🎗️ ONCOLOGY

Approach to Early Stage NSCLC (Stage I-II)

Primary Treatment Philosophy: Maximize local control while minimizing morbidity. Cure rates exceed 70-90% for stage IA disease with appropriate treatment.

• Surgical Resection (Preferred): Lobectomy provides optimal oncologic outcomes with lymph node assessment. Anatomic resection superior to wedge resection for staging and local control. Minimally invasive approaches (VATS, robotic) reduce morbidity without compromising oncologic outcomes.
• Medically Inoperable Patients: Stereotactic body radiotherapy (SBRT/SABR) delivers ablative radiation doses with outcomes approaching surgery in carefully selected patients. Typically 3-5 fractions of high-dose radiation.
• Adjuvant Therapy Rationale: Even after complete resection, microscopic disease may remain. Adjuvant therapy reduces recurrence risk:
  • Stage IB-II: Platinum-based chemotherapy reduces recurrence by 5-15% (absolute benefit)
  • EGFR-mutant: Osimertinib for 3 years reduces recurrence risk by 50% based on ADAURA trial
  • PD-L1 ≥1%: Atezolizumab after chemotherapy improves disease-free survival (IMpower010 trial)

Clinical Pearl: Oncotype DX testing may help select stage IB patients who benefit from adjuvant chemotherapy, avoiding overtreatment in low-risk patients.

Locally Advanced Disease (Stage III)

Treatment Philosophy: Multimodality therapy essential. Goal is to control local disease while addressing likely micrometastatic spread.

Why concurrent chemoradiation?: Chemotherapy acts as radiosensitizer, improving local control. Radiation sterilizes gross disease while chemotherapy addresses microscopic spread. Concurrent superior to sequential approach.

• Resectable IIIA: Neoadjuvant approach increasingly favored - allows assessment of tumor biology, treats micrometastases early, potentially improves R0 resection rate. Surgery performed 4-6 weeks after completing neoadjuvant therapy.
• Unresectable III: Standard is definitive concurrent chemoradiation followed by durvalumab consolidation. PACIFIC trial demonstrated durvalumab for 1 year post-chemoRT significantly improves progression-free and overall survival by harnessing anti-tumor immune response initiated by radiation.

Clinical Consideration: Patient selection critical - good performance status and adequate pulmonary reserve required for aggressive multimodality therapy.

Advanced/Metastatic NSCLC (Stage IV)

Treatment Strategy: Systemic therapy is cornerstone. Treatment selection based on molecular profile and PD-L1 expression.

Molecular Testing-Guided Approach:

• Driver Oncogene Present (EGFR, ALK, ROS1, BRAF, etc.):
  • Rationale: Targeted TKIs exploit oncogene addiction - tumors dependent on specific driver mutations are exquisitely sensitive to pathway inhibition
  • Response rates 60-80% with targeted therapy vs 20-30% with chemotherapy
  • Superior progression-free survival and quality of life compared to chemotherapy
  • Continue until progression or intolerable toxicity, then consider next-generation TKI or alternative therapy
• No Driver Mutation Identified: Treatment based on PD-L1 expression:
  • PD-L1 ≥50%: Pembrolizumab monotherapy appropriate - KEYNOTE-024 showed superior outcomes vs chemotherapy with better tolerability
  • PD-L1 1-49%: Combination chemo-immunotherapy synergistic - chemotherapy causes tumor cell death releasing antigens, primes immune system for checkpoint inhibitor activity
  • PD-L1 <1%: Chemotherapy backbone essential, immunotherapy benefit less clear but may be added in select cases

Chemotherapy Selection Rationale:

• Non-squamous: Platinum + pemetrexed preferred - pemetrexed maintenance continues after initial 4-6 cycles, extends progression-free survival
• Squamous: Platinum + taxane (paclitaxel or nab-paclitaxel) - pemetrexed less effective in squamous histology due to expression of thymidylate synthase

Clinical Decision Point: Patients with poor performance status (ECOG 3-4) unlikely to tolerate or benefit from aggressive systemic therapy - consider best supportive care or single-agent palliative chemotherapy.

Small Cell Lung Cancer (SCLC) - Distinct Biology, Different Approach

Why SCLC is Different: Neuroendocrine origin, exceptionally rapid growth, early dissemination. Nearly all patients have micrometastatic disease at diagnosis. Highly chemosensitive initially but develops resistance quickly.

Limited Stage (Confined to Hemithorax):

• Concurrent Chemoradiation: Platinum + etoposide with thoracic radiation. Concurrent superior to sequential - addresses rapid growth kinetics
• Prophylactic Cranial Irradiation (PCI): Brain sanctuary site due to poor chemotherapy penetration across blood-brain barrier. PCI reduces brain metastasis risk by 50% in responding patients
• Median survival: 18-24 months with combined modality therapy

Extensive Stage (Beyond Hemithorax):

• Immunotherapy Integration: Addition of atezolizumab or durvalumab to platinum-etoposide improves survival by ~3 months - represents first major advance in decades
• Maintenance Strategy: Continue immunotherapy after initial chemotherapy - sustains anti-tumor immune response
• Relapsed Disease: Platinum rechallenge if >90 days since completion, otherwise topotecan or lurbinectedin. Response duration typically brief

Prognostic Reality: Despite initial chemosensitivity, SCLC remains highly lethal. Extensive stage median survival 12-13 months even with modern therapy. Clinical trial participation should be strongly considered.

Early Stage Disease (Stage I-IIA) - Curative Intent

Surgical Decision-Making:

• Breast Conservation (Lumpectomy + Radiation): Equivalent survival to mastectomy for appropriately selected patients. Preserves breast, requires radiation to control microscopic disease in remaining breast tissue. Preferred when cosmetically feasible and patient accepts radiation commitment
• Mastectomy: Indicated for large tumors relative to breast size, multicentric disease, inability to achieve clear margins, patient preference, or contraindication to radiation. Reconstruction options available
• Sentinel Lymph Node Biopsy: Minimizes morbidity compared to axillary dissection. If positive, completion dissection or radiation based on tumor burden and surgical approach

Adjuvant Systemic Therapy - Preventing Distant Recurrence:

Locally Advanced Disease (Stage IIB-III) - Neoadjuvant Strategy

Why Neoadjuvant (Pre-operative) Therapy?

• Downstage tumor to enable breast conservation surgery
• Assess tumor biology in real-time (response predicts prognosis)
• Pathologic complete response (pCR) strongly correlates with cure, especially in HER2+ and triple negative disease
• Allows modification of post-operative therapy based on response

Neoadjuvant Regimens by Subtype:

• HR+/HER2-: Chemotherapy or endocrine therapy (if very hormone-sensitive, low proliferation). Post-operative therapy extended if residual disease
• HER2+: Chemotherapy + trastuzumab + pertuzumab. pCR rate 50-60%. If pCR achieved, excellent prognosis. If residual disease, consider trastuzumab emtansine (T-DM1) adjuvant
• Triple negative: Chemotherapy + pembrolizumab. If residual disease, continue pembrolizumab up to 1 year (KEYNOTE-522 showed improved survival)

Metastatic Breast Cancer (Stage IV) - Prolonging Survival, Maintaining Quality of Life

Treatment Philosophy: Metastatic breast cancer is generally incurable (5-10% exception for oligometastatic disease treated with local therapy). Goals: maximize survival while maintaining quality of life, delay need for chemotherapy when possible, sequence therapies strategically.

Clinical Pearls for Metastatic Disease:

• Biopsy metastatic site when feasible - receptor status can change (15-20% discordance)
• Bone-targeted therapy (denosumab or zoledronic acid) reduces skeletal events in bone metastases
• Local therapy (surgery, radiation) for oligometastatic disease may prolong survival in select patients
• Median survival: HR+/HER2- (3-5 years), HER2+ (4-6 years), triple negative (1-2 years) - highly variable

Stage I Colon Cancer - Surgery Cures

Treatment Philosophy: Complete surgical resection achieves cure in >90%. No additional therapy indicated.

• Surgical Approach: Segmental colectomy with adequate margins (5 cm) and regional lymphadenectomy. Laparoscopic approach equivalent to open with faster recovery
• Lymph Node Assessment: Minimum 12 lymph nodes must be examined for adequate staging. <12 nodes may indicate inadequate surgery or tumor biology affecting immune response
• Surveillance Strategy: Colonoscopy at 1 year (to clear synchronous lesions), then every 3-5 years. CEA every 3-6 months × 2 years, then every 6 months × 3 years. CT chest/abdomen/pelvis annually × 3 years

Stage II Colon Cancer - Selective Adjuvant Therapy

The Stage II Dilemma: Benefit of adjuvant chemotherapy modest and not proven in all stage II patients. Must identify high-risk subset likely to benefit.

Risk Stratification Approach:

Stage III Colon Cancer - Adjuvant Therapy Standard of Care

Evidence Base: Multiple randomized trials demonstrate 15-20% absolute survival benefit from adjuvant chemotherapy. Number needed to treat = 5-7 to prevent one death. Risk-benefit clearly favors treatment.

Regimen Selection:

• Standard: FOLFOX (5-FU/leucovorin/oxaliplatin) or CAPOX (capecitabine/oxaliplatin)
  • Oxaliplatin addition improves disease-free survival by 5-7% over 5-FU/leucovorin alone
  • CAPOX equivalent to FOLFOX, more convenient (less IV time)
• Duration Decision (IDEA Collaboration - Landmark Trial):
  • Low-risk (T1-3 N1): 3 months non-inferior to 6 months with significantly less neurotoxicity
  • High-risk (T4 or N2): 6 months preferred, modest benefit over 3 months
  • Clinical consideration: Individualize based on toxicity tolerance, comorbidities, patient preference
• Oxaliplatin toxicity management: Cumulative peripheral neuropathy dose-limiting. Consider stopping oxaliplatin at 3 months, continuing capecitabine/5-FU to complete 6 months if neuropathy significant

Special Populations:

• MSI-H stage III: Unclear benefit from chemotherapy, but given higher stage typically treated. Pembrolizumab under investigation in adjuvant setting
• Elderly (>70 years): Consider single-agent capecitabine or 5-FU/leucovorin if oxaliplatin-intolerant. Individualize based on physiologic age, not chronologic

Rectal Cancer (Stage II-III) - Multimodality Therapy

Anatomic Considerations Drive Approach: Mesorectal envelope contains tumor and lymphatics. Total mesorectal excision (TME) essential for local control. Neoadjuvant therapy downstages tumor, facilitates TME, reduces positive margin rate.

Alternative Approaches:

• Traditional long-course chemoRT: Capecitabine or 5-FU + radiation 50.4 Gy over 5-6 weeks → surgery 6-12 weeks → adjuvant chemotherapy 4-6 months
• Short-course RT: 25 Gy in 5 fractions → immediate surgery (Stockholm) OR delayed surgery allowing tumor regression (Polish trial). No concurrent chemotherapy. Equivalent outcomes, shorter treatment time

Surgery Timing: 6-12 week interval between completing neoadjuvant therapy and surgery allows maximal tumor downstaging, higher pCR rate. Do not rush to surgery.

MSI-H Rectal Cancer - Game Changer: Pembrolizumab neoadjuvant achieving remarkable pathologic complete response rates (80-100% in small series). Under investigation - may eliminate need for surgery/radiation in select cases.

Stage IV (Metastatic) CRC - Precision Medicine Paradigm

Treatment Philosophy: Metastatic CRC is heterogeneous. Molecular profiling, tumor sidedness, and metastatic burden guide personalized therapy. Median survival improved from 12 months (1990s) to 30+ months (current) with sequential therapy.

MSS (Microsatellite Stable) Metastatic CRC - Chemotherapy Backbone:

Chemotherapy Selection Based on Goals:

• Intensive therapy (goal: maximum response, potential resection): FOLFOXIRI (5-FU/leucovorin/oxaliplatin/irinotecan) + bevacizumab. Highest response rate (~70%) but most toxic. Reserved for fit patients, high disease burden
• Standard therapy: FOLFOX or FOLFIRI + bevacizumab OR anti-EGFR (if appropriate). Response rate 50-60%, better tolerability
• Less intensive therapy (goal: disease control, quality of life): Capecitabine + bevacizumab or FOLFOX/FOLFIRI without biologics. For elderly, frail, or patient preference

Biologic Agent Selection - Molecular Testing Critical:

Later-Line Therapies - Extending Survival:

• Second-line: Switch chemotherapy backbone (FOLFOX → FOLFIRI or vice versa), continue or add biologic agent
• Third-line and beyond:
  • Regorafenib: Multi-kinase inhibitor, modest benefit (median OS improvement 1-2 months) but quality of life impact. Reserved for fit patients
  • TAS-102 (trifluridine/tipiracil): Oral fluoropyrimidine, better tolerated than regorafenib, similar efficacy
  • Fruquintinib: Selective VEGFR inhibitor, recently approved, similar to regorafenib
  • HER2-amplified (3-5%): Trastuzumab + pertuzumab or tucatinib + trastuzumab, borrowed from breast cancer

Hepatic-Directed Therapies:

• Hepatic artery infusion (HAI): Direct chemotherapy delivery to liver, high local drug concentration. For liver-dominant metastases
• Selective internal radiation therapy (SIRT/Y90): Radioembolization for liver metastases
• Indications: Liver-only/dominant disease, refractory to systemic therapy, preserved liver function

Localized Disease Management - Matching Treatment to Risk

Biochemical Recurrence - Rising PSA After Definitive Treatment

Definition: PSA ≥0.2 ng/mL after prostatectomy OR PSA rise ≥2 ng/mL above nadir after radiation

Assessment Strategy:

• PSA kinetics: Doubling time <3 months suggests aggressive disease requiring immediate treatment. >12 months may warrant observation
• Imaging: PSMA PET/CT revolutionized detection - identifies metastases at low PSA levels (>0.5 ng/mL sensitivity ~50%, >2 ng/mL ~90%)
• Genomic classifiers: Decipher, Oncotype DX, Prolaris help predict metastatic risk, inform treatment decisions

Management Approach:

• Post-prostatectomy: Salvage radiation to prostate bed ± pelvic nodes. Best outcomes when PSA <0.5 ng/mL. Consider concurrent ADT for high-risk features
• Post-radiation: Salvage prostatectomy (select patients, challenging surgery) OR cryotherapy/HIFU OR ADT
• Observation: For slow PSA kinetics, elderly patients, significant comorbidities

Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

Paradigm Shift: Standard ADT alone is no longer adequate. Combination therapy with novel androgen axis drugs (or chemotherapy in select cases) is new standard based on multiple randomized trials demonstrating significant survival improvement.

Duration of Therapy: Continue until progression, unacceptable toxicity, or patient decision. Indefinite treatment is standard - stopping risks rapid progression.

Castration-Resistant Prostate Cancer (CRPC) - Sequential Therapy Approach

Definition: Rising PSA or radiographic progression despite castrate testosterone levels (<50 ng/dL). Keep ADT indefinitely - even with resistance, some androgen sensitivity persists.

Non-Metastatic CRPC (nmCRPC):

• Goal: Delay metastases, prolong survival without metastatic disease burden
• Treatment: Continue ADT + add apalutamide, enzalutamide, or darolutamide
• SPARTAN, PROSPER, ARAMIS trials: Delayed metastases by ~2 years, improved overall survival
• Patient selection: Rapidly rising PSA (doubling time <10 months) - predicts imminent metastatic disease

Treatment Selection Principles:

• Consider what patient received in earlier disease settings (avoid immediate re-exposure)
• Pace of disease progression (rapid = chemotherapy or Lutetium-PSMA, slow = novel androgen agent)
• Symptom burden (symptomatic bone pain = radium-223 or Lutetium-PSMA)
• Patient fitness and preferences
• Molecular biomarkers (HRR mutations, MSI-H, PSMA expression)
• Median survival with sequential therapies: 3-5 years from mCRPC diagnosis

Resectable Disease (15-20%) - Surgery Plus Systemic Therapy

Defining Resectability - Vascular Involvement Critical:

• Resectable criteria: No arterial (celiac, SMA) contact, ≤180° venous (SMV/PV) contact without contour irregularity, patent SMV-PV confluence
• Why vascular assessment matters: Arterial involvement typically precludes safe resection. Venous resection/reconstruction feasible but increases complexity and morbidity
• Imaging: High-quality pancreatic protocol CT with arterial and portal venous phases. 1mm slices, 3D reconstruction. Accuracy 85-90% for resectability prediction

Surveillance Post-Resection: CA19-9 every 3 months × 2 years then every 6 months, CT chest/abdomen every 3-6 months × 2 years then every 6-12 months. 80% recur within 2 years. Early detection of recurrence allows timely palliative therapy.

Borderline Resectable (20-25%) - Neoadjuvant Therapy Mandatory

Defining Borderline Resectable: Venous involvement (>180° SMV/PV contact, contour irregularity, short-segment occlusion with suitable vessel for reconstruction) OR limited arterial contact (≤180° SMA, <180° celiac, short-segment hepatic artery involvement)

Why immediate surgery inappropriate: R0 resection rate low (20-40%) without neoadjuvant therapy. R1 resection portends poor prognosis. Neoadjuvant therapy potentially converts borderline to resectable, improving R0 rate.

Locally Advanced Unresectable (30%) - Chemotherapy ± Radiation

Defining Locally Advanced: Extensive vascular involvement precluding safe resection (>180° SMA encasement, celiac encasement, unreconstructible SMV/PV occlusion) without distant metastases

Treatment Goals: Prolong survival, control local symptoms, maintain quality of life, occasionally convert to resectable (10-15% with excellent response)

Metastatic Disease (Stage IV - 50%) - Palliative Systemic Therapy

Common Metastatic Sites: Liver (most common), peritoneum, lung, distant lymph nodes

Treatment Philosophy: Goals are palliative - prolong survival, maintain quality of life, control symptoms. Not curable. Balance treatment efficacy against toxicity.

Survival Expectations: Median survival with modern therapy 6-11 months. 1-year survival 30-40%. 2-year survival 10-15%. Rare long-term survivors, typically with oligometastatic disease and excellent response to systemic therapy.

Treatment

Localized (I-III):

• Surgery: Subtotal or total gastrectomy + D2 lymphadenectomy
• Perioperative chemotherapy: FLOT (5-FU, leucovorin, oxaliplatin, docetaxel) × 4 pre-op, × 4 post-op (preferred)
• Alternative: Surgery → adjuvant chemoRT (5-FU/capecitabine + RT 45 Gy)

Metastatic:

• HER2+: Trastuzumab + cisplatin/oxaliplatin + 5-FU/capecitabine
• HER2-: FOLFOX or cisplatin + 5-FU/capecitabine ± nivolumab (PD-L1+ CPS ≥5)
• MSI-H: Pembrolizumab monotherapy
• Second-line: Ramucirumab + paclitaxel, or ramucirumab alone

Treatment

Localized (I-III):

• Preferred: Neoadjuvant chemoRT (carboplatin + paclitaxel + RT 41.4-50.4 Gy) → surgery (esophagectomy)
• Alternative (adenocarcinoma): Perioperative chemotherapy (FLOT)
• Definitive chemoRT: If medically inoperable

Metastatic:

• Adenocarcinoma HER2+: Trastuzumab + chemotherapy
• PD-L1+ (CPS ≥10): Nivolumab + chemotherapy
• Standard: FOLFOX or cisplatin + 5-FU

Treatment by Barcelona Clinic Liver Cancer (BCLC) Stage

Very Early/Early (BCLC 0-A):

• Resection: Single tumor, no vascular invasion, preserved liver function
• Liver transplantation: Milan criteria (single ≤5 cm or ≤3 nodules each ≤3 cm, no vascular invasion)
• Ablation: RFA or microwave ablation for tumors ≤3 cm
• 5-year survival: 50-70%

Intermediate (BCLC B):

• TACE (transarterial chemoembolization): Unresectable multinodular, preserved liver function
• Median survival: 20-30 months

Advanced (BCLC C):

• Systemic therapy:
  • First-line: Atezolizumab + bevacizumab (superior to sorafenib, median OS 19 months)
  • Alternative first-line: Durvalumab + tremelimumab, sorafenib, lenvatinib
  • Second-line: Cabozantinib, regorafenib, ramucirumab (AFP ≥400)
• Median survival: 8-19 months

Terminal (BCLC D): Best supportive care

Treatment

Resectable:

• Surgical resection ± adjuvant chemotherapy (capecitabine 6 months)

Advanced/Metastatic:

• First-line: Gemcitabine + cisplatin + durvalumab (TOPAZ-1 trial, median OS 12.9 months)
• Molecular testing: FGFR2 fusions (10-15%), IDH1 mutations (10-20%)
• FGFR2+: Pemigatinib or infigratinib
• IDH1 mutant: Ivosidenib
• HER2+: Trastuzumab + pertuzumab
• NTRK fusion, BRAF V600E, MSI-H: Targeted therapy or immunotherapy

Treatment

Localized (I-III):

• Surgery: Partial or radical nephrectomy
• Adjuvant therapy: Pembrolizumab for high-risk (≥pT2 or N+) - 1 year
• Ablation: Small (<3 cm) tumors, poor surgical candidates

Metastatic (Stage IV):

• Favorable/Intermediate Risk:
  • Pembrolizumab + axitinib (preferred)
  • Nivolumab + cabozantinib
  • Lenvatinib + pembrolizumab
• Poor Risk: Nivolumab + ipilimumab
• Cytoreductive nephrectomy: Selected patients
• Second-line: Cabozantinib, nivolumab, axitinib, lenvatinib + everolimus
• Median OS: 30-50 months with modern therapy

Treatment

Non-Muscle Invasive (Ta, T1, CIS):

• TURBT (transurethral resection)
• Intravesical therapy:
  • BCG (preferred for high-risk): 6-week induction → maintenance 1-3 years
  • Mitomycin C (alternative for intermediate-risk)
• BCG-unresponsive CIS: Pembrolizumab or radical cystectomy

Muscle-Invasive (T2-T4):

• Cisplatin-eligible: Neoadjuvant chemotherapy (dose-dense MVAC or gemcitabine + cisplatin) → radical cystectomy + lymphadenectomy
• Adjuvant: Nivolumab (1 year) if high-risk and didn't receive neoadjuvant
• Bladder preservation: Maximal TURBT + concurrent chemoRT (selected patients)

Metastatic:

• First-line (cisplatin-eligible): Gemcitabine + cisplatin OR enfortumab vedotin + pembrolizumab (superior)
• Cisplatin-ineligible, PD-L1+ or uncommon histology: Pembrolizumab or atezolizumab
• Second-line: Enfortumab vedotin (anti-Nectin-4 ADC), platinum rechallenge, taxanes
• FGFR2/3 alterations: Erdafitinib

Treatment

Early Stage (I-II):

• Surgery: Total hysterectomy, bilateral salpingo-oophorectomy, staging
• Adjuvant chemotherapy: Carboplatin + paclitaxel × 6 cycles (except IA/IB grade 1)

Advanced Stage (III-IV):

• Primary cytoreductive surgery (optimal <1 cm residual) → adjuvant chemotherapy
• OR Neoadjuvant chemotherapy → interval cytoreductive surgery → chemotherapy
• Chemotherapy: Carboplatin + paclitaxel ± bevacizumab
• Maintenance:
  • BRCA mutant or HRD+: Olaparib or niraparib (PARP inhibitors) up to 2 years
  • BRCA wild-type: Bevacizumab continuation

Recurrent:

• Platinum-sensitive (>6 months): Platinum rechallenge ± bevacizumab
• Platinum-resistant: Weekly paclitaxel, pegylated liposomal doxorubicin, gemcitabine, or bevacizumab
• BRCA mutant: PARP inhibitors (olaparib, rucaparib, niraparib)

Treatment

Early Stage (I-II):

• Surgery: Total hysterectomy + bilateral salpingo-oophorectomy ± lymphadenectomy
• Adjuvant: Vaginal brachytherapy or pelvic RT (high-intermediate/high-risk)
• Molecular classification: POLE-mutant (excellent prognosis), MMR-deficient, p53-abnormal (poor prognosis), NSMP

Advanced/Recurrent:

• dMMR/MSI-H: Pembrolizumab or dostarlimab monotherapy
• pMMR: Carboplatin + paclitaxel + pembrolizumab → pembrolizumab maintenance
• Hormone therapy: Progestins, aromatase inhibitors (low-grade, ER+)
• Targeted: Lenvatinib + pembrolizumab

Treatment

Early Stage (IA-IIA):

• Surgery: Radical hysterectomy + pelvic lymphadenectomy OR definitive chemoRT

Locally Advanced (IB3-IVA):

• Concurrent chemoRT: Weekly cisplatin + pelvic RT → brachytherapy

Recurrent/Metastatic:

• First-line: Carboplatin + paclitaxel + bevacizumab ± pembrolizumab (PD-L1+ CPS ≥1)
• Median OS: 24 months with pembrolizumab combination

APL (M3): ATRA + arsenic trioxide (chemotherapy-free for low-risk)

Non-APL AML (fit, <60 years): "7+3" induction → HiDAC consolidation OR allo-HSCT

Older/unfit: Azacitidine or decitabine + venetoclax (70% response)

FLT3+ relapsed: Gilteritinib

Standard: R-CHOP × 6 cycles

Relapsed/Refractory: CAR-T (axicabtagene, tisagenlecleucel, lisocabtagene) OR salvage → auto-HSCT

Transplant-eligible: VRd or DRd induction → auto-HSCT → lenalidomide maintenance

Transplant-ineligible: DRd until progression

Relapsed (≥4 lines): CAR-T (ide-cel, cilta-cel) OR bispecific antibodies (teclistamab)

Stage 0-II (Localized): Wide excision (1-2 cm margins) ± sentinel LN biopsy

Adjuvant (Stage IIB-IV): Nivolumab or pembrolizumab × 1 year (reduces recurrence)

Metastatic:

• BRAF V600 mutant (50%): Dabrafenib + trametinib OR encorafenib + binimetinib
• BRAF wild-type OR first-line immunotherapy: Nivolumab + ipilimumab (ORR 58%) OR pembrolizumab monotherapy
• Second-line: Alternative immunotherapy, targeted therapy, or T-VEC (intralesional)
• Median OS: 3-5 years with modern therapy

Early Stage (I-II): Surgery OR radiation (equivalent outcomes)

Locally Advanced (III-IV):

• Concurrent chemoRT: Cisplatin 100 mg/m² q3 weeks × 3 + RT 70 Gy
• OR Cetuximab + RT (if cisplatin contraindicated)
• OR Surgery → adjuvant chemoRT (if high-risk features)

Recurrent/Metastatic:

• First-line: Pembrolizumab or nivolumab (PD-L1+ CPS ≥1) OR platinum + 5-FU + cetuximab ± pembrolizumab
• Second-line: Immunotherapy, taxanes, methotrexate, or cetuximab