3.1.2. Multimodality Therapy Completion
shows the patients flowchart through the therapeutic algorithm.
Induction polychemotherapy included mFOLFOXIRI (n = 14; 35%), GEMOXEL (n = 21, 52.5%) and GEMOX (n = 5, 12.5%). The median number of cycles administered was 4 (range 2 to 9). Three patients (7.5%) did not receive preoperative radiation therapy and were scheduled to surgery after IPCT due to recurrent episodes of cholangitis (one patient), necrotizing pancreatitis after 3 cycles of IPCT (one patient), and a suspicious resectable liver node detected in the post-IPCT re-staging (one patient). An R0 resection was achieved in all of them, including the patient with a new liver node that turned to be a gallbladder adenomyosis.
Thirty-seven patients (92.5%) received CRT after IPCT, 54% of them with 3D-RT and 46% with an IMRT technique. Median treatment length was 32 days (range 10 to 45).
Four patients (10%) could not be operated on after CRT. Three of them had a systemic relapse at the time of preoperative re-staging (development of liver metastases and peritoneal carcinomatosis in 2 and 1 patient, respectively). The remaining patient died 16 days after CRT due to a massive hematemesis.
Overall, 36 patients (90%) underwent surgery: 33 patients after receiving the complete neoadjuvant schedule (IPCT + CRT), and 3 patients after being treated only with IPCT, as detailed above. The time frame from last neoadjuvant therapy administered (IPCT + CRT, or IPCT alone) to surgery ranged from 3.5 to 12.8 weeks.
After surgery, 9 patients (22.5%) received adjuvant treatment, most of them (77.8%) with the same protocol used in the neoadjuvant scenario. The median number of adjuvant cycles was 3 (range 1 to 4). One patient received adjuvant chemoradiation, because it had been omitted in the neoadjuvant setting. In this case, the patological report confirmed an R0 resection (minimal margin of 6 mm) and a ypT3N1 pancreatic adenocarcinoma with perineural invasion.
3.1.4. Toxicity Profile
Toxicities associated with IPCT and CRT are described in Table 2
During IPCT, all patients experienced at least one grade 1 or 2 adverse event. Sixteen patients (40%) had one or more grade 3–4 toxicities. Grade 3–4 toxicities included: neutropenia (10 patients, 25%), leukopenia (5 patients, 12.5%), cholangitis (5 patients, 12.5%), diarrhea (3 patients, 7.5%), asthenia (2 patients, 5%) and gastritis (1 patient, 2.5%). Up to 50% of grade 3–4 neutropenias were febrile neutropenias. Granulocyte colony-stimulating factors were used in 7 patients (17.5%). A dose reduction was required in 10 patients (25%), 9 of them in the group treated with mFOLFOXIRI and 1 in the Gemcitabine-based group. Ten patients (25%) had a treatment delay, 8 of them in the group treated with mFOLFOXIRI and 2 in the group treated with Gemcitabine-based chemotherapy. Thirteen patients (32.5%) required at least one hospital admission due to cholangitis (n = 5; 12.5%), diarrhea (n = 5; 12.5%: grade 2: n = 2; grade 3: n = 3), febrile neutropenia (n = 4; 10%: grade 3: n = 3; grade 4: n = 1), atrial fibrillation (n = 2; 5%), pulmonary embolism (n = 1; 2.5%), perianal abscess (n = 1; 2.5%), and necrotizing pancreatitis (n = 1; 2.5%).
Grade 3-4 leukopenia, neutropenia and febrile neutropenia were more common in the group of patients treated with mFOLFOXIRI (35.7% vs. 0%; 57.1% vs. 7.7%; and 28.6% vs. 7.7%, respectively), whereas cholangitis was more frequent in the Gemcitabine-based group (15.4% vs. 7.1%). Cholangitis was only observed in patients with an endobiliary stent (23.8% vs. 0%), with a ratio of plastic vs. metallic stent in this group of patients of 3:2.
Overall, 11 patients (29.7%) had any grade 3 toxicity during CRT, including: cholangitis (5 patients, 13.5%), thrombocytopenia (4 patients, 10.8%) and asthenia (2 patients, 5.4%). No grade 4 toxicity associated to CRT was reported. Six patients (16.2%) required at least one hospital admission due to cholangitis (n = 5; 13.5%), grade 1 fever (n = 1; 2.7%), grade 2 nausea (n = 1; 2.7%), and grade 3 asthenia (n = 1; 2.7%). One patient required CRT discontinuation due to cholangitis. Besides, 6 patients (16.2%) required concomitant capecitabine dose reduction.
There were no perioperative or in-hospital deaths related to the surgical procedure. Eight patients (22.2%) developed one or more early postoperative complications, including: paralytic ileus (n = 4; 11%), infected pancreatic fistula (n = 2; 5.6%), respiratory distress syndrome (n = 1; 2.8%), gastro-jejunal anastomosis bleeding (n = 1; 2.8%), hemoperitoneum secondary to pancreatic-duodenal artery bleeding (n = 1; 2.8%), left renal fossa hematoma (n = 1; 2.8%) and abdominal sepsis (n = 1; 2.8%). In the last 3 cases, an urgent exploratory laparotomy was needed, with a later ICU observation period. The median length of hospitalization was 8.36 days (range 4–35). Ten patients (27.8%) required a red blood cell transfusion.
Nine patients (25%) had late surgical complications, including: lymphocele (n = 2; 5.6%), peripancreatic collection, (n = 2; 5.6%), perihepatic collection (n = 1; 2.8%), gastric erosion bleeding (n = 1; 2.8%), splenectomy surgical site hematoma (n = 1; 2.8%), paralytic ileus (n = 1; 2.8%), inflammatory-infectious process (n = 1; 2.8%), antrum-pyloric stenosis, that required a surgical derivation (n = 1; 2.8%), and pancreatectomy site pseudo-cyst (n = 1; 2.8%). All these complications were uneventfully managed.
3.1.5. Patients Long-Term Outcome
After a median follow-up of 33.5 months (range 3 to 133 months), median progression-free survival (PFS) was 18 months and median overall survival (OS) was 39 months (Figure 2
). The 1, 2, 3 and 5-year actuarial PFS were 71.3%, 46.9%, 43.8% and 32.3% respectively. The 1, 2, 3 and 5-year actuarial OS were 89.9%, 71.4%, 51.5% and 34.8% respectively. Median PFS (37 months vs. 18 months; p
= 0.026) and OS (47 months vs. 8 months; p
= 0.003) were significantly longer in those patients able to complete the whole therapeutic program (IPCT, CRT and surgery), compared to those who did not receive CRT or surgery. The discrepancy between OS and PFS in this last group of patients may be explained by the reported death due to massive hematemesis before surgery, without evidence of relapse.
Surgical margins status and the presence of vascular invasion among ypN0 patients significantly correlated with survival outcomes. Among those patients who completed the whole therapeutic program, the median PFS was 37 months for those receiving FOLFOXIRI compared to 17 months for those receiving gemcitabine-based IPCT, with a 3-year PFS of 62.3% and 45.5%, respectively.
Twenty-four patients (60%) have relapsed. The pattern of relapse was distant in 18 cases (75%), locoregional in 1 case (4.2%), and both, local and distant in 5 cases (20.8%). Liver was the most common site for distant progression (27.5%). Twenty of the relapsed patients (83.3%) underwent a second-line treatment. Among them, 17 died due to disease progression, 1 died due to cardiological comorbidity and 2 patients were alive at the end of the follow-up.