Gynecologic Malignancies-1

[heading] FOCUS POINTS [/heading]

Cervical Cancer

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Endometrial Cancer

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Ovarian Cancer

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Summary

  1. . Carboplatin/paclitaxel for 6 cycles (not 3 cycles,  IB, high-grade serous ovarian cancer)
  2. b. Observation:  IA grade 1 ovarian cancer
  3. c. Dose-dense paclitaxel IV + carboplatin IV followed by interval debulking surgery
  4. c. Carboplatin + paclitaxel followed by interval debulking surgery
  5. b. Niraparib 300 mg once daily
  6. a. Niraparib 300 mg once daily
  7. d. Olaparib 300 mg oral twice daily plus bevacizumab 15 mg/kg every 3 weeks (if bevacizumab is used neoadjuvant and HRD positive)
  8. b. Pegylated liposomal doxorubicin
  9. a. IV carboplatin + gemcitabine
  10. a. Carboplatin + pegylated liposomal doxorubicin
  11. B. Pembrolizumab is only appropriate if MSI-H or dMMR when there is no satisfactory alternative
  12. D. Stop infusion, start oxygen, administer H1 and H2 blocker and corticosteroid
  13. C. Chemoradiation
  14. A. Cisplatin 50 mg/m2 + paclitaxel 175 mg/m2 + bevacizumab 15 mg/kg
  15. b. Observation or vaginal brachytherapy
  16. c. Pelvic EBRT and brachytherapy
  17. a. Chemotherapy
  18. D. Males 9 to 21 years old and females 9 to 26 years old
  19. A. Chemotherapy with cisplatin, paclitaxel, and bevacizumab
  20. B. HPV 16 and 18
  21. D. Intravenous paclitaxel on day 1, intraperitoneal cisplatin on day 2,and intraperitoneal paclitaxel on day 8 of a 21-day cycle for six cycles
  22. Observation (low malignant potential)
  23. B. National Comprehensive Cancer Network (NCCN) guidelines recommend genetic testing given her personal history of ovarian cancer
  24. B. Adjuvant radiation therapy
  25. C. Recommend age-appropriate colon cancer screening and immunohistochemical staining of tumor tissue for MLH1, MSH2, MSH6, and PMS2. Refer for genetic counseling if protein stains are absent
  26. A. Hormonal therapy with an aromatase inhibitor
  27. A. Observation
  28. b. Olaparib 300 mg twice daily (somatic deleterious mutation in BRCA1)
  29. a. IV carboplatin + liposomal doxorubicin
  30. d. Olaparib 300 mg twice daily plus bevacizumab 15 mg/kg every 3 weeks
[heading] EXAM QUESTIONS AND ANSWERS [/heading]

JJ is a 57-year-old female who presented to the emergency department with 17 days of abdominal distention and 3 days of abdominal pain. Physical exam revealed a mass in her right lower abdomen. Laboratory results were notable for Hgb 7.1 g/dL and CA-125 of 212 U/mL. Ultrasound confirmed the mass and imaging ruled out distant metastases. The patient is clinically staged with IB, high-grade serous ovarian cancer and underwent adequate surgical cytoreduction and staging.

Which of the following is the most appropriate management for JJ at this time?

The correct answer is C.

  • Six cycles of platinum-based combination chemotherapy are recommended as adjuvant therapy for patients with early stage, high-grade serous ovarian cancer.
  • Answer A is incorrect based on the subgroup analysis of GOG-157 exhibiting favorable recurrence free survival with six over three cycles for high-grade serous histology.
  • Answer B is incorrect because observation is only appropriate for stage IA/IB, low-grade serous or grade 1 of other histology.
  • Answer D is incorrect because bevacizumab -based combination therapies are not currently recommended for stage I disease; these may be utilized for stage II-IV disease.

JJ is a 57-year-old female who presented to the emergency department with 17 days of abdominal distention and abdominal pain for the past 3 days. Physical exam revealed a mass in her right lower abdomen. Laboratory results were notable for Hgb 7.1 g/dL and CA-125 of 212 U/mL. Ultrasound confirmed the mass and imaging ruled out distant metastases. The patient is eventually clinically staged with IA grade 1 ovarian cancer and underwent adequate surgical cytoreduction and staging.

Which of the following is the most appropriate management for JJ at this time?

Answer: b. Observation

The correct answer is B. Observation is recommended in patients with stage IA or IB disease who have been appropriately staged by a gynecologic oncologist as survival is >90% in this group with surgery alone.
Answers A and D are not appropriate treatment options for JJ as neoadjuvant chemotherapy and hormone therapy are not indicated in early stage disease. Also, the patient already underwent surgical staging and debulking so neoadjuvant therapy is not an appropriate option.
Answer C, adjuvant chemotherapy could be considered if the patient did not undergo adequate surgical staging. JJ did undergo appropriate surgical staging, so observation alone is appropriate.

SM presents for a pelvic ultrasound that confirms a left adnexa mass 3 x 2.6 x 2.3cm and subsequent biopsy reveals high-grade serous carcinoma. Additional staging confirms SM has clinical stage IVB (pleural effusions and liver lesions) ovarian cancer and is deemed upon imaging and in consultation with surgery to be unlikely to be optimally cytoreduced. Which of the following is the most appropriate initial therapy for SM?

The correct answer is C.

SM presents for a pelvic ultrasound that confirms a left adnexa mass 3 x 2.6 x 2.3 cm and subsequent biopsy reveals high-grade serous carcinoma. Additional staging confirms SM has clinical stage IVB (pleural effusions and liver lesions) ovarian cancer and is deemed upon imaging and in consultation with surgery to be unlikely to be optimally cytoreduced. Which of the following is the most appropriate initial therapy for SM?

The correct answer is C.

SM completed 3 cycles of neoadjuvant chemotherapy, underwent interval debulking surgery attaining optimal cytoreduction, and subsequently completed 3 more cycles of adjuvant chemotherapy with paclitaxel and carboplatin, achieving a complete response. Germline and tumor genetic testing were completed and no BRCA1/2 pathogenic alterations were reported. SM would like to pursue maintenance therapy. Which of the following would you recommend?

Correct answer is B.

  • Niraparib is the only PARP inhibitor approved for primary maintenance therapy following a CR or PR to platinum-based chemotherapy, independent of BRCA status.
  • Answer A is not appropriate because bevacizumab maintenance therapy should be reserved for patients who received bevacizumab-containing primary therapy as per GOG-218 or ICON-7.
  • Answer C is not appropriate because olaparib is recommended for use in patients with either somatic or germline deleterious or suspected deleterious BRCA1/2 alterations who are in a CR or PR to primary platinum-based chemotherapy.
  • Answer D is not as appropriate because niraparib primary maintenance therapy is approved for use in patients independent of BRCA status.

SM completed 3 cycles of neoadjuvant chemotherapy, underwent interval debulking surgery attaining optimal cytoreduction, and subsequently completed 3 more cycles of adjuvant chemotherapy with paclitaxel, carboplatin, and bevacizumab. Her response to therapy was a partial response (PR) and following germline genetic testing, she was found to be BRCA-wt. SM underwent additional tumor next generation sequencing and was found to be HRD negative. SM would like to pursue maintenance therapy. Which of the following would you recommend?

Correct answer is A.

  • Based on the PRIMA data niraparib was found to have a progression free survival benefit in all patients with a CR/PR to platinum-based therapy in the frontline setting. In the NCCN guidelines this is a category 2A recommendation as the progression free survival is minimal and would be a risk benefit discussion with the patient but given that she is interested in maintenance therapy it is an option for the patient.
  • Answer B is not appropriate because rucaparib is not currently recommended for primary maintenance therapy; however, it may be used as recurrent platinum-sensitive maintenance therapy or for treatment of recurrent disease after at least 2 prior lines of therapy.
  • Answer C is not correct because olaparib for frontline maintenance therapy requires that the patient have a germline or somatic deleterious BRCA mutation.
  • Answer D is incorrect because olaparib plus bevacizumab is only recommended in patients with BRCA mutated or HRD positive ovarian cancer in the frontline. This patient is BRCAwt and HRD negative.

SM completed 3 cycles of neoadjuvant chemotherapy, underwent interval debulking surgery attaining optimal cytoreduction, and subsequently completed 3 more cycles of adjuvant chemotherapy with paclitaxel, carboplatin, and bevacizumab. Her response to therapy was a partial response (PR) and following germline genetic testing, she was found to be negative for pathogenic/likely pathogen BRCA 1/2 mutations. SM underwent additional tumor next generation sequencing and was found to be homologous recombination deficient (HRD). SM would like to pursue maintenance therapy. Based on the NCCN guidelines which of the following would you recommend?

Correct answer is D

SM presents to clinic after 3 months of niraparib maintenance therapy. Her adjuvant chemotherapy was complicated by grade 2 peripheral neuropathy. She presents today with worsening abdominal distension. A CT scan was completed revealing new lymphadenopathy and confirmed disease recurrence.

Which of the following regimens is most appropriate for SM?

Correct answer is B.

  • SM experienced progression of disease 3 months following completion of initial platinum-based adjuvant chemotherapy, indicating a platinum-resistant recurrence. Pegylated liposomal doxorubicin monotherapy is a category 2A, preferred therapy for platinum-resistant recurrence.
  • Answer A is inappropriate as this a platinum-resistant recurrence, as such platinum-based regimens are no longer preferred.
  • Answer C is inappropriate as combination niraparib/bevacizumab should be reserved for platinum-sensitive recurrence, as a conventional chemotherapy sparing treatment option based on the AVANOVA2 trial.
  • Answer D is inappropriate as pembrolizumab is currently only approved for advanced solid tumors, including ovarian cancer, with dMMR, MSI, or TMB-h. This tumor was not determined to be dMMR by immunohistochemistry testing based on the information provided.

SM presents to clinic 2 years after completing adjuvant chemotherapy which was complicated by grade 2 peripheral neuropathy. She has remained on niraparib maintenance but due to recent symptoms of abdominal distension, a CT scan was completed revealing new lymphadenopathy and confirmed disease recurrence. SM states that she is concerned about worsening peripheral neuropathy with receiving treatment again.

Which of the following regimens is most appropriate for SM?

Correct answer is A.

  • Although carboplatin could worsen the patient’s peripheral neuropathy, platinum-based combination chemotherapy is recommended for patients with platinum-sensitive disease. Carboplatin can be given with either gemcitabine or liposomal doxorubicin +/- bevacizumab in lieu of paclitaxel to prevent further exacerbation of peripheral neuropathy.
  • Answer B is inappropriate as the patient had grade 2 neuropathy with previous treatment and explicitly expressed concern regarding this potential adverse effect. Therefore, exposing her to paclitaxel again is not ideal.
  • Answer C is inappropriate therapy for a patient with platinum-sensitive disease in the first relapse. This could be considered in a patient with platinum-resistant disease.
  • Answer D is inappropriate as cisplatin would be expected to cause more neuropathy than carboplatin.

SM presents to clinic after 10 months of olaparib plus bevacizumab maintenance therapy. Her adjuvant chemotherapy was complicated by grade 2 peripheral neuropathy. She presents today with worsening abdominal distension. A CT scan was completed revealing new lymphadenopathy and confirmed disease recurrence. Which of the following regimens is most appropriate for SM?

Correct answer is A.

  • SM experienced progression of disease 10 months following completion of initial platinum-based adjuvant chemotherapy, indicating a platinum-sensitive recurrence. Answer A is the only option that includes a platinum agent. Given the presence of neuropathy you would not want to go back to paclitaxel in combination with carboplatin. Carboplatin plus pegylated liposomal doxorubicin is a category 2A preferred regimen for platinum-sensitive recurrent ovarian cancer.
  • Answer B is inappropriate as this a platinum-sensitive recurrence, as such the patient should continue to receive a platinum combination therapy, if able to tolerate.
  • Answer C is inappropriate as mirvetuximab is only currently approved in platinum-resistant ovarian cancer. Additionally, we do not know the patient’s folate receptor status to know if she qualifies for this therapy.
  • Answer D is inappropriate as pembrolizumab is currently only approved for advanced solid tumors, including ovarian cancer, with dMMR, MSI, or TMB-h. This tumor was not determined to be dMMR by immunohistochemistry testing based on the information provided.

SM has now received 5 lines of chemotherapy, most recently topotecan monotherapy. She unfortunately complains of worsening abdominal pain and is confirmed to have progressive disease. She inquires about immunotherapy for treatment of ovarian cancer.

Which of the following is true?

The correct answer is B.

  • Pembrolizumab should be reserved for treatment of relapsed ovarian cancer that is MSI-H or dMMR in which there are “no satisfactory alternatives”.
  • Answer A is incorrect as pembrolizumab is the only PD-1 inhibitor FDA approved for MSI-H solid tumors
  • Answer C is incorrect as pembrolizumab is not appropriate for maintenance therapy. The recommended agents for maintenance following platinum-based therapy in recurrent disease are olaparib, rucaparib, and niraparib.
  • Answer D is incorrect because patients with platinum-sensitive relapse should continue to receive platinum-based therapy as they are able. Platinum-sensitive relapse would not qualify as having “no satisfactory alternative”.

During SM’s initial adjuvant chemotherapy with paclitaxel and carboplatin following interval debulking surgery, she experienced a severe hypersensitivity reaction on cycle 6 of carboplatin, characterized by cough and shortness of breath.

Which of the following is the proper management of a severe platinum hypersensitivity reaction?

  • A. Stop infusion, give corticosteroid, monitor for 30 minutes and resume at a slower rate
  • B. Stop infusion, start oxygen and observe
  • C. Administer IM epinephrine
  • D. Stop infusion, start oxygen, administer H1 and H2 blocker and corticosteroid

Correct answer is D.

  • Stopping the offending agent in any hypersensitivity reaction is the first step along with appropriate pharmacologic intervention which includes both H1 and H2 antagonists to stop the acute hypersensitivity reaction and steroid to prevent a delayed or rebound reaction.
  • Answer A is not correct as steroids alone do not provide immediate benefit in management of an acute hypersensitivity reaction; rather corticosteroids prevent rebound or delayed reactions.
  • Answer B is inappropriate as a pharmacologic intervention is needed to stop the hypersensitivity reaction.
  • Answer C is missing the most important step of stopping the offending agent as well as providing oxygen. Additionally, this is not reported to be a life threatening or anaphylactic reaction and other interventions should be considered first.

DD is a 55 year-old-female, ECOG status 0 who presents with complaints of severe fatigue, 6 months of post-menopausal bleeding and lab work revealing a Hgb of 7.8 g/dL. A pelvic ultrasound and endometrial biopsy reveal non-keratinizing squamous cell carcinoma, invasive, moderately to poorly differentiated, consistent with cervical origin. Surgical staging reveals a cervical lesion ~2 cm in diameter and firm with the uterus and cervix deviated left. On rectovaginal exam, there is left parametrium tethering and there is thickening of the parametrium, consistent with parametrial invasion. Cystoscopy and vaginal exam are normal. Unfortunately, imaging reveals rectal involvement not appreciated on exam; therefore, she has stage IVA cervical cancer.

What management options are available for this patient?

Correct answer is C.

  • Given the local metastatic disease, the therapy of choice would be primary chemoradiation. Therefore, the treatment will include external beam whole pelvic radiation therapy plus chemosensitization with weekly cisplatin 40 mg/m2 IV followed by high-dose rate brachytherapy.
  • Answer A is not the most appropriate treatment option as DD has stage IVA disease and therefore is not a surgical candidate.
  • Answers B and D as single modality therapy would not be the most appropriate treatment options as multiple trials have demonstrated the risk of death from cervical cancer is decreased by 30% to 50% by the addition of concurrent cisplatin to pelvic radiation.

DD completed successful chemoradiation and has been under active surveillance. DD presents to her 2-year follow-up feeling great and her only complaint is a new onset of a persistent dry cough. A CT of her chest is notable for diffuse pulmonary nodules, consistent with metastatic cervical cancer. PD-L1 testing was attempted on a prior tissue sample but failed.

Which of the following every 3 week treatment options would be most appropriate for DD according to the NCCN Guidelines?

Correct answer is A.

SK is a 64-year-old morbidly obese woman who presents to the emergency department complaining of one month of post-menopausal vaginal bleeding. Her last menstrual period was in 2005, and she has a history of estrogen therapy for 6 months in 1990s following heavy menstrual bleeding. She has never had children. The emergency department obtained a pelvic ultrasound, which demonstrated endometrial thickening at 4.5 mm. She is referred to OB/GYN who performs a colposcopy with endometrial biopsies at 10 and 2, which reveal FIGO grade 1 endometrioid adenocarcinoma as well as cervical intraepithelial neoplasia grade 1 at 10.

SK undergoes primary surgical management with a total laparoscopic hysterectomy and bilateral salpingo-oophorectomy, bilateral pelvic and para-aortic lymphadenectomy and biopsies. Her final pathology reveals a grade 1 endometrioid adenocarcinoma of the endometrium with tumor diameter 2.6x2.1x1.1 cm, depth of invasion 1.1 cm, into a 1.7 cm myometrium (more than one-half invasion), negative cervix, adnexa, and pelvic washing. There is no lymphovascular space invasion and negative lymph nodes.

What further therapy, if any, should SK receive?

Correct answer is B.

  • SK has early stage IB, grade 1 endometrial cancer (tumor invades more than one-half the myometrium). Given her low-risk, early-stage disease, and no known adverse risk factors, observation or vaginal brachytherapy is recommended.
  • Answer A, C and D are inappropriate as the patient has low-risk, early-stage disease and chemotherapy and anti-hormonal therapy would only be appropriate for advanced endometrial cancer.

SK has been appropriately undergoing active surveillance with visits every three to six months for the past 2 years. She is generally feeling well, but she does report intermittent bleeding. Upon further work-up SK is found to have local recurrence confined to the vagina.

Which of the following is the most appropriate treatment for SK at this time?

Correct answer is C.

  • SK has local recurrence confined to the vagina. Since she has not had prior radiation or brachytherapy to the site of recurrence, SK is eligible for pelvic EBRT plus brachytherapy or surgical exploration + resection. Isolated vaginal recurrences treated with radiation therapy alone have good local control with 5-year survival rates of 50 to 70%.
  • Answer A would not be most appropriate as intraoperative radiation therapy is a NCCN Guidelines category 3 recommendation.
  • Answer B and D would not be appropriate as chemotherapy and hormone therapy are considered for patients with local recurrence who have previously undergone previous external beam radiation therapy.

SK received EBRT and brachytherapy followed by active surveillance. At her follow-up she reports feeling well, other than shortness of breath she contributes to an ongoing cold. Unfortunately, laboratory tests show an elevated CA-125 and prompting imaging which reveals lung, pelvic and para-aortic metastases.

Which of the following is the most appropriate treatment for SK at this time?

Correct answer is A

  • SK has symptomatic disseminated metastases; therefore, chemotherapy would be most appropriate at this time.
  • Answer B would not be most appropriate as hormone therapy would only be considered in a patient with asymptomatic disseminated metastases or poor performance status.
  • Answer C and D would not be appropriate as SK has disseminated metastases and according to the NCCN Guidelines pharmacologic intervention is most appropriate.

It is recommended that a human papillomavirus (HPV) vaccine series be administered to which of the following patient populations:

  • A. Only males 9 to 21 years old
  • B. Only females 9 to 26 years old
  • C. All sexually active women
  • D. Males 9 to 21 years old and females 9 to 26 years old
  • E. It is not recommended as routine vaccination for any patients

Answer: D. Males 9 to 21 years old and females 9 to 26 years old

  • The Centers for Disease Control and Prevention recommends that an HPV vaccine series (consisting of three shots) be administered to males aged 9 to 21 and females aged 9 to 26 years. The preferred age for vaccination is 11 or 12 years old.
  • Males who are at high risk for HPV infection (homosexual, immunosuppressed) should receive a vaccination series up to age 26 if they have not been previously vaccinated.

A 32-year-old woman presents with stage IVB squamous cell carcinoma of the cervix. Preferred first-line treatment is:

Answer: A. Chemotherapy with cisplatin, paclitaxel, and bevacizumab.

The correct answer is A. Chemotherapy with cisplatin, paclitaxel, and bevacizumab.

According to the sources, the management of cervical cancer is determined by its stage, and Stage IVB is classified as distant metastatic disease.

  • Rationale for Chemotherapy (Option A): For patients with Stage IVB cervical cancer, the goal of therapy shifts from cure to palliation of symptoms and prolonging survival. Platinum-based combination chemotherapy is the standard of care for advanced (IVB) or recurrent disease. Specifically, the combination of cisplatin, paclitaxel, and bevacizumab is a preferred first-line regimen and an NCCN Category 1 recommendation based on phase III data (GOG-240) showing improved overall survival compared to chemotherapy alone.
  • Why Surgery (Options B and D) is incorrect: Surgery (including radical or simple hysterectomy) is generally reserved for early-stage disease (Stage I–IIA) and does not play a role in the primary treatment of metastatic Stage IVB disease.
  • Why Chemoradiation (Option C) is incorrect: While pelvic radiation with chemosensitization is the standard of care for locally advanced disease (bulky Stage IIB, III, and IVA), it is not the primary frontline treatment for distant metastatic Stage IVB disease, which requires systemic therapy. Radiation in Stage IVB is typically individualized and used for the palliation of specific symptoms or isolated metastases.

The majority of cervical cancer worldwide is believed to be secondary to infection with which strains of the human papillomavirus (HPV)?

  • A. HPV 6 and 11
  • B. HPV 16 and 18
  • C. HPV 34 and 36
  • D. HPV 56 and 62

Answer: B. HPV 16 and 18.

While HPV 6 and 11 are responsible for the majority of genital and anal warts, HPV 16 and 18 are believed to be associated with ~70% of cases of cervical cancer. In addition to cervical cancer, HPV infection is believed to be responsible for 90% of anal cancers; 71% of vulvar, vaginal, or penile cancers; and 72% of oropharyngeal cancers.

A 63-year-old woman presents with abdominal pain and bloating. Abdominal ultrasound demonstrates a complex adnexal mass and ascites. She undergoes a total abdominal hysterectomy, bilateral salpingo-oophorectomy, lymphadenectomy, and omental biopsies, which demonstrate bilateral ovarian tumors with lymph node involvement, omental caking, and ascites. Tumor was debulked to less than 1 cm of residual disease. Pathology demonstrates high-grade serous adenocarcinoma. She has recovered well from surgery and has no significant comorbidities. What is the next best step in treatment?

Answer: D. Intravenous paclitaxel on day 1, intraperitoneal cisplatin on day 2, and intraperitoneal paclitaxel on day 8 of a 21-day cycle for six cycles

In women with stage III “optimally debulked” (<1 cm of residual disease) high-grade epithelial ovarian cancer who are otherwise fit, intraperitoneal chemotherapy is recommended based on the overall survival benefit of 16 months demonstrated in GOG172 compared to standard platinum-based intravenous therapy.

5-A 42-year-old woman presents with a pelvic mass. Surgical staging demonstrates a 5 cm ovarian mass with capsular rupture and multiple peritoneal implants without evidence of invasion. She is optimally debulked with less than 1 cm of residual disease. Pathology demonstrates an epithelial serous ovarian tumor of low malignant potential. The patient recovers well from surgery and presents to discuss adjuvant treatment options. Which of the following is the best next step?

Answer:  C. Observation

The correct answer is C. Observation.

Based on the sources, the management for this patient is guided by her specific pathology:

  • Prognosis of LMP Tumors: The patient was diagnosed with an epithelial serous ovarian tumor of low malignant potential (LMP), also known as a borderline malignancy. The sources explicitly state that these tumors are associated with a good prognosis.
  • Rationale for Observation: Unlike invasive epithelial ovarian cancers (such as high-grade serous carcinoma), borderline tumors have a very low risk of aggressive recurrence when they are non-invasive. Even though this patient has peritoneal implants and capsular rupture, the absence of invasive disease and the achievement of optimal debulking (< 1 cm residual disease) mean that adjuvant chemotherapy or targeted therapies are not typically indicated.
  • Comparison to Invasive Cancer Treatment:

Because the pathology is borderline (LMP) and the surgery was successful in removing gross disease, observation is the most appropriate next step.

A 49-year-old woman presents for follow-up. She was diagnosed at age 43 with high-grade serous adenocarcinoma of the ovary and has had multiple recurrences. She is currently undergoing treatment with her third line of chemotherapy. She denies a family history of breast or ovarian cancer. Which of the following is correct?

Answer: B. National Comprehensive Cancer Network (NCCN) guidelines recommend genetic testing given her personal history of ovarian CANCER:

NCCN recommends genetic testing for all women diagnosed with ovarian cancer, regardless of family history. Olaparib, a (PARP) inhibitor, has recently been approved by FDA for the treatment of recurrent ovarian cancer in women with germline BRCA1/2 mutations. Therefore, mutational status may affect this patient’s treatment options. BRCA1/2 mutations are associated with a better prognosis and are predictive of response to platinum therapy. BRCA1 mutations convey a higher risk of earlier onset of ovarian cancer compared to BRCA2 mutations

A 71-year-old otherwise healthy female presents with postmenopausal bleeding. Endometrial biopsy demonstrates adenocarcinoma. Surgical staging, including total abdominal hysterectomy, bilateral salpingo-oophorectomy, and lymphadenectomy, was performed. Pathology demonstrates a 2.3 cm grade 1 endometroid adenocarcinoma invading 1.2 cm into a 2 cm myometrium with positive lymphovascular invasion. The disease was confined to the uterus without cervical involvement.

What is the next step in treatment?

The correct answer is B. Adjuvant radiation therapy.

Based on the sources, the management for this patient is determined by her surgical stage, grade, histology, and the presence of specific risk factors:

  • Staging: The patient has Stage IB endometrioid endometrial cancer because the tumor is confined to the uterus but invades more than one-half of the myometrium (1.2 cm invasion into a 2 cm myometrium).
  • Risk Factors: While she has a Grade 1 (well-differentiated) tumor, she possesses several high-intermediate risk factors, including older age (71 years), deep myometrial invasion (> 50%), and positive lymphovascular space invasion (LVSI).
  • Rationale for Radiation: According to the sources, the preferred adjuvant treatment for Stage IB, Grade 1 or 2 endometrioid endometrial cancer is vaginal brachytherapy (a form of radiation therapy). Adjuvant radiation is used in patients deemed to be at high risk for recurrence to reduce the risk of local pelvic relapse.
  • Why other options are incorrect:
    • Observation (Option A): While observation may be considered for low-risk Stage IA patients (Grade 1/2 with no LVSI), it is generally not the preferred next step for a Stage IB patient with multiple risk factors like LVSI and advanced age.
    • Adjuvant Chemotherapy (Option C): Adjuvant systemic therapy is typically reserved for patients with advanced-stage disease (Stage III–IV) or those with high-grade (Grade 3) Stage IB/II tumors. For a Stage IB Grade 1 tumor, chemotherapy is not the standard primary adjuvant therapy.
    • Concurrent Chemoradiation (Option D): This modality is standard for locally advanced cervical cancer (e.g., Stage IVA) but is not a standard primary adjuvant recommendation for Stage I endometrioid endometrial cancer.

A 56-year-old woman recently diagnosed with endometrial cancer presents to discuss recommended genetic screening. She was adopted and does not know any of her family history. She has not had a colonoscopy.

Which of the following is true?

  • A. No further testing is recommended
  • B. Recommend age-appropriate colon cancer screening and immunohistochemical staining of tumor tissue for MLH1, MSH2, MSH6, and PMS2. Refer for genetic counseling if protein stains are retained
  • C. Recommend age-appropriate colon cancer screening and immunohistochemical staining of tumor tissue for MLH1, MSH2, MSH6, and PMS2. Refer for genetic counseling if protein stains are absent
  • D. Recommend germline BRCA 1/2 testing

Answer: C. Recommend age-appropriate colon cancer screening and immunohistochemical staining of tumor tissue for MLH1, MSH2, MSH6, and PMS2.

Refer for genetic counseling if protein stains are absent, Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome is found in ~5% of women with endometrial cancer. It is a syndrome characterized by loss of DNA mismatch repair proteins including MLH1, MSH2, MSH6, and PMS2. Immunohistochemistry of tumor tissue looking for loss of these mismatch repair proteins is an accepted initial screening method to identify women who should be referred for germline genetic testing.

A 68-year-old female presents with biopsy-proven recurrent grade 1 endometrioid endometrial adenocarcinoma metastatic to the lung and pelvis. Tumor tissue stains positive for estrogen receptor (ER). She is asymptomatic from her current disease. She has residual peripheral neuropathy from her previous adjuvant carboplatin and paclitaxel chemotherapy completed 1 year ago.

What is the most appropriate next step in management?

Answer: A. Hormonal therapy with an aromatase inhibitor

Hormonal therapy (ie, aromatase inhibitors, megestrol, or tamoxifen) is a well-tolerated treatment in women with low-grade metastatic endometrial cancer, especially with ER positivity. Hormonal therapy is most appropriate in women without large symptom burden or rapidly growing disease as it is most effective in controlling and/or slowing disease growth

A 58-year-old woman is diagnosed with a 1 cm grade 1 endometrioid endometrial cancer after undergoing a total abdominal hysterectomy and bilateral salpingo-oophorectomy for presumed benign indications. Disease invaded 0.2 cm into a 2 cm myometrium without lymphovascular invasion.

What is the next best step in treatment?

Answer: A. Observation

Observation is appropriate in this case (stage la, grade1, no lymphovascular space involvement [LVS], and tumor <2 cm), given the low risk for disease recurrence. Further lymph node assessment is not needed for this early-stage tumor, given the very low risk of nodal involvemen

SM completed 3 cycles of neoadjuvant chemotherapy, underwent interval debulking surgery attaining optimal cytoreduction, and subsequently completed 3 more cycles of adjuvant chemotherapy with paclitaxel and carboplatin, achieving a partial response. Her tumor was also sent for genetic testing and was found to have a somatic deleterious mutation in BRCA1. SM would like to pursue maintenance therapy. Which of the following would you recommend?

Answer: b. Olaparib 300 mg twice daily

Correct answer is B. Olaparib is the only PARP inhibitor approved for primary maintenance therapy following a CR or PR to platinum-based chemotherapy.
Answer A is not appropriate because bevacizumab maintenance therapy should be reserved for patients who received bevacizumab-containing primary therapy as per GOG-218 or ICON-7.
Answer C is not appropriate because niraparib is not approved for primary maintenance therapy. Niraparib may be used in the maintenance setting following a CR or PR to platinum-based therapy for recurrent ovarian cancer.
Answer D is not as appropriate because olaparib primary maintenance therapy is approved for use in patients with both germline and somatic BRCA mutations.

SM presents to clinic 15 months after completing adjuvant chemotherapy which was complicated by grade 2 peripheral neuropathy. She has remained on olaparib maintenance but due to recent symptoms of abdominal distension, a CT scan was completed revealing new lymphadenopathy and confined disease recurrence. SM states that she is concerned about worsening peripheral neuropathy with receiving treatment again. Which of the following regimens is most appropriate for SM?

Answer: a. IV carboplatin + liposomal doxorubicin

Correct answer is A. Although carboplatin could worsen the patient's peripheral neuropathy, platinum-based combination chemotherapy is recommended for patients with platinum-sensitive disease. Carboplatin would be preferred over cisplatin with regard to potential for exacerbating peripheral neuropathy.

  • Answer B is inappropriate as the patient had grade 2 neuropathy with previous treatment and explicitly expressed concern regarding this potential adverse effect. Therefore, exposing her to a taxane again is not ideal.
  • Answer C is inappropriate therapy for a patient with platinum-sensitive disease in the first relapse. This could be considered in a patient with platinum-resistant disease.
  • Answer D is inappropriate as cisplatin would be expected to cause more neuropathy than carboplatin.

SM completed 3 cycles of neoadjuvant chemotherapy, underwent interval debulking surgery attaining optimal cytoreduction, and subsequently completed 3 more cycles of adjuvant chemotherapy with paclitaxel, carboplatin, and bevacizumab. Her response to therapy was a partial response (PR) and following germline genetic testing, she was found to be BRCA-wt. SM underwent additional tumor next generation sequencing and was found to be HRD negative. SM would like to pursue maintenance therapy.

Which of the following would you recommend?

Based on the clinical scenario described, the most appropriate recommendation for maintenance therapy is: d. Olaparib 300 mg twice daily plus bevacizumab 15 mg/kg every 3 weeks

Explanation:

This patient has stage III ovarian cancer and achieved a partial response (PR) to primary platinum-based chemotherapy that included bevacizumab. Her tumor is BRCA-wildtype and HRD-negative.

  • The PAOLA-1 clinical trial is the key evidence for this scenario. This trial demonstrated that for patients who receive first-line platinum-based chemotherapy with bevacizumab and achieve a complete or partial response, the combination of olaparib plus bevacizumab as maintenance therapy significantly improved progression-free survival compared to bevacizumab alone.
  • This benefit was observed not only in patients with BRCA mutations or HRD-positive tumors but also, to a lesser yet still significant degree, in the overall population, which includes HRD-negative patients like this one.
  • Continuing bevacizumab as part of maintenance therapy is the standard of care following a bevacizumab-containing frontline regimen (as established by trials like GOG-218 and ICON7). The PAOLA-1 trial builds on this by adding olaparib for additional benefit.

Why the other options are incorrect:

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