Moderate dose serial therapy for aged and resistant patients with cholangiocarcinomas.
Authors: Bruckner Howard , Hirschfeld Azriel , De Jager Robert L. , Bassali Fred , Gurell Daniel , Nghiem Van , Book AJ , Distenfeld Shoshana , Schwartz Myron E. 
Published: June 2021

e16160

Background: Advanced (Adv) intrahepatic IH Cholangiocarcinoma BD trials found multi-drug, sequences (GFLIO) safely expand eligibility (El) for patients (pts) of all ages -/+ resistant Ca (R). Two series had response/survival (S) of 80% / > 2 years (yr) (Bruckner et al Anti Ca Res 16). Therapy reverses R to key drugs, improves the pts' many immune functions and exposure to neoantigens, (Caraglia RT et al Front Oncol 19.) A.L.A.N.(AS) blood tests (Ts) predict chances of S (Salati et al EuJCa 18). Methods: Kaplan-Meier analyses examine prognostic Ts as El criteria for real-world pts. El included poor risk pts: any adult age, +/- R (-/+ prior test drugs). El: Intent to treat; consent; adv measurable IHBD; active progression (pg); Performance 0-2 and expected 6 wks S. The inE have 2ary CNS, require IVs; are unable to reach office, or have gr3-4 toxicity. GFLIO every 2 wks in mg/M2: Gemcitabine 500; 5-Fluorouracil 1200 over 24 hrs; Leucovovorin 180 Irinotecan 80 and day (D)2, Oxaliplatin 40. On pg, drugs are added, none are discontinued: D2 docetaxel 20-25, -/+ Mitomycin C 4-6; on 2nd pg, D1 Cetuximab is added (KRAS wild), wkly, and replaced on 3rd pg with D1 bevacizumab 10 mg/kg every 2 wks. Baseline A.L.A.N. assays (AS) are in Salati ibid. Results: Survival of the 35 pts, 19 R, is: 84% at 1 yr and 64% (CI 50-78%) at 2 yrs, median S CI 22.5 - > 24 mos; S at 12, 18 and 24 mos: with no unfavorable (UF) AS0 Ts (12 pts), is 100, 100, and 90%; with 1-2 UF Ts (15pts), is 76, 66 and 66% (CI > 56%). With 3-4 UF Ts (8 pts) S is 67, 34, and 13%. The old, 14 > 70, and young S similarly (̃); 4/4 > 75 S in remission for > 2 yr. p. 0.36, HR 1.68. Pts, 19R/16 - prior therapy, S similarlỹ, p 0.96, HR 1.03; both groups have similar ̃ Ts AS. Females, 17, and males, in spite of a cluster with UF AS 3-4, have similar ̃ S, p 0.6, HR 1.4. GFLIO induction produced neither hospitalizations, neutropenic fevers nor severe neuropathy and no initial need for prophylactic or high dose granulocyte factors. Favorable (Fav) Ts include: low < 3.1 neutrophile-lymphocyte ratio, 57%of pts, 81% S 2yr, p 0.005 HR 9.4; 2-4/4 fav ALAN Ts, 77% of pts,78% S 2 yr, p 0.007, hr 6.3; low < 300,000 platelets 71%, 80% S 2 yr, p 0.01, HR 1.7, and high > 3.5 albumin,74% of pts,72% S 2yr, p 0.03, HR 3.9. Groups defined by single UF Ts (except low albumin, 33% S 2 yr) S > ̃ 50% at 2 yr. Conclusions: A real world, safe, survival of > 2yr, is confirmed in this 3rd series. This meets NCI criteria for: selective use, and development of GFLIO's elements (lowest effective dosages and sequential regimens), and prognostic tests (criteria and models). Therapy can, in theory, correct UF T's - pathology. When matched for AScore, GFLIO is ̃ effective, -/+, R and at all ages. Tests and GFLIO can change practice, improve El and survival for under treated pts, some half of all pts, the aged and the Resistant, told they have "only 6 or 12 mos to live." Clinical trial information: NCT01905150.