Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• The addition of regional nodal irradiation (RNI) to WBI:
  • Improves DFS:
    • In women at high risk for recurrence
• The National Cancer Institute of Canada Clinical Trial Group (NCIC-CTG) MA.20 trial:
  • Randomized 1832 high-risk women to:
    • Either WBI alone or
    • WBI plus RNI:
      • Following partial mastectomy and axillary lymph node dissection
  • Regional nodal radiation (RNI) included:
    • The internal mammary, supraclavicular, and high axillary nodes
  • The trial included patients with:
    • Node-positive or
    • High-risk node-negative disease
  • Eighty-five percent of patients had 1 to 3 positive nodes, 5% had more than four positive nodes, and 10% were node negative
  • Node-negative patients with tumors greater than or equal to 2 cm who had fewer than 10 axillary nodes removed:
    • Were considered high risk if they had at least one of the following:
      • Estrogen receptor-negative
      • Lymphovascular invasion, or
      • Nuclear grade 3
  • All patients had systemic therapy
• Median follow-up of 62 months
• The addition of RNI improved:
  • Locoregional DFS from:
    • 94.5% to 96.8% (P=0.02) and
  • Distant DFS from:
    • 87% to 92.4% (P=0.002)
  • There was a non-statistically significant trend:
    • Toward improvement in OS from:
      • 90.7% to 92.3% (P=0.07)
  • The addition of RNI to WBI was associated with:
    • An increase in grade 2 or greater:
      • Pneumonitis:
        • From 0.2% to 1.3% (P=0.01) and
      • Lymphedema:
        • From 4.1% to 7.3% (P=0.004).
• European Organisation for Research and Treatment of Cancer (EORTC) 22922:
  • Randomized 4004 women:
    • Undergoing breast-conserving surgery or mastectomy and ALND for:
      • Histological stage I, II, or III breast cancer:
        • To RNI (supraclavicular and internal mammary nodal irradiation) or
        • No regional nodal irradiation
  • The primary endpoint of evaluation:
    • Was overall survival
  • Median follow-up of 10.9 years
  • The addition of regional nodal irradiation improved:
    • DFS:
      • From 69.1% to 72.1% (P=0.04)
    • Again, there was a non-significant trend toward improvement in OS:
      • From 80.7% to 82.3% (P=0.06 among the RNI group)
    • Patients undergoing regional nodal irradiation experienced:
      • Higher rates of pulmonary fibrosis (4.4% vs 1.7%, P<0.001).
• The results of NCIC-CTG MA.20:
  • Have led many to conclude:
    • That all patients with axillary nodal metastases, regardless of tumor size or extent of nodal involvement:
      • Should receive comprehensive nodal radiation therapy (RT)
• A major conundrum in current practice:
  • Is resolving the apparently contradictory findings of:
    • The American College of Surgeons Oncology Group (ACOSOG) Z0011 and After Mapping of the Axilla, Radiation or Surgery? (AMAROS) with those of MA.20:
      • The modest benefit in DFS with RNT in MA.20:
        • May reflect differences in patient populations between the studies
          • Patients with clinically positive nodes were excluded from ACOSOG Z0011 and AMAROS (and not MA.20)
  • In addition, fewer than 10 nodes were removed in one-third of patients in the MA.20 study and the median node count was 12 compared to a median of 17 in the ALND arms of Z0011 and AMAROS
  • The benefit of nodal RT therefore may be limited to:
    • Higher-risk patients:
      • With more extensive nodal disease and perhaps more limited axillary surgery

REFERENCES

1. Pepels MJ, de Boer M, Bult P, et al. Regional recurrence in breast cancer patients with sentinel node micrometastases and isolated tumor cells. Ann Surg. 2012;255:116-121.
2. Poortmans PM, Collette S, Kirkove C, et al. Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med. 2015;373:317-327.
3. Whelan TJ, Olivotto IA, Parulekar WR, et al; MA.20 Study Investigators. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015;373:307-316.

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• Mechanical ventilation:
  • Is a procedure often performed in patients in respiratory failure:
    • Which is defined broadly as:
      • The inability to meet the body’s needs:
        • For oxygen delivery or
        • Carbon dioxide removal
  • Ventilators delivers air:
    • Usually with an elevated oxygen content:
      • To a patient’s lungs via an endotracheal tube:
        • To facilitate:
          • The exchange of oxygen and carbon dioxide
  • The indications for mechanical ventilation include:
    • Airway protection
    • Treatment of hypoxemic respiratory failure:
      • Low blood oxygen
    • Treatment of hypercapnic respiratory failure:
      • Elevated carbon dioxide in the blood
    • Treatment of a combined hypoxic and hypercapnic respiratory failure
    • On some occasions:
      • Patients are also intubated and placed on mechanical ventilation for:
        • Procedures
    • However:
      • Intubation and initiation of mechanical ventilation require a great degree of vigilance:
        • As committing to this therapy can affect the patient’s overall course of treatment
• Mechanical ventilation is managed by:
  • Respiratory Therapists (RTs)
  • Highly-trained medical professionals:
    • Who specialize in the care of respiratory illnesses
• In addition to managing ventilators:
  • RTs have expertise in other forms of oxygen administration and respiratory support, provide medications for respiratory disorders, and assess patients for extubation readiness
  • RTs are essential for the appropriate care of mechanically ventilated patients
  • Conversely:
    • Mechanical ventilation traditionally has not been taught as a core component of many medical and nursing practices:
      • Outside of Critical Care and Anesthesiology
  • As such, to collaborate effectively with RTs in the care of ventilated patients:
    • Additional education is warranted
  • Ventilator management can seem intimidating due to varied and confusing terminology (with many clinicians using synonyms for the same modes or settings), slight variation among brands of ventilators, unfamiliarity, or ceding management to others.
• For COVID-19 patients:
  • Ventilators are often crucial:
    • Given the nature of the illness
  • But note that intubation and initiation of mechanical ventilation require a great degree of vigilance
  • The data supporting the importance of good ventilator management continues to increase, and appreciating the fundamental principles of ventilation is essential for all clinicians involved in the care of these patients

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• Sentinel node vs. axillary clearance (SNAC):
  • One-year outcomes from the SNAC trial:
    • Demonstrated that sentinel lymph node resection (SLNR) alone in the setting of a sentinel node (SN)-negative axilla:
      • Reduced arm morbidity:
        • While preserving oncologic safety
  • In this study (SNAC):
    • 1088 women
    • With clinically node-negative early-stage breast cancer:
      • Were assigned to receive either:
        • SLNR followed by ALND:
          • If the SN was positive or not detected, or
        • Routine ALND:
          • Defined as SLNR followed immediately by ALND
  • The primary endpoint was:
    • Increase in arm volume from baseline
  • Secondary endpoints included:
    • An increase in arm volume by 15%
    • Early axillary morbidity:
      • Defined as arm dysfunction, or disability
  • Arm volume increased:
    • In the SLNR group by 2.8%, and
    • By 4.2% in the ALND group
      • P=0.002
  • Lower rates of:
    • Arm swelling (P<0.001), symptoms (P<0.001), and dysfunction (P=0.02):
      • Were reported in the SLNR group:
        • While disability (P=0.5) was not
  • The study showed that SLNR:
    • Had a sensitivity of 94.5%
    • A false-negative rate of 5.5%, and
    • A negative predictive value of 98%
  • The study concluded:
    • That SLNR followed oncologic principles and
    • Resulted in significantly less morbidity than ALND
• The ALMANAC trial:
  • A randomized multicenter trial:
    • Of sentinel node (SN) biopsy versus standard axillary treatment:
      • In operable breast cancer:
    • It took the benefits of SLNR in the clinically node-negative axilla one step further:
      • By demonstrating improved quality of life:
        • In patients receiving SLNR versus ALND
• In this study (ALMANAC):
  • 1031 patients
  • Were assigned to undergo SLNR or ALND
  • Patients with a SN-positive axilla:
    • Were subsequently treated:
      • With delayed ALND or
      • Axillary radiation
  • Such measures as:
    • Usage of drains
    • Hospital length of stay, and
    • Time to resumption of daily activities postoperatively were monitored
  • All were statistically significant and lower:
    • In the SLNR group:
      • P<0.001
  • Quality of life and arm functioning scores as reported by patients were statistically significantly better:
    • In the SLNR group:
      • P≤0.003
  • From these results:
    • It was concluded that:
      • SLNR should be the treatment of choice for patients with early-stage breast cancer and clinically negative nodes:
        • Because it is associated with reduced arm morbidity and better quality of life when compared with ALND
• The ACOSOG Z0011 trial:
  • Took the results of previous trials on the safety and validity of SLNR and went one step further:
    • To suggest avoiding ALND for small cancers with clinically node-negative, SN-positive disease:
      • Provided that systemic therapy and whole-breast irradiation (WBI):
        • Is incorporated into the treatment strategy for early-stage breast cancer following breast-conserving surgery
  • Adverse surgical effects were reported:
    • In 70% of patients:
      • After SLND plus ALND, and
      • 25% after SLND alone:
        • P≤.001
  • Patients in the SLND plus ALND group had more:
    • Wound infections (P ≤ .0016)
    • Seromas (P≤ .0001), and
    • Paresthesias (P≤.0001):
      • Than those in the SLND alone group
• The NSABP B-32:
  • Demonstrated the superiority of SLNR over ALND:
    • In terms of morbidity
  • Three-year postsurgical morbidity levels were compared:
    • Between patients with negative SLNR alone and those with negative SLNR and negative ALND
  • Shoulder range-of-motion and arm volumes were assessed on:
    • 1975 ALND and
    • 2008 SLND:
      • Node-negative breast cancer patients
  • Shoulder abduction deficits and arm volume differences:
    • Between the affected arm and the contralateral arms were calculated
  • Shoulder abduction deficits greater than or equal to 10%:
    • Peaked at one week for the:
      • ALND (75%) and
      • SLND (41%) groups
  • Arm volume differences greater than or equal to 10% at 36 months:
    • Were 14% for the ALND group and
    • 8% for the SLND groups
  • Numbness and tingling peaked at 6 months:
    • For the ALND:
      • Numbness: 49%
      • Tingling: 23% and
    • SLNR:
      • Numbness: 15%
      • Tingling: 10%
  • These results indicate:
    • The superiority of SLNR compared to ALND:
      • In terms of postsurgical morbidity outcomes over a 3-year follow-up period

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• The NSABP P-2, or STAR trial:
  • Enrolled 19, 747 postmenopausal women with:
    • A 5-year Gail risk assessment score:
      • Of equal or greater 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
• In the updated results of the STAR trial:
  • Median follow-up 81 months
  • There were 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) and 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. 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.
2. Vogel VG. The NSABP Study of Tamoxifen and Raloxifene (STAR) trial. Expert Rev Anticancer Ther. 2009;9:51-60.
3. Vogel VG, Costantino JP, Wickerham DL, 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;295:2727-2741.

#Arrangoiz #BreastSurgeon #CancerSurgeon #SurgicalOncologist #BreastCancer #Teacher

👉In this pandemic (COVIDEN-19) all physicians must review the managment of ventilated patients just in case if they are called to help out in the ICU management of these sick patients.

• The Ventilator Training Alliance has released an app for the iPhone and iPad that provides free mobile access to video overviews, instruction manuals, and other training materials for equipment that is critical to treating patients suffering from respiratory distress. Manufacturers are responsible for their own content.
• EMCrit created a two-part podcast called Dominating the Vent and a follow up handout.
• Some medical professionals have turned to YouTube to upload ‘crash courses’ in ventilation basics. All the videos below are longer than 10 minutes and provide technical components to understand how or when to use a ventilator.
  • Ventilation Crash Course: Quick and Dirty Guide to Mechanical Ventilation by an independent doctor: provides an overview of how you would change a patient’s blood gas with different settings on a ventilator.
  • Mechanical Ventilation by Medicosis Perfectionalis: provides an overview of why someone needs ventilation and how to understand different settings.
  • Introduction to Mechanical Ventilation by a director of a ICU center: provides an introduction to mechanical ventilation.
  • Mechanical Ventilation crash course by a medical provider who records overviews on different topics and provides a high-level overview on when to use a ventilator.

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👉Novel Findings on SPECT-CT Tc-99 Sestamibi Imaging for Primary Hyperparathyroidism. Mallick R, Malik J, Yip L, Muthukrishnan A, Carty SE, McCoy KL. J Surg Res. 2020 Apr 11;252:216-221. PMID: 32289578 https://www.ncbi.nlm.nih.gov/pubmed/32289578

👉Short-term medical treatment of hypercalcaemia in primary hyperparathyroidism predicts symptomatic response after parathyroidectomy. Koman A, Ohlsson S, Bränström R, Pernow Y, Bränström R, Nilsson IL. Br J Surg. 2019 Dec;106(13):1810-1818. PMID: 31595982 https://www.ncbi.nlm.nih.gov/pubmed/31595982
American Association of Clinical Endocrinologists Endocrine Society

• After 10 years of follow-up from NSABP B-14:
  • A randomized, double-blind, placebo-controlled trial:
    • Comparing tamoxifen to placebo in women with node-negative estrogen receptor-positive invasive breast cancer
  • A statistically significant:
    • Disease-free survival (DFS) benefit was derived with the use of tamoxifen for 5 years:
      • 69% vs 57%, P<0.0001
  • Tamoxifen was also associated with:
    • A 37% reduction in contralateral breast cancers
• The NSABP B-24 trial:
  • Was designed to determine whether lumpectomy and postoperative breast irradiation plus prolonged tamoxifen therapy:
    • Is more effective than lumpectomy and breast irradiation without tamoxifen in preventing the subsequent occurrence of ipsilateral and contralateral breast cancers in patients with non-invasive ductal carcinoma in situ
• The results of NSABP B-14 paved the way:
  • For the administration of additional adjuvant hormonal therapy
  • More specifically:
  • The administration of aromatase inhibitors after completion of tamoxifen therapy became of interest
• NSABP B-33 was developed to compare:
  • Exemestane with placebo:
    • In recurrence-free postmenopausal women who completed 5 years of tamoxifen therapy
  • Accrual to this study was terminated prematurely:
    • When results of NCIC-CTG MA.17 showed:
      • A significant improvement with letrozole after 5 years of tamoxifen
      • With a median follow-up of 64 months, the hazard ratios of letrozole after 5 years of tamoxifen compared to placebo after similar tamoxifen therapy were:
        • 0.52 (95% confidence interval [CI], 0.45 to 0.61; P<.001) for DFS
        • 0.51 (95% CI, 0.42 to 0.61; P<.001) for distant DFS
        • 0.61 (95% CI, 0.52 to 0.71; P<.001) for overall survival
• The patients in NSABP B-33:
  • Were then unblinded and offered 5 years of exemestane
    • The improvement in relapse-free survival observed in NSABP B-33 with exemestane:
      • Was similar to that observed in the NCIC-CTG MA.17 trial with letrozole
• To further examine the benefits of aromatase inhibitors as primary therapy or after 2 to 5 years of tamoxifen in women with early-stage, hormone receptor-positive breast cancer:
  • The MA.17R trial:
    • Analyzed prolonging duration of therapy to 10 years:
      • With DFS as the primary endpoint
    • The results of this study were recently presented:
      • The study randomized 1918 women to placebo versus letrozole
      • Median follow-up of 6.3 years
      • DFS was 95% for the letrozole group and 91% for the placebo group
      • There was also an improvement in the annual incidence of contralateral breast cancer:
        • With the letrozole group at 0.21% versus 0.49% for the placebo group
      • These data support:
        • A new standard of care for this patient population, ie, to improve DFS through 10-year treatment with aromatase inhibitors

REFERENCES

1. Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst. 2001;93:684-690.
2. Fisher B, Jeong JH, Dignam J, et al. Findings from recent National Surgical Adjuvant Breast and Bowel Project studies in stage I breast cancer. J Natl Cancer Inst Monogr. 2001;93:62-66.
3. Ingle JN, Tu D, Pater JL, et al. Intent-to-treat analysis of the placebo-controlled trial of letrozole for extended adjuvant therapy in early breast cancer: NCIC CTG MA.17. Ann Oncol. 2008;19:877-882.
4. Jin H, Tu D, Zhao N, Shepherd LE, Goss PE. Long-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC CTG MA.17 trial: analyses adjusting for treatment crossover. J Clin Oncol. 2012;30:718-721.
5. Lemieux J, Goss PE, Parulekar WR, et al. Patient-reported outcomes from MA.17R: a randomized trial of extending adjuvant letrozole for 5 years after completing an initial 5 years of aromatase inhibitor therapy alone or preceded by tamoxifen in postmenopausal women with early-stage breast cancer. J Clin Oncol. 2016;34 (suppl; abstr LBA506).
6. Mamounas EP, Jeong JH, Wickerham DL, et al. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast and Bowel Project B-33 trial. J Clin Oncol. 2008;26:1965-1971.

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👉Fisher B, Dignam J, Mamounas EP, Costantino JP, Wickerham DL, Redmond C, Wolmark N, Dimitrov NV, Bowman DM, Glass AG, Atkins JN, Abramson N, Sutherland CM, Aron BS, Margolese RG.

PURPOSE: 

• To compare sequential methotrexate (M) and fluorouracil (F) (M–>F) with:
  • Surgery:
    • National Surgical Adjuvant Breast and Bowel Project [NSABP] B-13
  • Cyclophosphamide (C), M, and F with M–>F:
    • NSABP B-19
      • In patients with estrogen receptor (ER)-negative tumors and negative axillary nodes

PATIENTS AND METHODS:

• A total of 760 patients were randomized to B-13; 1,095 patients with the same eligibility requirements were randomized to B-19
• Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were determined using life-table estimates

RESULTS: 

• A significant benefit in overall DFS:
  • 74% vs 59%; P < .001:
    • Was demonstrated at eight years in all B-13 patients who received M–>F:
      • 69% vs 56% [P = .006]:
        • In those < or = 49 years of age
      • 81% v 63% [P = .002]:
        • In those > or = 50 years
• A survival advantage was evident:
  • In older patients:
    • 89% v 80%; P = .03
• In NSABP B-19:
  • Through five years:
    • An overall DFS advantage:
      • 82% v 73%; P < .001 and a borderline survival advantage 88% v 85%; P = .06:
        • Were evident with CMF
    • The DFS (84% v 72%; P < .001) and survival (89% v 84%; P = .04) benefits from CMF:
      • Were greater in women aged < or = 49 years
    • M–>F or CMF after lumpectomy and breast irradiation:
      • Resulted in a low probability of:
        • Ipsilateral breast tumor recurrence (IBTR)
• In NSABP B-13:
  • The frequency of IBTR was:
    • 2.6% following M–>F versus 13.4% in women treated by lumpectomy
      • It was 0.6% following CMF in NSABP B-19
  • Toxicity > or = grade 3 was:
    • More frequent among CMF patients in NSABP B-19
  • The age-related difference in CMF benefit was not related to amount of drug received

CONCLUSION: 

• M–>F and CMF:
  • Are effective for node-negative patients with ER-negative tumors
• The incidence of local-regional or distant metastases and IBTR decreased:
  • After either therapy
• The benefit from either therapy was evident in all patients:
  • But the CMF advantage was greater in those < or = 49 years
• Because it is less toxic:
  • M–>F may be used:
    • In patients with medical problems that would preclude CMF administration

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• 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 and transforming growth factor-beta:
        • By increasing the levels of:
          • Sex hormone-binding globulin in serum
          • Natural killer cell counts
        • By decreasing the levels of:
          • Insulin-like growth factor
  • Additional clinical information suggested that:
    • Tamoxifen prolongs disease-free survival (DFS):
      • Irrespective of receptor status:
        • Although with less magnitude of benefit in ER-negative tumors
• Due to these data, NSABP protocol B-23 was developed:
  • In an attempt to determine whether tamoxifen:
    • Has a role in patients with ER-negative tumors
  • Patients with ER-negative tumors were:
    • Randomized to four cycles of adjuvant doxorubicin and cyclophosphamide (AC) or six cycles of adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) with or without tamoxifen
  • The results of NSABP 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:
    • The NSABP B-23 confirmed the results of NSABP B-15:
      • That found that four cycles of AC are equivalent to six cycles of CMF:
        • In terms of DFS and OS

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• Background:
  • A significant amount of ductal carcinoma in situ (DCIS):
    • Is ER-negative and / or overexpresses HER2
  • DCIS is more likely to overexpress HER2:
    • Than invasive cancer, and it is possible that trastuzumab (T) is more likely to be effective in DCIS:
      • Because it intervenes earlier in the carcinogenic pathway
  • HER2 overexpression:
    • Occurs in 45% of estrogen receptor-negative DCIS
    • 20% of ER-positive DCIS
  • Preclinical data suggest that trastuzumab (T):
    • Enhances the effect of radiation in DCIS that overexpresses HER2
  • Based on these findings:
    • The NSABP protocol B-43 aims to evaluate:
      • The effect of trastuzumab in HER2-positive DCIS
    • Patients with HER2-positive DCIS treated with breast-conserving surgery were randomized to breast irradiation versus breast irradiation plus two doses of trastuzumab:
      • Starting on day one of breast irradiation and repeated three weeks later
    • The primary endpoint:
      • Is the development of any breast cancer
• Methods:
  • After lumpectomy (Lx) for pure DCIS:
    • Each patients (pts) DCIS lesion:
      • Is centrally tested for HER2 using ASCO / CAP guidelines
  • HER2+ pts are randomly assigned to:
    • Receive two doses of T:
      • Three weeks apart during whole breast radiation (WBI) or to WBI alone
• Eligibility:
  • Women ≥ 18 yrs
  • Margin-clear Lx for pure DCIS
  • ECOG status 0 / 1
  • Clinically or pathologically node negative
• ER and/or PR status must be known before random assignment
• Primary aims are to determine:
  • If T decreases:
    • Ipsilateral breast cancer (IBC) recurrence
    • Ipsilateral skin cancer recurrence, or
    • Ipsilateral DCIS
• Secondary aims are to determine:
  • The benefit of T in:
    • Preventing regional or distant recurrence
    • Contralateral invasive breast cancer or DCIS
• B-43 will determine if:
  • DFS, recurrence-free interval, and / or overall survival:
    • Can be improved with the use of T
• 2000 pts will be accrued over 7.9 yrs:
  • With a definitive analysis of primary endpoints performed at 163 IBC events:
    • 7.5 – 8 yrs after protocol initiation with an 80% power to detect a hazard reduction of 36%:
      • From 1.73 IBC events per 100 pt-yrs to 1.11 events per 100 pt-yrs
• The 36% observed reduction in the hazard of IIBCR-SCR-DCIS on the T arm is based on a projection of 40% hazard reduction if the compliance were perfect, with a 10% noncompliance rate
• As of January 1, 2013:
  • 1,127 pts have been randomized into the study
  • Support: PHS NCI-U10-CA-69651, -12027, and -P30-CA-14599 from the US NCI, and Genentech, Inc. Clinical trial information: NCT00769379
• Results:
  • NSABP B-43 opened 11/9/08
  • As of 7/31/2013:
    • 5,861 patients have had specimens received centrally
    • 5,645 of those had analyzable blocks
    • 1,969 (34.9 %) were HER2 positive
  • A total of 1,428 patients have been accrued:
    • 1,137 (79.6 %) of whom have follow-up information
  • The average follow-up time for the 1,137 patients:
    • Is 23.3 months
  • No grade 4 or 5 toxicity has been observed
  • In NSABP B-43 the HER2-positive rate for pure DCIS among patients undergoing breast-preserving surgery:
    • Is 34.9 %:
      • Lower than the previously reported rate
  • No trastuzumab-related safety signals have been observed
  • Interest in this trial has been robust

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