Principles of CancerTreatment¶

Chapter 78 | Part 4: Oncology and Hematology · Part 4 – Oncology: Solid Tumors · Chapter 78

Key Clinical Points¶

Cancer is defined as uncontrolled cellular proliferation with potential for metastasis.
Tumor growth follows a Gompertzian curve, where the highest growth rate occurs before the tumor is clinically detectable.
Treatment goals vary from curative (e.g., R0 resection) to palliation (symptom management and quality of life).
Radiation doses are standardized: 1 Gy = 100 cGy = 100 ergs/g tissue.
Systemic therapies include chemotherapy, molecular targeted agents, and immunotherapies (e.g., checkpoint inhibitors, CAR-T cells).
RECIST criteria define a partial response as ≥30% reduction in target lesion size.
Molecular profiling is essential for tailoring treatment (e.g., EGFR/ALK in lung cancer, BRCA1/2 in breast cancer).
Sentinel node biopsy reduces lymphedema risk compared to full lymphadenectomy while providing staging information.
Clinical trials progress through Phase I (safety), Phase II (efficacy), and Phase III (comparative effectiveness).
G-CSF and GM-CSF are primarily used for the prevention of febrile neutropenia in high-risk patients.

1. DEFINITION & OVERVIEW¶

• Definition (Harrison's 22e): Cancer is a group of diseases characterized by uncontrolled cell growth and potential for metastasis.

• Key Features: ◦ Leukemia: Presents as disseminated disease without solid tumor masses. ◦ Manifestations: Often presents as organ dysfunction (e.g., anemia, jaundice) or paraneoplastic syndromes (e.g., SIADH, hypercalcemia). ◦ Diagnostic Modalities: Physical exam, imaging (MRI/CT), and endoscopy.

1.1 Treatment Goals¶

• Curative Intent: Eradication of cancer. ◦ R0 resection: Defined as complete tumor removal with clear margins. • Palliation: Symptom control and quality-of-life preservation in advanced disease. • Multimodal Approach: Combination of local (surgery, radiation) and systemic (chemotherapy, targeted agents, immunotherapy) treatments improves outcomes.

2. ETIOLOGY & PATHOPHYSIOLOGY¶

• Tumor Growth Dynamics (Gompertzian Curve): ◦ Growth Fraction: Declines exponentially as tumor burden increases. ◦ Growth Rate: Peaks at the 1/e point (≈37% of maximum size). ◦ Clinical Thresholds: → Detected at 10^9 cells (1 cm³) → Lethal at 10^12 cells (1 kg) ◦ Key Insight: The highest growth rate occurs well before the tumor is clinically detectable. • Drivers of Progression: ◦ Angiogenesis, immune evasion, and stromal interactions. ◦ Metastasis via circulating tumor cells from primary or secondary sites.

3.2 Immunotherapy & Vaccines¶

• Approved Vaccines: ◦ BCG (bladder) ◦ sipuleucel-T (prostate) ◦ talimogene laherparepvec (melanoma) • Challenges: Balancing antitumor immunity with autoimmune toxicity.

4. CLINICAL PRESENTATION¶

• Local Symptoms: Masses (breast, lymph nodes), organ dysfunction (e.g., dyspnea from lung cancer, jaundice from bile duct obstruction). ◦ Systemic Manifestations: Paraneoplastic syndromes (SIADH, hypercalcemia) and constitutional symptoms (weight loss, fatigue). ◦ Diagnostic Clues: Physical exam findings, imaging abnormalities, and endoscopic visualization.

5. DIFFERENTIAL DIAGNOSIS¶

• Core Considerations: ◦ Distinguish paraneoplastic syndromes from primary disease manifestations. ◦ Identify patterns of growth (mass vs. diffuse infiltration). ◦ Utilize biomarker profiles (e.g., PSA elevation in prostate cancer).

6. INVESTIGATIONS & DIAGNOSIS¶

• Diagnostic Approach: 1. Biopsy Selection: Excisional > incisional > core-needle > fine-needle aspiration. 2. Molecular Profiling (Table 78-2): ◦ All solid tumors: TMB, MSI, DNA repair pathway status. ◦ Breast cancer: BRCA1/2, ER/PR/HER2, PI3K mutations. ◦ Lung cancer: EGFR, ALK, ROS1, NTRK, NRG1, PD-L1 expression. ◦ Colon cancer: KRAS, BRAF V600E mutations. ◦ Gliomas: 1p/19q co-deletion, IDH1/2 mutations. ◦ Leukemia: Cytogenetics, FLT3, NPM1 mutations. 3. Staging (TNM System): ◦ T: Primary tumor size/invasion. ◦ N: Lymph node involvement. ◦ M: Metastasis presence. ◦ Note: TNM is not used for leukemia or CNS tumors (where resection feasibility > TNM).

6.1 Staging Details¶

• Standard: Stage I–IV classifications correlate with survival outcomes. ◦ Exceptions: → Leukemia: No localized staging. → CNS tumors: Resection feasibility is the primary consideration.

7. MANAGEMENT & TREATMENT¶

Surgical Principles: ◦ R0 resection (clear margins) is curative. ◦ Sentinel node biopsy: Reduces lymphedema risk vs. full lymphadenectomy while providing staging. ◦ Neoadjuvant therapy: Used for bulky disease to improve local and systemic results.
Radiation Therapy: ◦ Dose quantification: 1 Gy = 100 cGy = 100 ergs/g tissue. ◦ Toxicity: Acute (mucositis, dermatitis) vs. Late effects (fibrosis, secondary malignancies).
Systemic Therapies: ◦ Chemotherapy: Cytotoxic agents (e.g., Platinum-based for ovarian cancer, Anthracyclines for breast cancer). ◦ Targeted Therapy: EGFR inhibitors, BRAF inhibitors, Trastuzumab (HER2+), Imatinib (CML). ◦ Immunotherapy: Checkpoint inhibitors (anti-PD-1, anti-CTLA4), CAR-T cells.
Clinical Trial Progression: ◦ Phase I: Safety and dose-finding. ◦ Phase II: Efficacy in specific tumor types. ◦ Phase III: Comparative effectiveness studies.

7.2 Systemic Cancer Therapy (Table 78-5 & 78-6)¶

• Chemotherapy Agents: ◦ Bleomycin: Monitor DLCO before/during treatment due to pulmonary toxicity. ◦ Doxorubicin: Risk of cardiotoxicity (↓LVEF). ◦ Ifosfamide: Must use concomitant mesna to protect bladder. ◦ Irinotecan: Dose may depend on UGT1A1 genotype; manage diarrhea with loperamide. • Antibody-Drug Conjugates (ADCs): ◦ Gemtuzumab ozogamicin: Target CD33 (AML). ◦ Inotuzumab ozogamicin: Target CD22 (Pre-B ALL). ◦ Loncastuximab tesirine-lpyl: Target CD19 (DLBCL). ◦ Sacituzumab govitecan: Target Trop2 (Triple-negative BC, Urothelial cancer).

7.3 Molecularly Targeted Agents (Table 78-7)¶

• Nirogacestat: Targets γ-secretase to inhibit Notch signaling in desmoid tumors. ◦ Sonidegib/Vismodegib: Target SMO receptor in basal cell carcinoma. ◦ Tretinoin: Target PML-RARα in acute promyelocytic leukemia (APML). ◦ Everolimus: mTOR inhibitor for RCC and other malignancies. ◦ Enasidenib/Ivosidenib: IDH inhibitors for AML and other myeloid disorders.

7.4 G-CSF / GM-CSF (Table 78-8)¶

• Preventive Use: ◦ Indicated if probability of febrile neutropenia is ≥20%. ◦ Used for patients with pre-existing neutropenia, age >65, or poor performance status. ◦ Dose: G-CSF 5 mg/kg per day; GM-CSF 250 mg/m^2 per day. • Therapeutic Use: ◦ For febrile neutropenic patients (no evidence of benefit for other indications). ◦ Used in bone marrow or peripheral blood stem cell transplantation to mobilize cells.

8. PROGNOSIS & COMPLICATIONS¶

• Prognostic Factors: Stage at diagnosis, molecular markers, performance status. ◦ Treatment-related complications: ◦ Chemotherapy: Myelosuppression, neuropathy. ◦ Radiation: Acute toxicity (dermatitis), late effects (fibrosis, secondary malignancies). ◦ Immunotherapy: Immune-related adverse events (pneumonitis, colitis).

Clinical Impact of Chemotherapy (Table 78-3)¶

• Curable: AML, Hodgkin's disease, Germ cell neoplasms. ◦ Palliation Only: Bladder carcinoma, CML, Hairy cell leukemia, Gastric carcinoma, Cervix carcinoma.

9. SPECIAL CONSIDERATIONS¶

• Geriatric Oncology: Comorbidities influence treatment selection. ◦ Palliative Care: Early referral improves quality of life. ◦ Genetic Counseling: Required for hereditary cancer syndromes (e.g., BRCA1/2).

10. KEY PEARLS & CLINICAL TRAPS¶

• Pearls: ◦ Sentinel node biopsy avoids lymphedema risks while providing staging. ◦ RECIST criteria define response thresholds precisely (≥30% reduction = Partial Response). ◦ Neoadjuvant therapy may enable curative surgery in bulky disease.

• Traps: ◦ Fine-needle aspiration cannot confirm tumor absence. ◦ TNM staging is irrelevant for leukemia or CNS tumors. ◦ Immunotherapy requires careful monitoring for autoimmune toxicity.

Reference Tables¶

Harrison's 22e, p.552

Asymptomatic patient screening (breast, cervix, colon, some lung)
Consideration of cancer in a differential diagnosis
Physical examination, imaging, or endoscopy to define a possible tumor
Phlebotomy for molecular studies and circulating tumor cell characterization
Diagnosis of cancer by biopsy or removal:
Routine histology
Specialized histology: immunohistochemistry
Molecular studies
Cytogenetic studies
Staging the cancer: Where has it spread?
Imaging (computed tomography, magnetic resonance imaging, positron emission
tomography)
Treatment
Localized (surgical removal with or without local radiation therapy and/or
topical therapy; may be curative)
Local plus systemic, multimodality: cure advanced disease, reverse organ
compromise
Systemic, adjuvant (cure micrometastases; all evident disease has been
locally treated)
Systemic, neoadjuvant (before local therapy to improve local and systemic
results)
Systemic, palliative (improve symptoms, quality of life, progression-free
survival)
Supportive care
During treatment: related to tumor effects on patient
During treatment: to counteract side effects of treatment
After treatment: to ameliorate the adverse effects of treatment
Palliative and end of life
When useful treatments are not feasible or desired

TABLE 78-2 Diagnostic Biopsy: Standard-of-Care Molecular and Special Studies to Be Considered

All solid tumors
Tumor mutational burden
Microsatellite instability DNA repair pathway intactness
Homologous recombination DNA repair pathway intactness
Breast cancer: primary and suspected metastatic
Breast cancer susceptibility 1 and 2 (BRCA1/2) gene mutations
Hormone receptor expression: estrogen, progesterone
HER2/neu oncoprotein
PI3KA mutation status
Lung cancer: primary and suspected metastatic
If nonsquamous non-small-cell:
Epidermal growth factor receptor (EGFR) mutation
ALK, ROS1, NRTK, NRG1 gene fusion
BRAF V600E mutation
Programmed cell death ligand 1 (PD-L1) expression
Colon cancer: suspected metastatic
KRAS mutation
BRAF V600E mutation
Gastrointestinal stromal tumor
KIT mutation
Melanoma
BRAF mutation
c-kit expression and KIT mutation if present
Pancreatic cancer
BRCA1/2 mutation
Prostate cancer
BRCA1/2 mutation
Thyroid cancer
RET gene alterations (mutations, translocations, amplification)
Gliomas
1p/19q co-deletion
Alkylguanine alkyltransferase promoter methylation
Isocitrate dehydrogenase 1 and 2 mutation
Leukemia (peripheral blood mononuclear cells and/or bone marrow)
Cytogenetics
Flow cytometry
Treatment-defining chromosomal translocations/mutations
Bcr-Abl fusion protein
t(15;17)
Inversion 16
t(8;21)
FMS-associated tyrosine kinase (FLT3) mutation
Nucleophosmin gene mutational status
Isocitrate dehydrogenase 1 and 2 mutation
Lymphoma
Immunohistochemistry for CD20, CD30, and B- and T-cell markers
Treatment-defining chromosomal translocations:
t(14;18)
t(8;14)
Translocations involving ALK gene

TABLE 78-3 Clinical Impact on Cancers with Cytotoxic Chemotherapy A. A dvanced Cancers with Possible Acute lymphoid and…¶

Harrison's 22e, p.558

A. A dvanced Cancers with Possible
Cure
Acute lymphoid and acute myeloid
leukemia (pediatric/adult)
Hodgkin’s disease (pediatric/adult)
Lymphomas—certain types (pediatric/
adult)
Germ cell neoplasms
Embryonal carcinoma
Teratocarcinoma
Seminoma or dysgerminoma
Choriocarcinoma
Gestational trophoblastic neoplasia
Pediatric neoplasms
Wilms’ tumor
Embryonal rhabdomyosarcoma
Ewing’s sarcoma
Peripheral neuroepithelioma
Neuroblastoma
Small-cell lung carcinoma
Ovarian carcinoma
B. A dvanced Cancers Possibly Cured by
Chemotherapy, Radiation, ± Surgery
Squamous carcinoma (head and neck)
Squamous carcinoma (anus)
Bladder carcinoma
Breast carcinoma
Carcinoma of the uterine cervix
Esophageal carcinoma
Non-small-cell lung carcinoma (stage III)
Small-cell lung carcinoma
C. Cancers Possibly Cured with
Chemotherapy as Adjuvant to Surgery
Breast carcinoma
Colorectal carcinomaa
Osteogenic sarcoma
Soft tissue sarcoma

D. Cancers Possibly Cured with
High-Dose Chemotherapy with
Stem Cell Support
Relapsed leukemias, lymphoid and
myeloid
Relapsed lymphomas, Hodgkin’s and
non-Hodgkin’s
Chronic myeloid leukemia
Multiple myeloma
E. Cancers Responsive with Useful
Palliation, But Not Cured, by
Chemotherapy
Bladder carcinoma
Chronic myeloid leukemia
Hairy cell leukemia
Chronic lymphocytic leukemia
Lymphoma—certain types
Multiple myeloma
Gastric carcinoma
Cervix carcinoma
Endometrial carcinoma
Soft tissue sarcoma
Head and neck cancer
Adrenocortical carcinoma
Islet cell neoplasms
Breast carcinoma
Colorectal carcinoma
Glioma
Lung cancer
Small-cell
Non-small-cell
F. Tumors Poorly Responsive
in Advanced Stages to
Chemotherapy
Pancreatic carcinoma
Biliary tract neoplasms
Thyroid carcinoma
Carcinoma of the vulva
Prostate carcinoma
Melanoma
Hepatocellular carcinoma
Salivary gland cancer

TABLE 78-4 Clinical Impact of Host T Lymphocyte–Modified Cells a or Host T Lymphocyte–Directed Immunoregulatory…¶

Harrison's 22e, p.560

A. Advanced Cancers with Positive Effect (at least 25% of treated patients
have stable disease or progression-free survival of ≥27 weeks or better) or
Frequent or Unexpected Prolonged Responders (efficacy may be limited to
CD expression–dependent or PD-1 ligand–expressing subtypes)
Acute lymphoid leukemiab
Adrenocortical carcinomac
Breast cancer, hormone receptor negative, HER2 negative (with chemotherapy)c
Colorectal cancer (microsatellite instability-high [MSI-H] or mismatch repair
deficient, usually with fluoropyrimidine, oxaliplatin, or irinotecan)c
Cervix, squamous carcinomac
Cutaneous, squamous carcinomac
Diffuse large B-cell non-Hodgkin’s lymphoma, not otherwise specifieda
Diffuse large B-cell non-Hodgkin’s lymphoma, primary mediastinal subtypeb
Endometrial carcinoma (with lenvatinib, if microsatellite instability-stable
[MSI-S] or mismatch repair wild-type)c
Esophageal squamous carcinomac
Gastric/gastroesophageal adenocarcinomac
Head and neck squamous carcinomac
Hepatocellular cancer (after sorafenib)c
Hodgkin’s diseasec
Mantle cell lymphomaa
Melanomac
Merkel cell carcinomac
Mesotheliomac
MSI-H or mismatch repair–deficient solid tumors without satisfactory
alternativec
Mycosis fungoidesc
Multiple myelomaa
Non-small-cell lung carcinomac
Paraganglioma/pheochromocytomac
Renal cell carcinomac
Sarcoma, alveolar soft partc
Small-cell lung carcinomac
Solid tumors with high tumor mutational burden (TMB) (≥10 mutations/
megabase) that have progressed following prior therapy without satisfactory
alternative treatmentc
Urothelial carcinomac (including bladder, ureter)
B. Advanced Cancers with Insufficient Data to Support Host-Derived
T Lymphocyte or Immunoregulatory Antibody Treatmentd
Acute myeloid leukemia
Anus, squamous carcinoma
Breast cancer, hormone receptor positive
Breast cancer, hormone receptor negative, HER2 positive
Biliary tract cancers (if MSI-S or mismatch repair wild-type)
Chronic lymphocytic leukemia
Chronic myeloid leukemia
Gastrointestinal neuroendocrine/islet cell carcinoma
Glioma, all grades including glioblastoma
Germ cell neoplasms
Ovarian cancer
Osteogenic sarcoma
Pancreas adenocarcinoma
Pediatric tumors (Wilms’, rhabdomyosarcoma, Ewing’s, neuroblastoma,
osteosarcoma)
Prostate adenocarcinoma
Salivary gland carcinoma
Soft tissue sarcoma (except alveolar soft part)
T-cell non-Hodgkin’s lymphoma (except mycosis fungoides)
Vulva, squamous carcinoma

TABLE 78-5 Commonly Used Cytotoxic Chemotherapy Agents DRUG Direct DNA-Interacting Agents a Alkylator or platinating…¶

Harrison's 22e, p.562

DRUG	ADVERSE EVENTS	NOTES
Direct DNA-Interacting Agentsa
Alkylator or platinating drug
Bendamustine	Vehicle allergy, My, Der, ↑LFTs	TLS, Ves, IR, DA-R, DA-H
Carboplatin	My, N, V, R	Dose according to CrCl: to AUC of 5–7 mg/mL per min [AUC = dose/(CrCl + 25)]
Chlorambucil	Common alkylator
Cisplatin	N, V, Neu, My, R, Ototoxic, ↓K+, ↓Mg2+, ↓Ca2+	Osmotic diuresis, N, V prophylaxis, DA-R
Cyclophosphamide	Common alkylator, cystitis, cardiac (high dose)	Liver required to activate, DA-R, DA-H, hydration ± mesna protects bladder
Dacarbazine (DTIC)	Common alkylator, Ves	DA-R
Ifosfamide	My, common alkylator, bladder, CNS	DA-R, must use concomitant mesna
Lomustine (CCNU)	Common alkylator but My, has delayed nadir, ↑LFTs	Plm ± fibrosis: PFTs prior to treatment and repeat frequently; cease if fibrosis occurs
Lurbinectedin	My, ↑LFTs, N, V	CYP3A4
Melphalan	Common alkylator but My, has delayed nadir	DA-R
Oxaliplatin	N, V, My, Neu	Reversible laryngopharyngeal spasm risk
Procarbazine	Common alkylator, CNS	Disulfiram-like effect with alcohol, MAOI, like HBP after tyramine-rich foods
Temozolomide	Common alkylator but My, has delayed nadir	Pneumocystis prophylaxis
Antitumor antibiotics and topoisomerase poisons
Bleomycin	Plm (↑FIO worsen), Der, Raynaud’s, IR* 2	Monitor DLCO before/during treatment, DA-R
Dactinomycin	My, N, V, mucositis, Ves, alopecia	Radiation recall
Doxorubicin, daunorubicin, epirubicin, idarubicin	TOPOII; My, mucositis, alopecia, ↓LVEF acute/chronic, Ves	Co-administration with heparin aggregate, secondary leukemia, DA-H, radiation recall
Doxorubicin, liposomal	TOPOII; My, ↓LVEF, IR*, PPED	DA-H, radiation recall
Etoposide	TOPOII; My, alopecia, IR with rapid IV, N, V, mucositis	DA-H, DA-R
Irinotecan	TOPOI; My, D: “early onset” with cramping, flushing, vomiting: treat with atropine; “late onset” after several doses: use loperamide 4 mg with first stool then 2 mg q2h until 12 h without stool up to 16 mg/24 h; My dependent on UGT1A1 phenotype, R, ILD	Prodrug requires metabolism to active drug SN-38, which is cleared by UGT1A1 with degree of My dependent on patient UGT1A1 genotype, DA-H
Irinotecan, liposomal	TOPOI; My, D (administer loperamide for D of any severity), IR*, ILD	Consider guide dosing by UGT1A1 genotype testing, CYP3A4; NO recommended dose for T Bili >ULN
Mitoxantrone	TOPOII; Ves, blue urine, nails, and sclerae	Interacts with heparin; DA-H, alopecia, N, V, radiation recall
Topotecan	TOPOI; My, mucositis, N, V, alopecia	DA-R, rare ILD
Indirectly DNA-Interacting Agents
Miscellaneous Antimetabolite-Like Agents
Asparaginase	Thrombosis by decrease of antithrombin IIII, but ↓fibrinogen can cause hemorrhage; ↑glucose; ↓albumin, hypersensitivity; CNS; pancreatitis; ↑LFTs	Decrease protein synthesis; indirect inhibition of DNA synthesis by decreased histone synthesis; blocks methotrexate action
Hydroxyurea	My, N, mucositis, rare ↓CrCl	DA-R, augments antimetabolite effect

TABLE 78-6 Antibody-Drug Conjugates¶

Harrison's 22e, p.566

TOXIC MECHANISM	TARGET ANTIGEN	DISEASE ACTIVITY	NOTES
DNA Structure
Gemtuzumab ozogamicin	CD33	Acute myeloid leukemia, CD33+	IR*, My, ↑LFTs ± VOD
Inotuzumab ozogamicin	CD22	Pre-B acute lymphoid leukemia	IR*, My, ↑LFTs ± VOD, ↑QT
Loncastuximab tesirine-lpyl	CD19	Diffuse large B-cell lymphoma	VLS, My, Der
Microtubule Structure
HER2 CD38 CD30 Nectin-4 Folate receptor α (FRα+) CD79b Tissue factor	Breast cancer, HER2+ Myeloma Hodgkin’s disease; anaplastic large-cell lymphoma; mycosis fungoides, CD30+ Urothelial cancer Ovary, peritoneal, fallopian tube cancer, FRα+ High-grade B-cell lymphoma Uterine cervix cancer
Topoisomerase I
Fam-trastuzumab deruxtecan-nxki	HER2	HER2 1+/weak BC, HER2 activating mutation+ NSCLC, HER2+ gastric	N/V prophylaxis, ILD prompt evaluate cough, dyspnea, My, ↓LVEF
Sacituzumab govitecan-bziy	Trop2	Triple-negative BC, HR+/HER2– BC, urothelial cancer	IR, N/V prophylaxis, diarrhea consider loperamide, My esp UGT1A128, consider G-CSF

TABLE 78-7 Molecularly Targeted Agents DRUG Nirogacestat¶

Harrison's 22e, p.571

DRUG	TARGET/INDICATION	ADVERSE EVENTS	NOTES
Nirogacestat	Targets γ-secretase to inhibit Notch signaling/desmoid tumor	D (can be severe), ovarian dysfunction, ↑LFTs, PO and K+ abnormalities 4	CYP3A4; avoid PPIs and stagger doses with H2 blockers; nonmelanoma skin cancers; Der: monitor before and during treatment
Sonidegib	Targets smoothened receptor in hedgehog pathway/basal cell carcinoma locally advanced or metastatic	Musculoskeletal adverse events with ↑CPK, potential R, N, V, D	As with glasdegib
Tretinoin	Target PML-RARα/t(15;17) acute promyelocytic leukemia	Der including cheilitis, skin dryness; ↑ intracranial pressure; ↑lipids, ↑LFT, usually resolve	As with arsenic trioxide; also headache, visual changes may indicate ↑intracranial pressure; check for papilledema
Vismodegib	As with sonidegib	Musculoskeletal adverse events, N, V, D, C	Transmission to potentially pregnant partner through semen or to blood product recipient
Apoptosis Modulation
Targets BCL2/CLL, SLL; AML + azacytidine, decitabine, or low-dose cytarabine	My, D, TLS
Metabolism Modulation: mTOR Inhibitors/PI Kinase/IDH Inhibitors
Alpelisib	PIK3CA mutated/HR+HER2– BC	Der, hypersensitivity, ↑glucose, ILD, D	CYP3A, CYP2C9, BCRP substrates
Copanlisib	PI3Kα,δ/FL	My, HBP, noninfectious pneumonitis, ↑glucose, Der	CYP3A4
Duvelisib	PI3Kδ,γ/CLL, SLL, FL	My, infection, D, colitis, Der, pneumonitis, ↑LFTs	CYP3A4
Enasidenib	IDH2 mutated/AML	N, V, D, ↑LFTs	AML differentiation syndrome with pulmonary dysfunction/infiltrate, pleural/pericardial effusion, fever treat with dexamethasone ± hydroxyurea
Everolimus	mTOR/RCC, tuberous sclerosis– associated neoplasms, HR+ BC, neuroendocrine, pancreatic, lung, GI NOT functional carcinoid	My, noninfectious pneumonitis, infections, hypersensitivity reactions, R, impaired wound healing, ↑glucose, ↑lipids, stomatitis	CYP3A4, Pgp substrates, angioedema with concomitant ACE inhibitors, consider alcohol-free mouthwash when starting treatment; risk of reduced efficacy of vaccination
Ivosidenib	IDH1 mutated/AML, cholangiocarcinoma, MDS	↑QT, Guillain-Barré syndrome	CYP3A4, QT-prolonging agents; AML differentiation syndrome requiring corticosteroid treatment
Idelalisib	PI3Kδ/non-first-line CLL, SLL, FL	Fatal or serious ↑LFTs, D, colitis with GI perforation, pneumonitis, infection, Der, hypersensitivity	CYP3A4, not with bendamustine or rituximab
Olutasidenib	IDH1/AML	↑LFTs	CYP3A4, differentiation syndrome requiring corticosteroid ± hydroxyurea treatment
Sirolimus protein bound particles	mTOR/perivascular epithelioid cell tumor (PEComa)	My, stomatitis, infection, ↓K+, IR, ↑glucose, ILD, hemorrhage, male infertility	CYP3A4, avoid live vaccines
Temsirolimus	mTOR/RCC	Hypersensitivity, ↑LFTs, infection, ILD, stomatitis, thrombocytopenia, N, ↑glucose, ↑lipids, ↓wound healing, GI perforation, R ± proteinuria	DA-H, CYP3A4
Poly-ADP Ribose Polymerase (PARP) Inhibitors
Ovarian, fallopian tube, or primary peritoneal cancer with good response to Pt Ovarian: as with niraparib also with various BRCA or HRR mutations; BC mutant BRCA, HER2–; pancreatic mutant BRCA with good response to Pt; prostate with BRCA or HRR mutations As with niraparib; prostate BRCA mutated after hormone and after taxane BC BRCA mutated HER2–; prostate cancer, castrate-resistant HRR mutation(+), with enzalutamide	My, N, V, D, HBP, PRES My, N, stomatitis, DVT ± PE, rare ILD My, stomatitis, N, V, D, ↑LFTs My, N, V, D, ↑LFTs
Miscellaneous
177Lu-dotatate	Target somatostatin receptor (SSR)/ gastroenterohepatic neuroendocrine tumors (SSR)+	My, R, ↑LFTs, IR,	Neuroendocrine hormonal crisis including flushing, diarrhea, hypotension, bronchoconstriction; secondary MDS, risks from radiation exposure
177Lu-vipivotide tetraxetan	Target prostate-specific membrane antigen (PSMA)/refractory prostate cancer	My, R	Temporary or permanent infertility, risks from radiation exposure

TABLE 78-8 Indications for the Clinical Use of G-CSF or GM-CSF Preventive Uses With the first cycle of chemotherapy…¶

Harrison's 22e, p.575

Preventive Uses
With the first cycle of chemotherapy (so-called primary CSF administration)
Not needed on a routine basis
Use if the probability of febrile neutropenia is ≥20%
Use if patient has preexisting neutropenia or active infection
Age >65 years treated for lymphoma with curative intent or other tumors
treated by similar regimens
Poor performance status
Extensive prior chemotherapy
Dose-dense regimens in a clinical trial or with strong evidence of benefit
With subsequent cycles if febrile neutropenia has previously occurred (so-called
secondary CSF administration)
Not needed after short-duration neutropenia without fever
Use if patient had febrile neutropenia in previous cycle
Use if prolonged neutropenia (even without fever) delays therapy
Therapeutic Uses
Afebrile neutropenic patients
No evidence of benefit
Febrile neutropenic patients
No evidence of benefit
May feel compelled to use in the face of clinical deterioration from sepsis,
pneumonia, or fungal infection, but benefit unclear
In bone marrow or peripheral blood stem cell transplantation
Use to mobilize stem cells from marrow
Use to hasten myeloid recovery
In acute myeloid leukemia
G-CSF of minor or no benefit
GM-CSF of no benefit and may be harmful
In myelodysplastic syndromes
Not routinely beneficial
Use intermittently in subset with neutropenia and recurrent infection
What Dose and Schedule Should Be Used?
G-CSF: 5 mg/kg per day subcutaneously
GM-CSF: 250 mg/m2 per day subcutaneously
Pegfilgrastim: one dose of 6 mg 24 h after chemotherapy
When Should Therapy Begin and End?
When indicated, start 24–72 h after chemotherapy
Continue until absolute neutrophil count is 10,000/μL
Do not use concurrently with chemotherapy or radiation therapy