Metastatic pancreatic cancer

 Initial evaluation: 80% metastatic at the time of diagnosis

1. Imaging: CT CAP,  port placement

2. Labs: CBC, CMP, CA 19-9, INR, albumin. CA 19-9 may be negative in Lewis antigen neg individuals ( false neg) and falsely elevated in infection or obstruction of the biliary tract. Therefore CA 19-9 should only be measured after biliary obstruction relieved.

3. Germline and somatic tumor profiling: 3-5 % may have germline BRCA or PALB2 alterations. If insufficient tissue, ct DNA can be used for somatic tumor profiling for other  HRD gene alterations. These HRD alterations can be present in upto 40% of pt with pancreatic cancer stage 4. Comprehensive somatic tumor NGS helps identify : ALK, NRG1, ROS1, FGFR2, KRAS, HER2, and high tumor mutational burden (TMB-H). Such alterations either have clinical relevance in second- and later-line therapy .

Treatment:  The approach to initial systemic therapy for metastatic exocrine pancreatic cancer is based on the presence or absence of specific germline pathogenic variants and/or actionable molecular alterations in the tumor. Clinical factors that also influence selection of therapy include patient performance status (PS) and comorbidities, laboratory values (including serum total bilirubin levels), symptom burden, and goals of care.

• Performance status:
• Geriatric assessment: 
• Comorbidities:
• Symptom burden: high/low
• Goals of care: palliative. Patient's goals: 
• Labs influencing initial choice: LFT, renal function

1. Systemic therapy: Gemcitabine was established as the cornerstone of treatment in 1996. Subsequently, the four-drug combination ­FOLFIRINOX assumed that position when the PRODIGE 4/ACCORD 1 ­trial established it as the standard of care for fit patients. Disease control and survival are identical with FOLFIRINOX and mFOLFIRINOX. mFOLFIRNOX has 25% less 5FU and irinotecan. Other front line options include NALIRIFOX which has a 2 month survival benefit over Gem- Abraxane.

FOLFIRINOX median OS 1 yr

IMPACT study Gem Abraxane median OS 9 months

Gemcitabine1L- CONKO001- median OS 22 months. Fixed dose rate gem 10 mg/m2 /minute better than standard 30 minute infusion.

-We do not offer gem-cis to unselected patients without known germline or somatic HRD mutations either core or non-core. The core HRD mutations are BRCA and PALB2. 

-While awaiting results of the germline and somatic profiling, a safe bet is to start mFOLFIRINOX if good PS.

Targeted agents used in first line: NTRK, RET

2. Maintenance Olaparib 300 mg BID ( germline BRCA only) improved PFS by 12% over 2 yr, no OS benefit. Rucaparib can be used for germline and somatic HRD.

3. Supportive care:

- biliary obstruction

-cancer pain

-cachexia, loss of appetite

-pancreatic exocrine insufficiency

4. Prognosis: median OS with platinum regimen and core HRD mutations: 25 months. 

If no HRD mutations, platinum based agents-- meian OS 15 months

If no HRD and non platinum 1st line- 13 months 

5. Counseling regarding side effects:

The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel–gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the two groups (MPACT trial)

FOLFIRINOX- neutropenia 45%, febrile neutropenia 5%, deaths occurred. Alopecia 11%, low blood counts10%, neuropathy , fatigue 23%, GI toxicity 15%, blood clots 6%.

6. Evaluating need for prophylactic DOAC: Khorana score 2 or higher. ONKOTEV-2 trial

A note on oligometastatic pancreatic cancer

EXTEND phase II trial with metastases directed therapy for oligometastatic pancreatic ca 5 or less sites of mets, treated with SBAR with PFS of 10 months versus 2.5 months.

Reference: JCO Nov 2024