Cancer of Unknown Primary with Peritoneal Carcinomatosis

Cancer of unknown primary with peritoneal carcinomatosis is widespread peritoneal tumour deposits, usually adenocarcinoma, in which the primary site is not found after clinical, radiological and pathological assessment. In women the picture is often a papillary serous carcinoma of ovarian, fallopian tube or primary peritoneal type, and these tumours respond to platinum based chemotherapy.

Cancers of unknown primary form 3% to 5% of cancers, and a peritoneal predominant pattern accounts for about 5% to 10% of them. Median age at diagnosis is 60 to 65. The serous papillary form is predominantly a disease of women, with a germline BRCA1 or BRCA2 variant in 10% to 15%.

Possible origins are ovary, fallopian tube, primary peritoneum, stomach, appendix, colorectum, pancreas and biliary tract, lobular breast cancer, and peritoneal mesothelioma. Lynch syndrome and BRCA carrier status raise the risk.

Pathophysiology. Spread is transcoelomic: tumour cells shed into the peritoneal fluid and implant on the omentum, mesentery and peritoneal surfaces, with obstruction of lymphatic drainage causing ascites. Gene expression profiling and molecular tests can suggest a tissue of origin when immunohistochemistry is not decisive.

Prognosis. Median survival is about 6 to 12 months overall. Women with serous papillary histology treated with platinum chemotherapy reach a median of 18 to 30 months, and responses are best with a favourable profile (female, serous histology, good performance status, low CA 125 burden).

• Abdominal distension and ascites, abdominal pain, early satiety, nausea, change in bowel habit, weight loss.
• Omental mass ("cake"), umbilical nodule (Sister Mary Joseph nodule), pelvic mass.
• Bowel obstruction, pleural effusion, venous thromboembolism.

Red flags.

• Vomiting with distension and absent bowel sounds (obstruction).
• Tense ascites with breathlessness or renal impairment.
• Fever with abdominal pain (infected ascites or perforation).

• Contrast CT of the chest, abdomen and pelvis (peritoneal thickening, omental caking, ascites, scalloping of the liver) and pelvic ultrasound or MRI.
• Diagnostic paracentesis for cytology with a cell block (cytology is positive in about 60% to 97% of peritoneal carcinomatosis), protein, serum ascites albumin gradient (under 11 g/L favours peritoneal disease), cell count and culture. Core biopsy (ultrasound or CT-directed) or laparoscopic biopsy for histology.
• Immunohistochemistry: CK7, CK20, PAX8, WT1, p53, oestrogen receptor, CDX2, SATB2, GATA3, calretinin, napsin A and TTF-1. A CK7-positive, PAX8 and WT1-positive profile supports a serous Müllerian origin.
• Markers: CA 125, CEA, CA 19-9, CA 15-3, AFP, beta-hCG, LDH. Pregnancy test in women of childbearing age.
• Mammography or breast MRI, gastroscopy and colonoscopy directed by symptoms and histology, and FDG-PET-CT for occult primaries.
• Germline BRCA1 and BRCA2 and mismatch repair testing, and tumour next generation sequencing (homologous recombination deficiency, microsatellite instability, HER2, BRAF, NTRK).

Differential diagnosis.

• Ovarian, fallopian tube and primary peritoneal serous carcinoma
• Gastric (signet ring), appendiceal and pancreatic carcinoma
• Peritoneal mesothelioma and pseudomyxoma peritonei
• Tuberculous peritonitis, lymphoma and lobular breast cancer

Management is decided by a multidisciplinary team after pathological review.

Women with serous papillary histology (ovarian type). Treat with the approach used for advanced ovarian cancer: cytoreductive surgery when complete resection is possible, with platinum taxane chemotherapy.

• Carboplatin with paclitaxel: carboplatin AUC 5 to 6 IV on day 1 with paclitaxel 175 mg/m2 IV over 3 hours on day 1, every 21 days for 4 to 6 cycles; carboplatin dose in mg is AUC x (GFR + 25), with GFR capped at 125 mL/min; maximum carboplatin about 900 mg and paclitaxel 175 mg/m2 each cycle; monitoring: FBC (nadir around days 10 to 21), creatinine, magnesium, liver tests, neuropathy, hypersensitivity; adjustment: premedicate with dexamethasone 20 mg, an antihistamine and an H2 blocker, reduce paclitaxel by about 25% in moderate hepatic impairment and avoid it when bilirubin is over 5 times the upper limit, recalculate carboplatin with each creatinine, avoid carboplatin when GFR is under 20 mL/min
• Maintenance after response, with a BRCA mutation or homologous recombination deficiency: olaparib 300 mg orally twice daily for up to 2 years (or until progression or unacceptable toxicity) as maintenance after a response to platinum chemotherapy in tumours with a BRCA mutation or homologous recombination deficiency; maximum 600 mg daily; monitoring: FBC at baseline, monthly for the first year and then every 3 months, creatinine, signs of myelodysplasia or acute myeloid leukaemia, pneumonitis, nausea; adjustment: reduce to 250 mg then 200 mg twice daily for toxicity, use 200 mg twice daily when creatinine clearance is 31 to 50 mL/min and avoid under 30 mL/min, reduce to 100 mg twice daily with strong CYP3A inhibitors (150 mg with moderate inhibitors), avoid strong inducers, hold for haemoglobin under 8 g/dL until recovery

Men and non-serous histology (gastrointestinal type or undefined).

• Cisplatin with gemcitabine: cisplatin 70 mg/m2 IV on day 1 with gemcitabine 1000 mg/m2 IV over 30 minutes on days 1 and 8, every 21 days for 4 to 6 cycles; maximum cisplatin 100 mg/m2 and gemcitabine 1250 mg/m2 each dose; monitoring: FBC before each dose, creatinine, magnesium, potassium, liver tests, audiometry, neuropathy; adjustment: give cisplatin only when creatinine clearance is 60 mL/min or more (carboplatin AUC 5 is the alternative), omit the day 8 gemcitabine for neutrophils under 1.0 x 10^9/L or platelets under 75 x 10^9/L, reduce gemcitabine by 25% when bilirubin is raised
• Oxaliplatin fluorouracil regimen for a colorectal type profile: oxaliplatin 85 mg/m2 IV over 2 hours on day 1, levoleucovorin 200 mg/m2 (or leucovorin 400 mg/m2) IV over 2 hours on day 1 and fluorouracil 400 mg/m2 IV bolus on day 1 followed by 2400 mg/m2 by continuous infusion over 46 hours, every 14 days for 12 cycles after resection or until progression in advanced disease; maximum oxaliplatin cumulative 850 mg/m2 because of cumulative neuropathy; monitoring: FBC, creatinine, liver tests, neuropathy and cold sensitivity, mucositis, diarrhoea, DPYD genotype before starting; adjustment: reduce oxaliplatin to 65 mg/m2 for persistent grade 2 neuropathy and stop for grade 3, reduce fluorouracil by 20% after grade 3 mucositis or diarrhoea, use oxaliplatin 65 mg/m2 when creatinine clearance is 30 to 50 mL/min and avoid under 30 mL/min, delay for neutrophils under 1.0 x 10^9/L or platelets under 75 x 10^9/L
• Immunotherapy for mismatch repair deficiency or high microsatellite instability: pembrolizumab 200 mg IV over 30 minutes every 3 weeks (or 400 mg every 6 weeks) for up to 24 months or until progression or unacceptable toxicity; maximum 200 mg each 3-week dose; monitoring: thyroid function, liver tests, creatinine, glucose and morning cortisol before each dose, symptoms of colitis, pneumonitis and hypophysitis, infusion reactions; adjustment: no renal or mild hepatic dose adjustment, withhold for grade 2 immune toxicity and give prednisolone 0.5 to 1 mg/kg daily, stop permanently for grade 3 to 4 toxicity (except endocrinopathies controlled on replacement) and give prednisolone 1 to 2 mg/kg daily tapered over at least 4 to 6 weeks

Targeted therapy. Directed by tumour sequencing (for example BRAF, HER2, NTRK or RET alterations), at a specialist centre.

Local therapy. Cytoreductive surgery with heated intraperitoneal chemotherapy is considered in selected patients with limited peritoneal disease and a likely mucinous or appendiceal origin.

Supportive care.

• Ascites: therapeutic paracentesis, with albumin for large volumes: albumin 20% 6 to 8 g for each litre of ascites removed, given IV over 1 to 2 hours during or immediately after paracentesis of more than 5 L; maximum 100 g in one session; monitoring: blood pressure, creatinine, sodium, signs of fluid overload; adjustment: omit for small volume paracentesis in non-cirrhotic ascites, reduce in heart failure, give for any volume when cirrhosis and renal impairment coexist
• Thromboprophylaxis: enoxaparin 40 mg subcutaneously once daily for thromboprophylaxis during active disease and for 4 weeks after surgery (therapeutic dosing of 1 mg/kg twice daily if thrombosis is established); maximum 40 mg daily for prophylaxis; monitoring: platelet count at baseline and every 2 to 4 weeks, creatinine, signs of bleeding, anti-Xa level in obesity or renal impairment; adjustment: 20 mg daily when creatinine clearance is under 30 mL/min, hold for platelets under 50 x 10^9/L or active bleeding, time the dose at least 12 hours before and 4 hours after a neuraxial procedure
• Malignant bowel obstruction: decompression, antiemetics, corticosteroids and somatostatin analogue, and a venting gastrostomy or surgery in selected patients. Parenteral nutrition for those with a longer expected survival.

Monitoring. Imaging and CA 125 (when raised) every 2 to 3 cycles, then every 3 months. Performance status, nutrition and symptom review at each visit.

Referral and escalation.

• Referral to a cancer-of-unknown-primary or gynaecological oncology team on suspicion.
• Same day assessment for obstruction, perforation or sepsis.

Special groups.

• BRCA carriers: genetic counselling and cascade testing of relatives.
• Older or frail patients: single agent or dose reduced chemotherapy, with early palliative care.
• Pregnancy: individualised management with obstetric and oncology teams.