Section 1: Lung Cancer

▼1.1 Epidemiology & Global Burden

Lung cancer remains the leading cause of cancer-related mortality worldwide, responsible for approximately 1.8 million deaths annually (GLOBOCAN 2020). In Thailand, lung cancer is the second most common cancer in males and ranks among the top 5 in females, with an estimated 25,000+ new cases per year and a grim 5-year survival rate of 15–20% overall.

Histologic Distribution:
- Non-Small Cell Lung Cancer (NSCLC) — ~85% of all lung cancers
  - Adenocarcinoma (ADC) — most common overall (~40%), more common in non-smokers, peripheral predominant, characterized by glandular differentiation
  - Squamous Cell Carcinoma (SqCC) — ~25–30%, strongly smoking-related, central/hilar location, cavitation common, expresses squamous markers (p40, p63, CK5/6)
  - Large Cell Carcinoma (LCC) — ~5%, poorly differentiated, diagnosis of exclusion
- Small Cell Lung Cancer (SCLC) — ~15%, aggressive neuroendocrine tumor, strongly smoking-related, central location, early dissemination
Risk Factors: Tobacco smoking (accounts for ~85% of cases), environmental/secondhand smoke, radon exposure, asbestos, air pollution (PM 2.5), prior thoracic radiation, chronic lung disease, genetic predisposition (e.g., EGFR mutations more common in Asian non-smokers)
Molecular Epidemiology: EGFR mutations found in ~50% of Asian patients with lung adenocarcinoma vs. ~10–15% in Caucasian populations. KRAS G12C, ALK rearrangements, ROS1, BRAF, NTRK, RET, and MET exon 14 skipping mutations each occur in 1–3% of NSCLC.

💡 Clinical Pearl: In Thai patients with lung adenocarcinoma — especially non-smokers or light smokers — always order comprehensive molecular profiling upfront. EGFR mutation rates in Thai patients with adenocarcinoma are among the highest in Asia (~50%), rivaling rates in Japan and Taiwan.

📖 References & Guidelines

GLOBOCAN 2020 — Ferlay J et al. Global Cancer Statistics 2020. CA Cancer J Clin. 2021.
WHO Classification of Thoracic Tumours, 5th Edition (2022) — Travis WD et al. WHO Press.
Thai Cancer Registry 2021 — National Cancer Institute Thailand.

▶1.2 NSCLC Staging — TNM 8th Edition (IASLC)

The 8th edition AJCC/UICC TNM staging for lung cancer (effective 2018) incorporates the findings of the IASLC Lung Cancer Staging Project based on analysis of >70,000 cases.

🚀 Key Changes from 7th → 8th Edition

T classification — Subdivided T1a/b/c (≤2cm, >2–3cm, >3–4cm); T2 now includes tumors >4–5cm (was >3–5cm); T3 includes tumors >5–7cm (was >5–7cm with additional nodules); T4 now includes tumors >7cm (previously all T3)
M classification — M1a (contralateral lung nodules, pleural/pericardial nodules); M1b (single extrathoracic metastasis); M1c (multiple extrathoracic metastases or multiple involvement of a single organ)
Stage grouping — T3N0 now Stage IIB (was IIA); T3N1 now Stage IIIA (was IIB); M1a always Stage IVA; M1c always Stage IVB

T (Primary Tumor)	Description
Tx	Tumor proven by malignant cells but not visualized
Tis	Carcinoma in situ
T1	≤3 cm, surrounded by lung/visceral pleura, not main bronchus T1a: ≤1 cm; T1b: >1–2 cm; T1c: >2–3 cm
T2	>3–5 cm OR involves main bronchus (not carina) OR invades visceral pleura OR associated atelectasis/post-obstructive pneumonitis extending to hilar region T2a: >3–4 cm; T2b: >4–5 cm
T3	>5–7 cm OR with additional tumor nodules in same lobe OR invades chest wall, pericardium, phrenic nerve, or associated atelectasis of entire lung
T4	>7 cm OR additional tumor nodules in different ipsilateral lobe OR invades mediastinum, heart, great vessels, carina, trachea, esophagus, vertebral body, recurrent laryngeal nerve

N (Lymph Nodes)	Description
Nx	Regional nodes cannot be assessed
N0	No regional node metastasis
N1	Metastasis to ipsilateral peribronchial, hilar, and intrapulmonary nodes
N2	Metastasis to ipsilateral mediastinal or subcarinal nodes
N3	Metastasis to contralateral mediastinal, hilar, or supraclavicular nodes

📖 References & Guidelines

IASLC Staging Project — Detterbeck FC et al. The IASLC Lung Cancer Staging Project. J Thorac Oncol. 2016.
AJCC Cancer Staging Manual, 8th Edition (2018) — Amin MB et al. Springer.
UICC TNM Classification of Malignant Tumours, 8th Edition — Brierley JD et al.

▶1.3 Molecular Drivers & Targeted Therapy

Molecular profiling of NSCLC — particularly adenocarcinoma — has revolutionized treatment. Comprehensive next-generation sequencing (NGS) or multiplex PCR should be performed at diagnosis to identify actionable driver mutations.

🚀 Actionable Drivers — Quick Reference

EGFR (ex19del, L858R) → Osimertinib (preferred 1st-line)
EGFR exon 20 ins → Amivantamab, Mobocertinib
ALK rearrangement → Alectinib (preferred), Brigatinib, Lorlatinib
ROS1 rearrangement → Crizotinib, Entrectinib, Lorlatinib
BRAF V600E → Dabrafenib + Trametinib
KRAS G12C → Sotorasib, Adagrasib
NTRK fusion → Larotrectinib, Entrectinib
RET rearrangement → Selpercatinib, Pralsetinib
MET exon 14 skipping → Capmatinib, Tepotinib
HER2 (ERBB2) mutation → Trastuzumab deruxtecan, Poziotinib

EGFR (Epidermal Growth Factor Receptor) — 10–15% of ADC (higher in Asian non-smokers)

Common sensitizing mutations:
- Exon 19 deletions (ex19del) — ~45% of EGFR mutations; in-frame deletion of 4 amino acids (LREA), results in constitutive kinase activation
- L858R point mutation (exon 21) — ~40% of EGFR mutations; leucine-to-arginine substitution at codon 858
- Less common: G719X (exon 18), L861Q (exon 21), S768I (exon 20)
First-generation TKIs: Erlotinib, Gefitinib — reversible EGFR inhibitors; PFS benefit vs. chemotherapy in first-line (IPASS, EURTAC, OPTIMAL trials)
Second-generation TKIs: Afatinib, Dacomitinib — irreversible ErbB family blockers; superior to gefitinib in ARCHER 1050 (dacomitinib)
Third-generation TKIs: Osimertinib — irreversible EGFR inhibitor active against T790M and CNS disease; FLAURA trial (1st-line osimertinib vs. erlotinib/gefitinib) showed OS benefit (38.6 vs 31.8 months); preferred 1st-line agent for EGFR-mutant NSCLC
T790M resistance mutation — occurs in ~50–60% of patients progressing on 1st/2nd-gen TKIs; detected by tissue or plasma (liquid) biopsy; osimertinib is the standard treatment
C797S mutation — tertiary resistance mechanism to osimertinib (on-target); newer agents (allosteric inhibitors) in development

EGFR Exon 20 Insertion Mutations (~2–3% of ADC)

Distinct from classic EGFR mutations; less responsive to conventional EGFR TKIs
Amivantamab — bispecific antibody (EGFR + MET); FDA-approved for EGFR ex20ins after platinum chemotherapy; ORR ~40%
Mobocertinib — TKI with activity against EGFR ex20ins (now withdrawn from market due to hepatotoxicity concerns)
Poziotinib — potent EGFR ex20ins inhibitor; under investigation

ALK Rearrangement (EML4-ALK) — 3–7% of ADC

Inversion in chromosome 2p resulting in fusion oncogene; more common in young non-smokers or light smokers with signet ring cell morphology
Crizotinib — first-generation ALK TKI; PROFILE 1007 (2nd-line vs. chemo), PROFILE 1014 (1st-line vs. chemo); significant PFS benefit
Alectinib — preferred 1st-line; ALEX trial (alectinib vs. crizotinib): PFS 34.8 vs. 10.9 months, CNS activity, better tolerated; superior outcomes in Asian subgroups
Brigatinib — ALK/ROS1 TKI; ALTA-1L (brigatinib vs. crizotinib): PFS 24 vs. 11 months; robust CNS activity
Lorlatinib — 3rd-generation ALK/ROS1 TKI; CROWN trial (lorlatinib vs. crizotinib 1st-line): dramatic PFS improvement (not reached vs. 9.3 months); excellent CNS penetration; active against all known ALK resistance mutations
Resistance mechanisms: ALK-dominant (G1202R, I1171X, V1180L, F1174X) and ALK-independent (MET amplification, EGFR activation, KRAS mutations)

ROS1 Rearrangement — 1–2% of ADC

Receptor tyrosine kinase fusion; similar demographic to ALK (young, non-smokers)
Crizotinib — ROS1 TKI; phase II trial: ORR 72%, median PFS 19.2 months
Entrectinib — ROS1/NTRK inhibitor; ROS1-population: ORR 77%, CNS activity
Lorlatinib — active in ROS1 TKI-naïve and resistant settings

BRAF V600E Mutation — 1–3% of NSCLC

Dabrafenib + Trametinib — combination BRAF + MEK inhibition; phase II trial: ORR 64%, median PFS 10.9 months; FDA-approved for BRAF V600E-mutant NSCLC

KRAS G12C Mutation — ~13% of ADC

Historically "undruggable"; now targetable with covalent KRAS G12C inhibitors
Sotorasib — CodeBreaK 100: ORR 37%, median PFS 6.3 months; FDA-approved for KRAS G12C-mutant NSCLC after ≥1 prior systemic therapy
Adagrasib — KRYSTAL-1: ORR 45%, CNS activity; FDA-approved; slightly higher response rate than sotorasib
Resistance mechanisms: Secondary KRAS mutations, activation of bypass pathways (MET, HER, RAS); combination strategies with SHP2 inhibitors, EGFR inhibitors, or immunotherapy under investigation

NTRK Fusion — <1% of NSCLC

Neurotrophic tyrosine receptor kinase (NTRK1/2/3) gene fusions; agnostic histology
Larotrectinib — NTRK inhibitor; LOXO-TRK-14001/SCOUT: ORR 75%; FDA-approved for NTRK fusion+ solid tumors
Entrectinib — NTRK + ROS1 + ALK inhibitor; ORR 57%; FDA-approved

RET Rearrangement — 1–2% of ADC

KIF5B-RET most common fusion partner
Selpercatinib — highly selective RET TKI; LIBRETTO-001: ORR 85% (treatment-naïve), 64% (prior chemo); CNS activity; FDA-approved
Pralsetinib — RET TKI; ARROW trial: ORR 70% (prior platinum), 79% (treatment-naïve); FDA-approved

MET Exon 14 Skipping Mutation — 2–4% of ADC

Splice site mutation leading to MET receptor constitutive activation; more common in older patients, sarcomatoid carcinoma
Capmatinib — GEOMETRY mono-1: ORR 68% (treatment-naïve), 41% (prior chemo); FDA-approved; CNS activity
Tepotinib — VISION trial: ORR 46% (cohort A), 50% (treatment-naïve); FDA-approved

HER2 (ERBB2) Mutation — 1–2% of ADC

Exon 20 insertions most common; distinct from HER2 gene amplification (breast cancer)
Trastuzumab deruxtecan (T-DXd) — DESTINY-Lung01: ORR 55%; FDA-approved for HER2-mutant NSCLC after prior systemic therapy
Poziotinib — EGFR/HER2 exon 20 TKI; phase II: ORR 27–35%

💡 Clinical Pearl: Liquid biopsy (plasma ctDNA) is increasingly important for molecular profiling — it is non-invasive, rapid, and detects resistance mutations (T790M, C797S, ALK resistance mutations) at progression. However, tissue biopsy remains gold standard for initial diagnosis and has higher sensitivity for some mutations. Use liquid biopsy when tissue is unavailable or to guide treatment selection at progression.

📖 References & Guidelines

FLAURA — Soria JC et al. Osimertinib in Untreated EGFR-Mutated NSCLC. N Engl J Med. 2018.
ALEX — Peters S et al. Alectinib in Untreated ALK-Positive NSCLC. N Engl J Med. 2017.
CROWN — Shaw AT et al. Lorlatinib in ALK-Positive NSCLC. N Engl J Med. 2020.
CodeBreaK 100 — Skoulidis F et al. Sotorasib in KRAS G12C NSCLC. N Engl J Med. 2021.
NCCN Guidelines Version 2024.3 — NSCLC
ESMO Living Guidelines — Metastatic NSCLC (2024)

▶1.4 Immunotherapy in NSCLC

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have transformed NSCLC treatment. PD-L1 expression is the primary predictive biomarker, though tumor mutational burden (TMB) and tumor microenvironment also play roles.

🚀 PD-L1 Expression Thresholds — Clinical Practice

TPS ≥50% — pembrolizumab monotherapy 1st-line approved (KEYNOTE-024); also nivolumab+ipilimumab, atezolizumab
TPS 1–49% — pembrolizumab+chemotherapy (KEYNOTE-189/407); nivolumab+ipilimumab; pembrolizumab monotherapy acceptable for elderly/unfit
TPS <1% (PD-L1 negative) — pembrolizumab+chemotherapy still approved (KEYNOTE-189/407 showed benefit across PD-L1 levels); nivolumab+ipilimumab; dual checkpoint inhibition
TPS vs. CPS: TPS (tumor proportion score) = % of viable tumor cells with membrane staining; CPS (combined positive score) = (tumor cells + lymphocytes + macrophages with PD-L1 staining) / total viable tumor cells × 100. CPS used in HNSCC, gastric, cervical, esophageal, TNBC, and urothelial carcinoma.

PD-1/PD-L1 Inhibitors — Key Agents

Pembrolizumab — humanized IgG4 anti-PD-1; approved in 1st-line (monotherapy TPS≥50%, combo chemo for all-comers), 2nd-line monotherapy, and adjuvant (KEYNOTE-091)
Nivolumab — fully human IgG4 anti-PD-1; approved with ipilimumab (1st-line), and as monotherapy 2nd-line (CheckMate 017/057)
Atezolizumab — Fc-engineered IgG1 anti-PD-L1; approved 1st-line with chemo (IMpower130, IMpower150, IMpower132), 2nd-line monotherapy (OAK)
Cemiplimab — anti-PD-1; approved for NSCLC with PD-L1≥50% (EMPOWER-Lung 1)
Durvalumab — anti-PD-L1; approved for stage III NSCLC post-CRT (PACIFIC trial); also SCLC (CASPIAN) and HCC (HIMALAYA)

Landmark Clinical Trials

KEYNOTE-024 — pembrolizumab vs. platinum doublet chemotherapy 1st-line in TPS≥50% metastatic NSCLC (no EGFR/ALK). Result: OS 30.0 vs. 14.2 months; changed standard of care. Schiller JH et al. N Engl J Med 2016.
KEYNOTE-042 — pembrolizumab vs. chemotherapy 1st-line TPS≥1%. OS benefit extended across all PD-L1 levels (1%, 20%, 50%). Mok TSK et al. Lancet 2019.
KEYNOTE-189 — pembrolizumab + pemetrexed/platinum vs. placebo + chemo 1st-line non-squamous NSCLC. OS 22.6 vs. 10.6 months; benefit regardless of PD-L1. Gandhi L et al. N Engl J Med 2018.
KEYNOTE-407 — pembrolizumab + carboplatin/paclitaxel vs. placebo + chemo 1st-line squamous NSCLC. OS 17.1 vs. 11.6 months. Paz-Ares L et al. N Engl J Med 2018.
CheckMate 227 — nivolumab + ipilimumab vs. chemotherapy 1st-line metastatic NSCLC (all PD-L1 levels). OS benefit; no PFS benefit in PD-L1<1%. Hellmann MD et al. N Engl J Med 2018.
CheckMate 9LA — nivolumab + ipilimumab + 2 cycles chemo vs. chemo alone 1st-line. OS benefit regardless of PD-L1; FDA-approved. Reck M et al. Lancet Oncol 2021.
IMpower150 — atezolizumab + bevacizumab + carboplatin/paclitaxel (ABCP) vs. BCP vs. ACP in non-squamous NSCLC. ABCP improved OS; benefit seen in EGFR/ALK mutated and liver mets. Socinski MA et al. N Engl J Med 2018.
IMpower010 — atezolizumab vs. BSC adjuvant stage IB–IIIA NSCLC (≥1% PD-L1) post adjuvant chemo. DFS benefit; FDA-approved. Felip E et al. Lancet 2021.
PACIFIC — durvalumab vs. placebo consolidation after concurrent CRT for stage III unresectable NSCLC. PFS 16.9 vs. 5.6 months; OS at 5 years 42.9% vs. 33.4%; standard of care. Antonia SJ et al. N Engl J Med 2017; updated 2020.
POSEIDON — durvalumab + tremelimumab + chemo vs. chemo alone 1st-line metastatic NSCLC. OS benefit for triplet vs. chemo. Johnson ML et al. J Thorac Oncol 2023.

Immune-Related Adverse Events (irAEs)

Pneumonitis — most feared; grade 1: monitor, hold ICPI; grade 2: hold ICPI, prednisone 1–2 mg/kg/day; grade 3–4: permanently discontinue, high-dose steroids ± infliximab or mycophenolate
Colitis — grade 2: hold ICPI, budesonide or prednisone; grade 3–4: permanently discontinue, high-dose steroids, infliximab if refractory
Hepatitis — AST/ALT >3× ULN (grade 2): hold ICPI, monitor; grade 3+: permanently discontinue, prednisone 1–2 mg/kg; consider mycophenolate if refractory
Thyroid disorders — thyroiditis (transient thyrotoxicosis → hypothyroidism): levothyroxine replacement; most can continue ICPI
Adrenal insufficiency — requires glucocorticoid ± mineralocorticoid replacement; hold ICPI until stable on replacement
Type 1 diabetes mellitus — new-onset insulin-dependent diabetes; requires permanent discontinuation of ICPI in most cases; manage with insulin
Myocarditis — high mortality; grade 1–2: hold ICPI, start methylpred 1–2 mg/kg + mycophenolate; grade 3–4: permanently discontinue, methylpred 1–2 mg/kg + mycophenolate; infliximab generally avoided (hepatotoxicity risk)
Neurotoxicity — myasthenia gravis: hold ICPI, plasmapheresis, steroids; Guillain-Barré: permanent discontinuation, IVIG or plasmapheresis, steroids

💡 Clinical Pearl: Combination of CTLA-4 (ipilimumab) + PD-1 (nivolumab) produces higher response rates but significantly more toxicity than PD-1 monotherapy — especially colitis and hypophysitis. In clinical practice, the choice between mono vs. combo immunotherapy depends on PD-L1 expression, tumor burden, symptoms, comorbidities, and performance status.

📖 References & Guidelines

KEYNOTE-024 — Schiller JH et al. N Engl J Med. 2016.
KEYNOTE-189 — Gandhi L et al. N Engl J Med. 2018.
CheckMate 227 — Hellmann MD et al. N Engl J Med. 2018.
PACIFIC — Antonia SJ et al. N Engl J Med. 2017.
ASCO Guidelines on ICI Toxicity Management (2023)
ESMO Clinical Practice Guidelines — NSCLC (2024)

▶1.5 Small Cell Lung Cancer (SCLC)

SCLC is a high-grade neuroendocrine carcinoma characterized by rapid doubling time, early metastasis, and strong association with smoking. It is staged using the VALG (Veterans Administration Lung Cancer Group) system, supplemented by TNM for prognostic and treatment planning purposes.

🚀 SCLC Staging — VALG System

Limited Stage (LS-SCLC) — Disease confined to one hemithorax, ipsilateral mediastinal and supraclavicular nodes, and can be encompassed within a single tolerable radiotherapy port. Approximately 30% of patients at diagnosis.
Extensive Stage (ES-SCLC) — Any disease beyond limited stage definition: contralateral lung, distant metastases, malignant pleural or pericardial effusion. Approximately 70% of patients.

First-Line Treatment

Limited Stage: Concurrent chemoradiation — cisplatin + etoposide (or carboplatin if cisplatin-ineligible) combined with thoracic radiotherapy (TRT) initiated with cycle 1 or 2 of chemotherapy. Standard dose: 45 Gy in 30 fractions BID (preferred) or 60–70 Gy in 30–35 fractions QD. Concurrent CRT offers cure rates of 20–25% in localized disease.
Extensive Stage: Standard: carboplatin + etoposide + atezolizumab or durvalumab (IMpower133: atezolizumab added to carbo/etoposide improved OS 12.3→15.9 months; CASPIAN: durvalumab improved OS 10.3→12.9 months). Alternatively: pembrolizumab (after MAVERICK, KEYNOTE-604 failed OS endpoint but pembrolizumab is approved). Platinum-etoposide alone remains an option.

Second-Line Treatment

Topotecan — oral or IV; standard 2nd-line; approved for sensitive and refractory relapse; oral topotecan (1 mg/m² days 1–5 q21) equivalent to IV
Lurbinectedin — trabectedin analog; FDA-approved 2nd-line for SCLC based on ATLANTIS trial (OS benefit vs. topotecan or CAV in sensitive relapse); works via transcriptional inhibition
Irinotecan — alternative to etoposide re-challenge; manageable toxicity profile; can be used as monotherapy or in combinations
Platinum re-challenge — for patients with sensitive relapse (≥6-month platinum-free interval); re-challenge with original platinum + etoposide is an option
Clinical trial / novel agents — encouraged at any line; SCLC remains an area of high unmet need

Novel Therapies in SCLC

Tarlatamab — DLL3-targeting bispecific T-cell engager (BiTE); delta-like ligand 3 (DLL3) is expressed on ~80% of SCLC cells but not on normal tissue. Phase II DeLLphi-301: ORR 40% (10 mg dose) in 3rd-line+ SCLC; FDA-approved 2024. CRS and neurotoxicity are key adverse events.
Oljasertib (DLL3 ADC) — rovalpituzumab tesirine (Rova-T) — DLL3-targeting ADC; initial promise in 2nd-line but phase III TAHOE failed (OS inferior to topotecan); further development discontinued

Prophylactic Cranial Irradiation (PCI)

In LS-SCLC who respond to CRT: PCI reduces brain metastasis risk and improves OS (Auperin 1999 meta-analysis). Standard: 25 Gy in 10 fractions.
In ES-SCLC: PCI reduces symptomatic brain mets but no overall survival benefit in the era of MRI surveillance (European EORTC trial). PCI remains optional and requires shared decision-making with patient. MRI brain surveillance every 3 months is an alternative approach.
Contraindications: Poor PS, extensive brain mets, significant cognitive impairment. Modern approach often substitutes with regular MRI surveillance.

💡 Clinical Pearl: SCLC is highly chemosensitive but almost universally relapses. The platinum-free interval is the most important prognostic factor: <3 months = refractory (median survival ~3–4 months); ≥3 months = sensitive relapse. Treatment selection at relapse depends on platinum sensitivity, performance status, prior toxicities, and patient preferences. Newer agents like lurbinectedin and tarlatamab have changed the treatment landscape in 2nd/3rd line.

📖 References & Guidelines

IMpower133 — Horn L et al. Atezolizumab plus Carboplatin and Etoposide in ES-SCLC. N Engl J Med. 2018.
CASPIAN — Paz-Ares L et al. Durvalumab ± Tremelimumab + Chemo in ES-SCLC. Lancet. 2019.
DeLLphi-301 — Ahn MJ et al. Tarlatamab in SCLC. J Clin Oncol. 2023.
ATLANTIS — Trigo J et al. Lurbinectedin + Doxorubicin vs. Topotecan/CAV. Lancet Oncol. 2020.
NCCN Guidelines Version 2024 — SCLC
ESMO SCLC Consensus Recommendations (2022)

Section 2: Breast Cancer

▶2.1 Molecular Subtypes & Biomarkers

Breast cancer is classified into molecular subtypes based on gene expression profiling (or surrogate immunohistochemistry), which drives treatment decisions and prognostication.

Subtype	IHC Surrogate	Frequency	Behavior
Luminal A	ER+/PR+ (PR≥20%), HER2−, Ki-67 low (<14%)	~40%	Best prognosis; indolent; endocrine-sensitive
Luminal B (HER2−)	ER+/PR+ (PR<20%) or HER2+, Ki-67 high (≥14%)	~20%	Intermediate prognosis; endocrine ± chemo
Luminal B (HER2+)	ER+, HER2+, any PR, any Ki-67	~10%	Poorer than HER2− luminal; endocrine + anti-HER2 + chemo
HER2-enriched	ER−, PR−, HER2+ (non-luminal)	~10%	Aggressive; HER2-targeted therapy has dramatically improved outcomes
Triple-negative (TNBC)	ER−, PR−, HER2−	~15%	Worst prognosis; no targeted therapy; chemo + immunotherapy + ADC

ER/PR positivity: ≥1%阳性细胞 (ASCO/CAP 2010 guidelines); previously 10% cutoff. ER/PR status determines eligibility for endocrine therapy.
HER2 (ERBB2): IHC 3+ or ISH-positive (HER2/CEP17 ratio ≥2.0 or average HER2 copy number ≥6.0 signals/cell) — qualifies for HER2-targeted therapy
Ki-67: Proliferation marker; useful for distinguishing Luminal A vs. B; high Ki-67 (≥14–20%) associated with worse prognosis and indicates benefit from chemotherapy
Oncotype DX / MammaPrint: Multigene assays for HR+/HER2− early breast cancer to predict chemotherapy benefit. RS >26 (Oncotype DX) → chemo + endocrine; RS 0–25 → endocrine alone for node-negative; RS 0–25 + 1–3 positive nodes → consider chemo in selected patients (TAILORx, RxPONDER).

📖 References & Guidelines

TAILORx — Sparano JA et al. N Engl J Med. 2018.
RxPONDER — Kalinsky K et al. N Engl J Med. 2021.
ASCO/CAP HER2 Testing Guidelines (2018)
NCCN Guidelines Breast Cancer Version 2024.2

▶2.2 Early Breast Cancer — Surgery, Systemic Therapy

Surgical Management

Breast-conserving surgery (BCS) + whole breast irradiation — equivalent survival to mastectomy for stage I–II disease; cosmesis and quality of life advantages
Mastectomy — indicated for large tumor-to-breast ratio, multicentric disease, patient preference, contraindication to RT; skin-sparing/nipple-sparing mastectomy for selected patients
Axillary staging: Sentinel lymph node biopsy (SLNB) — standard for clinically node-negative disease (cN0); if 1–2 positive nodes with BCS → axillary dissection may be avoided with modern radiation (AMAROS, ACOZOG Z0011)
Axillary lymph node dissection (ALND) — for clinically node-positive disease or positive SLNB in mastectomy patients

Endocrine Therapy

Premenopausal women:
- Tamoxifen — selective estrogen receptor modulator (SERM); 5–10 years; reduces recurrence by 50% and mortality by 30%; main toxicity: endometrial cancer (slightly increased), thromboembolism, hot flashes
- Aromatase Inhibitors (AIs) — Letrozole, Anastrozole, Exemestane; require ovarian suppression (OFS) in premenopausal women — Goserelin or Leuprolide; SOFT/TEXT trials: AI+OFS superior to tamoxifen in high-risk premenopausal women
Postmenopausal women:
- Aromatase Inhibitors — standard of care; 5 years (or extended to 7–8 years in high-risk); superior to tamoxifen for DFS; side effects: bone loss, arthralgias, CVD risk
- Tamoxifen — alternative if AI intolerance; 5 years; residual risk after 5 years of AI (extend with tamoxifen or AI)

Chemotherapy

Anthracycline + Taxane regimens:
- AC-T (doxorubicin + cyclophosphamide → paclitaxel) — standard dose-dense or every-3-week regimen
- TC (docetaxel + cyclophosphamide) — non-anthracycline alternative; similar efficacy with less cardiotoxicity
- Dose-dense AC (every 2 weeks with G-CSF) — superior to standard AC in CALGB 9741
Indications: Triple-negative, HER2+, high-risk HR+/HER2−, node-positive, large tumor size, high grade, high Ki-67, young age

HER2-Targeted Therapy

Trastuzumab — humanized anti-HER2 IgG1; 1 year standard adjuvant; OPTIMA and Short-HER suggested non-inferiority of 9 weeks in low-risk; pertuzumab added in neoadjuvant setting (NEOSPHERE, TRYPHAENA)
Pertuzumab — added to trastuzumab + chemotherapy in neoadjuvant/adjuvant setting for HER2+ disease (Node-positive or high-risk node-negative); 18 doses total (neoadjuvant + adjuvant)
T-DM1 (Trastuzumab emtansine) — ADC ( trastuzumab + DM1 cytotoxic agent); APHINITY trial: pertuzumab + trastuzumab + chemo → T-DM1 adjuvant for residual disease (non-pCR); superior to trastuzumab alone
T-DXd (Trastuzumab deruxtecan) — new HER2-low ADC (HER2 IHC 1+ or 2+/ISH−); DESTINY-Breast04: superior OS vs. TPC in HER2-low metastatic; also approved in adjuvant for HER2+ residual disease (DESTINY-Breast05 ongoing)
Neratinib — irreversible pan-HER TKI; Extended adjuvant (1 year) after trastuzumab in high-risk HER2+ patients (ExteNET trial); diarrhea is dose-limiting toxicity

PARP Inhibitors — BRCA-Mutated Breast Cancer

gBRCA1/2 mutations: ~5% of breast cancer; associated with TNBC and high-grade serous ovarian cancer
Olaparib — OlympiA trial: adjuvant olaparib 1 year after chemo + surgery for gBRCA1/2, HER2− high-risk early BC; DFS benefit 8.6% absolute; OS benefit at 3 years; FDA-approved
Talazoparib — EMBRACA trial: PARP inhibitor vs. chemo in gBRCA1/2, HER2− advanced BC; ORR 62.6% vs. 27.2%; PFS benefit; FDA-approved

CDK4/6 Inhibitors — HR+/HER2− Early Breast Cancer

monarchE — Abemaciclib + endocrine therapy vs. endocrine alone in HR+/HER2−, node-positive, high-risk early BC. At 3 years: iDFS 86.1% vs. 79.0%; benefit in Ki-67 high (≥20%). FDA-approved. Johnston SRD et al. J Clin Oncol 2023.
NATALEE — Ribociclib + endocrine therapy vs. endocrine alone in HR+/HER2− stage II–III early BC (including node-negative). iDFS benefit 90.4% vs. 87.1% at 3 years. FDA-approved 2024.

💡 Clinical Pearl: For HR+/HER2− early breast cancer, the decision to add chemotherapy (in addition to endocrine therapy) should be informed by clinical risk (nodal status, tumor size, grade) and genomic risk (Oncotype DX, MammaPrint, Ki-67). CDK4/6 inhibitors (abemaciclib) are now a new standard in the adjuvant setting for high-risk node-positive HR+/HER2− disease (monarchE).

📖 References & Guidelines

OlympiA — Tutt ANJ et al. N Engl J Med. 2021.
monarchE — Johnston SRD et al. J Clin Oncol. 2023.
NATALEE — Slamon DJ et al. J Clin Oncol. 2023.
APHINITY — von Minckwitz G et al. N Engl J Med. 2017.
NCCN Guidelines Breast Cancer Version 2024.2
ESMO Early Breast Cancer Guidelines (2023)

▶2.3 Locally Advanced & Metastatic Breast Cancer

Metastatic Breast Cancer (MBC) — HR+/HER2−

First-line endocrine therapy + CDK4/6 inhibitor (palbociclib, ribociclib, abemaciclib) is standard for HR+/HER2− MBC — significantly improved PFS and OS (PALOMA-2, MONALEESA-2/3, MONARCH-2/3)
Palbociclib — PALOMA-2: PFS 24.8 vs. 14.5 months; MONALEESA-3: OS benefit (ribociclib); MONARCH-2: OS benefit (abemaciclib)
Endocrine therapy options: Aromatase inhibitor (letrozole, anastrozole, exemestane), fulvestrant (SERD), tamoxifen
Chemotherapy: For visceral crisis (liver mets with liver dysfunction, symptomatic lung mets, CNS mets), rapid progression, or endocrine resistance; taxanes (paclitaxel, docetaxel), anthracyclines, capecitabine, eribulin, vinorelbine, gemcitabine

Metastatic HER2+ Breast Cancer

T-DXd (Trastuzumab deruxtecan) — DESTINY-Breast03: T-DXd vs. T-DM1 in 2nd-line HER2+ MBC; ORR 79% vs. 34%; PFS 28.8 vs. 6.8 months; OS benefit. Now standard 2nd-line.
T-DM1 — EMILIA: T-DM1 vs. lapatinib + capecitabine in 2nd-line; OS benefit; previously standard before T-DXd
Pertuzumab + Trastuzumab + chemo — CLEOPATRA: dual HER2 blockade + docetaxel 1st-line; PFS 18.7 vs. 12.4 months; OS 57.1 vs. 40.8 months
Tucatinib — HER2CLIMB: tucatinib + trastuzumab + capecitabine in heavily pretreated HER2+ MBC (including brain mets); OS benefit; FDA-approved
ADC sequencing: T-DXd → T-DM1 → other HER2-targeted options (tucatinib-containing regimens, margetuximab, neratinib)

Triple-Negative Metastatic Breast Cancer (TNBC)

Chemotherapy — backbone of treatment; agents: paclitaxel, docetaxel, capecitabine, eribulin, vinorelbine, gemcitabine, platinum (cisplatin/carboplatin)
Pembrolizumab — KEYNOTE-355: pembrolizumab + chemo (nab-paclitaxel, paclitaxel, or gemcitabine-carboplatin) vs. placebo + chemo for PD-L1+ (CPS≥10) TNBC; OS benefit in PD-L1+ population; FDA-approved
Sacituzumab govitecan (SG) — Trop-2 ADC; ASCENT trial: SG vs. chemo in relapsed/refractory metastatic TNBC; ORR 35% vs. 5%; PFS 5.6 vs. 1.7 months; OS 12.1 vs. 6.7 months; FDA-approved 2020
Datopotamab deruxtecan (Dato-DXd) — Trop-2 ADC; TROPION-Breast01: superior PFS vs. chemo in pretreated TNBC; FDA approval pending
PARP inhibitors — olaparib or talazoparib for gBRCA1/2 carriers
HER2-low TNBC (IHC 1+/2+, ISH−): T-DXd — DESTINY-Breast04 confirmed benefit in HER2-low (HR+ and TNBC); new treatment paradigm for HER2-low TNBC

💡 Clinical Pearl: The distinction between HER2-zero (IHC 0) and HER2-low (IHC 1+ or 2+/ISH−) is now clinically critical. HER2-low patients with TNBC may benefit from T-DXd (DESTINY-Breast04) or T-DM1 in earlier lines. Make sure HER2 is reported as IHC 0, 1+, 2+ (with ISH), or 3+ to guide treatment.

📖 References & Guidelines

DESTINY-Breast03 — Cortes J et al. N Engl J Med. 2022.
DESTINY-Breast04 — Modi S et al. N Engl J Med. 2022.
ASCENT — Bardia A et al. N Engl J Med. 2021.
KEYNOTE-355 — Cortes J et al. Lancet. 2020.
NCCN Guidelines Breast Cancer Version 2024.2
ABC6 Consensus — Locally Advanced/metastatic Breast Cancer (2024)

Section 3: Gastrointestinal Cancers

▶3.1 Colorectal Cancer

Epidemiology & Risk Factors

Thailand: 3rd–4th most common cancer; rising incidence attributed to Westernized diet, obesity, physical inactivity
Sporadic (70–80%) — diet (red/processed meat, low fiber), obesity, smoking, alcohol, IBD
Hereditary Syndromes:
- FAP (Familial Adenomatous Polyposis) — APC gene mutation; hundreds to thousands of adenomatous polyps; attenuated FAP (10–100 polyps); prophylactic colectomy recommended
- Lynch Syndrome (HNPCC) — DNA mismatch repair gene mutations (MLH1, MSH2, MSH6, PMS2); Amsterdam II criteria; increased risk of colorectal (right-sided), endometrial, ovarian, gastric, urinary tract, small bowel, brain tumors; MSI-H/dMMR phenotype; annual colonoscopy starting age 20–25 or 2–5 years before earliest family case; aspirin chemoprevention (CAPP2)

Molecular Classification

MSI-H/dMMR (~15%) — microsatellite instability-high/deficient mismatch repair; associated with Lynch syndrome, serrated polyp pathway; good prognosis in stage II (no benefit from adjuvant chemo); highly responsive to immunotherapy
MSS/pMMR (~85%) — microsatellite stable/proficient mismatch repair; standard chemotherapy ± targeted therapy

Targeted Therapy — Metastatic CRC

Anti-EGFR (RAS wild-type only):
- Cetuximab — IgG1 chimeric anti-EGFR; FIRE-3 (FOLFIRI+ cetuximab vs. FOLFIRI+bevacizumab 1st-line): OS benefit in KRAS wt; CRYSTAL: FOLFIRI±cetuximab improved OS
- Panitumumab — fully human anti-EGFR IgG2; PEAK trial: panitumumab + FOLFOX improved OS vs. bevacizumab + FOLFOX in KRAS wt
- Left-sided tumors (descending colon, sigmoid, rectum) — anti-EGFR superior to anti-VEGF in 1st-line RAS wt; right-sided tumors — bevacizumab preferred
Anti-VEGF:
- Bevacizumab — AVAiTRO trial (IFL ± bevacizumab): OS 20.3 vs. 15.6 months; standard 1st-line with chemo in mCRC
- Aflibercept — VEGF trap; VELOUR trial (FOLFIRI ± aflibercept 2nd-line): OS benefit; only after bevacizumab failure
- Ramucirumab — VEGFR2 IgG1; RAISE trial (FOLFIRI ± ramucirumab 2nd-line): OS benefit; biomarker: none validated
- Regorafenib — oral multi-TKI (VEGFR, PDGFR, RAF, KIT); CORRECT trial: OS benefit vs. placebo in 3rd-line; approved for mCRC after fluoropyrimidine, oxaliplatin, irinotecan, anti-VEGF, anti-EGFR (if RAS wt)

Immunotherapy — MSI-H/dMMR mCRC

KEYNOTE-177 — Pembrolizumab vs. chemotherapy 1st-line MSI-H/dMMR mCRC. PFS 16.5 vs. 8.2 months; fewer grade 3 AEs; FDA-approved 1st-line. André T et al. N Engl J Med 2020.
CheckMate-142 — Nivolumab ± ipilimumab in MSI-H/dMMR mCRC (2nd-line+); ORR 55–71%; durable responses; FDA-approved. Overman MJ et al. J Clin Oncol 2018.
Dostarlimab — anti-PD-1; GARNET trial: ORR 44% in MSI-H/dMMR mCRC; FDA-approved for MSI-H/dMMR solid tumors

Adjuvant Chemotherapy — Colon Cancer

Stage III (node-positive): FOLFOX or CAPOX × 6 months — standard of care; reduces recurrence by 30%; PORTEC-adjunct data
Stage II (node-negative, high-risk): High-risk features: T4, <12 lymph nodes examined, LVI, PNI, bowel obstruction, poorly differentiated, <50 years; consider single-agent fluoropyrimidine (capecitabine or 5-FU/LV) for high-risk stage II; no OS benefit from oxaliplatin in stage II (MOSAIC subanalysis)
IDEA Collaboration: 3 months CAPOX = 6 months FOLFOX in stage III for low-risk (T1-3, N1); 6 months preferred for high-risk stage III (T4 or N2); updated analysis confirmed non-inferiority in low-risk with less neuropathy

Metastatic CRC — Regimens

1st-line: FOLFOX or FOLFIRI ± bevacizumab or anti-EGFR (RAS wt, left-sided); CAPOX ± bevacizumab
2nd-line: Switch chemo backbone (FOLFOX→FOLFIRI or vice versa) + targeted agent not used in 1st-line; FOLFOX ± aflibercept or ramucirumab
BRAF V600E mutation (~8%): BEACON CRC — Encorafenib + Cetuximab ± Binimetinib (BRAF inhibitor + anti-EGFR ± MEK inhibitor) vs. chemo; OS benefit 9.3 vs. 5.9 months; ORR 27% vs. 2%; FDA-approved for 2nd-line+ BRAF V600E mCRC
HER2 amplification (2–3%): Trastuzumab + Pertuzumab (MyPathway); T-DXd (DESTINY-CRC01); FDA-approved for HER2+ mCRC after prior chemo
Later-line: Regorafenib, Trifluridine-tipiracil (TAS-102) — RECOURSE trial: OS benefit vs. placebo; main toxicity: myelosuppression

💡 Clinical Pearl: In mCRC, primary tumor sidedness strongly predicts benefit from anti-EGFR therapy. Left-sided (descending colon, sigmoid, rectum): RAS wild-type → anti-EGFR preferred 1st-line; Right-sided (cecum to transverse): bevacizumab preferred. This is based on CALGB/SWOG 80405, FIRE-3, and other trials showing significant OS advantage for anti-EGFR in left-sided disease.

📖 References & Guidelines

KEYNOTE-177 — André T et al. N Engl J Med. 2020.
BEACON CRC — Kopetz S et al. N Engl J Med. 2019.
IDEA Collaboration — Grothey A et al. J Clin Oncol. 2020.
NCCN Guidelines Colon Cancer Version 2.2024
ESMO Consensus — mCRC (2024)

▶3.2 Hepatocellular Carcinoma (HCC)

Etiology & Surveillance

Major etiologies: Chronic HBV (~50% globally), HCV, alcoholic liver disease, NAFLD/NASH, AFLD, hemochromatosis, Wilson disease, alpha-1 antitrypsin deficiency
Surveillance: Ultrasound ± AFP every 6 months in patients with cirrhosis, chronic HBV, or other high-risk conditions; surveillance improves early detection and access to curative therapies

Diagnosis — Non-invasive Criteria

AASLD/LI-RADS: In cirrhosis/HBV, characteristic imaging (arterial phase hyperenhancement [APHE] + washout + capsule appearance) on multi-phasic CT/MRI is diagnostic of HCC without biopsy
LI-RADS categories: LR-1 (definitely benign), LR-2 (probably benign), LR-3 (intermediate probability), LR-4 (probably HCC), LR-5 (definitely HCC), LR-M (malignant but not HCC-specific)
BI-RADS-like system: LR-4 (65% HCC), LR-5 (95% HCC)
Biopsy: Indicated when imaging is indeterminate, or in non-cirrhotic patients where diagnosis is uncertain; risk of bleeding and needle track seeding

Staging — BCLC System

Stage	PS	Tumor	Liver Function	Treatment
0 (Very early)	0	Single <2cm	Preserved (Child A)	Ablation, Resection
A (Early)	0	Single or 3 nodules ≤3cm	Child A–B	Resection, Transplant (Milan), Ablation
B (Intermediate)	0	Multinodular	Child A–B	TACE
C (Advanced)	1–2	Vascular invasion / mets	Child A–B	Systemic therapy
D (Terminal)	3–4	Any	Child C	BSC

Systemic Therapy for Advanced HCC

IMbrave150 — Atezolizumab + Bevacizumab (PD-L1 inhibitor + anti-VEGF) vs. sorafenib 1st-line. OS 19.2 vs. 13.4 months; PFS 6.9 vs. 2.8 months; improved QoL; NEW STANDARD OF CARE. Contraindicated in portal vein thrombosis, high bleeding risk, Child-Pugh B>. Finn RS et al. N Engl J Med 2020.
HIMALAYA — Tremelimumab + Durvalumab (anti-CTLA4 + anti-PD-L1) vs. sorafenib 1st-line. OS benefit: 16.4 vs. 13.8 months; FDA-approved; useful alternative when atezolizumab-bevacizumab contraindicated. Abou-Alfa GK et al. N Engl J Med 2022.
REFLECT — Lenvatinib vs. sorafenib 1st-line. Non-inferior OS (13.6 vs. 12.3 months); superior PFS (7.4 vs. 3.7 months); FDA-approved. Kudo M et al. Lancet 2018.
Sorafenib — SHARP (OS 10.7 vs. 7.9 months) and Asia-Pacific trials; first TKI approved for HCC; now largely superseded by atezo-bev but still used in some settings
CELESTIAL — Cabozantinib vs. placebo 2nd-line (after sorafenib); OS 10.2 vs. 8.0 months; approved. Abou-Alfa GK et al. Lancet 2018.
RESORCE — Regorafenib vs. placebo 2nd-line after sorafenib; OS 10.6 vs. 7.8 months; approved. Bruix J et al. Lancet 2017.
REACH-2 — Ramucirumab vs. placebo 2nd-line in AFP ≥400 ng/mL; OS 8.5 vs. 7.3 months; approved. Zhu AX et al. Lancet Oncol 2019.
Pembrolizumab — KEYNOTE-224 (ORR 17% in 2nd-line); KEYNOTE-240 failed OS endpoint but showed PFS benefit; approved
Tislelizumab — RATIONALE-301: OS non-inferior to sorafenib; approved in China and other regions

Loco-Regional Therapies

TACE (Transarterial Chemoembolization): Standard of care for BCLC B; conventional TACE (cTACE) with doxorubicin/lipiodol vs. DEB-TACE (drug-eluting beads); contraindicated in Child-Pugh C, biliary obstruction, portosystemic shunt, prior liver resection
Radioembolization (Y-90): SIRT; useful for portal vein thrombosis; SARAH and SIRFLOX trials showed PFS benefit but not OS vs. TACE/Sorafenib; considered in selected patients
SBRT — stereotactic body radiation; effective for early-stage patients who are not candidates for ablation/surgery; oligometastatic disease
Ablation: RFA (radiofrequency), MWA (microwave) — standard for very early/early HCC (BCLC 0/A); better outcomes with tumor <3cm

💡 Clinical Pearl: The IMbrave150 regimen (atezolizumab-bevacizumab) is the global standard 1st-line for advanced HCC unless contraindicated (portal vein invasion/thrombosis, significant cardiovascular disease, bleeding risk, varices requiring treatment, or Child-Pugh B >7). For patients with contraindications, the HIMALAYA regimen (tremelimumab-durvalumab) is the preferred alternative. Both have transformed HCC treatment landscape with ~20-month median OS.

📖 References & Guidelines

IMbrave150 — Finn RS et al. N Engl J Med. 2020.
HIMALAYA — Abou-Alfa GK et al. N Engl J Med. 2022.
REFLECT — Kudo M et al. Lancet. 2018.
AASLD Guidelines for the Treatment of HCC (2022)
ESMO HCC Clinical Practice Guidelines (2022)
NCCN Guidelines Hepatobiliary Cancers Version 2.2024

▶3.3 Pancreatic Cancer

Epidemiology & Risk Factors

3rd leading cause of cancer death in the US; 5-year survival ~12% (all stages); ~3–6% in metastatic disease
Risk factors: Smoking, obesity, chronic pancreatitis, diabetes mellitus (new-onset in elderly is red flag), family history, hereditary syndromes: BRCA2, PALB2, CDKN2A (p16), Lynch syndrome, Peutz-Jeghers, FAMMM
CA 19-9: Most used serum marker; sensitivity 70–80%, specificity 80–90%; not diagnostic alone; useful for monitoring treatment response and recurrence; elevated in biliary obstruction (false positive)

Staging & Resectability

Resectability	Criteria (CT findings)	Management
Resectable	No contact with SMA/celiac axis; no SMV/PV contact or ≤180° contact without contour irregularity	Surgery → adjuvant chemo (mFOLFIRINOX or GemCap)
Borderline Resectable	SMA ≤180°; celiac axis ≤180°; CHA/ hepatoceliac; SMV/PV >180° or <180° with contour irregularity; venous reconstruction possible	Neoadjuvant FOLFIRINOX or chemoradiation → surgery → adjuvant
Locally Advanced	SMA >180°; celiac axis >180°; unreconstructable SMV/PV; aortic invasion	Systemic therapy (mFOLFIRINOX); consider chemoradiation; surgery rarely possible
Metastatic	Distant metastases (liver, peritoneum, lung, distant nodes)	Systemic therapy (mFOLFIRINOX, GemNab)

Systemic Therapy

mFOLFIRINOX (oxaliplatin + irinotecan + 5-FU/leucovorin) — CONKO-001 (adjuvant gemcitabine vs. observation); PRODIGE-24 (adjuvant mFOLFIRINOX vs. gemcitabine): DFS 21.6 vs. 12.8 months; OS 54.5 vs. 35.5 months; standard adjuvant for fit patients with resected PDAC
Gemcitabine + Nab-paclitaxel — MPACT trial (metastatic): OS 8.5 vs. 6.7 months vs. gemcitabine alone; approved 1st-line metastatic; also used in adjuvant (APACT: OS not statistically significant vs. gemcitabine alone but DFS improved)
Maintenance: Olaparib — POLO trial: olaparib maintenance vs. placebo in gBRCA1/2 metastatic PDAC after platinum-based chemo; PFS 7.4 vs. 3.8 months; FDA-approved
Later-line: NALIRIFOX (5-FU + nal-IRI + oxaliplatin) — NAPOLI-3: OS non-inferior/superior to gemcitabine+nab-paclitaxel in metastatic; FDA-approved

Special Considerations

Pancoast tumor: Superior sulcus tumor; treat with concurrent CRT (45 Gy + surgery) or definitive CRT if unresectable
IPMN surveillance: Intraductal papillary mucinous neoplasms — main duct IPMN: higher malignancy risk (40–50%); branch duct IPMN: lower risk (10–25%); surveillance with MRI/MRCP per guidelines; surgical resection for main duct IPMN, BD-IPMN with concerning features (mural nodules, >3cm, positive cytology, rapid growth)

💡 Clinical Pearl: In PDAC, germline BRCA1/2 testing should be offered to all patients with pancreatic cancer regardless of family history (NCCN 2024). Additionally, BRCA2 is the most commonly mutated gene in familial pancreatic cancer. Patients with gBRCA2 and metastatic PDAC who respond to platinum-based chemotherapy are candidates for olaparib maintenance (POLO trial — first biomarker-selected maintenance therapy in PDAC).

📖 References & Guidelines

PRODIGE-24 — Conroy T et al. N Engl J Med. 2018.
POLO — Golan T et al. N Engl J Med. 2019.
MPACT — Von Hoff DD et al. N Engl J Med. 2013.
NCCN Guidelines Pancreatic Adenocarcinoma Version 2.2024
ASCO Guidelines Metastatic Pancreatic Cancer (2024)

Section 4: Genitourinary Cancers

▶4.1 Prostate Cancer

Epidemiology & Screening

Most common cancer in Thai males (age-standardized incidence rising); 2nd leading cause of cancer death in males in Western countries
PSA screening: Controversial — USPSTF 2018: shared decision-making age 55–69; higher-risk populations (African American, family history, BRCA1/2) — consider earlier (age 40–45)
Gleason Grade Group (ISUP 2019): Replaced traditional Gleason scoring
- Grade Group 1: Gleason ≤6
- Grade Group 2: Gleason 3+4=7
- Grade Group 3: Gleason 4+3=7
- Grade Group 4: Gleason 4+4=8
- Grade Group 5: Gleason 9–10

Risk Stratification (NCCN/D'Amico)

Low risk: Grade Group 1, PSA <10 ng/mL, cT1c–T2a
Intermediate risk: Grade Group 2–3, or PSA 10–20, or cT2b
High risk: Grade Group 4–5, or PSA >20, or ≥cT2c
Locally advanced: Any T3–T4 or N1

Localized Disease Management

Low risk: Active surveillance — standard; RP or RT acceptable for those not suitable for surveillance
Intermediate risk: RP or RT ± ADT; BCS (brachytherapy monotherapy) for selected patients; unfavorable intermediate (Grade Group 3 or ≥2 intermediate factors) → EBRT + short-term ADT + brachy boost
High risk/Locally advanced: EBRT + long-term ADT (18–36 months) ± brachytherapy boost; RP + PLND for selected patients; multimodal therapy standard

Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

ADT (androgen deprivation therapy) — LHRH agonist/antagonist (leuprolide, goserelin, degarelix); orchiectomy; combined with systemic therapy
LATITUDE — Abiraterone acetate + prednisone + ADT vs. ADT alone in high-risk mHSPC. OS 53.3 vs. 36.5 months; radiographic PFS benefit. Fizazi K et al. N Engl J Med 2017.
ARCHES — Enzalutamide + ADT vs. placebo in mHSPC; OS benefit; FDA-approved. Armstrong AJ et al. J Clin Oncol 2019.
TITAN — Apalutamide + ADT vs. placebo in mHSPC; OS benefit at 2 years 82% vs. 74%; FDA-approved. Chi KN et al. N Engl J Med 2019.
ARAMIS — Darolutamide + ADT vs. placebo in nmCRPC; OS benefit 31.9 vs. 19.0 months; FDA-approved. Fizazi K et al. N Engl J Med 2019.
Docetaxel + ADT: CHAARTED (high-volume disease: visceral mets or ≥4 bone mets): OS 57.6 vs. 44.0 months; STAMPEDE (high-risk locally advanced): OS benefit
Doublet vs. triplet: PEACE-1: ADT + docetaxel + abiraterone superior to ADT + docetaxel in high-volume mHSPC; newer standard for fit patients with high-volume disease

Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Novel hormonal agents (NHAs): enzalutamide, abiraterone, apalutamide, darolutamide — all approved in mCRPC and improve OS
Taxanes: Docetaxel (first chemo; OS benefit in mCRPC); Cabazitaxel (TROPIC trial: cabazitaxel vs. mitoxantrone after docetaxel; OS 15.1 vs. 12.7 months)
PROFOUND — Olaparib vs. enzalutamide/abiraterone in mCRPC with HRR gene alterations (BRCA1/2, ATM). OS benefit in BRCA1/2 and ATM cohorts; FDA-approved. de Bono J et al. N Engl J Med 2020.
TRITON3 — Rucaparib vs. docetaxel/NHA in mCRPC with BRCA1/2 or ATM alterations; FDA-approved. Fizazi K et al. Lancet Oncol 2023.
Sipuleucel-T — APC (antigen-presenting cell) vaccine; IMPACT trial: OS 25.8 vs. 21.7 months vs. placebo; approved for asymptomatic/minimally symptomatic mCRPC
Radium-223 — alpha-emitting radiopharmaceutical; targets bone metastases; ALSYMPCA: OS 14.9 vs. 11.3 months; approved for mCRPC with bone mets (not visceral)
VISION — ¹⁷⁷Lu-PSMA-617 (PSMA-targeted radioligand) + SOC vs. SOC alone in PSMA-positive mCRPC after ≥1 NHA + 1–2 taxane. OS 15.3 vs. 11.3 months; PFS 8.7 vs. 3.4 months; FDA-approved. Sartor O et al. N Engl J Med 2021.
PSMAfore — ¹⁷⁷Lu-PSMA-617 vs. NHA in PSMA-positive mCRPC before taxane; imaging-based PFS benefit; FDA approval pending at time of writing.

💡 Clinical Pearl: In mHSPC, the choice between ADT + NHA vs. ADT + docetaxel vs. triplet therapy (ADT + docetaxel + abiraterone) depends on disease volume (high vs. low), performance status, comorbidities, and patient preference. High-volume disease (visceral or ≥4 bone mets with ≥1 axial skeleton) benefits most from triplet or doublet with chemo. Low-volume disease may be adequately controlled with ADT + NHA alone. Once castration resistance develops, sequential use of NHAs, chemotherapy, PARP inhibitors (for HRR+), and PSMA-targeted therapy (¹⁷⁷Lu-PSMA-617) extends survival.

📖 References & Guidelines

LATITUDE — Fizazi K et al. N Engl J Med. 2017.
ARCHES — Armstrong AJ et al. J Clin Oncol. 2019.
VISION — Sartor O et al. N Engl J Med. 2021.
PROFOUND — de Bono J et al. N Engl J Med. 2020.
NCCN Guidelines Prostate Cancer Version 3.2024
EAU/ESTRO/SIOG Guidelines on Prostate Cancer (2024)

▶4.2 Renal Cell Carcinoma (RCC)

Histology & Molecular Classification

Clear cell (ccRCC) — 75–80%; most common; associated with VHL gene inactivation (3p deletion); most aggressive histology; best response to anti-VEGF/TKI and mTOR therapy
Papillary RCC (Type 1 & Type 2) — 15%; Type 1 (hereditary, associated with MET mutations); Type 2 (more aggressive, associated with TFE3 fusions, CDKN2A loss)
Chromophobe RCC — 5%; good prognosis; associated with mitochondrial dysfunction
Other rare types: Collecting duct (Bellini), medullary, MiT family translocation (TFE3/TFEB), sarcoma, XP11.2 translocation/TFE3 fusion

Prognostic Models

IMDC (International Metastatic RCC Database Consortium) / Heng Criteria: Validated in the era of targeted therapy; 6 adverse prognostic factors: KPS <80%, time from diagnosis to treatment <1 year, anemia, hypercalcemia, neutrophilia, thrombocytosis; 0 = favorable, 1–2 = intermediate, ≥3 = poor risk
MSKCC (Memorial Sloan Kettering Cancer Center) Prognostic Model: 5 factors: KPS <80%, elevated LDH, anemia, hypercalcemia, absence of nephrectomy; 3 risk groups

Advanced/Metastatic ccRCC — First-Line Therapy

IMDC favorable risk: Sunitinib (original standard) or pazopanib or tivozanib or pembrolizumab monotherapy — TKIs with proven OS benefit
IMDC intermediate/poor risk: IO+IO or IO+TKI combinations preferred
- CheckMate 214 — Ipilimumab + Nivolumab (anti-CTLA4 + anti-PD-1) vs. sunitinib in IMDC intermediate/poor risk; OS HR 0.63; ORR 42% vs. 27%; CR 9% vs. 1%; PD-L1+ patients derive greater benefit. Motzer RJ et al. N Engl J Med 2018.
- KEYNOTE-426 — Pembrolizumab + Axitinib (anti-PD-1 + VEGFR TKI) vs. sunitinib 1st-line; OS and PFS benefit at 12-month OS 89% vs. 78%; ORR 59% vs. 36%; approved. Rini BI et al. N Engl J Med 2019.
- JAVELIN Renal 101 — Avelumab + Axitinib vs. sunitinib; PFS benefit (13.8 vs. 8.4 months); OS benefit at 30-month FU. Motzer RJ et al. Lancet Oncol 2019.
- CLEAR — Pembrolizumab + Lenvatinib vs. lenvatinib + everolimus vs. sunitinib; PFS and OS benefit for pembro+lenvatinib (ORR 71%); FDA-approved. Motzer RJ et al. J Clin Oncol 2021.
Cabozantinib + Nivolumab — CheckMate 9ER: cabozantinib + nivolumab vs. sunitinib; PFS and OS benefit; FDA-approved
Atezolizumab + Bevacizumab — IMmotion151: atezo + bev vs. sunitinib in PD-L1+ ccRCC; PFS benefit but no OS difference at interim analysis

Non-Clear Cell RCC

Cabozantinib — SWOG 1500: cabozantinib vs. sunitinib in non-clear cell RCC; PFS 8.9 vs. 5.6 months; cabozantinib preferred TKI for non-ccRCC
Pembrolizumab — KEYNOTE-427 (cohort B): ORR 26% in non-ccRCC; some activity across histologies

SBRT for Oligometastases

SBRT (stereotactic body radiotherapy) for limited metastases (1–5 lesions) — growing evidence for local control and delaying systemic therapy; oligometastatic RCC

💡 Clinical Pearl: The first-line treatment landscape for metastatic ccRCC is now dominated by combination immunotherapy (IO+IO or IO+TKI). For IMDC intermediate/poor risk patients, ipilimumab-nivolumab (CheckMate 214) or pembrolizumab-axitinib (KEYNOTE-426) or cabozantinib-nivolumab (CheckMate 9ER) are preferred. For favorable-risk patients, sunitinib or pazopanib monotherapy or the newer IO+TKI combinations are appropriate. Non-clear cell RCC lacks level 1 evidence; cabozantinib (SWOG 1500) is the preferred TKI.

📖 References & Guidelines

CheckMate 214 — Motzer RJ et al. N Engl J Med. 2018.
KEYNOTE-426 — Rini BI et al. N Engl J Med. 2019.
CheckMate 9ER — Choueiri TK et al. N Engl J Med. 2021.
SWOG 1500 — Papandreou CN et al. Lancet. 2023.
NCCN Guidelines Kidney Cancer Version 2.2024
ESMO Guidelines — Renal Cell Carcinoma (2023)

▶4.3 Bladder Cancer (Urothelial Carcinoma)

Non-Muscle-Invasive Bladder Cancer (NMIBC)

TURBT (transurethral resection of bladder tumor) — diagnostic and therapeutic; complete resection of all visible tumors
Intravesical therapy:
- BCG (Bacillus Calmette-Guérin) — standard of care for high-risk NMIBC (CIS, T1, high-grade Ta); Connaught, TICE, Tokyo strains; induction (weekly × 6) + maintenance (weekly × 3 at months 3, 6, 12, 18, 24); reduces recurrence and progression; main toxicity: BCGitis (systemic infection), cystitis
- Mitomycin C (MMC) — optimized: EMDA (electromotive drug administration) MMC improves outcomes vs. standard MMC; used for intermediate-risk NMIBC; also used for BCG-unresponsive disease
- Valrubicin — for BCG-unresponsive NMIBC (CIS); FDA-approved
- Nadofaragene firadenovec — intravesical gene therapy (IFNα2b); FDA-approved for BCG-unresponsive NMIBC
- TAR-200 — intravesical drug-release system (gemcitabine); BCG-unresponsive NMIBC; phase II data promising

Muscle-Invasive Bladder Cancer (MIBC)

Neoadjuvant cisplatin-based chemotherapy before radical cystectomy improves OS (MVA 0.57 vs. 0.78 at 5 years in CUA meta-analysis); standard: dose-dense MVAC (ddMVAC) or gemcitabine + cisplatin (GC); at least 3 cycles before cystectomy
Radical cystectomy + pelvic lymph node dissection (PLND) — gold standard for non-metastatic MIBC; neobladder reconstruction for selected patients
Trimodal therapy (TMT) — maximal TURBT + concurrent chemoradiation (cisplatin or 5-FU/mitomycin C); bladder preservation for muscle-invasive disease in selected patients; comparable survival to RC in retrospective series; appropriate for patients who are not candidates for or refuse RC
Adjuvant therapy:
- IMpower010 — Atezolizumab vs. observation adjuvant after RC for pT2+ or N+ UC (PD-L1+); DFS benefit; FDA-approved. Bellmunt J et al. J Clin Oncol 2021.
- CheckMate 274 — Nivolumab vs. placebo adjuvant after RC for ypT2+ or N+ UC; DFS benefit 74% vs. 55% at 6 months; FDA-approved. Bajorin DF et al. N Engl J Med 2021.

Metastatic Urothelial Carcinoma — Systemic Therapy

First-line cisplatin-eligible: Gemcitabine + Cisplatin ± Atezolizumab (IMvigor130: atezo + GC improved PFS but not OS at interim); Pembrolizumab for cisplatin-ineligible (KEYNOTE-361: pembro + chemo vs. chemo — OS not improved); Avelumab maintenance (JAVELIN Bladder 100) after 4–6 cycles of 1st-line chemo (OS 21.4 vs. 14.3 months); standard of care
After platinum failure:
- Enfortumab vedotin (EV) — Nectin-4 ADC; EV-301: OS 12.9 vs. 9.0 months vs. chemo; FDA-approved for prior platinum + IO; EV-201: ORR 52% in post-IO and post-platinum; now moved earlier
- Erdafitinib — FGFR1-4 TKI; THOR (erdafitinib vs. chemo in FGFRalt+ after prior treatment): OS benefit (12.1 vs. 7.8 months); FDA-approved for FGFR2/3 alterations. Loriot Y et al. N Engl J Med 2019.
- Sacituzumab govitecan — Trop-2 ADC; TROPHY-u-01 (cohort 1): ORR 27% in post-platinum and post-IO; FDA-approved
- Pembrolizumab — approved for UC after platinum-containing chemo or within 12 months of perioperative cisplatin

💡 Clinical Pearl: The treatment of metastatic UC has evolved rapidly with antibody-drug conjugates (EV, SG) and FGFR inhibitors (erdafitinib). Erdafitinib requires FGFR3 or FGFR2 alterations (assessed by NGS) — present in ~20% of UC. Always test for FGFR alterations at diagnosis of metastatic UC. EV is the preferred post-platinum + post-IO agent, and SG is another ADC option with a different Trop-2 target.

📖 References & Guidelines

EV-301 — Powles T et al. N Engl J Med. 2021.
THOR — Loriot Y et al. N Engl J Med. 2019.
CheckMate 274 — Bajorin DF et al. N Engl J Med. 2021.
JAVELIN Bladder 100 — Powles T et al. N Engl J Med. 2020.
NCCN Guidelines Bladder Cancer Version 3.2024
ESMO GU Cancers — Bladder (2024)

Section 5: Gynecologic Cancers

▶5.1 Cervical Cancer

Etiology & Prevention

HPV (Human Papillomavirus) — necessary cause of cervical cancer; HPV types 16 and 18 cause ~70% of cervical cancers; types 31, 33, 45, 52, 58 also significant
HPV vaccination: 9-valent Gardasil 9 — quadrivalent (6, 11, 16, 18) + five additional types (31, 33, 45, 52, 58); approved for males and females ages 9–26; catch-up vaccination to age 45; prevents 90% of HPV-related cancers
Screening in Thailand: VIA (visual inspection with acetic acid) in resource-limited settings; cytology (Pap smear) and/or HPV DNA testing (co-testing preferred age 30–65 every 5 years)

Staging

FIGO 2018 staging — clinical staging supplemented by imaging (MRI, PET-CT) and surgical findings; key stages:
- Stage IA: Microscopic disease (IA1: <3mm depth, <7mm width; IA2: >3–5mm depth, <7mm width)
- Stage IB: Visible lesion ≤4cm (IB1), >4cm (IB2), >4cm with invasion >4mm (IB3)
- Stage II: Parametrial involvement (IIA: upper 2/3 vagina; IIB: parametrial)
- Stage III: Lower 1/3 vagina, pelvic wall, hydronephrosis, non-functioning kidney, pelvic nodes
- Stage IVA: Adjacent organs (bladder, rectum); IVB: Distant mets

Treatment by Stage

Microinvasive (IA1, no LVSI): Cone biopsy (cold knife or LEEP) — fertility-sparing; simple hysterectomy if child-bearing complete
Early-stage IB1–IB3, IIA: Radical hysterectomy (Querleu-Morrow type C) + pelvic lymph node dissection ± para-aortic dissection; OR radical trachelectomy (fertility-sparing) for selected IB1 (<2cm); alternative: definitive chemoradiation with equal outcomes
Locally advanced (IB3, IIA2, IIB–IVA): Concurrent chemoradiation (CRT) — cisplatin 40 mg/m² weekly during radiation; extended field RT for para-aortic nodes; brachytherapy mandatory
Concurrent chemotherapy: Cisplatin alone or cisplatin + 5-FU; paclitaxel-cisplatin vs. paclitaxel-carboplatin non-inferior (GOG-204)

Metastatic/Recurrent Cervical Cancer

KEYNOTE-826 — Pembrolizumab + chemo ± bevacizumab vs. placebo + chemo for persistent, recurrent, or metastatic CC (PD-L1 CPS≥1); OS 23.0 vs. 16.3 months; PFS benefit; FDA-approved. Colombo N et al. N Engl J Med 2021.
GOG-240 — Bevacizumab + paclitaxel-topotecan vs. paclitaxel-topotecan; OS 17.0 vs. 13.3 months; FDA-approved for recurrent/metastatic CC. Tewari KS et al. N Engl J Med 2014.
Tisotumab vedotin — Tissue Factor ADC; innovaTV 204: ORR 24% in 2nd/3rd-line recurrent/metastatic CC; FDA-approved. Coleman RL et al. Lancet Oncol 2021.

💡 Clinical Pearl: Bevacizumab has been a cornerstone of recurrent/metastatic cervical cancer treatment since GOG-240 (OS benefit). With KEYNOTE-826, pembrolizumab + chemotherapy ± bevacizumab is now the preferred 1st-line regimen for PD-L1 positive (CPS≥1) recurrent/metastatic disease, marking the first significant OS improvement in this setting in decades. For PD-L1 negative patients, chemotherapy ± bevacizumab remains standard.

📖 References & Guidelines

KEYNOTE-826 — Colombo N et al. N Engl J Med. 2021.
GOG-240 — Tewari KS et al. N Engl J Med. 2014.
innovaTV 204 — Coleman RL et al. Lancet Oncol. 2021.
NCCN Guidelines Cervical Cancer Version 2.2024
ESGO/ESTRO/ESP Guidelines — Cervical Cancer (2023)

▶5.2 Endometrial Cancer

Risk Factors & Molecular Classification

Risk factors: Obesity, anovulation (PCOS), unopposed estrogen, tamoxifen use, nulliparity, early menarche/late menopause, hereditary (Lynch syndrome — Muir-Torre, Turcot variants)
TCGA Molecular Classification (2013):
- POLEmut (ultramutated) — best prognosis; exonuclease domain mutations in POLE (polymerase epsilon); <1% of endometrial cancers; these patients may be candidates for de-escalation therapy
- MSI-H/dMMR (hypermutated) — 30%; Lynch syndrome associated; intermediate prognosis; responds to immunotherapy
- Copy Number High (serous-like) — ~25%; TP53 mutations dominant; worst prognosis; behaves like high-grade serous ovarian; frequently has HER2 amplification
- Copy Number Low (endometrioid) — ~40%; intermediate prognosis; CTNNB1 mutations common

Clinical Risk Groups & Adjuvant Therapy

Low-risk: Grade 1–2 endometrioid, stage IA (no myometrial invasion), POLEmut or no specific molecular profile (NSMP); observation
High-intermediate risk: Grade 3 or deep invasion or LVSI; vaginal brachytherapy ± chemotherapy
High-risk: Stage III–IVA, grade 3 with deep invasion, serous/clear cell histology, stage I–II with substantial LVSI; chemotherapy (paclitaxel-carboplatin) ± RT

Advanced/Recurrent Endometrial Cancer

KEYNOTE-775 / Study 309 — Pembrolizumab + Lenvatinib vs. chemo (doxorubicin or paclitaxel) in advanced/recurrent endometrial cancer (all-comers, not selected for MSI-H). OS 18.0 vs. 11.7 months; PFS 7.2 vs. 3.8 months; FDA-approved. Makker V et al. N Engl J Med 2022.
Pembrolizumab — alone for MSI-H/dMMR recurrent endometrial cancer; KEYNOTE-158: ORR 57%; FDA-approved
Dostarlimab — anti-PD-1; GARNET trial: ORR 44% in dMMR/MSI-H EC; FDA-approved
Carboplatin-paclitaxel — standard chemotherapy for advanced/recurrent EC

💡 Clinical Pearl: The TCGA molecular classification has changed how we approach endometrial cancer. POLEmut tumors have excellent prognosis and may not require adjuvant therapy; serous-like (copy number high) tumors are aggressive and benefit from aggressive treatment (similar to high-grade serous ovarian cancer); MSI-H/dMMR tumors respond to immunotherapy (pembrolizumab, dostarlimab). In practice, comprehensive molecular profiling (MSI, POLE, TP53) should be performed on all endometrial cancers to guide adjuvant therapy and systemic treatment decisions.

📖 References & Guidelines

KEYNOTE-775 — Makker V et al. N Engl J Med. 2022.
TCGA — Cancer Genome Atlas Research Network. Nature. 2013.
NCCN Guidelines Uterine Neoplasms Version 1.2024
ESGO/ESTRO/ESP Endometrial Cancer Guidelines (2023)

▶5.3 Ovarian Cancer

Histotypes & Molecular Biology

High-grade serous carcinoma (HGSC) — 70%; TP53 mutation near-universal; BRCA1/2 mutations in 15–20%; homologous recombination deficiency (HRD) in ~50%; originates from fallopian tube secretory epithelial cells (STIC — serous tubal intraepithelial carcinoma)
Endometrioid carcinoma — 10%; associated with endometriosis; often MSI-H; ARID1A mutations; better prognosis than HGSC
Clear cell carcinoma — 10%; associated with endometriosis; ARID1A, PIK3CA mutations; chemoresistant; poor prognosis; HNF-1β positive
Mucinous carcinoma — 3%; large bulky unilateral ovarian mass; CK7+/CK20−; usually metastatic from GI tract; poor response to platinum chemo
Low-grade serous carcinoma — rare; driven by MAPK pathway (KRAS, BRAF mutations); indolent; resistant to chemotherapy; MEK inhibitors active

HRD Testing

BRCA1/2 germline and somatic testing: Recommended for all patients with HGSC, endometrioid, or clear cell carcinoma (NCCN 2024)
HRD score (myChoice CDx, ThermoFisher): Measures loss-of-heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST); HRD score ≥42 = HRD-positive; predicts response to PARP inhibitors (PRIMA, VELIA trials) and platinum sensitivity

Frontline Treatment — Advanced Disease (III–IV)

Surgery: PDS (primary debulking surgery) with goal of R0 (complete cytoreduction, no visible residual disease) OR NACT (neoadjuvant chemotherapy) → IDS (interval debulking surgery)
- EORTC 55971 — NACT→IDS non-inferior to PDS→adjuvant chemo; CHORUS confirmed; NACT preferred when complete resection unlikely with PDS; less surgical morbidity
Chemotherapy: Carboplatin-paclitaxel × 6 cycles; dose-dense (weekly paclitaxel) may improve outcomes (JGOG 3016, especially in suboptimally debulked patients)
PARP inhibitor maintenance:
- SOLO1 — Olaparib vs. placebo maintenance after 1st-line chemo in BRCA1/2 mutated ovarian cancer; PFS at 3 years 60% vs. 27%; OS benefit at 7-year FU; standard of care. Moore K et al. N Engl J Med 2018.
- PRIMA — Niraparib vs. placebo 1st-line maintenance (all-comers, but HRD+ derived greatest benefit); FDA-approved. González-Martín A et al. N Engl J Med 2019.
- ARIEL3 — Rucaparib vs. placebo 2nd-line (or 1st-line) maintenance; FDA-approved. Coleman RL et al. Lancet 2017.
Bevacizumab maintenance: ICON7 and GOG-218: bevacizumab added to carbo/taxol and continued maintenance improved PFS in high-risk patients (stage III with residual disease after surgery, stage IV)

Recurrent Ovarian Cancer

Platinum-sensitive relapse (≥6 months platinum-free interval): Platinum-based re-challenge ± bevacizumab; combinations: carboplatin-gemcitabine ± bevacizumab (OCEANS), carboplatin-PLD ± bevacizumab (MITO16b); surgery (secondary cytoreduction) for selected patients with limited disease
Platinum-resistant relapse (<6 months): Non-platinum agents: PLD (pegylated liposomal doxorubicin), topotecan, gemcitabine, weekly paclitaxel, trabectedin + PLD (OVINUS); no OS benefit from combinations; bevacizumab + chemo improves PFS (AURELIA)
PARPi re-challenge: Benefit if prior response to PARPi was >6–12 months; if prior response <6 months, limited benefit
Low-grade serous: Trametinib — GOG-281/LOGS: trametinib vs. physician's choice (hormonal or chemo); PFS 13.0 vs. 7.2 months; FDA-approved. Gershenson DM et al. Lancet 2022.

💡 Clinical Pearl: For advanced HGSC, BRCA1/2 and HRD testing must be performed at diagnosis to guide PARP inhibitor maintenance (olaparib SOLO1 in 1st-line for BRCA mutated; niraparib PRIMA in 1st-line for HRD+). In clinical practice, NACT→IDS is increasingly preferred over PDS when complete resection is uncertain, as it reduces surgical morbidity without compromising survival. The goal of any surgery is R0 — even 1mm of residual disease significantly worsens prognosis.

📖 References & Guidelines

SOLO1 — Moore K et al. N Engl J Med. 2018.
PRIMA — González-Martín A et al. N Engl J Med. 2019.
EORTC 55971 — Vergote I et al. N Engl J Med. 2010.
GOG-281/LOGS — Gershenson DM et al. Lancet. 2022.
NCCN Guidelines Ovarian Cancer Version 2.2024
ESGO Guidelines — Ovarian Cancer (2023)

Section 6: Hematologic Malignancies

▶6.1 Acute Myeloid Leukemia (AML)

Classification & Genetics

WHO 2022 (ICC) / FAB classification: AML is defined by ≥20% blasts in bone marrow or peripheral blood (except for AML with recurring genetic abnormalities which can have <20% blasts)
ELN 2022 Genetic Risk Stratification (for adults):
- Favorable: t(8;21)(q22;q22)/RUNX1::RUNX1T1; inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFB::MYH11; NPM1 mutation without FLT3-ITD (normal karyotype); biallelic CEBPA mutations (normal karyotype)
- Intermediate: NPM1 mutation with FLT3-ITD (normal karyotype); wild-type NPM1 without FLT3-ITD or with FLT3-ITD low (normal karyotype); t(9;11)(p21.3;q23.3)/MLLT3::KMT2A
- Adverse: Complex karyotype (≥3 unrelated abnormalities); monosomal karyotype; del(5q)/−5, del(7q)/−7; t(6;9)(p23;q34.1)/DEK::NUP214; t(v;11q23.3)/KMT2A-rearranged (except t(9;11)); inv(3)(q21.3q26.2)/t(3;3)(q21.3;q26.2)/GATA2, MECOM (EVI1); t(9;22)(q34.1;q11.2)/BCR::ABL1; RUNX1 mutation (normal karyotype); ASXL1 mutation (normal karyotype); TP53 mutation

Key Mutations & Targeted Therapies

FLT3-ITD: Midostaurin (FLT3 inhibitor) — RATIFY trial: added to standard 7+3 chemo 1st-line; OS benefit; FDA-approved. Gilteritinib — ADMIRAL trial: superior to salvage chemo in relapsed/refractory FLT3-mutant AML; FDA-approved. Quizartinib — approved outside US
IDH1/IDH2 mutations: Ivosidenib (IDH1) — AGILE trial: ivosidenib + azacitidine vs. azacitidine alone for IDH1-mutant AML; OS benefit; FDA-approved. Enasidenib (IDH2) — approved for IDH2-mutant R/R AML; differentiation syndrome (IDH syndrome) is a notable AE (retinoic acid syndrome-like)
Hyperdiploid/MDS-related: Hypomethylating agents (HMA): Azacitidine (VIALE-A: azacitidine + venetoclax superior to azacitidine alone in unfit AML); Decitabine; Venetoclax + HMA — new standard for unfit AML (age ≥75 or comorbidities)

Acute Promyelocytic Leukemia (APL) — AML with t(15;17)/PML::RARA

Medical emergency — high early death rate from DIC and hemorrhage; characterized by t(15;17), Auer rods (faggot cells), pancytopenia
ATRA (All-trans retinoic acid) + ATO (Arsenic trioxide) — standard of care; ATRA+ATO ± idarubicin (GIMEMA); ATRA+ATO for low/intermediate risk; high-risk (WBC >10,000/μL) — add idarubicin; cure rates >90% with modern therapy
ATRA + ATO differentiation syndrome: Presents with fever, dyspnea, pulmonary infiltrates, pleural effusions, hypotension — treat with dexamethasone and hold ATRA/ATO if severe; occurs in first 2–3 weeks
Intrathecal prophylaxis: Not routinely indicated in APL unless CNS symptoms

Philadelphia Chromosome+ ALL

Dasatinib, Ponatinib (T315I), Bosutinib — BCR::ABL1 TKIs; combined with mini-hyper-CVD (dose-reduced chemo) + ponatinib shows excellent outcomes; Blinatumomab (bispecific CD3/CD19 BiTE) — approved for Ph+ ALL after prior TKI; Inotuzumab ozogamicin (CD22 ADC) — approved for R/R B-ALL

💡 Clinical Pearl: APL is a medical emergency — early deaths from coagulopathy (DIC) are the main cause of mortality. Start ATRA immediately upon clinical suspicion (even before genetic confirmation). ATRA+ATO has transformed APL into one of the most curable adult leukemias. The key is prompt recognition and immediate initiation of targeted therapy before hemorrhagic complications.

📖 References & Guidelines

RATIFY — Stone RM et al. N Engl J Med. 2017.
ADMIRAL — Perl AE et al. N Engl J Med. 2019.
AGILE — Montesinos P et al. N Engl J Med. 2022.
ELN Recommendations on AML (2022) — Döhner H et al. Blood.
NCCN Guidelines AML Version 2.2024
ASH Guidelines on AML (2023)

▶6.2 Chronic Myeloid Leukemia (CML)

Pathophysiology & Phases

Philadelphia chromosome — t(9;22)(q34;q11) resulting in BCR::ABL1 fusion gene; encodes constitutively active tyrosine kinase
Chronic Phase (CP): 85% at diagnosis; orderly proliferation of maturing granulocytes; responds well to TKIs
Accelerated Phase (AP): Basophilia >20%, eosinophilia, clonal evolution (additional chromosomal abnormalities), BCR::ABL1 >10% at 6 months, or other criteria; TKI response less predictable
Blast Phase (BP): Blasts ≥20% in marrow or blood (or extramedullary blast proliferation); AML-like behavior; poor prognosis; TKIs + intensive chemo + possibly transplant

Treatment Response Milestones (ELN 2020)

3 months: BCR::ABL1 ≤10% (IS) — optimal; >10% — warning/failure
6 months: BCR::ABL1 ≤1% (MMR) — optimal; >10% — failure; 1–10% — warning
12 months: BCR::ABL1 ≤0.1% (MR3 — MMR) — optimal; >1% — failure; 0.1–1% — warning
18 months: BCR::ABL1 ≤0.1% (MMR) — optimal; >1% — failure
BCR::ABL1 ≤0.01% (MR4) and ≤0.0032% (MR4.5) and ≤0.001% (MR5) — deeper responses associated with better outcomes

TKIs — Key Agents

Imatinib — first-generation TKI; IRIS trial: 10-year OS 83%; standard dose 400 mg/day; still a valid 1st-line option
Dasatinib, Nilotinib, Bosutinib — second-generation TKIs; faster and deeper molecular responses than imatinib (ENESTnd, DASISION, BELA trials); some approved for 1st-line
Ponatinib — 3rd-gen TKI; active against T315I and all BCR::ABL1 mutants; used in T315I mutation, 3rd-line, or ponatinib-intolerant CML; cardiovascular toxicity (HTN, PAD, CVE) requires monitoring
Asciminib — allosteric BCR::ABL1 inhibitor (STAMP); approved for CML-CP after ≥2 TKIs (CABL001X2201); well-tolerated; works by binding to myristoyl pocket (distinct from ATP-binding site)

Treatment-Free Remission (TFR)

Eligible after ≥3 years on TKI with stable MR4.5 (BCR::ABL1 ≤0.0032% IS for ≥2 years); candidate selection important; close monitoring (q1–2 months for first year, then q3 months); ~50% of eligible patients maintain TFR at 2 years

💡 Clinical Pearl: The goal of CML treatment is achieving deep molecular response (MR4.5 or better) to enable treatment-free remission (TFR). Monitoring with quantitative PCR (qPCR) every 3 months is essential. If a patient fails a 1st-line TKI, switch to a 2nd-gen TKI. If BCR::ABL1 rises >10-fold on 2 consecutive tests, consider mutation analysis and switch to an appropriate TKI. Ponatinib is reserved for T315I mutation and ponatinib-intolerant disease.

📖 References & Guidelines

IRIS — O'Brien SG et al. N Engl J Med. 2003.
ELN Recommendations for CML (2020) — Hochhaus A et al. Leukemia. 2020.
NCCN Guidelines CML Version 2.2024

▶6.3 Hodgkin Lymphoma (HL)

Histologic Subtypes (WHO 2017)

Nodular sclerosis (NSCHL) — ~70%; lacunar Reed-Sternberg cells; collagen bands; best prognosis of classical HL
Mixed cellularity — ~20%; pleomorphic RS cells; intermediate prognosis
Lymphocyte-rich — rare; favorable prognosis
Lymphocyte-depleted — rare; HIV-associated; poor prognosis
Nodular lymphocyte-predominant HL (NLPHL) — distinct biology; LP cells ("popcorn cells"); CD20+; CD15/CD30−; indolent; treated with anti-CD20 (rituximab) ± local RT

Early-Stage (I–II, non-bulky) — ABVD × 2–4 + IFRT

ABVD regimen: Adriamycin (doxorubicin) + Bleomycin + Vinblastine + Dacarbazine × 2 cycles + IFRT 20–30 Gy; GHSG HD10: 2× ABVD + 20 Gy IFRT non-inferior to 4× ABVD + 30 Gy; standard approach
Unfavorable early stage: escalated BEACOPP × 2 + IFRT (4 cycles if interim PET-negative) — higher cure rates but more toxicity
Interim PET-adapted: Response-adapted therapy based on Deauville score (DS) after 2 cycles; DS 1–2 (negative) → de-escalate; DS 4–5 (positive) → escalate; HD18 trial: negative PET after 2× eBEACOPP → 2 more cycles sufficient

Advanced (III–IV) — ABVD vs. Escalated BEACOPP

RATHL — ABVD × 6 cycles (or AVD if PET-negative after 2 cycles) vs. escalated BEACOPP × 6; no OS difference at 3 years; ABVD is standard with de-escalation for PET-negative; eBEACOPP for patients with high-risk features (high IPS, bulk). Johnson P et al. N Engl J Med 2016.
Brentuximab vedotin + AVD (Bv-AVD) — ECHELON-1: brentuximab + AVD vs. ABVD in advanced HL; improved modified PFS (88% vs. 86% at 2 years); approved for stage III–IV HL; less gonadotoxicity than ABVD

Relapsed/Refractory HL

Brentuximab vedotin — anti-CD30 ADC; pivotal trial: ORR 75% in relapsed/refractory HL after autoSCT; approved; also used as consolidation post-autoSCT (AETHERA: PFS benefit)
Pembrolizumab — KEYNOTE-087: ORR 69% in R/R HL; CR 22%; FDA-approved. Chen R et al. Lancet Oncol 2017.
Nivolumab — CheckMate 205: ORR 66–80%; FDA-approved. Ansell SM et al. N Engl J Med 2015.
Chemotherapy salvage: ICE, DHAP, ESHAP, BEACOPP → autoSCT (gold standard for chemosensitive relapse)
Allo-SCT — for patients relapsing after autoSCT or chemorefractory; reduced-intensity conditioning preferred

💡 Clinical Pearl: The Deauville 5-point scale (5PS) is the standard for interpreting interim PET in HL. DS 1–3 after 2 cycles ABVD → continue ABVD (de-escalation); DS 4–5 → escalate to eBEACOPP. Brentuximab vedotin (ECHELON-1) is now an alternative to ABVD in advanced HL with comparable or better efficacy and less gonadotoxicity. For R/R disease, checkpoint inhibitors (pembrolizumab, nivolumab) and brentuximab vedotin have transformed outcomes, with CR rates enabling bridge to transplant.

📖 References & Guidelines

RATHL — Johnson P et al. N Engl J Med. 2016.
ECHELON-1 — Connors JM et al. N Engl J Med. 2018.
KEYNOTE-087 — Chen R et al. Lancet Oncol. 2017.
NCCN Guidelines Hodgkin Lymphoma Version 2.2024
ESMO Guidelines — Hodgkin Lymphoma (2022)

▶6.4 Diffuse Large B-Cell Lymphoma (DLBCL)

Molecular Subtypes & High-Risk Features

Cell of Origin (COO) classification:
- GCB (germinal center B-cell) — better prognosis; Hans IHC algorithm: CD10+, orBCL6+ and MUM1−; or gene expression profiling
- ABC (activated B-cell) — worse prognosis; chronic BCR signaling, NF-κB activation; mutational landscape includes MYD88, CD79B, CARD11
Double-hit lymphoma (DH/TH): Co-deletion of MYC + BCL2 (double-expressor) or MYC + BCL6 or MYC + BCL2 + BCL6 (triple-hit); aggressive; MYC rearrangement + BCL2 and/or BCL6 rearrangements detected by FISH; R-CHOP often insufficient; consider R-DA-EPOCH or Pola-R-CHP
TP53 mutation: Associated with poor outcomes in DLBCL, especially ABC subtype

First-Line Treatment

R-CHOP × 6 cycles — standard of care for advanced DLBCL; rituximab 375 mg/m², cyclophosphamide, doxorubicin, vincristine, prednisone; excellent outcomes in limited-stage (low IPI)
Limited-stage (I–II, non-bulky): R-CHOP × 3–6 + IFRT vs. R-CHOP × 6 alone; 6 cycles R-CHOP may suffice without RT in selected patients (FLYSSTM 1)
Double-hit / High-grade BCL with MYC rearrangement: R-DA-EPOCH (dose-adjusted EPOCH) ± rituximab — infusional etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone; superior to R-CHOP in some series; polatuzumab vedotin + R-CHP (Pola-R-CHP) is an emerging standard
Primary mediastinal large B-cell lymphoma (PMBCL): R-DA-EPOCH ± RT; pembrolizumab for relapsed/refractory

CNS Prophylaxis

High-risk features:睾丸/extranodal testicular, breast, or renal involvement;IPI≥3; MYC rearrangement; >1 extranodal site; skin (leg type), adrenal; IVLBCL
Methods: Intrathecal methotrexate (IT-MTX) × 4–6 doses with R-CHOP cycles; or systemic high-dose methotrexate (3–3.5 g/m²) after R-CHOP cycles 3–4

Relapsed/Refractory DLBCL

Salvage chemo: R-ICE, R-DHAP, R-GDP → autoSCT if chemosensitive; Pola-BR (polatuzumab vedotin + bendamustine + rituximab) — GO29365: better ORR and OS than BR alone
Polatuzumab vedotin — anti-CD79b ADC; approved with BR for R/R DLBCL
CAR-T cell therapy: Axicabtagene ciloleucel (axi-cel), Tisagenlecleucel (tisa-cel), Lisocabtagene maraleucel (liso-cel) — ZUMA-7 (axi-cel vs. SOC), BELINDA (tisa-cel vs. SOC), TRANSFORM (liso-cel vs. SOC): all showed EFS or ORR benefit in 2nd-line R/R DLBCL; CAR-T now standard 2nd-line for transplant-eligible patients
Bispecific antibodies: Epcoritamab (CD3/CD20 BiTe) — EPCORE NHL-1: ORR 63% in R/R DLBCL; FDA-approved. Glofitamab — NP30179: ORR 56% in R/R DLBCL; FDA-approved. Both cause CRS and neurotoxicity.

💡 Clinical Pearl: In newly diagnosed DLBCL, always obtain cell of origin (COO) and test for MYC/BCL2/BCL6 by FISH (double/triple-hit). Double-hit DLBCL (MYC + BCL2 and/or BCL6) should be treated with R-DA-EPOCH or Pola-R-CHP, not standard R-CHOP. For 2nd-line R/R DLBCL, CAR-T (axi-cel, tisa-cel, liso-cel) has replaced salvage chemo + autoSCT as the standard for transplant-eligible patients (ZUMA-7, TRANSFORM). Bispecific antibodies (epcoritamab, glofitamab) offer an off-the-shelf alternative for transplant-ineligible patients.

📖 References & Guidelines

ZUMA-7 — Locke FL et al. N Engl J Med. 2022.
TRANSFORM — Kamdar M et al. Lancet Oncol. 2022.
GO29365 — Sehn LH et al. J Clin Oncol. 2020.
NCCN Guidelines B-Cell Lymphomas Version 2.2024
ESMO Guidelines — DLBCL (2023)

▶6.5 Mantle Cell Lymphoma (MCL)

Pathophysiology & Aggressive Features

t(11;14)(q13;q32) — CCND1-IGH fusion; constitutive cyclin D1 overexpression → cell cycle dysregulation; SOX11 expression distinguishes MCL from other small B-cell lymphomas
Blastoid variant: More aggressive; high Ki-67 (>80%); pleomorphic cells; worse prognosis
TP53 mutation/deletion: Associated with very poor outcomes and resistance to chemoimmunotherapy

First-Line Treatment

Young/fit: R-HyperCVAD/R-MA alternating × 6–8 cycles (M.D. Anderson protocol) or Nordic protocol (maxi-CHOP + alternating R-high-dose Ara-C); cytarabine-containing regimens superior for CR rates
TRIANGLE — Ibrutinib + ASCT + ibrutinib maintenance = ASCT + ibrutinib (no R-CHOP/R-HyperCVAD); ibrutinib + ASCT + ibrutinib non-inferior and potentially superior to ASCT alone; ibrutinib-based regimens emerging as 1st-line. Dreyling M et al. J Clin Oncol 2023.
Elderly/unfit: Bendamustine + rituximab (BR) is common; ibrutinib + rituximab is another option

Relapsed/Refractory MCL

BTK inhibitors: Ibrutinib (PCI-32765) — phase II: ORR 68%, CR 21%; approved. Acalabrutinib — ACE-LY-003: ORR 81%, CR 43%; better tolerated than ibrutinib; FDA-approved. Zanubrutinib — BGB-3111-206: ORR 84%, CR 77%; FDA-approved; more BTK selectivity
Venetoclax — MCL2001: ORR 53% in R/R MCL; AIM trial: venetoclax + ibrutinib OR
83%; FDA-approved. Brexucabtagene autoleucel (Tecartus) — ZUMA-2: CAR-T for R/R MCL; ORR 93%, CR 67%; FDA-approved for R/R MCL after BTK inhibitor. Epcoritamab — EPCORE NHL-1: ORR 54% in R/R MCL

📖 References & Guidelines

TRIANGLE — Dreyling M et al. J Clin Oncol. 2023.
ZUMA-2 — Wang M et al. N Engl J Med. 2020.
NCCN Guidelines MCL Version 2.2024

▶6.6 CLL/SLL

Diagnosis & Staging

Diagnosis: Absolute lymphocytosis (>5,000/μL), small mature lymphocytes, CLL score: CD5+, CD23+, FMC7−, surface Ig weak; smudge cells on peripheral smear
IgHV mutation status: Mutated (M-CLL, better prognosis) vs. unmutated (U-CLL, worse prognosis); key prognostic factor
Staging: Rai (US): 0 (lymphocytosis), I–II (lymphadenopathy ± organomegaly), III–IV (anemia, thrombocytopenia); Binet (Europe): A (<3 lymphoid sites, no anemia/thrombocytopenia), B (≥3 sites), C (anemia/thrombocytopenia)

First-Line Treatment

TP53 deletion (17p−) or ATM deletion (11q−): contraindicated to chemoimmunotherapy; use covalent BTK inhibitors (ibrutinib, acalabrutinib) or venetoclax + obinutuzumab
Fit patients, IgHV-mutated, TP53wt: FCR (fludarabine + cyclophosphamide + rituximab) — excellent response, potential for prolonged remission and even "functional cure"
Elderly/unfit: Obinutuzumab + chlorambucil (CLL11) — less toxic; or BTK inhibitors (ibrutinib, acalabrutinib)
CLL14 — Venetoclax + Obinutuzumab vs. chlorambucil + obinutuzumab in untreated CLL; MRD-negative remission in 75%; PFS at 5 years 81%; FDA-approved. Fischer K et al. N Engl J Med 2019.

Relapsed/Refractory CLL

Ibrutinib — RESONATE-17: ORR 90% in del(17p) R/R CLL; FDA-approved
Venetoclax + Rituximab — MURANO trial: fixed duration (2 years) venetoclax + rituximab vs. bendamustine + rituximab in R/R CLL; PFS benefit; MRD-negativity in 62%; FDA-approved
Acalabrutinib — ASCEND: acalabrutinib vs. investigator's choice in R/R CLL; PFS benefit; approved
Pirtobrutinib (LOXO-305) — BRUIN: non-covalent BTK inhibitor; active in BTK inhibitor-resistant CLL (C481S mutation); ORR 70%; FDA-approved 2023 for R/R CLL after ≥2 prior lines including covalent BTK inhibitor
Bispecifics/CAR-T: epcoritamab, glofitamab (CD3/CD20) and brexucabtagene autoleucel are emerging options

📖 References & Guidelines

CLL14 — Fischer K et al. N Engl J Med. 2019.
MURANO — Seymour JF et al. N Engl J Med. 2018.
BRUIN — Mato AR et al. Lancet. 2021.
NCCN Guidelines CLL/SLL Version 2.2024
iwCLL Guidelines (2018)

▶6.7 Multiple Myeloma

Diagnostic Criteria

CRAB criteria: HyperCalcemia, Renal insufficiency, Anemia, Bone lesions (lytic)
SLiM criteria: Sixty percent clonal plasma cells, Serum light chain ratio ≥100, MRI with >1 focal lesion
Diagnosis requires ≥1 CRAB or SLiM feature plus proof of clonal plasma cell neoplasm

Cytogenetics & Risk Stratification

High-risk: t(4;14), t(14;16), del(17p), t(14;20) — shortened OS even with modern therapy; considered for quad or penta therapy and transplant
Standard-risk: Hyperdiploidy, t(11;14), del(13q (monoallelic), trisomies
Double-hit myeloma: Any two of t(4;14), t(14;16), del(17p) — very high-risk

Frontline Treatment (Transplant-Eligible)

Induction: VRd (bortezomib + lenalidomide + dexamethasone) × 4 cycles → ASCT (melphalan 200 mg/m²) → VRd consolidation × 2 cycles → Lenalidomide maintenance; GRIFFIN trial: Dara-VRd (daratumumab + VRd) → Dara-VRd consolidation → daratumumab maintenance: superior sCR rate 63.6% vs. 47.1%
VTD (bortezomib + thalidomide + dex) — alternative

Transplant-Ineligible / Older Patients

Dara-VRd — MAIA: daratumumab + VRd vs. VRd; PFS benefit at 5 years; standard
Rd (lenalidomide + dexamethasone) — suitable for frail patients

Relapsed Myeloma — Key Regimens

Daratumumab-based rechallenge: dara + VD (VELA), dara + Rd, dara + Pom-D (APOLLO)
Carfilzomib + Lenalidomide + Dex (ASPIRE): PFS 26.3 vs. 17.6 months vs. Rd; approved
Elotuzumab + Pomalidomide + Dex (ELOQUENT-3): PFS 10.3 vs. 4.7 months; approved for RRMM
Isatuximab + Carfilzomib + Dex (IKEMA): PFS not reached vs. 19.4 months; approved
Selinexor + Bortezomib + Dex (BOSTON): PFS 13.9 vs. 8.6 months; FDA-approved
Belantamab mafodotin — BCMA ADC; DREAMM-2: ORR 31% in 5th+ line; eye toxicity (keratopathy) is dose-limiting
CAR-T cell therapy:
- Idecabtagene vicleucel (ide-cel) — Abecma; KarMMa: ORR 73%, CR 33%; FDA-approved for ≥4 prior lines
- Ciltacabtagene autoleucel (cilta-cel) — CARTITUDE-1: ORR 97%, CR 67%; FDA-approved for ≥4 prior lines
Bispecific antibodies (T-cell redirecting):
- Teclistamab — BCMA×CD3 BiTe; MajesTEC-1: ORR 63% in 5th+ line; FDA-approved
- Elranatamab — BCMA×CD3; MagnetisMM-3: ORR 61%; FDA-approved
- Talquetamab — GPRC5D×CD3 BiTe; MonumenTAL-1: ORR 73% (SC doses); FDA-approved

💡 Clinical Pearl: The treatment of multiple myeloma has evolved from alkylator-based to proteasome inhibitor-based (bortezomib/ixazomib/carfilzomib) and immunomodulatory drug-based (lenalidomide/pomalidomide) to the current era of anti-CD38 monoclonal antibodies (daratumumab, isatuximab) and BCMA-targeted therapies (CAR-T, bispecifics, ADC). The typical sequencing for RRMM is: VRd → ASCT → lenalidomide maintenance → daratumumab-based regimens → carfilzomib-based → BCMA-targeted (CAR-T or bispecifics). Response assessment with MRD (minimal residual disease) testing by NGF or MFC (<10⁻⁵) is increasingly used to guide treatment duration.

📖 References & Guidelines

GRIFFIN — Voorhees PM et al. Blood. 2020.
MAIA — Facon T et al. Lancet. 2019.
CARTITUDE-1 — Berdeja JG et al. Lancet. 2021.
NCCN Guidelines Multiple Myeloma Version 3.2024
IMWG Guidelines on Diagnosis and Management of MM (2024)

Section 7: Head and Neck Cancer

▶7.1 Squamous Cell Carcinoma of the Head and Neck (HNSCC)

Sites & Risk Factors

Sites: Oral cavity, oropharynx, larynx, hypopharynx, nasopharynx, salivary glands, nasal cavity/ sinuses
Major risk factors: Tobacco (smoking + betel quid — especially relevant in Thailand), alcohol, HPV (oropharyngeal SCC), EBV (nasopharyngeal carcinoma)
Betel quid chewing — major risk factor for oral cavity SCC in Southeast Asia (Thailand, India, Taiwan); often combined with tobacco and lime

HPV-Related Oropharyngeal SCC

Epidemiology: Rising incidence of oropharyngeal SCC (OPSCC) driven by HPV; now >70% of OPSCC in Western countries are HPV-related
p16 immunohistochemistry — surrogate marker for HPV; p16+ OPSCC has better prognosis than p16−; AJCC 8th edition staging uses p16 status to determine T categories
Mechanism: HPV E6 inactivates p53; HPV E7 inactivates Rb — two hits in tumor suppressor pathways
Prognosis: HPV+ OPSCC has significantly better survival than HPV−; but smoking history modifies the prognosis: current smokers with HPV+ have intermediate survival between never-smoker HPV+ and HPV−

Treatment of Locally Advanced HNSCC

Concurrent cisplatin-RT: Standard for locally advanced; cisplatin 100 mg/m² q3 weeks × 3 doses OR 40 mg/m² weekly; weekly cisplatin is better tolerated and increasingly preferred (ASCO guidelines); improves OS and LRF
EXTREME — Cetuximab + cisplatin/carboplatin + 5-FU vs. cisplatin/carboplatin + 5-FU alone in recurrent/metastatic (R/M) HNSCC; OS 10.1 vs. 7.4 months; first targeted therapy approval in HNSCC. Vermorken JB et al. N Engl J Med 2007.
KEYNOTE-048 — Pembrolizumab ± chemo (cisplatin/carboplatin + 5-FU) vs. EXTREME in R/M HNSCC 1st-line. pembrolizumab + chemo vs. EXTREME: OS 13.0 vs. 10.7 months; pembrolizumab alone vs. EXTREME: OS 11.5 vs. 10.7 months (CPS≥1); changed paradigm in R/M HNSCC; pembrolizumab ± chemo now standard 1st-line for R/M HNSCC. Burtness B et al. Lancet 2019.
CheckMate 141 — Nivolumab vs. investigator's choice chemo in R/M HNSCC after platinum failure; OS 7.5 vs. 5.1 months; FDA-approved. Ferris RL et al. N Engl J Med 2016.

Nasopharyngeal Carcinoma (NPC)

EBV-associated — particularly endemic type (non-keratinizing SCC); EBV DNA titer used for diagnosis, monitoring, and prognosis
Standard treatment: Cisplatin + RT (IMRT) ± adjuvant cisplatin/5-FU (NPC-9901, NPC-9902); gemcitabine + cisplatin (NJCC 2013) — improved OS vs. cisplatin/5-FU
TPF induction (docetaxel + cisplatin + 5-FU) — improved OS but more toxic; used in selected patients
Immune checkpoint inhibitors: Toripalimab — JUPITER-02: toripalimab + GP (gemcitabine-cisplatin) vs. placebo + GP 1st-line; OS benefit; PFS benefit; FDA-approved. Mai HQ et al. N Engl J Med 2021. Camrelizumab — CAPTAIN-1: similar design; FDA-approved

💡 Clinical Pearl: HPV status (p16 IHC) is critical in oropharyngeal SCC — it determines staging (AJCC 8th), prognosis, and treatment intensity. p16+ OPSCC has significantly better survival and may be treated with de-intensified therapy in clinical trials (e.g., lower RT dose, less extensive neck dissection). In R/M HNSCC, pembrolizumab ± chemotherapy (KEYNOTE-048) is now standard 1st-line for CPS≥1, while nivolumab (CheckMate 141) remains an important 2nd-line option. For NPC, EBV DNA monitoring is a powerful tool for surveillance and detecting recurrence.

📖 References & Guidelines

KEYNOTE-048 — Burtness B et al. Lancet. 2019.
CheckMate 141 — Ferris RL et al. N Engl J Med. 2016.
JUPITER-02 — Mai HQ et al. N Engl J Med. 2021.
NCCN Guidelines Head and Neck Cancers Version 2.2024
ASCO Guidelines — HNSCC (2023)

Section 8: Skin Cancer & Melanoma

▶8.1 Melanoma

Staging & Prognostic Factors

Breslow thickness (mm) — most important prognostic factor; deeper = worse
Ulceration — adverse prognostic factor; mitotic rate (mitoses/mm²)
Sentinel lymph node biopsy (SLNB): Indicated for T1b+ (T1b: >0.8mm or <0.8mm with ulceration); most important staging procedure for localized melanoma; nodal positivity upstages to stage III
BRAF V600E/K mutation — ~50% of melanomas; predictive of response to BRAF/MEK inhibition

Localized Melanoma (Stage I–II)

Wide local excision: Margins: 1cm (T1a), 1–2cm (T1b–T2), 2cm (T3–T4)
SLNB for T1b+: Guides adjuvant therapy decision
Adjuvant immunotherapy for stage IIB/C:
- KEYNOTE-716 — Pembrolizumab vs. placebo adjuvant in resected stage IIB/C; DFS benefit; FDA-approved. Luke JJ et al. Lancet 2021.
- CheckMate 76K — Nivolumab vs. placebo adjuvant in resected stage IIB/C; DFS benefit. Long G et al. Lancet 2022.
- COMBI-AD — Dabrafenib + Trametinib vs. placebo adjuvant in resected BRAF V600E/K stage III; 5-year RFS 52% vs. 36%; FDA-approved for BRAF mutant adjuvant. Dummer R et al. N Engl J Med 2020.

Stage III (Regional Node Involvement)

MSLT-II — Completion lymph node dissection (CLND) vs. observation after positive SLNB; no OS difference at 3 years; CLND may be avoided with nodal ultrasound surveillance; CLND still recommended for clinically detected nodal disease. Faries MB et al. N Engl J Med 2017.
Adjuvant therapy: Anti-PD-1 (pembrolizumab KEYNOTE-054, nivolumab CheckMate 238) or BRAF/MEK inhibition (dabrafenib+trametinib for BRAF mutant)
Neoadjuvant: Pembrolizumab neoadjuvant (OpACIN, Keynote-173, PRADO) — high pCR rates; under investigation as standard

Metastatic Melanoma (Stage IV)

CheckMate 067 — Nivolumab + Ipilimumab vs. nivolumab alone vs. ipilimumab alone in treatment-naïve metastatic melanoma; OS at 6.5 years: 49% vs. 42% vs. 23%; combo has highest response but more toxicity; anti-PD-1 alone preferred in many patients; BRAF/MEK preferred for high tumor burden/symptomatic disease. Wolchok JD et al. N Engl J Med 2017.
COMBI-v / COMBI-d — Dabrafenib + Trametinib vs. BRAF inhibitor alone; OS 25.1 vs. 18.7 months (COMBI-v); FDA-approved. Robert C et al. N Engl J Med 2015.
Later-line: Encorafenib + Binimetinib (BEACON Melanoma); Vemurafenib + Cobimetinib (coBRIM)
Retreatment with ICIs possible after initial response followed by progression

Uveal Melanoma

Tebentafusp (IMCgp100) — HLA-A*0201 restricted GP100×CD3 bispecific; phase III trial: OS benefit vs. investigator's choice in previously untreated metastatic uveal melanoma; FDA-approved 2022

💡 Clinical Pearl: The treatment of metastatic melanoma has been revolutionized by immune checkpoint inhibitors (anti-PD-1 ± anti-CTLA-4) and BRAF/MEK inhibitors. For BRAF wild-type metastatic melanoma, anti-PD-1 monotherapy (nivolumab or pembrolizumab) is preferred for low tumor burden/asymptomatic patients; combination ipilimumab-nivolumab for high burden/symptomatic. For BRAF V600 mutant, BRAF/MEK inhibition provides rapid response in symptomatic patients; ICIs are also effective and can be sequenced. Always test for BRAF V600 before initiating targeted therapy.

📖 References & Guidelines

CheckMate 067 — Wolchok JD et al. N Engl J Med. 2017.
COMBI-AD — Dummer R et al. N Engl J Med. 2020.
KEYNOTE-716 — Luke JJ et al. Lancet. 2021.
NCCN Guidelines Melanoma Version 2.2024
ESMO Melanoma Consensus (2024)

▶8.2 Non-Melanoma Skin Cancers

Basal Cell Carcinoma (BCC)

Clinical variants: Nodular (most common), superficial, morpheaform (infiltrative/sclerosing — most aggressive), pigmented
Locally advanced/metastatic:
- Vismodegib — hedgehog pathway inhibitor (Smoothened); ERIVANCE BCC: ORR 30–60%; FDA-approved for LA/mets BCC
- Sonidegib — another SMO inhibitor; Basal Cell Cancer Outcomes with LDE225 Treatment (BOLT): ORR 47–60%; FDA-approved
Gorlin-Goltz syndrome (nevoid BCC syndrome) — PTCH1 mutation; hedgehog pathway hyperactivation; multiple BCCs; treated with vismodegib or sonidegib

Squamous Cell Carcinoma (SCC)

High-risk features: Size >2cm, ear/lip/perineum/nail unit, poor differentiation, invasion >4mm, perineural invasion (PNI), immunosuppression
Metastatic/Advanced:
- KEYNOTE-629 — Pembrolizumab in recurrent/metastatic cutaneous SCC; ORR 34%; FDA-approved. Gross ND et al. J Clin Oncol 2022.
- Cemiplimab — EMPOWER-CSCC 1: ORR 47% in metastatic CSCC; FDA-approved. Migden MR et al. Lancet Oncol 2020.
Surgery + RT ± chemo — standard curative approach for locally advanced

📖 References & Guidelines

EMPOWER-CSCC 1 — Migden MR et al. Lancet Oncol. 2020.
KEYNOTE-629 — Gross ND et al. J Clin Oncol. 2022.
NCCN Guidelines Basal Cell Skin Cancer Version 1.2024
NCCN Guidelines Squamous Cell Skin Cancer Version 1.2024

Section 9: Sarcoma & GIST

▶9.1 Soft Tissue Sarcoma (STS)

Histologic Subtypes & Grading

Major subtypes: Liposarcoma (well-differentiated, dedifferentiated, myxoid, pleomorphic), leiomyosarcoma, undifferentiated pleomorphic sarcoma (UPS/MPNST), synovial sarcoma, rhabdomyosarcoma (alveolar, embryonal), dermatofibrosarcoma protuberans (DFSP), GIST
FNCLCC Grading: Tubule formation + nuclear pleomorphism + mitoses → grade 1–3; low-grade (1–2) vs. high-grade (3); AJCC stage incorporates grade

Localized STS — Surgery ± RT ± Chemo

Surgery: Wide excision with R0 margins (1cm cuff); limb-sparing surgery + RT is equivalent to amputation with better function
RT: 50–66 Gy adjuvant or neoadjuvant; improves local control but no OS benefit; neoadjuvant may allow lower dose and better functional outcomes; RT for extremity/body wall STS
Chemotherapy:
- Benefit in extremity/body wall STS: ~18% absolute benefit in DFS (pooled analysis); doxorubicin ± ifosfamide; considered for high-grade, large (>5cm), deep tumors
- No clear benefit in retroperitoneal sarcoma (RPS), well-differentiated LPS, or low-grade tumors

Advanced/Metastatic STS

Doxorubicin — first-line standard; ORR 20–30%; 75 mg/m² q3 weeks
Ifosfamide — higher response rate than doxorubicin; used with doxorubicin (AIM) or as second-line; MESNA for hemorrhagic cystitis prophylaxis
Trabectedin (ET743) — marine-derived alkaloid; active in leiomyosarcoma, LPS, synovial sarcoma; L-SARCOME (EORTC 62992): OS benefit vs. dacarbazine in L-sarcoma; approved for 2nd+ line
Pazopanib — VEGFR TKI; VEGETABLE (PALETTE): pazopanib vs. placebo in non-adipogenic STS; PFS 4.6 vs. 1.8 months; OS not improved; FDA-approved for advanced STS after prior chemo
Eribulin — HALIS: eribulin vs. dacarbazine in leiomyosarcoma/LPS; OS benefit in leiomyosarcoma subgroup; approved
Gemcitabine + Docetaxel — active in LMS, UPS
Specific subtype-directed therapy:
- ALCL (anaplastic large cell lymphoma) — ALK inhibitors (crizotinib, alectinib)
- Dermatofibrosarcoma protuberans (DFSP) — imatinib (response rates ~80%)
- Solitary fibrous tumor / hemangiopericytoma: anti-VEGF therapy; temozolomide + bevacizumab

Desmoid (Aggressive Fibromatosis)

Non-metastasizing but locally aggressive; surgery NOT first-line unless symptomatic/worsening
Observation — 30% spontaneously regress; first-line in asymptomatic patients
NSAIDs: Sulindac, celecoxib
Hormonal therapy: Tamoxifen ± sulindac (combined)
Sorafenib — phase III data: improved ORR and PFS vs. placebo; FDA-approved for desmoid tumors

💡 Clinical Pearl: Retroperitoneal sarcoma (RPS) is a distinct entity — avoid pre-operative radiation (bowel toxicity) and routine adjuvant RT; well-differentiated LPS and dedifferentiated LPS (DDLPS) do not benefit from adjuvant RT. For desmoid tumors, non-operative management is preferred — observation, NSAIDs, hormonal therapy, or sorafenib. Surgery should be deferred unless there is rapid growth, functional impairment, or intractable pain.

📖 References & Guidelines

PALETTE — van der Graaf WTA et al. Lancet. 2012.
L-SARCOME — Fayette J et al. Lancet. 2017.
NCCN Guidelines Soft Tissue Sarcoma Version 2.2024
ESMO Soft Tissue Sarcoma Guidelines (2022)

▶9.2 Gastrointestinal Stromal Tumor (GIST)

Molecular Drivers

KIT (CD117): ~80% of GISTs; exon 11 (juxtamembrane) most common; exon 9 (extracellular), 13, 17 also seen
PDGFRA: ~10%; D842V mutation in exon 18 is imatinib-resistant
SDH-deficient: Succinate dehydrogenase (SDHB) loss; no KIT/PDGFRA mutation; often gastric, wild-type GIST; Carney triad (GIST + paraganglioma + pulmonary chondroma); Carney-Stratakis syndrome; no benefit from imatinib
NF1-associated: Neurofibromatosis type 1; multiple small bowel GISTs
BRAF, KRAS: Rare; NTRK fusion also reported

Treatment

Resectable: Surgery with R0 margins; imatinib 400 mg 1 year adjuvant for high-risk (ACOSOG Z9001, SSGXVIII/AIO — 3 years vs. 1 year: 3 years superior); neoadjuvant imatinib for borderline resectable (40–80% response, significant downstaging)
Metastatic:
- Imatinib 400 mg q12h — first-line; dose escalation to 800 mg if progression; KIT exon 9 mutant: higher starting dose (800 mg) recommended
- Sunitinib — SU11248: KIT exon 9 mutant and wild-type; approved 2nd-line
- Regorafenib — GRID: regorafenib vs. placebo 3rd-line; PFS 4.8 vs. 0.9 months; approved
- Ripretinib — QINRIK: ripretinib vs. placebo 4th-line; OS benefit; FDA-approved
- Avapritinib — VOYAGER: PDGFRA D842V mutant GIST; near-complete response rates; FDA-approved
SDH-deficient GIST: No benefit from imatinib; sunitinib and everolimus have limited activity; debulking surgery; PRRT with ¹⁷⁷Lu-DOTATATE considered

💡 Clinical Pearl: In GIST, PDGFRA D842V mutation (exon 18) is completely imatinib-resistant — these patients should receive avapritinib instead. SDH-deficient GISTs are also imatinib-resistant. KIT exon 9 mutations (common in small bowel GIST) benefit from higher-dose imatinib (800 mg) and respond better to sunitinib. Risk stratification using the AFIP/Miettinen criteria or NIH modified criteria determines which patients benefit from adjuvant imatinib.

📖 References & Guidelines

SSGXVIII/AIO — Joensuu H et al. JAMA. 2012.
GRID — Demetri GD et al. Lancet. 2013.
NCCN Guidelines GIST Version 1.2024
ESMO Sarcoma/GIST Guidelines (2022)

Section 10: Supportive Care, Toxicity & Survivorship

▶10.1 Chemotherapy Toxicity Management

Febrile Neutropenia (FN)

G-CSF prophylaxis: Primary (before first cycle) — indicated if >20% FN risk or >40% infection risk (MASCC score <21); secondary prophylaxis after prior FN
Neulasta (pegfilgrastim) — 6mg SC given 24h after chemo; preferred over daily filgrastim
Antibiotics: Fluoroquinolone (ciprofloxacin or levofloxacin) ± beta-lactam; inpatient vs. outpatient based on clinical status

Anthracycline Cardiotoxicity

Dexrazoxane — cardioprotectant (iron chelator); recommended when cumulative doxorubicin dose >250–300 mg/m² or epirubicin >600 mg/m²
Cumulative dose limits: Doxorubicin 450 mg/m²; epirubicin 900 mg/m²; liposomal doxorubicin reduces cardiotoxicity
LVEF monitoring: Baseline and at cumulative doses; hold if LVEF drops >10% from baseline or below 50%

Chemotherapy-Induced Peripheral Neuropathy (CIPN)

Oxaliplatin: Acute (cold-induced, perioral/digital paresthesias during infusion — prevent with calcium/magnesium infusions); chronic (cumulative dose-dependent sensory neuropathy)
Cisplatin: Dose-dependent; affects proprioception and vibration sense; can be permanent
Taxanes: Sensory > motor; stocking-glove distribution; grade 2+ often requires dose reduction
Duloxetine — only agent with randomized data showing benefit for painful CIPN; 30–60 mg/day

Nausea & Vomiting (CINV)

Prophylaxis: 5-HT3 RA (ondansetron, palonosetron) + dexamethasone + NK1 RA (aprepitant, fosaprepitant, rolapitant) for highly emetogenic chemo (cisplatin, anthracycline+cyclophosphamide, etc.)
Olanzapine — FDA-approved 2016 for CINV; multi-receptor antagonist; effective for breakthrough nausea; 2.5–10mg at night; causes sedation
Medical cannabis: Nabilone, dronabinol — approved for refractory CINV

Irinotecan Toxicities

Cholinergic syndrome (acute): Diarrhea, cramping, salivation — treat with Atropine 0.5–1mg SC/IV
Delayed diarrhea: Loperamide 4mg initially then 2mg q2h; UGT1A1 polymorphism (Gilbert syndrome) — increased risk; Neostigmine for refractory cases

Extravasation

Vesicants: Doxorubicin (anthracyclines) — cold compress, dexrazoxane; Vinca alkaloids — warm compress; taxanes — cold compress

📖 References & Guidelines

ASCO Guidelines on CINV (2023)
NCCN Guidelines — Antiemesis Version 2.2024
MASCC/ESMO Febrile Neutropenia Guidelines (2022)

▶10.2 Cancer Immunotherapy Toxicity (irAEs)

General Principles

Any organ can be affected; onset typically weeks to months after ICPI initiation
CTLA-4 inhibitors (ipilimumab) — earlier onset, more severe GI and dermatologic irAEs
PD-1/PD-L1 inhibitors — pneumonitis, thyroid, neurologic more common
Combination ICPI (PD-1 + CTLA-4) — higher incidence and severity of all irAEs

Management Algorithm

Grade 1: Hold ICPI (permanent for ipilimumab); monitor; symptomatic treatment
Grade 2: Hold ICPI; start prednisone 0.5–1 mg/kg/day; resume when ≤grade 1
Grade 3–4: Permanently discontinue ICPI; high-dose corticosteroids (prednisone 1–2 mg/kg/day or methylprednisone 1–2 mg/kg/day); consider infliximab 5 mg/kg (colitis, hepatitis), mycophenolate (hepatitis), plasmapheresis (neurologic)

Specific irAE Management

Pneumonitis: Grade 2 — hold ICPI, prednisone 1–2 mg/kg; grade 3–4 — permanently discontinue, high-dose steroids, consider infliximab
Colitis: Grade 2 — budesonide or prednisone; grade 3–4 — permanently discontinue, high-dose steroids, infliximab if no improvement in 48–72h; avoid anti-diarrheals before colonoscopy
Hepatitis: AST/ALT >3× ULN (grade 2) — hold ICPI; >5× ULN (grade 3) — permanently discontinue, prednisone 1–2 mg/kg; mycophenolate if refractory
Myocarditis: High mortality (up to 50%); grade 1 — hold ICPI; grade 2–4 — permanently discontinue, methylpred + mycophenolate; avoid infliximab (hepatotoxicity)
Neuro (myasthenia gravis): Hold ICPI; plasmapheresis + high-dose steroids; permanent discontinuation usually required
Type 1 DM: New-onset insulin-dependent; permanent discontinuation usually required

📖 References & Guidelines

ASCO Guidelines on Management of irAEs from ICIs (2023)
NCCN Guidelines — Management of Immunotherapy-Related Toxicity Version 2.2024
ESMO irAE Management Consensus (2022)

▶10.3 Cancer Pain Management

WHO Analgesic Ladder

Step 1: Non-opioid (acetaminophen, NSAIDs) ± adjuvant
Step 2: Mild opioid (codeine, tramadol) ± non-opioid ± adjuvant
Step 3: Strong opioid (morphine, oxycodone, hydromorphone, fentanyl) ± non-opioid ± adjuvant

Opioid Selection & Dosing

Morphine: Standard starting dose — IR 15mg q4h PRN or SR 30mg q12h; breakthrough dose = total daily dose ÷ 6
Opioid rotation: When opioid switching, calculate equianalgesic dose and reduce by 25% (cross-tolerance incomplete)
Opioid-induced constipation (OIC): Prophylactic bowel regimen; methylnaltrexone or naloxegol for refractory

Bone Metastases Pain

Denosumab — RANKL inhibitor; superior to zoledronic acid for preventing skeletal-related events; 120mg SC monthly
Bisphosphonates: Zoledronic acid, pamidronate — prevent SREs
Radiopharmaceuticals: Strontium-89, samarium-153; Radium-223 (alpharadin) — specifically for mCRPC bone mets with OS benefit
Steroids: Dexamethasone 4–8mg q6–12h for rapid pain relief in bone metastases

Neuropathic Pain

Gabapentin, Pregabalin — first-line; titrate to effect
Duloxetine — also effective for CIPN and diabetic neuropathy
TCAs: Amitriptyline, nortriptyline — useful but anticholinergic side effects limit use in elderly

📖 References & Guidelines

NCCN Guidelines — Adult Cancer Pain Version 2.2024
WHO Cancer Pain Ladder (2018 revision)

▶10.4 Oncologic Emergencies

Malignant Spinal Cord Compression (MSCC)

Urgent MRI whole spine — gold standard; do not delay
Dexamethasone: 10mg IV bolus immediately, then 4mg q6h; high-dose (16mg) preferred in severe cases
Surgery: Indicated for radiographically confirmed MSCC with: spinal instability, compressed vertebra collapse >50%, Bilsky grade 3 (complete) compression, disease progression during or after RT, and ability to survive >3 months; decompressive surgery + RT superior to RT alone in selected patients (Patchell 2005)
RT alone: Poor surgical candidates; 30 Gy in 10 fractions or 20 Gy in 5 fractions

Brain Metastases

Dexamethasone 4mg q6h for symptomatic edema; PPI for prophylaxis
SRS vs. WBRT: SRS (stereotactic radiosurgery) preferred for ≤3–4 lesions, <3cm; preserves cognition; improved QoL; SRT (fractionated stereotactic) for larger lesions near eloquent cortex
Hippocampal avoidance WBRT + memantine (NRG CC001): better cognitive outcomes than standard WBRT
Leptomeningeal disease: Intrathecal chemo (MTX, thiotepa, cytarabine) limited by poor CNS penetration; systemic therapy (RT + systemic agents); IT trastuzumab for HER2+ breast cancer; novel approaches emerging

Hypercalcemia of Malignancy

Hydration (NS 200–500ml/h) — first step; loop diuretics only after hydration achieved
Zoledronic acid 4mg IV or Pamidronate 60–90mg IV — inhibit osteoclast activity; effect in 2–4 days; duration weeks–months
Denosumab 120mg SC — preferred if renal impairment; faster onset than bisphosphonates
Calcitonin — rapid onset (hours) but tachyphylaxis; bridge therapy while waiting for bisphosphonate

Tumor Lysis Syndrome (TLS)

Prophylaxis: Aggressive hydration, allopurinol (xanthine oxidase inhibitor), rasburicase (recombinant urate oxidase) for high-risk patients (uric acid >450 μmol/L)
High-risk: Acute leukemia (especially ALL with high WBC), high-grade NHL (Burkitt, lymphoblastic), bulky masses, pre-existing hyperuricemia, renal dysfunction
Monitoring: K, phosphate, calcium, uric acid, LDH every 6–8h × 24–48h

Superior Vena Cava Syndrome (SVCS)

Mediastinal mass; lung cancer (especially SCLC), lymphoma, germ cell tumors
Urgent intervention: Corticosteroids (dexamethasone 10–16mg q6–12h); endovascular stenting; RT (for radiosensitive tumors: lymphoma, SCLC); chemotherapy (lymphoma, SCLC)

📖 References & Guidelines

Patchell — Patchell RA et al. Direct decompressive surgical resection in treatment of spinal cord compression. Lancet. 2005.
NCCN Guidelines — Central Nervous System Cancers Version 2.2024
NCCN Guidelines — Survivorship Version 3.2024

Section 11: Cancer Screening & Prevention

▶11.1 Major Cancer Screening Guidelines

Cancer	Screening Modality	Target Population	Key Trials/Guidelines
Breast	Mammography	USPSTF: 40–75 (biennial to 75); ACS: 45–54 annual, ≥50 biennial; BRCA carriers: annual MRI+ mammo	USPSTF 2021, ACS 2023
Colorectal	Colonoscopy q10yr, FIT annual, flex sig + FIT, capsule colonoscopy	Age 45–75 (updated USPSTF 2021); Lynch: start 20–25 or 2–5yr before earliest family case	USPSTF 2021, ACS 2023
Cervical	Co-test (cytology + HPV) q5yr age 30–65; cytology alone q3yr age 21–29	Age 21+; HPV vaccination reduces but doesn't eliminate risk	USPSTF 2024, ASCCP
Lung	Low-dose CT annual	Age 50–80, ≥20 pack-year history, current/quit <15yr	USPSTF 2021; NELSON trial (Europe)
Prostate	PSA ± DRE, shared decision-making	Age 55–69; earlier (40–45) for high-risk (AA, family history, BRCA1/2)	USPSTF 2018
Gastric	H. pylori eradication + endoscopic surveillance (high-risk)	Japan, Korea guidelines; high-prevalence areas	JGCA, Korean guidelines
Liver	US ± AFP q6 months	Cirrhosis, chronic HBV, chronic HCV	AASLD 2022

Thailand-Specific Considerations

Cholangiocarcinoma: Elevated in Northeastern Thailand (Khon Kaen region) due to liver fluke (Opisthorchis viverrini) and bile duct stones; surveillance with US ± CA 19-9 in known biliary disease
Nasopharyngeal carcinoma: Endemic in Southern Thailand; EBV serology (VCA IgA, EA IgA) used in screening in high-risk areas
Betel quid + tobacco oral cancer: Visual oral examination in high-risk populations with betel chewing habit

📖 References & Guidelines

USPSTF Cancer Screening Recommendations (2021–2024)
American Cancer Society Screening Guidelines 2024
Thai National Cancer Prevention and Control Plan 2024

▶11.2 Hereditary Cancer Syndromes

Syndrome	Gene(s)	Cancers	Surveillance
Hereditary Breast & Ovarian Cancer (HBOC)	BRCA1, BRCA2	Breast (M>F), ovarian, prostate, pancreatic	Mammo/MRI annual from 30; risk-reducing mastectomy/oophorectomy considered
Lynch Syndrome (HNPCC)	MLH1, MSH2, MSH6, PMS2	CRC, endometrial, ovarian, gastric, urinary tract	Colonoscopy 1–2yr from 20–25; endometrial sampling; risk-reducing hysterectomy ± oophorectomy
FAP / Attenuated FAP	APC	Colorectal (100s of polyps → carcinoma)	Annual colonoscopy from puberty; prophylactic colectomy when polyps too numerous to manage
Li-Fraumeni	TP53	Soft tissue sarcoma, osteosarcoma, breast, brain, adrenocortical, multiple primaries	Whole-body MRI; breast MRI annual from 20; limited efficacy
Peutz-Jeghers	STK11	GI polyps, breast, pancreatic, ovarian (sex cord tumor with annular tubules)	Upper endoscopy, colonoscopy, pancreatic cancer screening (MRI/EUS)
PTEN Hamartoma (Cowden)	PTEN	Breast, thyroid, endometrial, renal	Breast annual mammo/MRI from 30; thyroid US annual
MUTYH-Associated Polyposis	MUTYH (biallelic)	Colorectal (10–100+ adenomas)	Colonoscopy; prophylactic colectomy when indicated
SDH-Associated	SDHB/C/D	Pheochromocytoma/paraganglioma, GIST, renal cell carcinoma	Annual plasma metanephrines, annual renal imaging

💡 Clinical Pearl: Genetic testing for hereditary cancer syndromes should be offered to patients with: (1) early-onset cancer (<50 years), (2) multiple primary cancers, (3) rare cancer types, (4) cancer associated with known syndromes (e.g., endometrial + colorectal = Lynch), (5) strong family history (≥2 first-degree relatives with same/related cancers), or (6) specific ancestry with high carrier rates (e.g., Ashkenazi Jewish heritage for BRCA1/2). Pre-test and post-test genetic counseling is recommended.

📖 References & Guidelines

NCCN Genetic/Familial High-Risk Assessment Version 2.2024
ACMG Secondary Findings v3.1 (2023)

▶11.3 Chemoprevention

Breast cancer prevention:
- Tamoxifen, Raloxifene — SERMs; reduce ER+ breast cancer incidence by 50–65% in high-risk women; STAR trial showed comparable efficacy between tamoxifen and raloxifene with different side effect profiles. Tamoxifen increases endometrial cancer risk; raloxifene does not.
- Aromatase inhibitors (exemestane, anastrozole) — MAP.3 (exemestane) and IBIS-II (anastrozole) showed ~65% reduction in ER+ breast cancer; approved for postmenopausal high-risk women
Cervical cancer prevention: HPV vaccination — Gardasil 9 prevents ~90% of HPV-related cancers; most effective when given before sexual debut
Colorectal cancer prevention: Aspirin — CAPP2 (Lynch syndrome): 600mg aspirin daily reduced CRC incidence at 10+ years; JAVA trial in sporadic adenoma; NSAIDs (celecoxib, sulindac) — adenoma regression in FAP; aspirin 81–325mg may be recommended for average-risk individuals after discussion of risks/benefits
HCC prevention: Antiviral therapy for HBV (tenofovir, entecavir) and HCV (DAA — sofosbuvir/ledipasvir, glecaprevir/pibrentasvir) — reduces risk of cirrhosis and HCC; coffee consumption shows inverse association with HCC risk in multiple cohort studies
Prostate cancer prevention: 5-alpha reductase inhibitors (finasteride, dutasteride) — reduce PSA by ~50% and PCa incidence by ~25%; Gleason 7+ risk slightly increased (controversial); not widely adopted for chemoprevention due to sexual side effects and concern about higher-grade disease

📖 References & Guidelines

STAR Trial — Vogel VG et al. JAMA. 2006.
MAP.3 — Goss PE et al. N Engl J Med. 2011.
CAPP2 — Burn J et al. Lancet. 2011.
ACS Cancer Prevention Guidelines 2024
USPSTF Chemoprevention Recommendations (2024)