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• Though the absolute numbers were low

• Identical at 2.7% in both groups

• Omitting SLNB significantly reduced rates of lymphedema (5.7% vs. 1.8%), arm mobility restrictions (3.5% vs.
  and pain with arm or shoulder movement (4.2% vs. 2.0%).
  • Context Within Ongoing De-Escalation Trials
    • The INSEMA trial is one of four ongoing studies exploring the omission of axillary surgery in select patients with early-stage breast cancer. These include:
      • SOUND trial: Published results demonstrated no difference in 5-year DFS or OS between patients undergoing or omitting axillary surgery for small (≤ 2 cm) breast tumors.
      • BOOG 2013-08 and NAUTILUS trials: Expected to further validate and refine patient selection criteria for omitting axillary surgery.
    • Clinical Implications
    • The INSEMA trial strengthens the case for omitting SLNB in carefully selected patients, particularly for tumors ≤ 2 cm. However, the continued role of SLNB as a staging tool in certain patients and the need for shared decision-making with multidisciplinary teams.
    • This trial represents a key milestone in an ongoing paradigm shift, aligning with earlier data (e.g., Danish Breast Cancer Cooperative Group studies from the 1980s) that suggested no survival benefit from extensive axillary node removal.
    • Conclusion:
      • The findings from the INSEMA trial provide compelling evidence supporting deescalation of axillary surgery in early-stage breast cancer, with a significant reduction in morbidity and no compromise in survival outcomes.
      • Further results from ongoing trials such as BOOG 2013-08 and NAUTILUS will likely cement this strategy as standard practice for patients with low axillary disease burden.
        
        
        
        
        
        
        

• With early-stage, clinically node-negative breast cancer with negative axillary ultrasound (AUS), without compromising oncologic outcomes

• Tumor ≤ 2.0 cm (cT1)

• Underwent sentinel lymph node biopsy

• No axillary surgery

• Sweden, Denmark, Germany, Greece, Italy

• cN0, cT1 to cT3 tumors with 1 to 2 SLN macrometastases:
  • BCS or mastectomy allowed
• Extra capsular extension (ECE) and cT3 permitted
• SENOMAC did allow patients who had SLNB before neoadjuvant systemic therapy (NAST) to be enrolled if cN0 and with ≤ 2 SLN macrometastases:
  • Randomization was recommended before starting NAST

• Adjuvant therapy and radiation therapy (RT) per national guidelines

• N=2766 enrolled:
  • Per-protocol N=2540:
    • SLNB 1335
    • cALND 1205
  • Mastectomy ≈ 36% in each arm:
    • SLNB 490 / 1335
    • cALND 430 / 1205

• RT including nodal volumes given to ~ 90% in both arms:
  • SLNB 89.9%; cALND 88.4%
• Quality assessment (QA) check showed:
  • 99.3% concordance for breast / chest-wall fields and 96.6% for nodal targets

• Switched the primary endpoint to overall survival (OS):
  • To declare non-inferiority on OS, the trial needs 190 deaths:
    • At last analysis there weren’t enough events:
      • So OS is not yet formally tested

• ≈ 92.9% vs 92.0%

• HR 0.89 (95% CI 0.66–1.19) → non-inferior

• cALND upstaged more often (pN2 – 9.9%, pN3 – 3.0%) vs SLNB-only (pN2 – 0.5%):
  • Without outcome benefit
• Additional non-SLN metastasis on cALND in 34.5% overall:
  • If 1 SLN macrometatases:
    • 31.3% had more positive nodes
  • If 2 macrometastases:
    • 51.3% had more positive nodes

• SLNB-only patients reported less arm pain / symptoms and better function than cALND

• To prevent 1 iDFS event at 5 yrs via identifying ≥ pN2-pN3 with cALND:
  • ~ 104 cALNDs would be needed:
    • Causing severe / very severe arm dysfunction in ~ 9 / 104 at 1 year:
      • Discourages ALND purely to find pN2-pN3 for CDK4/6 indication

• Omitting cALND preserved control and survival and minimized arm morbidity:
  • Supports SLNB-only + RNI / PMRT for 1 to 2 SLN macrometastases after mastectomy

• ~ 90% received nodal RT

• Though granular nodal-level dose / field details were not yet available at reporting

• But event counts and narrow CIs yield precise estimates for NI

• Omitting cALND maintains disease control with less arm morbidity

• While acknowledging the need for longer follow-up and more granular RT-field reporting

• All favored cisplatin PubMed+1

• Discuss RT + cetuximab (Bonner) or altered-fractionation RT

• To cisplatin-eligible patients is incorrect New England Journal of Medicine
• Bonner:
  • 5-yr OS 45.6% with RT + cetuximab vs 36.4% RT alone:
    • Not a comparison to cisplatin

• Document shared decision-making when deviating

RTOG – 1016 (NI trial, Lancet 2019):

De-ESCALaTE HPV (Lancet 2019):

• Cells need “molecular Velcro” that works under shear.

• E-selectin:
  • Induced by TNF-α / IL-1
• P-selectin:
  • Rapidly mobilized from Weibel–Palade bodies
  • Also on platelets

• PSGL-1 and other sialyl-Lewis^x (sLe^x):
  • Decorated glycoproteins
• L-selectin (CD62L) is on leukocytes:
  • Not endothelium:
    • It helps secondary capture / rolling:
      • Leukocyte–leukocyte interactions
        • Binds Peripheral Node Addressin on High Endothelial Venules (PNAd on HEVs)
• Mechanics: 
  • “Catch bonds” let cells roll, sampling endothelium for activating cues
• ✅ Fix to your line: 
  • Rolling is mainly:
    • E-selectin / P-selectin (endothelium) ↔ sLe^x/PSGL-1 (leukocyte)
  • L-selectin:
    • Is leukocyte-borne:
      • It augments rolling
  • P-selectin:
    • Is not on neutrophils

• For example:
  • CXCL8 /IL-8 (neutrophils), CCL2 / MCP-1(monocytes):
    • Bind GPCRs (CXCR1/2, CCR2…), engaging Gαi → Rap1 → talin / kindlin:
      • To flip integrins into high-affinity and clustered states

• β2 family: 
  • LFA-1 (αLβ2; CD11a/CD18)
  • Mac-1 (αMβ2; CD11b/CD18).
• β1 family: 
  • VLA-4 (α4β1):
    • Prominent in monocytes / lymphocytes

• Through junctions

• Through individual endothelial cells

• Mostly homophilic interactions at junctions

• Chemokines: 
  • CXCL8 (neutrophils), CCL2 (monocytes), CCL19/21 (lymphocyte homing)
• Lipid mediators: 
  • LTB4, PGE₂ (context-dependent)
• Complement & danger cues: 
  • C5a, fMLP from bacteria

• Strong recommendation, Moderate certainty evidence

• Oral cavity, oropharynx, or larynx:
  • Hypopharynx excluded

• Pernineural invasion (PNI)
• Lymphovascular ivasion (LVI)
• ≥ 2 lymph nodes (LNs) (all < 6 cm) or one LN > 3 cm (no extranodal extension (ENE))
• Close margin(s) < 5 mm or focally positive then re-resected negative
• pT3 to pT4a primary, or T2 oral cavity with DOI > 5 mm ozarkscancerresearch.org

• Majority HPV-negative (~ 80%)
• Oral cavity ~ 64%
• EGFR high expression in ~ 85%(assayed for stratification, not a requirement) NRG Oncology+1

• PORT alone vs PORT + cetuximab

• IMRT 60 Gy in 30 fx (66 Gy allowed) ozarkscancerresearch.org

• 400 mg/m² loading, then 250 mg/m² weekly x 6 during RT + 4 weekly doses post-RT (total 11) ozarkscancerresearch.org

• Overall survival (OS) in all randomized / eligible
  • Pre-specified plan to test in HPV-negative subgroup

• Disease-free survival (DFS), toxicity, others PubMed

• OS HR 0.81; one-sided p=0.075 (did not meet significance)
• 5-yr OS: 
  • 76.5% (PORT+cetuximab) vs 68.7% (PORT) NRG Oncology

• DFS HR 0.75; one-sided p=0.017
• 5-yr DFS: 
  • 71.7% (PORT+cetuximab) vs 63.6% (PORT)
    • Benefit limited to HPV-negative population NRG Oncology+1

• Acute grade 3 to 4: 
  • 70.3% (PORT+cetuximab) vs 39.7% (PORT); p<0.0001:
    • Largely more mucositis / dermatitis NRG Oncology
• Late grade 3 to 4: 
  • 33.2% vs 29.0%, p=0.31 (no significant increase)
• No grade-5 events NRG Oncology

• A dedicated RTOG-0920 QoL analysis was presented at ASCO 2025:
  • Aligns with the toxicity profile (no long-term penalty reported in the abstract listing). ASC Publications+1

• With trade-off of substantially higher acute toxicity
• OS was not improved PubMed+1
• HPV-positive:
  • No signal of benefit:
    • Do not extrapolate a DFS advantage here. PubMed

• Those are high-risk → cisplatin-based CRT

• HR ~ 0.83; ~ 6.5% 5-yr OS gain:
  • Driven by improved locoregional control

• Overall survival: 
  • HR 0.83 (95% CI 0.79–0.86):
    • Absolute OS gain + 6.5% at 5 yr and + 3.6% at 10 yr (≈ NNT ~ 15 at 5 yr)
• EFS:
  • HR 0.80 with + 5.8% at 5 yr
• No increase in 120-day mortality:
  • HR 1.07, p=0.37 Groningen Research Portal
• Patterns of failure: 
  • Marked LRF reduction (sub-HR 0.71)
  • No DF effect (HR 1.04)
  • Survival benefit driven by lower cancer mortality (HR 0.79; − 9.8% at 5 yr):
    • With no change in non-cancer deaths (HR 1.01) Groningen Research Portal
• Regimen effects: 
  • Greatest effect for platinum-containing polychemotherapy (EFS HR 0.74)
  • Smallest for non-platinum monochemotherapy (HR 0.86)
  • Benefit consistent across eras and RT modalities Groningen Research Portal

• No significant benefit:
  • OS HR 0.96
  • EFS HR 0.96
• DF decreases (HR 0.76):
  • But no LRF improvement (sub-HR 1.07)
• Benefit attenuates with worse performance status Groningen Research Portal

• No benefit:
  • OS HR 1.02
  • EFS HR 0.98

• Higher 120-day mortality (HR 1.89, p=0.0003)
• Some reduction in LRF (sub-HR 0.84) and DF(HR 0.77) without survival gain Groningen Research Portal

• OS HR 0.84 (≈ + 6.2% absolute OS at 5 yr)
• EFS HR 0.85
• LRF HR 0.86

• Benefit of concomitant chemotherapy decreases with increasing age:
  • Use added caution > 70 yr Groningen Research Portal

• Poorer PS attenuates benefit:
  • Noted in induction analyses:
    • Similar theme in concomitant Groningen Research Portal

• Not evaluable here (most trials pre-HPV era)
• Don’t expect HPV-specific signals from MACH-NC Groningen Research Portal

• The only timing with proven OS benefit is concomitant chemo with RT
• Expect ~ 6% to 7% absolute 5-yr OS gain:
  • Driven by better loco-regional control Groningen Research Portal

• Platinum-containing regimens carry the strongest signal:
  • This underpins cisplatin-based CRT as the benchmark Groningen Research Portal

• Cr, BUN, Mg, K, Ca, Na, PO₄

• Why: 
  • Baseline renal reserve; cisplatin causes salt wasting (especially Mg) and AKI eviQ

• Why:
  • Myelosuppression risk DailyMed+1

• Why:
  • Ototoxicity risk:
    • Establish baseline threshold:
      • Audiology societies and monographs recommend baseline and interval monitoring American Academy of Audiology+2audiology-web.s3.amazonaws.com+2

• Hold / avoid nephrotoxins:
  • NSAIDs, IV contrast, aminoglycosides
• Assess fluid status eviQ

• Day 1: 
  • NK1RA + 5-HT3RA + dexamethasone + olanzapine
• Continue dexamethasone ± olanzapine Days 2 to 4 American Society of Clinical Oncology+2Janet Abrahm, M.D.+2

• Act: 
  • Replete Mg (often 10 mmol MgSO₄ pre-hydration) and correct K / Ca before dosing
  • If eGFR ↓ or SCr ↑:
    • Evaluate per KDIGO, hydrate, and hold / modify eviQ

• Act: 
  • Use isotonic saline pre / post hydration:
    • Typical total 2.5 to 3.0 L around infusion
  • Routine mannitol not required:
    • Consider only for very high-dose eviQ

• Tinnitus, hearing change, paresthesias, nausea / vomiting, cramps (hypo-Mg), mucositis, dysphagia
• Act:
  • Audiogram if otologic symptoms
  • Neuro exam each visit American Academy of Audiology+1

• Why:
  • Catch AKI and hypomagnesemia early
  • Track cytopenias and dehydration eviQ+1

• Repeat before each cycle (q3-weekly) or sooner if symptoms; for weekly cisplatin, obtain symptom-triggered or mid-course checks per local protocol American Academy of Audiology+1

• ≥ 0.3 mg/dL increase or ≥ 1.5 × baseline (KDIGO stage 1+):
  • Hold cisplatin, hydrate (NS), replete Mg / K, stop nephrotoxins, reassess in 24 to 72 hours

• Include MgSO₄ in pre-hydration (e.g., 10 mmol in 1 L NS) and replete as needed:
  • Mg protects against cisplatin nephrotoxicity eviQ+1

• Optimize 4-drug regimen (ensure NK1RA)
• Consider scheduled olanzapine days 2 oto 4
• Add rescue (metoclopramide, prochlorperazine) American Society of Clinical Oncology+1

• Prompt audiogram:
  • If confirmed / worsening:
    • Discuss dose holding or regimen change (risk rises with cumulative dose) American Academy of Audiology+1

• Encourage oral fluids (≥ 500 mL if tolerated)

• To fight infection and promote tissue repair:
  • But also contributes to inflammation and disease when overactivated

• Anaphylatoxins and form a membrane attack complex (MAC) that can kill pathogens

• But inappropriate activation can cause:
  • Chronic pain, autoimmune disease, and organ damage

• Classical Pathway: 
  • Activated by the binding of antibodies (like IgG and IgM) to antigens:
    • On the surface of a pathogen
• Lectin Pathway: 
  • Initiated when mannose-binding lectin (MBL):
    • Binds to carbohydrate structures on bacterial cell walls 
• Alternative Pathway: 
  • Triggered by the direct binding of complement components to foreign surfaces, such as pathogens, without the need for antibodies 

• Trigger: 
  • C1q, a component of the C1 protein complex:
    • Binds to an antibody-antigen complex:
      • On a pathogen surface
    • The C1 complex is composed of:
      • C1q, C1r, and C1s
• Cascade:
  • C1r and C1s are activated:
    • Which then cleave complement proteins C4 and C2
    • The larger fragments, C4b and C2b (also called C2a):
      • Bind together to form the classical pathway’s C3 convertase (C4b2b) 
• Antigen – antibody complexes:
  • Best: 
    • IgM:
      • Then IgG1 / IgG3
• Early components unique to this pathway: 
  • C1 (C1q, C1r, C1s), C2, C4
• C1 protein complex:
  • Needs Ca²⁺:
    • To stay assembled

• Trigger: 
  • The pattern recognition molecule:
    • Mannose-binding lectin (MBL) or ficolins:
      • Bind to specific carbohydrate patterns (like mannose) on the surface of pathogens
• Cascade:
  • This binding activates MBL-associated serine proteases (MASPs):
    • Which are functionally similar to C1r and C1s
  • The MASPs cleave C4 and C2:
    • Forming the same C3 convertase (C4b2b) used by the classical pathway 
• Mannose-binding lectin (MBL) or ficolins binding microbial sugars:
  • Enzymes: 
    • MASP-1 / MASP-2 cleave C4 and C2:
      • Merges with classic pathway a:
        • C3 convertase (C4b2a)

• Trigger: 
  • This pathway is always active at a low level through a “tickover” mechanism:
    • Where C3 is spontaneously hydrolyzed
  • It is further activated when C3b, a fragment of C3:
    • Binds directly to the surface of a pathogen or foreign material
• Cascade:
  • Factor B binds to the surface-bound C3b and is then cleaved by Factor D to form C3bBb:
    • The alternative pathway’s C3 convertase
  • The protein properdin stabilizes this complex:
    • Amplifying the cascade
  • This pathway also acts as an amplification loop for the classical and lectin pathways
• Spontaneous C3 hydrolysis on microbial / endotoxin surfaces:
  • Amplified by Factor B, Factor D, Properdin (P)
  • Note: 
    • Mg²⁺ is required for Factor B binding to C3b
    • Properdin stabilizes the convertase
• Common note: 
  • C3:
    • Common to and is the convergence point for the three pathways

• All three initiation pathways converge to form a C3 convertase:
  • Which ultimately leads to the creation of the:
    • Membrane attack complex (MAC) 
• C3 cleavage:
  • A C3 convertase cleaves C3 into two pieces:
    • C3a:
      • A small fragment that acts as a potent:
        • Anaphylatoxin, triggering inflammation
    • C3b:
      • A larger fragment that acts as an opsonin, or “tag,” marking the pathogen for destruction
      • It also attaches to the C3 convertase to create a C5 convertase
• C5 cleavage:
  • The C5 convertase cleaves C5 into C5a (a potent anaphylatoxin and chemoattractant) and C5b
• Membrane Attack Complex (MAC):
  • The C5b fragment recruits and assembles the remaining complement proteins (C6, C7, C8, and multiple C9 molecules):
    • To form a cylindrical pore in the pathogen’s membrane:
      • This pore disrupts the cell’s osmotic balance:
        • Causing it to lyse and die

• Classical / Lectin pathway:
  • C3 convertase: 
    • C4b2a
  • C5 convertase: 
    • C4b2a3b
• Alternative pathway:
  • C3 convertase: 
    • C3bBb:
      • Stabilized by Properdin / P
  • C5 convertase: 
    • C3bBb3b
• Effector Functions (the “what does each piece do?”):
  • Anaphylatoxins: 
    • C3a, C4a, C5a:
      • ↑ vascular permeability
      • Vasodilation
      • Bronchoconstriction
      • Mast cell / basophil degranulation
    • Potency: 
      • C5a > C3a >> C4a (C4a is weak)
  • Chemotaxis (especially neutrophils): 
    • C5a is the major chemoattractant:
      • C3a contributes mainly as anaphylatoxin
    • C5a drives:
      • Leukocyte recruitment
      • Adhesion up-regulation
      • Oxidative burst
  • Opsonization: 
    • C3b (and iC3b), C4b
    • Coat pathogens (marks them for destruction):
      • CR1 / CR3 on phagocytes bind → enhanced phagocytosis
  • Membrane Attack Complex (MAC): 
    • C5b to C9
    • C5b:
      • Nucleates assembly with C6, C7, C8, C9 (polymerizes) → pore → osmotic lysis (classically Neisseria)
• Ion Requirements (exam-friendly correction):
  • Classical and Lectin Pathway: 
    • Ca²⁺ required for C1qrs (classical) and MBL – MASP (lectin) complexes:
      • Mg²⁺ also involved downstream
  • Alternative pathway: 
    • Mg²⁺ essential for Factor B – C3b interaction and convertase formation:
      • So: not “Mg for both pathways”:
        • Only – Classical / Lectin need Ca²⁺
        • Alternative needs Mg²⁺ (and Properdin)
• Regulation (why we don’t self-destruct):
  • C1 inhibitor (C1-INH): 
    • Blocks C1r / C1s and MASPs 1/2 (MASP-1 / MASP-2 cleave C4 and C2):
      • Turns off classic / lectin pathways early
  • Factor H and Factor I: 
    • Inactivate C3b (→ iC3b) on host cells:
      • Factor H prefers sialic acid – rich self surfaces
  • DAF / CD55: 
    • Disrupts C3 / C5 convertases on host cells
  • CD59 (Protectin): 
    • Blocks C9 polymerization:
      • Prevents MAC on self cells
  • Clinical Correlates (high-yield):
    • C1-INH deficiency → Hereditary angioedema:
      • Bradykinin-mediated edema:
        • ACE inhibitors worsen
      • Treat with C1-INH concentrate, bradykinin pathway blockers
    • C2 deficiency (most common classic pathway deficiency):
      • SLE-like disease, recurrent sinopulmonary infections
    • C3 deficiency:
      • Recurrent severe pyogenic infections:
        • Especially encapsulated bacteria; immune complex disease.
    • Terminal complement (C5 to C9) deficiency:
      • Recurrent Neisseria (meningitidis, gonorrhoeae)
    • DAF / CD55 or CD59 deficiency (e.g., PNH via PIGA mutation):
      • Intravascular hemolysis, hemoglobinuria, thrombosis
      • Treat with C5 inhibitors:
        • Eculizumab / ravulizumab
    • Factor H / I abnormalities:
      • Atypical HUS, C3 glomerulopathy
  • Laboratory Assessment:
    • CH50:
      • Total classic pathway function:
        • Low in classic component defects or terminal pathway defects
    • AH50:
      • Total alternative pathway function
    • Heat-labile:
      • Complement activity falls if serum is mishandled / warmed
• Quick “Apply It” Pearls:
  • Suspected meningococcemia with recurrence:
    • Check terminal complement (C5 to C9)
  • Recurrent pyogenic infections with low C3:
    • Evaluate classic / alternative convertase regulation
  • Episodic angioedema without urticaria:
    • Think C1-INH deficiency
  • Autoimmunity in a young patient + low early classic components (C1q/C2/C4) → screen for complement deficiencies
• One-Page Memory Map:
  • Triggers:
    • Classic pathway: 
      • IgM / IgG immune complexes → C1qrs (Ca²⁺)
    • Lectin pathway: 
      • MBL / ficolin (MASPs) → C4, C2
    • Alternative pathway: 
      • C3 tackover + B, D, Properdin (Mg²⁺)
    • Convertases:
      • Classic / Lectin: 
        • C4b2a (C3), C4b2a3b (C5)
      • Alternative:
        • C3bBb (C3), C3bBb3b (C5)
    • Effectors:
      • Opsonins: 
        • C3b/iC3b (± C4b)
      • Anaphylatoxins: 
        • C5a > C3a >> C4a
      • Chemotaxis: 
        • C5a
      • MAC: C5b to C9
    • Regulators: 
      • C1-INH, Factor H / I, DAF (CD55), CD59
    • Deficiencies (buzzwords): 
      • C1-INH—HAE
      • C2—SLE-like
      • C3—pyogenic infections
      • C5–C9—Neisseria
      • DAF/CD59—PNH
      • Factor H/I—aHUS