My name is Rodrigo Arrangoiz I am a breast surgeon/ thyroid surgeon / parathyroid surgeon / head and neck surgeon / surgical oncologist that works at Center for Advanced Surgical Oncology in Miami, Florida.
I was trained as a surgeon at Michigan State University from (2005 to 2010) where I was a chief resident in 2010. My surgical oncology and head and neck training was performed at the Fox Chase Cancer Center in Philadelphia from 2010 to 2012. At the same time I underwent a masters in science (Clinical research for health professionals) at the University of Drexel. Through the International Federation of Head and Neck Societies / Memorial Sloan Kettering Cancer Center I performed a two year head and neck surgery and oncology / endocrine fellowship that ended in 2016.
Mi nombre es Rodrigo Arrangoiz, soy cirujano oncólogo / cirujano de tumores de cabeza y cuello / cirujano endocrino que trabaja Center for Advanced Surgical Oncology en Miami, Florida.
Fui entrenado como cirujano en Michigan State University (2005 a 2010 ) donde fui jefe de residentes en 2010. Mi formación en oncología quirúrgica y e n tumores de cabeza y cuello se realizó en el Fox Chase Cancer Center en Filadelfia de 2010 a 2012. Al mismo tiempo, me sometí a una maestría en ciencias (investigación clínica para profesionales de la salud) en la Universidad de Drexel. A través de la Federación Internacional de Sociedades de Cabeza y Cuello / Memorial Sloan Kettering Cancer Center realicé una sub especialidad en cirugía de cabeza y cuello / cirugia endocrina de dos años que terminó en 2016.
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
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.
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
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.
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.
Without specific defining characteristics on mammography, ultrasound, or MRI
A palpable breast mass which yields ALH at core needle biopsy:
Is not clinically concordant and should prompt further diagnostic workup with a second biopsy:
Either core or excisional
ALH alone confers a 4 to 5 fold increased risk of breast cancer
Risk reducing mastectomy (RRM):
Can be considered in patients with a lifetime risk of breast cancer ≥ 20% based on history of:
ADH / ALH or family history:
But this risk must be quantified using a risk assessment tool such as the Gail or Tyrer-Cuzick model
ALH should only be considered for observation:
When it is diagnosed incidentally and there is radiologic, pathologic, and clinical concordance
Relevant indications for genetic testing include:
Personal history of breast cancer ≤ 45 years of age
Triple negative breast cancer ≤ 60 years of age
A first-degree relative with breast cancer≤ 50 years of age
Two or more first- or second-degree relatives with breast cancer at any age
Patient or relative with bilateral breast cancer
Male breast cancer in a relative at any age
The Gail Model:
Should only be used in patients ≥ 35 years of age:
May underestimate risk in patients with strong family history or non-Caucasian ethnicity
The Tyrer-Cuzick model:
May be more appropriate in this setting
References:
Morrow M, Schnitt SJ, Norton L. Current management of lesions associated with an increased risk of breast cancer. Nat Rev Clin Oncol. 2015; 12: 227-238. National Comprehensive Cancer Network (NCCN) Guidelines (Login Required): Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 1.2021. Breast Cancer Risk Reduction, Version 1.2020.
Rodrigo Arrangoiz MS, MD, FACS, FSSO 