Chemotherapy: PARP-I, Bevacizumab, and Ovarian Cytotoxics

Episode Notes

1. PARP-Inhibitors

1. Mechanism of Action (MOA) of Poly (ADP-ribose) polymerase (aka PARP): identify single-stranded DNA breaks and recruit DNA repair proteins

1. If PARP unable to do their job, single strand breaks turn into double strand breaks

2. MOA of PARP-I: inhibit PARP and the repair of single strand breaks, forcing the cell to rely on double strand break repair. 

1. Double strand break repair typically occurs via homologous recombination (HR) (the most reliable mechanism for double strand break repair): if HR unavailable, more error-prone methods to repair double-strand breaks are relied upon (like non-homologous end joining)

3. Defining Homologous recombination deficiency (HRD)

1. Germline/somatic BRCA deficiency (or other gene-specific causes of HRD)

2. HRD: available testing does not describe real-time/current HRD, but can pick up on markers of historic HRD. So, if cells have regained their homologous recombination function, these tests may not be accurate depictions of what is happening in the cell in the present tense. 

1. LOH: this is a genomic signature (like a scar). Will remain “positive”/LOH high even if cells have restored their HR

1. The implications of LOH are disease-site specific: in endometrial cancer, LOH doesn’t actually represent HRD but rather correlates with p53 mutations

2. The most common mechanism of developing resistance to PARPi is through restoration of HR

3. Up to 50% of all ovarian cancer patients will meet criteria for HRD of some type

4. Company specific tests

1. Myriad “mychoice” test: use a Genomic Instability Score (GIS): incorporates LOH, telomeric allelic imbalance, and large scale state transitions

2. FoundationOne: measures LOH

3. These two tests use tumor tissue, so incorporate/analyze both gene mutations and consequences like LOH

4. FDA approval of PARPi: refer back to our ovarian cancer series for specifics.

   1. Generally, PARPi are most effective in patients with BRCA mutations, next best in those with HRD, and have the least benefit in HR proficient tumors.

5. Administration and toxicities of PARPi

1. Administered orally

2. Toxicities:  

1. Nausea/vomiting most common (up to 75%): administer with anti-emetics. Nausea tends to improve over time.

2. Hematologic toxicities most concerning

1. Short term: myelosuppression (RBCs and platelets)

1. Manage anemia w/ dose interruption or reduction, transfusion if symptomatic

2. Thrombocytopenia: Niraparib has highest rate of grade 3 thrombocytopenia: weekly CBC when starting (monthly after the first month)

1. Manage thrombocytopenia with dose reductions or cessation (monitor CBCs weekly until recovery)

3. Starting dose of niraparib incorporates patients’ platelet levels and weight to decrease risk of myelosuppression

2. Long term: myelodysplastic syndrome or AML: risk increases with duration of exposure (8% in exposure group in SOLO2 vs. 4% in control group)

3. Fatigue: make sure to rule out other modifiable causes of fatigue before attributing all fatigue to PARPi

4. Insomnia: emphasize sleep hygiene

5. Nephrotoxicity: rucaparib and olaparib: tends to stabilize/downtrend over time

6. Choice of agent: 

1. refer to FDA recommendations for each agent (which are based off of trial design), incoporating mutation and/or HRD status

2. Consider drug administration considerations: olaparib is twice daily and has more drug interactions; niraparib is once daily dosing and nighttime dosing can help mitigate nausea; rucaparib has flexible dosing in mg

3. Consider side effects of concomitant chemo agents

2. Bevacizumab

1. MOA: monoclonal antibody against VEG-F. Prevents angiogenesis in tumors

2. Dosing: weight based!  Multiple options

3. Toxicities: unique due to anti-angiogenesis properties

1. VTE: in up to 8% of patients. History of prior VTE not a contraindication. 

1. Arterial thrmobotic events also more common. If patients experience an ATE, need to permanently discontinue bev

2. Bleeding: most commonly epistaxis, <1% chance of CNS-related hemorrhage

3. GI perforation and fistula: history of inflammatory bowel disease and history of bowel resection are both risk factors

1. Presence of disease bowel involvement or signs of bowel obstruction are contraindications!

4. Delayed wound healing: discontinue for the month before and after surgery

5. Hypertension: 25% of patients experience ≥grade 2 HTN. Manage with antihypertensives. Pre-existing HTN is not a contraindication, if managed. 

6. Proteinuria: if 2+ protein on UA, do a 24-hr collection of urine protein/creatinine ratio.

1. If nephrotic syndrome (>3g protein in 24 hours): discontinue bevacizumab indefinitely

7. Reversible posterior leukoencephalopathy syndrome: very rare (<1%). Preceded by uncontrolled HTN, presents with headache, lethargy, confusion, seizure, blindness

4. Utility in ovarian cancer

1. KELIM score: validated, predictive score that can help guide decision to use bevacizumab.  Unfavorable score (<1) predicts response/benefit of bevacizumab in ovarian cancer

1. Calculate with rate of change of serial CA-125 levels during initial chemotherapy treatment

3. Cytotoxics

1. Carbo/taxol! Refer back to episode 7, uterine cytotoxics, for details

2. Antimetabolites: previously reviewed gemcitabine

1. Capecitabine

1. Used in mucinous ovarian cancer in CAPOX (capecitabine-oxaliplatin) regimen

2. Oral fluorouracil prodrug, gets converted to 5-FU in tumor tissue>> has same MOA as 5-FU. Thought to inhibit thymidylate synthase

3. Adverse Effects (AE)

1. Severe watery diarrhea can be life threatening!

2. Other GI effects: stomatitis, mucositis

3. 3-5% of the population has a deficiency in metabolizing capecitabine/5-FU, resulting in severe toxicity

1. Recommend pharmacogenomic testing for dihydropyrimidine dehydrogenase if concerned

4. Hepatotoxicity

5. Renal dosing

6. Myelosuppression days 9-14

7. Dermatologic: hand-foot syndrome, photosensitivity/hyperpigmentation

1. Urea cream can prevent

8. Cerebellar syndrome: typically reversible but rarely can be permanent

2. Pemetrexed: inhibits synthesis of purine and pyrimidine. A derivative of folic acid

1. Toxicities: myelosuppression, rash, diarrhea, N/V, anorexia, fatigue

2. Give folic acid and B12 supplementation starting 1 week prior to initiation of therapy to reduce GI toxicity!

3. Steroids can help reduce risk of infusion-related rashes

3. Alkylating agents: previously reviewed ifosfamide, trabectedine

1. MOA: positively charged alkyl groups bind to negatively charged sites on DNA to form DNA adducts > DNA strand breaks/cross-links

2. Cyclophosphamide

1. Used in recurrent epithelial ovarian cancers, in some combinations for ovarian germ cell tumors, and is in the EMA-CO regimen for GTN

2. AE

1. Hemorrhagic cystitis: common with high-dose therapies. Mesna prevents

2. Alopecia, N/V, myelosuppression: tends to be brief, occurring 8-14 days after treatment

3. Dermatologic AE: nail changes, facial flushin, dermatitis

4. Rare: secondary leukemias

4. Antitumor antibiotics: previously reviewed doxorubicin, doxil

1. Bleomycin: 

1. Part of the BEP regimen for germ cell tumors

2. MOA: interacts with copper or iron ion cofactors > forms superoxide anions and hydroxyl radicals > single-stranded DNA breaks. Cell-specific for G2 phase.

3. AE:

1. Pulmonary toxicity: dose-limiting! Can present as interstitial pneumonitis, pulmonary fibrosis

1. Increased risk with total lifetime dose >500U

2. Risk factors: smoking/vaping, exposure to high oxygen concentrations

3. In our ovary part 6 lecture we described the workup for starting patients on Bleomycin: With bleomycin, due to risk of lung toxicity, it’s important to get a chest xray, PFTs including a diffusing capacity for carbon monoxide (DLCO), and to do a good lung exam before starting.  If there are rales on lung auscultation, or consolidation on chest xray, or if DLCO decreases by 30%, then bleomycin should be omitted.  A decline in DLCO is the most sensitive marker for early lung injury. 

2. Dermatologic: Hyperpigmentation, pruritis, hyperkeratosis, alopecia, rash, skin peeling, mucositis

3. Mild myelosuppression, N/V, anorexia

4. Fever and chills can show up within 4-10 hours of administration, last for 12 hours

5. Plant-derived agents: previously discussed paclitaxel, abraxane, docetaxel, topotecan (here)

1. Etoposide: used on treatment of ovarian germ cell tumors and advanced epithelial ovarian cancer, as well as in EMA-CO for GTN and some uterine sarcomas

1. MOA: interferes with topoisomerase II > single and double stranded DNA breaks > DNA supercoiling

2. AE

1. Anaphylactoid reactions: rare

2. Secondary leukemias: related to dose: increased markedly with doses >2g/m2

3. Common: myelosuppression with leukemia, with nadirs at 7-14 days; N/V, mucositis, alopecia, peripheral neuropathy

2. Vinka alkaloids: 

1. MOA: inhibit microtubular polymerization > mitotic arrest

2. Vinblastine: can be used in germ cell tumors

3. Vinorelbine: can be used in recurrent ovarian and cervical cancer

4. Vincristine: EMA-CO regimen

5. AE:

1. Dose limiting: leukopenia, hypersensitivity reactions

2. Obstipation due to neuropathic ileus, abdominal cramps

3. Dermatologic: skin necrosis and soulghing if extravasate during infusion!

1. Other: rash, photosensitivity (with vinblastine)

4. Neurologic: peripheral neuropathy, autonomic neuropathy, headaches. Rare seizures and cortical blindness.

5. Other: alopecia, AST/ALT elevation (mild), joint pain, SIADH

References

See main references