        • Only 21 of the deaths (6.3%) resulted from breast cancer:
          • 13 in the TamRT arm and eight in the Tam arm (HR, 1.55; 95% CI, 0.64 to 3.74)
        • The respective 10-year breast cancer–specific survival estimates were:
          • 97% (95% CI, 94% to 99%) and 98% (95% CI, 95% to 99%)
• Conclusion:
  • Long-term follow-up of CALGB 9343 confirms and extends the earlier report that in women age equal or greater than 70 years with clinical stage I, ER-positive breast cancer treated with lumpectomy followed by tamoxifen:
    • Irradiation adds no significant benefit in terms of survival, time to distant metastasis, or ultimate breast preservation, even though it provides a small decrease in IBTR

#Arrangoiz #BreastCancer #Radiation #BreastSurgeon #CancerSurgeon #SurgicalOncologist #Mount Sinai Medical Center #MSMC #Miami #Mexico

• The Arimidex, Tamoxifen, Alone or in Combination trial (ATAC):
  • Was designed to compare the efficacy and safety of anastrozole (1 mg) with tamoxifen (20 mg):
    • As adjuvant treatment for postmenopausal women with early-stage breast cancer
  • Patients were treated every day for 5 years
  • The study was a double-blind, prospective, randomized trial:
    • With 9,366 postmenopausal women
  • A proportional hazards model was used to assess the:
    • Primary endpoints of:
      • DFS
    • Secondary endpoints of:
      • Time to recurrence
      • Time to distant recurrence
      • Overall survival
      • Death with or without recurrence
  • The combination arm of anastrozole and tamoxifen:
    • Was discontinued after the initial analysis as it was found to have no efficacy or tolerability benefits over tamoxifen alone
• Long-term follow-up of 120 months:
  • Showed significant improvements in the anastrozole group versus the tamoxifen group for:
    • DFS
    • Time to recurrence
    • Time to distant recurrence
  • In hormone receptor-positive patients:
    • These benefits were seen to increase over time
  • Recurrence rates:
    • Were found to remain lower on anastrozole after treatment was completed
  • There was little difference in overall survival between anastrazole and tamoxifen:
    • Hazard ratio, 0.95; 95% confidence interval, 0.84–1.06; P=0.4
• Fractures:
  • Were more frequent during the active treatment in patients receiving anastrozole:
    • But were similar between the two groups in post-treatment follow-up
• Treatment-related serious adverse events were less common in the anastrozole group:
  • But were also found to be similar between the two groups after treatment completion
• Anastrozole showed a non-significant increased incidence of colorectal cancer and lung cancers, and a decreased incidence of endometrial, melanoma, and ovarian cancers:
  • However, only the decrease in endometrial cancers remained statistically significant after Bonferroni correction (P<0.001)
• Overall, anastrozole was found to have superior long-term efficacy and safety than tamoxifen:
  • As initial adjuvant therapy for postmenopausal women with hormone-sensitive early-stage breast cancer
• Outcomes from the ATAC trial:
  • Made anastrozole the preferred treatment for postmenopausal women with localized hormone receptor-positive breast cancer
• References
  • Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, et al. Results of the ATAC (arimidex, tamoxifen, alone or in combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet. 2005;365(9453):60-62.
  • Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, et al; ATAC/LATTE Investigators. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol. 2010;11(12):1135-1141.

• Melanoma of the anal canal:
  • Is rare:
    • Of all melanomas diagnosed:
      • Only 0.4% to 1.6% arise in the anal canal
• Lesions tend to be diagnosed at an advanced stage:
  • With the onset of symptoms such as pruritus and bleeding
• Often, these tumors are diagnosed in a delayed fashion:
  • Because of confusion with more common lesions of the anal canal:
    • Such as hemorrhoids
• Once a biopsy specimen was evaluated, the histology and immunohistochemistry was diagnostic of an anal melanoma:
  • A staging work-up in the form of cross-sectional imaging:
    • Is the standard of care for determining whether distant or regional disease may be present
  • If staging studies are negative for metastatic disease:
    • Then the next step is to control the primary lesion:
      • There are two reasonable options for controlling the primary lesion in the setting of anal canal melanoma:
        • Abdominoperineal resection or local excision
      • Both are accepted practices; however, over the past several decades, there has been a trend toward less aggressive surgery:
        • In the form of local excision
      • The findings of retrospective studies support a less aggressive approach:
        • Because of a lack of difference in overall or disease-free survival between groups treated with either radical surgery or local excision:
          • Ross et al reported on 26 patients with anal melanoma treated with either radical surgery (abdominoperineal resection) or local excision and found no difference in overall and recurrence-free survival between the two groups
• References:
  • Iversen K, Robins RE. Mucosal malignant melanomas. Am J Surg. 1980;139:660-664.
  • Nigro ND, Vaitkevicius VK, Considine B Jr. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum. 1974;17:354-356.
  • Ross M, Pezzi C, Pezzi T, Meurer D, Hickey R, Balch C. Patterns of failure in anorectal melanoma: a guide to surgical therapy. Arch Surg. 1990;125:313-316.

• Patients considered at high risk for regional recurrence following lymphadenectomy for melanoma:
  • May be considered for adjuvant radiation:
    • Which may decrease regional recurrence:
      • By approximately 50%
• High-risk patients include:
  • Those with extranodal spread
  • Multiple nodes involved:
    • ≥ 2 nodes in the neck or axilla
    • ≥ 3 nodes in the inguinal basin
  • Those with large positive nodes:
    • ≥ 3 cm nodes in the neck
    • ≥ 4 cm in the inguinal or axillary basins
• While adjuvant radiation may decrease regional recurrence by approximately 50%:
  • There is no survival benefit seen
• Radiation is known to increase the rate of lymphedema
• References:
  • Burmeister BH, Henderson MA, Ainslie J, et al. Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial. Lancet Oncol. 2012; 13(6): 589-97.

#Arrangoiz #SurgicalOncologist #CancerSurgeon #HeadandNeckSurgeon #ThyroidSurgeon #ParathyroidSurgeon #SkinCancer #Melanoma #MountSinaiMedicalCenter #MSMC #Miami #Mexico

• Despite recent advances in systemic therapy for advanced melanoma:
  • This disease will eventually fail to respond to systemic therapies in the majority of patients with stage IV disease:
    • And surgical resection (metastasectomy) thus remains an important consideration
  • The findings of retrospective series and prospective registries:
    • Have confirmed that long-term survival is possible for a substantial minority of appropriately selected patients who have resection for stage IV disease
  • With appropriate patient selection, metastasectomy:
    • May be the initial preferred modality rather than systemic therapy
  • A history of significant autoimmune disease, such as colitis:
    • Could exclude a patient from consideration of checkpoint blockade drugs:
      • However, metastasectomy would be a reasonable consideration even in patients who are candidates for systemic treatment
• Appropriate selection of candidates for metastasectomy is crucial:
  • Although solitary metastases are most favorable:
    • The presence of more than one nodule is not an absolute contraindication to resection
    • Selection factors include:
      • The extent of disease:
        • The number of metastases
        • The number of involved sites
      • The tumor growth rate or doubling time
      • The patient’s comorbidities
      • It must be possible to remove all evident disease:
        • As incomplete resection of metastases has not been beneficial in some patients relative to nonsurgical treatment
      • Palliative intent is another potential indication for surgery in stage IV melanoma:
        • But this is not the only indication for surgery
• References:
  • Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2616.
  • Morton DL, Foshag LJ, Hoon DS, et al. Prolongation of survival in metastatic melanoma after active specific immunotherapy with a new polyvalent melanoma vaccine. Ann Surg. 1992;216:463-482.
  • Ollila DW. Complete metastasectomy in patients with stage IV metastatic melanoma. Lancet Oncol. 2006;7:919-924.
  • Sosman JA, Moon J, Tuthill RJ, et al. A phase 2 trial of complete resection for stage IV melanoma: Results of Southwest Oncology Group Clinical Trial S9430. Cancer. 2011;117:4740-4746.

• The NSABP P-2, or the Study of Tamoxifen and Raloxifene trial (STAR trial):
  • Enrolled 19,747 postmenopausal women:
    • With a 5-year Gail risk assessment score of ≧ 1.66%:
      • For the development of invasive breast cancer at 5 years
  • The women were randomized to receive:
    • 20 mg of tamoxifen plus placebo or 60 mg of raloxifene plus placebo
  • The updated results of the STAR trial:
    • Median follow-up 81 months
    • Reported more cases of invasive breast cancer in the raloxifene group than the tamoxifen group:
      • Risk ratio [RR]: 1.24; 95% confidence interval [CI]: 1.05–1.47:
        • Demonstrating that raloxifene is about 76% as effective as tamoxifen in reducing breast cancer risk
    • There were significantly fewer cases of invasive uterine cancer with raloxifene compared to tamoxifen:
      • RR: 0.55; 95% CI, 0.36–0.83
    • Thromboembolic events occurred less often in the raloxifene group:
      • RR: 0.75; 95% CI: 0.6–0.93
    • There were fewer cataracts and cataract surgeries in the women taking raloxifene:
      • RR: 0.79; 95% CI: 0.68–0.92
    • Importantly, there was no significant difference in mortality between the two groups.

References

1. Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, et al; for the National Surgical Adjuvant Breast and Bowel Project (NSABP). Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295(23):2727-2741.

2. Vogel VG. The NSABP Study of Tamoxifen and Raloxifene (STAR) trial. Expert Rev Anticancer Ther. 2009;9(1):51-60.

3. Mamounas EP, Wicherham DL, Fisher B, Geyer CE, Julian TB, Wolmark N. The NSABP experience. In: Kuerer HM, ed. Kuerer’s Breast Surgical Oncology. New York, NY: McGraw-Hill Companies; 2010:475-508.

• Several preclinical studies have demonstrated that tamoxifen acts:
  • Not only by blocking the ER pathway:
    • But also by modulating the production of:
      • Transforming growth factor-alpha
      • Transforming growth factor-beta
      • By increasing the levels of sex hormone-binding globulin in serum
      • Increasing natural killer cell counts
      • By decreasing insulin-like growth factor
• The NSABP protocol B-23:
  • Was developed to determine whether:
    • Tamoxifen has a role in patients with ER negative cancer
  • Patients with ER negative tumors were randomized to:
    • Four cycles of adjuvant doxorubicin and cyclophosphamide (AC) or 6 cycles of adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) with or without tamoxifen
  • The results of B-23 demonstrated:
    • No significant improvement in DFS or overall survival (OS) with tamoxifen added to chemotherapy:
      • DFS:
        • CMF, 83%; CMF plus tamoxifen, 83%
        • AC, 83%; AC plus tamoxifen, 82%
      • OS:
        • CMF, 89%; CMF plus tamoxifen, 89%
        • AC, 90%; AC plus tamoxifen, 91%
    • Additionally, protocol B-23 confirmed the results of protocol B-15:
      • That found that four cycles of AC are equivalent to 6 cycles of CMF in terms of DFS and OS
• NSABP B-24:
  • Also demonstrated the effectiveness of tamoxifen only on ER+ ductal carcinoma in situ (DCIS):
    • As did a study by Allred et al. on the risk reduction of a subsequent breast cancer in ER+ DCIS treated with tamoxifen

References

1. Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER,et al. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol. 2001;19(4):931-942.

2. Wapnir IL, Dignam JJ, Fisher B, Mamounas EP, Anderson SJ, Julian TB, et al. Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst. 2011;103(6):478-488.

3. Allred DC, Anderson SJ, Paik S, Wickerham DL, Nagtegaal ID, Swain SM, et al. Adjuvant tamoxifen reduces subsequent breast cancer in women with estrogen receptor-positive ductal carcinoma in situ: a study based on NSABP protocol B-24. J Clin Oncol. 2012;30(12):1268-1273.