Recurrent Ovarian Cancer with BRCAness Phenotype: A Treatment Challenge

Case 1

A fit and apparently healthy 55-year-old woman with no relevant medical or family history presented with a 3-week history of abdominal pain and distention. Computed tomography (CT) scan of the thorax, abdomen, and pelvis revealed multiple peritoneal implants (the largest being 5.3 × 4.2 cm in the pelvic cavity), bilateral ovarian masses (both 4.5 × 4 cm), and suspicious peri-aortic lymphadenopathies. Laboratory tests showed increased levels of cancer antigen 125 (CA-125; 750 U/mL) and normocytic/normochromic anemia (hemoglobin [Hb] 10.6 g/dL).

The patient underwent primary debulking surgery with hysterectomy, bilateral salpingo-oophorectomy, complete omentectomy, lymphadenectomy of the suspicious lymph nodes, excision of peritoneal implants and an implant located on the duodenum wall, and ascitic cytology. The anatomopathological examination led to the diagnosis of bilateral ovarian serous cystadenocarcinoma with multiple peritoneal pelvic and extra-pelvic implants, malignant ascites, and macroscopic residual tumor invading the margins (International Federation of Gynaecology and Obstetrics [FIGO] stage IIIC R2). Post-surgery CT scan revealed a paraduodenal mass with no other suspicious lesions, and laboratory tests showed a CA-125 of 338 U/mL.

The patient was proposed for adjuvant chemotherapy. She completed six 3-week cycles of gemcitabine 800 mg/m2 on days 1 and 8 and carboplatin AUC 5 on day 1 in combination with bevacizumab 15 mg/kg body weight, which was maintained for 22 cycles. No relevant toxicities were reported. After five cycles, complete remission of the duodenal metastasis and CA-125 normalization were achieved. The patient did well for the first 15 months following the last platinum administration, then the CA-125 level began to rise (69.2 U/mL), and thorax, abdomen, and pelvis CT confirmed disease progression, with three de novo lymph nodes in the pelvic cavity. The patient started first-line palliative chemotherapy with 3-week cycles of paclitaxel 175 mg/m2 and carboplatin AUC 6. After six cycles, complete imagiological response was achieved. However, the patient presented peripheral sensory neuropathy grade 3 on both feet and grade 2 on the hands, and chemotherapy was suspended.

Approximately 6 months later, disease progression was documented by biochemical (increased CA-125 to 140 U/mL) and imagiological methods, with multiple hepatic lesions, lymph nodes, and peritoneal implants. The patient started second-line palliative chemotherapy with 3-week trabectedin 1.1 mg/m2 and pegylated liposomal doxorubicin 30 mg/m2. After nine treatment cycles, partial response was achieved, but grade 3 neutropenia and grade 3 cholestasis prompted doxorubicin suspension, and the patient maintained only trabectedin monotherapy. After three cycles, disease progression was again documented, and the patient received doxorubicin monotherapy, but after three more cycles, the disease again progressed with peritoneal carcinomatosis and lymph nodes.

At this time, the patient was tested for germline BRCA mutations, with a negative result, and started on 3 weeks of gemcitabine 800 mg/m2 on days 1 and 8 and carboplatin AUC 5 on day 1. After six cycles of gemcitabine and carboplatin with partial response and good tolerability, she started maintenance therapy with niraparib 300 mg daily. The patient has currently maintained niraparib therapy for 15 months, with stable disease and manageable toxicity (mainly grade 2 fatigue).

Case 2

A 71-year-old woman presented with a 3-month history of diarrhea and progressive abdominal distention. More recently, she developed orthopnea and epigastric discomfort. She denied nausea or vomiting. On physical examination, the woman exhibited signs of large-volume ascites and bilateral malleolar edema, with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2.

Colonoscopy and endoscopy were performed, both without relevant findings. Thoracoabdominal-pelvic CT revealed peritoneal carcinomatosis and ascites but no signs of the primary tumor. Abdominal drainage was performed, and peritoneal fluid cytology revealed a carcinoma, not likely of pulmonary or intestinal origin (no CDX2 or TTF1 expression). CA-125 and CA-15.3 levels were elevated (395 and 321 U/mL, respectively). The gynecologic examination also showed no evidence of the primary tumor. Positron emission tomography (PET)/CT scan with 2-deoxy-2-[fluorine-18]fluoro-D-glucose (18F-FDG) confirmed diffuse peritoneal carcinomatosis with uptake in numerous lymph nodes, including the left retro-clavicular, mediastinal, left internal mammary, left inter-aorta-cava, and right external iliac. Guided biopsy of one of these sites was proposed, but no visible lesion amenable to the procedure was identified on CT scan.

At this point, the form of presentation and exclusion of most common digestive tumors in a female patient favored the diagnosis of ovarian or primary peritoneal carcinoma. Although other etiologies could not be completely excluded, treatment of an occult primary tumor was started accordingly.

Considering the patient’s age and PS, treatment with carboplatin AUC 2 and paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28-day cycle was initiated. The last abdominal drainage was performed 4 days before treatment initiation and was not necessary again. Pelvic magnetic resonance imaging (MRI) was performed before cycle two, revealing only small-volume ascites and right external iliac nodes, the most prominent being 11 × 8 and 10 × 6 mm. After six cycles, tumor markers were within normal range, and the patient underwent exploratory laparoscopy, with identification of peritoneal carcinomatosis with ileum involvement. Histological testing suggested a carcinoma of gynecological origin, although a peritoneal primary could not be excluded. After 6 months of follow-up, abdominal-pelvic MRI showed numerous omental nodular lesions consistent with peritoneal carcinomatosis, right external iliac nodes (the largest being 23 mm), and a 14-mm nodule on the left flank. The patient received another six courses of the previous chemotherapy schedule, with complete response on MRI. At this point, niraparib therapy was started.

The patient remains on niraparib, having completed 17 months of treatment with no evidence of disease recurrence. At month 7, she reported insomnia and confusion episodes. After excluding cerebral metastases and electrolytic disturbances, the niraparib dose was reduced to 200 mg daily, with resolution of the complaints.

Case 3

A 62-year-old woman with a history of depression under treatment with escitalopram complained of decreased appetite, weight loss, and abdominal pain. Abdomen and pelvis CT revealed a left ovarian mass incarcerating part of the ileum and lombo-aortic and bilateral iliopelvic nodes, peritoneal carcinomatosis, and ascites. Guided biopsy of the major iliopelvic adenopathy revealed a lymph node metastasis morphologically and immunophenotypically compatible with high-grade serous ovarian carcinoma (CK7+, CK20-, PAX8+ , WT1+, p53+, RE+). Radiological assessment was concordant with non-resectable International Federation of Gynecology and Obstetrics (FIGO) stage IIIC ovarian cancer.

Perioperative platinum-based chemotherapy was started. After paclitaxel anaphylaxis during the first cycle, docetaxel was the taxane of choice. Interval cytoreduction was incomplete, with documented miliary disease throughout the entire parietal peritoneum. Even after postoperative platinum-based chemotherapy, persistent disease was identified in CT scan (peritoneal implants lining the liver capsule, diaphragm, and paracolic recesses). The patient was started on maintenance hormone therapy with exemestane. BRCA1/2 testing disclosed no pathogenic variants.

Nine months after the last platinum-based chemotherapy cycle, disease progression was observed by biochemical (CA-125) and radiological (new peritoneal implants and lymph nodes) methods, and platinum-based chemotherapy (cisplatin + gemcitabine) was resumed. Complete biochemical and partial radiological response (only residual peritoneal implants and pathological densification on the right vaginal apex) was observed, and maintenance therapy with niraparib 300 mg/day was initiated 7 weeks after chemotherapy conclusion.

During the first 6 months of niraparib maintenance therapy, grade 1 constipation was the only adverse event reported, and no dose reductions were required. No rise in CA-125 level was observed, and abdomen and pelvis CT confirmed sustained response with at least stable disease, with no new lesions or any increase of previous ones. During the seventh month of treatment, the patient presented with erythema of the chest and scapular regions compatible with photosensitivity and sunburn (Fig. 1) and with erythema and edema of the palms compatible with acral erythema (Fig. 2). Since no other drug had been prescribed, adverse skin reactions were attributed to niraparib, probably exacerbated by sun exposure and alcoholic skin disinfection related to SARS-CoV2 infection prophylaxis. Photoprotection and the use of sunscreen were started. One month later, slight erythema was still present on the palms (Fig. 3), and previous areas of hypersensitivity displayed brown spots compatible with solar lentigines (Fig. 4a, b). Sun avoidance measures were reinforced, emollients were initiated, and niraparib maintenance was continued with no dose reduction.

Fig. 1figure 1

Erythema of the chest and scapular regions compatible with photosensitivity and sunburn

Fig. 2figure 2

Erythema and edema of the palms compatible with acral erythema

Fig. 3figure 3

Slight erythema of the palms

Fig. 4figure 4

a, b Previous areas of hypersensitivity displaying brown spots compatible with solar lentigines

The patient currently remains on niraparib 300 mg daily, with documented stable disease.

Case 4

A 66-year-old woman presented with a growing complex cyst on the right ovary. She had a personal history of atrial fibrillation and glaucoma, and a family history of colon cancer diagnosed in her sister at the age of 74 and urologic cancer diagnosed in a second-degree cousin of the father at the age of 80.

The patient underwent hysterectomy, bilateral salpingo-oophorectomy, infracolic omentectomy, pelvic and para-aortic lymphadenectomy, and appendectomy. The histopathological evaluation reported a borderline serous tumor on the right ovary, grade 1, with neoplastic cells identified in peritoneal washings. The patient was maintained under surveillance.

Ten months later, a rise in CA-125 level was observed (185 U/mL), with no associated symptoms. A thoracoabdominal CT scan was performed, revealing a growing solid and heterogeneous nodular lesion of 43 × 31 mm on the right side of the vaginal dome, suggestive of an implant. Results of vaginal cytology, upper gastrointestinal endoscopy, and colonoscopy were unremarkable. Lesion biopsy disclosed a low-grade serous ovarian cancer consistent with ovarian cancer metastases. A FDG-PET scan was performed, revealing an abnormal single focus with significant FDG avidity corresponding to a mass on the right pelvic region near the right external iliac vessels, also consistent with tumor recurrence. Pelvic MRI confirmed previous findings of a solid mass suggestive of a tumor implant, 5.2 × 4.0 × 3.2 cm, in close contact with but apparently without invasion of other pelvic organs. Genetic testing revealed no pathogenic BRCA 1/2 variants.

The patient underwent resection of the pelvic mass near the vaginal dome, with identification of clear-cell ovarian carcinoma in most of the sample and some areas displaying borderline serous tumor. Peritoneal washing was negative for malignant cells, and the patient was proposed for adjuvant chemotherapy.

Two months later, the patient underwent ureteroneocystostomy and segmental colonic resection with anastomosis for closure of an ureterocolic fistula, and 1 month later she started chemotherapy with weekly carboplatin + paclitaxel, completing the six protocol-defined cycles with no evidence of active disease. However, hematological toxicity was observed, with grade 1/2 thrombocytopenia (69–76 × 109/L platelets) and grade 3 neutropenia (7.20–9.30 × 109/L neutrophils); this resulted in treatment cycle delay and the need for dose reduction. The CA-125 remained within the normal range after surgery and throughout chemotherapy. At this time, the patient was proposed for maintenance therapy with niraparib, starting on a daily dose of 200 mg due to previous toxicities.

Two months after starting niraparib, the patient developed grade 2 thrombocytopenia (73 × 109/L), and the drug was suspended for 3 weeks to enable hematological recovery. It was then resumed at the reduced dose of 100 mg daily, which the patient currently maintains.

The patient has been regularly evaluated since, remaining asymptomatic, with good PS and quality of life. Approximately 8 months after starting niraparib, she has no evidence of disease activity (normal CA-125 and radiological assessment with no signs of recurrence/metastases).

Case 5

A 53-year-old woman with no relevant personal or family history presented a pelvic mass during a routine gynecology appointment. She had no complaints or associated symptoms.

An ultrasound examinationt revealed a complex cystic and dense pelvic mass on both ovaries. Blood tests showed elevated CA-125 (1386 U/L). A subsequent thoracoabdominopelvic CT scan confirmed the presence of a complex pelvic mass with dimensions 16 × 14 × 13 cm, both cystic and solid, involving both ovaries and the uterus, as well as multiple nodules throughout the abdominal cavity compatible with peritoneal implants. Metastatic disease involving the liver (3 hypovascular nodes) and spleen (8 splenic hypovascular nodes) was also detected. CT-guided biopsy of a hepatic lesion revealed an adenocarcinoma CK7+, CK20-, intense and diffuse estrogen receptor-positive, Ca-125+, CDX2-, TTF1-, and P53-, and the patient was diagnosed with stage IV hormone receptor-positive, high-grade ovarian papillary serous cystadenocarcinoma.

The patient received three cycles of platinum-based (carboplatin + paclitaxel) neoadjuvant chemotherapy, followed by interval debulking surgery consisting of hysterectomy, bilateral salpingo-oophorectomy, removal of para-aortic, mesenteric and pelvic lymph nodes, resection of a metastatic nodule on the umbilical scar, right parietocolic biopsy, and splenectomy. The anatomopathological study revealed a high-grade tumor with peritoneal involvement and lymphovascular invasion, stage pT3cN0M1 R2. The patient completed three more cycles of adjuvant chemotherapy and 1-year maintenance with bevacizumab, with complete response shown on the PET-CT scan. Germinative and somatic BRCA testing were negative.

Two years and 6 months after diagnosis (1 year and 6 months after complete response), the disease relapsed with a right inguinal node, later confirmed by biopsy. New staging revealed no distant disease. The patient underwent another six cycles of carboplatin + paclitaxel, with complete biochemical and imaging response shown on the CT and PET-CT scan.

Two years after the first relapse, a progressive increase in the level of the CA-125 tumor marker was observed. New imaging and staging exams showed two hepatic metastases and a nodular lesion on the left flank in L2 plane, compatible with a peritoneal implant, and the patient underwent a second cytoreductive surgery. Anatomopathological study of the hepatic VI–VII posterior sectors, VIII sector, and peritoneal implant was compatible with high-grade ovarian papillary serous cystadenocarcinoma. Due to the high morbidity associated with these metastases and lesions, and known difficult surgery recovery, the patient did not complete adjuvant chemotherapy and was maintained on close surveillance.

Eight months after surgery, a new increase in CA-125 levels prompted a CT scan, revealing hepatic and pulmonary metastatic disease. The patient restarted chemotherapy with carboplatin + paclitaxel, completing a total of six cycles. On the last cycle, she developed grade 3 angioedema (CTCAE [Common Terminology Criteria for Adverse Events] v5.0) attributed to paclitaxel, which resolved in < 24 h. Response assessment on CT scan revealed a very good response, with dimensional reduction or disappearance of hepatic and pulmonary metastases. In this setting, the patient started maintenance therapy with niraparib at a daily dose of 300 mg.

After starting niraparib 300 mg daily, the patient displayed good tolerability and no adverse reactions until the fourth week of treatment. At that time, she developed grade 3 thrombocytopenia, with oral mucosal bleeding and petechial lesions on the oral cavity and skin. Niraparib therapy was suspended, and the patient was admitted for surveillance due to the high risk of bleeding. She was discharged after 2 weeks, with recommendation of hemogram with full blood cell count every 3 days.

Twenty-eight days after suspension, the patient restarted niraparib at a daily dose of 200 mg. Two months later, she developed anemia, with Hb < 8 g/dL, and was in need of transfusion support; niraparib was suspended for another 28 days. During this period, the patient maintained normal CA-125 levels and stable disease on the CT scan.

Niraparib was restarted at the lowest daily dose of 100 mg, with no adverse events. The patient gradually became more active and resumed her everyday activities. Five months after starting the lowest niraparib dose, disease progression was documented, mainly on the lung metastasis, with a concomitant CA-125 increase.

Almost 7 years after diagnosis, the patient has good PS and performs her normal daily life. She has no intention of restarting chemotherapy, has started hormone therapy and undergoes monthly clinical and analytical evaluations.

留言 (0)

沒有登入
gif