Treatment Algorithms

First-line driver-directed therapy by mutation (EGFR, ALK, ROS1, BRAF, MET, RET, NTRK, KRAS G12C, HER2).

Confirmed EGFR mutation → first-line by subtype, sequenced through later lines.

First-line by PD-L1 and histology → progression → second- and third-line options.

Extensive/limited-stage first-line → progression → later lines by performance status.

Neoadjuvant, adjuvant, and unresectable stage III pathways by stage and driver (CheckMate 816, KEYNOTE-671, IMpower010, ADAURA, ALINA, PACIFIC).

First-line CNS-penetrant ALK TKIs (lorlatinib, alectinib, brigatinib), then later-line options.

Multimodality therapy: early concurrent chemoRT, consolidation durvalumab (ADRIATIC), and PCI vs MRI surveillance.

By size/nodal status → surgery and (neo)adjuvant pembrolizumab-based therapy (KEYNOTE-522).

First-line by PD-L1 and gBRCA → later-line antibody-drug conjugates by HER2 status.

By size/nodal status → (neo)adjuvant trastuzumab/pertuzumab; T-DM1 for residual disease.

By CNS involvement → sequential anti-HER2 lines (THP, T-DXd, tucatinib).

By nodal status and recurrence score → chemo/endocrine therapy and adjuvant escalation.

Endocrine-sensitive vs resistant → targeted therapy by mutation → ADCs by HER2 status.

By T/N stage → surgery vs RT; neoadjuvant/adjuvant pembrolizumab (KEYNOTE-689) for resectable LA; adjuvant by pathologic risk.

Favorable-prognosis HPV+ disease by stage → surgery vs definitive chemoRT; adjuvant by pathologic risk.

HPV-negative disease by T/N stage; neoadjuvant/adjuvant pembrolizumab (KEYNOTE-689) for resectable LA.

By T/N stage → larynx preservation vs surgery; neoadjuvant/adjuvant pembrolizumab (KEYNOTE-689); adjuvant by risk.

First-line by PD-L1 CPS (KEYNOTE-048), later lines, and biomarker-selected options.

Radiation-based primary therapy by stage; chemo-immunotherapy for recurrent/metastatic disease.

Biomarker-directed therapy (AR, HER2, NTRK, RET, BRAF), chemotherapy, and ACC-specific options.

By biomarker (MMR/MSI, RAS, BRAF, HER2, KRAS G12C) and tumor sidedness → first-line and biomarker-agnostic later lines.

First-line by HER2, PD-L1 CPS, MSI and CLDN18.2 → second- and third-line options.

Localized multimodality therapy; advanced disease split by histology (adenocarcinoma vs squamous) and biomarkers.

Resectable/adjuvant, metastatic by performance status, germline/biomarker-directed therapy, and second-line.

Child-Pugh A → immunotherapy-based first-line, then second-line TKIs and antiangiogenics.

Chemo-immunotherapy backbone plus molecularly targeted options (FGFR2, IDH1, HER2, BRAF) and second-line chemo.

Organ-preserving definitive chemoradiation for localized disease; chemo-immunotherapy for advanced disease.

Mutation-driven therapy (KIT, PDGFRA D842V, SDH-deficient), sequential TKI lines, and adjuvant imatinib.

Somatostatin analogs and PRRT for well-differentiated SSTR+ disease; targeted/chemo on progression; platinum-etoposide for high-grade NEC.

By disease state (mHSPC, nmCRPC, mCRPC) with biomarker-directed options (PARP inhibitors, 177Lu-PSMA, MSI).

First-line antibody-drug conjugate + immunotherapy or platinum chemo with maintenance avelumab; later lines including FGFR-directed therapy.

Clear-cell RCC first-line by IMDC risk (IO+TKI or IO+IO), later-line TKIs and belzutifan; non-clear-cell options.

Post-orchiectomy management by histology, stage, and IGCCCG risk, plus salvage therapy for relapse.

Risk-stratified intravesical therapy and BCG-unresponsive options (pembrolizumab, gene therapy, cystectomy).

Neoadjuvant cisplatin chemo, perioperative durvalumab (NIAGARA), adjuvant nivolumab (CheckMate 274), and bladder preservation.

Risk-stratified local therapy and ADT duration; abiraterone for high-risk disease (STAMPEDE).

Frontline cytoreduction + chemotherapy, maintenance by BRCA/HRD status, and recurrence by platinum sensitivity.

First-line chemo-immunotherapy by MMR status, then later-line targeted and checkpoint options.

Cisplatin-based chemoradiation for locally advanced disease; chemo-immunotherapy then antibody-drug conjugate for advanced/recurrent disease.

Adjuvant/neoadjuvant therapy for resected high-risk disease, first-line immunotherapy for metastatic disease, BRAF-targeted options, and later-line TIL therapy.

Advanced Merkel cell carcinoma, cutaneous squamous cell carcinoma, and basal cell carcinoma → immunotherapy and hedgehog-pathway inhibition.

Maximal safe resection then chemoradiation (Stupp) with adjuvant temozolomide ± tumor-treating fields; age-adapted regimens and recurrence options.

Anthracycline-based first-line therapy, histology-directed chemotherapy, and subtype-specific targeted options.

By type — RAI-refractory differentiated, medullary, and anaplastic — with antiangiogenic and mutation-directed therapy.

Thymoma and thymic carcinoma by stage: resection, multimodality therapy, and systemic options (avoid PD-1 in thymoma).

Osteosarcoma (MAP), Ewing sarcoma (VDC/IE), and chondrosarcoma (surgery); relapsed options including regorafenib.

Localized resection ± RT; advanced first-line taxane/anthracycline and later-line pazopanib or checkpoint inhibition.

Grade-based management of checkpoint-inhibitor toxicity, steroid-refractory escalation, and special cases (myocarditis, endocrine).

First-line steroids/IVIG, second-line TPO-RA/rituximab/fostamatinib, refractory splenectomy.

Plasma exchange + steroids + caplacizumab (HERCULES); rituximab and relapse prevention.

Stop heparin, start a non-heparin anticoagulant (argatroban), transition after recovery.

Corticosteroids ± rituximab, then splenectomy and immunosuppressants.

Identify the source, oral iron first-line, IV iron for intolerance/malabsorption/CKD.

Allogeneic HSCT for young matched-donor patients; ATG + cyclosporine + eltrombopag otherwise.

Hydroxyurea foundation; crizanlizumab/voxelotor add-ons; transplant or gene therapy for cure.

Factor replacement / emicizumab prophylaxis (HAVEN); bypassing agents and ITI for inhibitors.

Desmopressin for type 1; VWF concentrate for type 2/3; tranexamic acid adjunct.

DOAC first-line (AMPLIFY/EINSTEIN); cancer-associated and special-situation choices; duration.

By fitness and genetics — APL, intensive induction with mutation-directed additions, lower-intensity therapy, and post-remission/relapse options.

By Philadelphia-chromosome status and lineage, with MRD-directed intensification and relapsed/refractory immunotherapy.

Frontline by del(17p)/TP53 status (continuous BTK inhibitor vs fixed-duration venetoclax-obinutuzumab), then relapsed options.

By phase → frontline TKI selection by risk, management of resistance (including T315I), and advanced-phase therapy.

Purine analog ± rituximab first-line; vemurafenib (BRAF) and moxetumomab for relapse.

Combined-modality early-stage therapy, novel-agent advanced-stage regimens, and relapsed/refractory options.

Frontline immunochemotherapy, then relapsed/refractory therapy by transplant eligibility including CD19 CAR-T and bispecifics.

Observation for low burden, immunochemotherapy for high tumor burden, and relapsed options including CAR-T and bispecifics.

Frontline by fitness (intensive + ASCT vs bendamustine-rituximab), and relapsed/refractory BTK-inhibitor and CAR-T options.

HD-methotrexate induction (MATRix), autologous HSCT or WBRT consolidation, relapse options.

CHOP/CHOEP or brentuximab+CHP (ECHELON-2), autologous HSCT, then HDACi/pralatrexate.

Plasmapheresis for hyperviscosity; BTKi (ASPEN) or bendamustine-rituximab; relapse options.

Frontline by transplant eligibility (quadruplet induction ± ASCT), then relapsed/refractory therapy including BCMA CAR-T and bispecifics.

Monoclonal gammopathy work-up and risk-adapted follow-up; IgM MGUS surveillance.

Risk-adapted observation vs early therapy for high-risk (20/2/20) disease (E3A06, AQUILA).

Daratumumab-based therapy (ANDROMEDA), transplant in selected patients, and relapsed options.

Stratified by IPSS-R risk → supportive/disease-modifying therapy for lower-risk disease, hypomethylating agents/transplant for higher-risk.

Ph-negative MPNs (polycythemia vera, essential thrombocythemia, myelofibrosis) → risk-adapted cytoreduction, JAK inhibitors, and transplant.