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Gynecologic Cancer Pharmacology

Obstetrics and Gynecology
Oncology
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Endometrial Cancer

Endometrial cancer is the most common gynecologic cancer in the United States and the 6th most common in the world.[1,2,3] Endometrial cancer is diagnosed at local stage in 67% of patients resulting in a 5-year overall survival of 81.3%.[4] Localized disease is often managed with surgical intervention (total hysterectomy, bilateral salpingo-oopherectomy along with surgical staging) in patients who are suitable.
Radiation or hormonal therapy (progestin-based IUD) are the treatments of choice if a patient is not suitable for surgery. Advanced disease is initially treated with platinum in combination with taxane (and/or hormonal therapy for patients with low-grade or indolent tumors). These multiagent chemotherapy regimens are difficult to tolerate, associated with short progression-free survival (PFS), and patients typically experience recurrence at locoregional or distant sites.[5]
Systemic therapies for recurrent or metastatic endometrial cancers require an analysis of tumor biomarkers to determine the most optimal therapy.[6] Biomarkers of interest include microsatellite stability (MSI-high or non-MSI-High), tumor mutational burden (TMB), MMR deficiency (dMMR), and HER2-positivity. If a patient is found to have TMB-high (TMB-H), MSI-H/dMMR disease, she is eligible for treatment with pembrolizumab.
If a patient is found to have non-MSI-H/non-dMMR tumor, she is eligible for lenvatinib and pembrolizumab or re-treatment with the platinum-taxane combination therapy. Patients found to have HER2-positive uterine serous carcinoma are eligible to receive platinum and taxane with trastuzumab.[5]

Ovarian Cancer

Ovarian cancer is the leading cause of death in women diagnosed with gynecological cancers. It is also the fifth most frequent cause of death in women, in general.[6] In 2022, it is estimated that 19,880 new cases and 12,810 deaths will occur. Most of the cases are diagnosed at an advanced stage, which leads to poor outcomes of this disease.
The 5-year overall survival is 49.7%.[7] The standard treatment includes surgery and platinum-based chemotherapy. Surgery generally includes bilateral salpingo-oophorectomy, hysterectomy, omentectomy, and resection of any other gross visible disease. The most common histologic subtype of ovarian cancer is epithelial ovarian cancer.[8]
Upon pathologic confirmation of ovarian cancer, patients should be referred for a genetic risk evaluation and germline and somatic testing.[9] Patients can receive maintenance therapy with bevacizumab or oral chemotherapy such as olaparib or niraparib after completion of first line therapy.[10,11]
A high rate of recurrence (~70-80%) following the initial treatment has been observed. Most of these relapsed cases are less curable and known to have an increased incidence of treatment failures. When ovarian cancer recurs more than 6 months after first-line platinum-based chemotherapy, it is referred to as “platinum sensitive” and when it recurs less than 6 months after first-line platinum-based chemotherapy, it is referred to as “platinum resistant.”[10]
Chemotherapy with a platinum-based doublet is preferred for patients with platinum sensitive ovarian cancer. They can then receive maintenance therapy with a PARP inhibitor or bevacizumab. On the other hand, the outcome of patients with platinum resistant ovarian cancer is generally poor, with low response rates to further chemotherapy and a median survival of less than 12 months.[10]

Cervical Cancer

Cervical cancer is the fourth most common female malignancy worldwide ranking after breast, colorectal, and lung cancer.[12] Management is determined based on the stage at diagnosis, presence or absence of metastatic disease, tumor size, and the patient performance status.[13] 44% of cervical cancer diagnoses occur at an early stage, resulting in a 5-year overall survival of 92% in these patients.
The mainstay of treatment for early-stage disease is surgery. Those with early-stage disease and high-risk features often go on to receive adjuvant chemotherapy in combination with radiation therapy.[14] Guideline recommended chemotherapy for this combination includes platinum-based treatment (weekly cisplatin or carboplatin) in combination with radiation for five to six weeks.[14]
In contrast, cervical cancer found to be advanced at diagnosis or recurrent and no longer operable or amenable to radiation is managed with systemic chemotherapy (often given as doublet or triplet therapy).[13]
Options used in this setting include platinum in combination with taxane; platinum and taxane in combination with bevacizumab; topotecan in combination with taxane and bevacizumab; or topotecan in combination with cisplatin.[13,14] In patients with PD-L1 positive disease, pembrolizumab may be used (in combination with chemotherapy or following progression of disease after chemotherapy).[15,16] Upon further progression of disease, single-agent chemotherapy can be considered. Possible agents include tisotumab vedotin, pemetrexed, topotecan, and gemcitabine.[17]
RegimenLiterature Support
OVARIAN CANCER
Carboplatin AUC 5-6 and paclitaxel 175 mg/m2 +/- Bevacizumab 15 mg/kg every 3 weeksGOG 158
ICON 7
Paclitaxel 135 mg/m2 IV on day 1 and cisplatin 75-100 mg/m2 IP D2 and paclitaxel 60 mg/m2 IP D8 every 3 weeksGOG 172
Carboplatin AUC 5-6 and docetaxel 60-75 mg/m2 every 3 weeksSCOTROC
Carboplatin AUC 5-6 and liposomal doxorubicin 30 mg/m2 day 1 +/- bevacizumab 10 mg/kg days 1 and 15 every 4 weeksMITO 2
CALYPSO
GOG 213
Carboplatin AUC 4-5 day 1 and Gemcitabine 800-1000 mg/m2 day 1 and 8 +/- bevacizumab 15 mg/kg day 1 every 3 weeksOCEANS
Cisplatin 30-40 mg/m2 and gemcitabine 800-100 mg/m2 days 1 and 15 every 4 weeks or Cisplatin 30-40 mg/m2 day 1 and gemcitabine 800-1000 mg/m2 days 1 and 8 every 3 weeks 
Olaparib 300 mg PO BID Niraparib 300 mg PO daily Rucaparib 600 mg PO BIDSOLO
NOVA
ARIEL 3
Paclitaxel 60-8 mg/m2 days 1,8,15, and 22 +/- bevacizumab 10 mg/kg days 1 and 15 every 4 weeksAURELIA
Topotecan 3-4 mg/m2 days 1,8, and 15 +/- bevacizumab 10 mg/kg days 1 and 15 every 4 weeksAURELIA
Liposomal doxorubicin 40 mg/m2 day 1 +/- bevacizumab 10 mg/kg days 1 and 15 every 4 weeks AURELIA
Cyclophosphamide 50 mg PO daily +/- bevacizumab 15 mg/kg every 3 weeks or Cyclophosphamide 50 mg PO daily +/- bevacizumab 10 mg/kg days 1 and 15 every 4 weeks 
ENDOMETRIAL CANCER
Carboplatin AUC 5-6 and paclitaxel 175 mg/m2 +/- Bevacizumab 15 mg/kg every 3 weeksGOG 209
Carboplatin AUC 5-6 and paclitaxel 175 mg/m2 and Trastuzumab 8 mg/kg x1 dose followed by 6 mg/kg in subsequent doses every 3 weeks (if HER2+)NCT03167002
Carboplatin AUC 5-6 and docetaxel 60-75 mg/m2 every 3 weeks 
Liposomal doxorubicin 40 mg/m2 every 4 weeksMuggia Study
Pembrolizumab 200 mg every 3 weeks (if MSI-H)KEYNOTE-158
Pembrolizumab 200 mg and Lenvatinib 20 mg PO daily every 3 weeks (if MSS)KEYNOTE-775/Study 309
JEYNOTE-146/Study 111
Dostarlimab 500 mg every 3 weeks (if dMMR)GARNET
Letrozole 2.5 mg PO +/- Everolimus 10 mg PO dailySlomovitz
Study
Tamoxifen 20 mg PO BID +/- Megesterol acetate 
CERVICAL CANCER
Cisplatin 40 mg/m2 weekly with radiation or Carboplatin AUC 2 weekly with radiation 
Cisplatin 50 mg/m2 and paclitaxel 175 mg/m2 +/- bevacizumab 15 mg/kg every 3 weeksGOG 240
Carboplatin AUC 4-5 and paclitaxel 175 mg/m2 +/- bevacizumab 15 mg/kg every 3 weeksJCO GO505
Carboplatin AUC 4-5 and paclitaxel 175 mg/m2 +/- bevacizumab 15 mg/kg +/- pembrolizumab 200 mg every 3 weeks (if PD-L1 positive)KEYNOTE 826
Topotecan and paclitaxel and bevacizumab every 3 weeksGOG 240
Pembrolizumab 200 mg every 3 weeks (if PD-L1 positive)KEYNOTE-158
Tisotumab vedotin 2 mg/kg every 3 weeksINNOVA TV 204
Common toxicity by drug classes
Drug ClassToxicities
Platinums (Carboplatin and Cisplatin)• Hypersensitivity reactions
• Myelosuppression
• Nausea/Vomiting
• Ototoxicity (cisplatin specific)
• Peripheral neuropathy
• Renal dysfunction (cisplatin specific)
Taxanes (Docetaxel and Paclitaxel)• Arthralgia/Myalgia
• Fluid retention (docetaxel specific)
• Hair loss
• Hepatic dysfunction
• Hypersensitivity reaction Peripheral neuropathy
• Skin and nail discoloration
VEGF-Inhibitors (Bevacizumab and Lenvatinib)• Blood pressure
• Clotting dysfunction (bleeding and clotting)
• Diarrhea (lenvatinib specific)
• GI perforation and fistula formation Impaired wound healing
• Nose bleeds
• Proteinuria
• Thyroid dysfunction (lenvatinib specific)
Liposomal doxorubicin• Body fluid discoloration
• Cardiac toxicity (cardiomyopathies; dose related)
• Diarrhea
• Hair thinning
• Infusion reaction
• Mouth sores
• Palmar plantar erythrodysesthesia
Gemcitabine• Flu-like syndrome
• Hair thinning
• Hepatic dysfunction
• Myelosuppression
• Nausea/vomiting
• Peripheral edema
• Proteinuria
• Skin rash
Topotecan• Hair thinning
• Myelosuppression
Cylophosphamide• Nausea/vomiting
• Hair thinning
PARPi (niraparib, rucaparib, olaparib)GENERAL
• Fatigue
• Increased serum creatinine
• Myelosuppression
• Nausea/vomiting

NIRAPARIB
• High blood pressure
• Increased heart rate Insomnia
• Thrombocytopenia

RUCAPARIB
• Hepatic dysfunction
• Hypercholesterolemia
• Rash  

OLAPARIB
• Anemia
• Pneumonitis  Immunotherapy (pembrolizumab and dostarlimab)
• Arthralgia/myalgia
• Colitis
• Dermatitis
• Hepatitis
• Hypothyroidism/hyperthyroidism
• Hyophysitis
• PneumonitisHormonal therapy
• Arthralgia/myalgia
• Changes in bone density (osteopenia/osteoporosis)
• Fatigue
• Hot flashes
• Injection site reactionTisotumab Vedotin• Arthralgia/myalgia
• Clotting dysfunction (bleeding and clotting)
• Hair loss
• Myelosuppression
• Nose bleeds
• Ocular toxicity
• Peripheral neuropathy  Trastuzumab• Cardiotoxicity
• Infusion reaction
Immunotherapy (pembrolizumab and dostarlimab)• Arthralgia/myalgia
• Colitis
• Dermatitis
• Hepatitis
• Hypothyroidism/hyperthyroidism
• Hyophysitis
• Pneumonitis
Hormonal therapy• Arthralgia/myalgia
• Changes in bone density (osteopenia/osteoporosis)
• Fatigue
• Hot flashes
• Injection site reaction
Tisotumab Vedotin• Arthralgia/myalgia
• Clotting dysfunction (bleeding and clotting)
• Hair loss
• Myelosuppression
• Nose bleeds
• Ocular toxicity
• Peripheral neuropathy  
Trastuzumab• Cardiotoxicity
• Infusion reaction  

Myelosuppression

Myelosuppression is considered a common and anticipated side effect of treatment with cytotoxic chemotherapy. Neutropenia and thrombocytopenia are toxicities that require holding treatment, with possible subsequent dose reduction, whereas anemia may require blood transfusion, but may not require holding the dose.
The National Comprehensive Cancer Network (NCCN) classifies chemotherapy regimens based on the likelihood they will cause neutropenia. Regimens classified as high-risk require the use of prophylactic granulocyte colony stimulating factor support (G-CSF).[46] Currently, there are only a few agents in this category for treatment of gynecology oncology patients. These agents include docetaxel and topotecan.[46]
Most agents used in gynecology oncology cancers are classified as intermediate or low risk, meaning primary prophylaxis is not recommended but secondary prophylaxis should be considered in patients who have already suffered an incidence of neutropenia or febrile neutropenia requiring a delay in therapy.[46] Filgrastim, Tbo-filgrastim, pegfilgrastim, and their respective biosimilars are among the most commonly used agents for prophylaxis of neutropenia in these patients.
In instances of thrombocytopenia, decisions for use of platelet transfusions, dose reductions, and Romiplostim should be made on the specific case basis.[46]

Nausea and Vomiting

Nausea and vomiting are among the most common side effects experienced by patients undergoing chemotherapy.[47] Nausea can lead to loss of appetite, decreased food and water intake, and in more severe cases, can lead to significant dehydration and weight loss. Prevention of nausea is key in patients receiving treatment, but immediate control and treatment is imperative if nausea and vomiting does occur.
NCCN categorizes all intravenous chemotherapy agents and oral chemotherapy medications based on their emetogenic potential. Platinums and PARPi’s are among the agents used in gynecologic oncology malignancies that are considered high-risk, with all other agents classified as minimal to low.[48]
Antinausea regimens should be tailored to the risk category of the agent and include combination or single agent antiemetics.[47,48] The major classes of antiemetics used in the prevention of chemotherapy induced nausea and vomiting include NK1 receptor antagonists, 5HT3 receptor antagonists, corticosteroids, and olanzapine.[47] Breakthrough nausea, which occurs despite appropriate antiemetic premedication, can be managed with the use benzodiazepines, phenothiazines, prokinetics, haloperidol, and cannabinoids.[48]
It is important to evaluate patients for the type of nausea they are experiencing as the type of nausea may help to guide treatment options.[47] For example: patients with anticipatory nausea should be managed differently than those experiencing nausea due to gastrointestinal motility impairment.

Peripheral Neuropathy

Platinums and taxanes are among a group of chemotherapy agents associated with a high incidence of peripheral neuropathy (PN).[49,50] Unfortunately, there is no consensus on the ideal prevention strategy for PN to date, so adequate management is key.[49,50]
PN can present a variety of ways including numbness, tingling, burning, and pain and can worsen with repeat exposure to the offending agent. It is important to identify the presence of PN, dose reduce the offending agent if necessary, and consider an alternative agent if supportive therapy and dose reduction prove ineffective.
The American Society of Clinical Oncology (ASCO) practice guidelines for management of PN lists some pharmacologic interventions for patients experiencing PN. Duloxetine, a selective serotonin norepinephrine reuptake inhibitor should be considered in patients with painful neuropathy. Other agents such as the tricyclic antidepressants (amitriptyline and nortriptyline) and GABA analogs (gabapentin and pregabalin) can be considered as well for PN.[49,50]

Blood Pressure

Prior to starting a VEGF-inhibitor, patients should be screened for the presence of hypertension. If present, blood pressure should be stable and antihypertensives should be optimized.[51]
Early initiation of antihypertensives has been shown to reduce complications and prevent or minimize hypertension while continuing treatment.
While no specific antihypertensive agents provides superior control of bevacizumab-induced hypertension, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, beta blockers, and calcium channel blockers are among the commonly used agents for treatment of angiogenesis inhibitor-induced hypertension.[52] Bevacizumab should be temporarily suspended in patients with severe, uncontrollable hypertension and discontinued in the event of hypertensive crisis or hypertensive encephalopathy.
In cases of lenvatinib induced hypertension, dose adjustments should be considered if blood pressure is not managed with antihypertensives or if hypertension becomes recurrent or persistent.
Recommended lenvatinib dose reductions for endometrial cancer are as follows: 20 mg daily –> 14 mg daily –> 10 mg daily –> 8 mg daily.[53]

Mouth Sores

Mucositis is defined as mucosal damage due to cancer therapy (Liposomal doxorubicin) in the oral cavity; pharyngeal, laryngeal, and esophageal regions; and other areas of the gastrointestinal tract[54]
Prevention and patient education is key, this includes use of good oral hygiene (brushing with soft bristled toothbrushes), adopting a soft food diet, and avoiding crunchy or abrasive foods. Medicated mouth rinses may provide short-term relief to patients.[55]
Mucositis may require holding Liposomal doxorubicin until symptoms resolve, Liposomal doxorubicin dose reduction may be considered in severe or persistent cases.

Palmar Plantar Erythrodysethesia (PPE)

Palmar plantar erythrodysethesia is a skin toxicity that occurs in areas of compressed skin. It manifests mainly in the palms of the hands and the soles of the feet or in erythematous areas on the extremities. PPE is notably caused by liposomal doxorubicin[56]
Prevention and patient education is key, this includes reducing skin friction, avoidance of heat, use of emollients and creams. Corticosteroids (topical and oral) and nonsteroidal anti-inflammatory drugs (NSAIDs) can help to decrease the inflammatory response. [57] May require holding Liposomal doxorubicin until symptoms resolve, Liposomal doxorubicin dose reduction may be considered in severe or persistent cases.

Immunotherapy Related Toxicities

Since immune checkpoint inhibitors (ICI’s) work by manipulating the body’s immune system to mount a response against cancer cells, adverse events typically have a delayed onset and are inflammatory or autoimmune in nature.[58] The side effect profile is often related to the agent in question (PD-L1 inhibitor vs CTLA-4 inhibitor), whether the agent is given as monotherapy or as combination therapy, and whether the patient has underlying risk factors for immunotherapy related adverse events (irAE’s).[58,59]
In gynecologic malignancies, typically patients are treated with a single agent ICI (most commonly pembrolizumab). The most common adverse event with single agent PD-1/PD-L1 inhibitors is dermatologic malignancies (30-40%).[58,59] Other adverse events seen in these patients include colitis, endocrinopathies, hepatitis, and pneumonitis.[58,59]
The NCCN recommends using a grading scale for these adverse events and using this grade to guide treatment decisions.[59] Symptomatic management is often used first including topical corticosteroids for rash, antimotility agents in cases of diarrhea, and thyroid replacement in patients with hypothyroidism.
Systemic corticosteroids are often used when symptomatic management is ineffective, with immunosuppressants being used in certain cases.[59]

Ocular Toxicity

Tisotumab vedotin carries a unique black boxed warning for ocular toxicity. In the clinical trial, ocular toxicities reported included conjunctivitis, dry eye, keratitis, and ulcerative keratitis.[44]
Due to the potential of these ocular toxicities, the package insert recommends visual acuity test and slit lamp eye exam at baseline, prior to each cycle, and as clinically indicated. It is also recommended that patients be prescribed corticosteroid eye drops, vasoconstrictor eye drops, and lubricating eye drops.
Patients should be provided cold packs to place on their eyes for the duration of the infusion and use of contact lenses should be avoided during treatment.[60] Patients should be counseled extensively on all possible toxicities, ocular precautions, and use of the eye drops prior to starting treatment.

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