1. in locally advanced rectal carcinoma (LARC): The phase II TRUST trial
Induction treatment with FOLFOXIRI + bevacizumab (BV) followed by chemo-radiotherapy (CRT) + BV and surgery
in locally advanced rectal carcinoma (LARC): The phase II TRUST trial
Caterina Vivaldi1, Aldo Sainato2, Sara Lonardi3, Piero Buccianti4, Lorenzo Marcucci5, Francesco Di Clemente6, Gianna Musettini1, Sabrina Montrone2, Francesca Bergamo 3, Matteo Franceschi4, Laura Ginocchi5, Angelo Martignetti6,
Concetta La Liscia2, Francesca Battaglin3, Lucio Urbani4, Bruno Manfredi2, Laura Rumano’3, Francesco Sidoti4, Alfredo Falcone1,7, Gianluca Masi7.
 1Università di Pisa, Pisa, Italy; 2 U.O. Radioterapia, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy ; 3 Dipartimento di Oncologia Clinica e Sperimentale, UOC Oncologia Medica I, Istituto Oncologico Veneto-IRCCS, Padova, Italy; 4 U.O. Chirurgia Generale, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy;
5Division of Medical Oncology, USL 5 Pontedera, Pontedera, Italy; 6 Dipartimento Oncologico, Siena, Italy; 7Oncology Unit II, University Hospital of Pisa, Pisa, Italy
Abstr 673
Poster J12
Background
Matherials and Methods
Main inclusion criteria:
Rectal adenocarcinoma at <12 cm from the anal verge
Stage N+ or cT4 or high risk cT3 (MRI criteria)
Patients were treated with 6 cycles of biweekly FOLFOXIRI (irinotecan 165mg/m2 day 1; oxaliplatin 85 mg/m2 day1; folinate mg/m2 day 1; 5FU 3200 mg/m2 48h continuous infusion starting on day 1) and BV (5mg/kg day 1).
After 3 weeks patients underwent concomitant CRT (50.4 Gy in 28 fractions over 5.5 weeks + 5FU 225 mg/m2/day continuous infusion or capecitabine 825 mg/m2/bid continuously plus BV 5mg/kg on day 1,15,28)
After amendment dose of concomitant capecitabine was modified as follow: 800 mg/m2/bid 5 days/week
Surgery is planned 7-9 weeks after the end of CRT (Figure 1).
Primary endpoint is 2-year disease-free survival (DFS)
Neoadjuvant fluoropyrimidine-based CRT in LARC does not achieve effective control of distant micrometastases
Induction CT before CRT is promising option in LARC
BV improves the results of fluoropyrimidine-based CT
FOLFOXIRI plus BV is an effective treatment option in metastatic colorectal cancer
Figure 1, Study Schedule
Results
Patients’ characteristics
Induction Chemotherapy
Concomitant Chemo-radiotherapy
Surgical Procedures
Forty-five patients started CRT (1 patient underwent surgery after induction CT because of SAE - pneumonia )
All patients received 50.4 Gy
After the first 13 patients, protocol was amended due to an excessive rate of G3 toxicities during CRT: hand-foot syndrome (HFS) (23%), proctalgia (23%), proctitis (23%) and diarrhea (15%).
After amendment all patients completed CRT with acceptable toxicities (Table 3).
RR after CRT was 78%
44 patients underwent surgery: one patient experienced disease progression after the end of CRT and died
Surgery was low anterior resection in 86% of pts, abdomino- perineal resection 7%, other 7%.
Radical resection was achieved in 98%
Early post-surgical complication rate was 30%
This is a multicentric study (4 centers)
From April 2012 to April patients were enrolled
Main patients’ characteristics are summerized in Table 1
Toxicities observed during induction treatment are summarized in Table 2. As expected main grade (G) 3/4 toxicities were neutropenia (42%) and diarrhea (12,5%)
Two patients did not completed induction CT: the first died due to bowel perforation and febrile neutropenia with sepsis after the first cycle, the second one had acute renal injury without sequelae and decided to stop chemotherapy
Response rate (RR) after induction CT was 77%
Characteristic No
(%)
Number of patients enrolled 48
100
Sex , Male/Female
31/17
64,6/35,4
Median Age, years (range)
53 (30-74)
ECOG PS, 0 / 1-2
47/1
97,/2,1
Clinical Tumor Category, T2/T3/T4
2/29/17
4,2/60,4/35,4
Clinical Nodal Category, N0/N1-2
8/40
16,7/83,3
Activity
Histopathological results are available for 43 patients
Pathologic complete response was reached in 15/43 patients (35%)
Pathological downstaging was obtained in 56% of patients
No. of patients = 32 (%)
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Total
Anemia
15 (46,9) -
15(46,9)
Neutropenia
13(40,6)
5(15,6)
18(56,2)
Thrombocytopenia
9(28,1)
Hand Foot Syndrome
7(21,9)
2(6,2)
Neurotoxicity
11(34,4)
Stomatitis
1(3,1)
Hypertension
Nausea
Vomiting
Cystitis
Radiation dermatitis
16(50)
6(18,7)
32(68,7)
Diarrhea
20(62,4)
Rectal Bleeding
Proctalgia
3(9,4)
Proctitis
24(74,8)
No. of patients = 48 (%)
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Total
Anemia
32(66,6)
3(6,3) -
35 (72,9)
Thrombocytopenia
9(18,7)
1(2,1)
10(20,8)
Neutropenia
5(10,4)
13(27,1)
11(22,9)
38(79,1)
Febrile neutropenia
2 (4,2)
2(4,2)
Nausea
23(47,9)
36(75)
Vomiting
8(16,6)
4(8,3)
12(24,9)
Diarrhea
17(35,4)
32(66,7)
Hand Foot Syndrome
Stomatitis
8(16,2)
27(56,8)
Rectal Bleeding
Asthenia
28(58,3)
Hypertension
6(12,5)
Neurotoxicity
25(52,1)
7(14,6)
At a median follow up of 22 months, 7 patients had PD: 1 experienced locoregional recurrence and 6 distant metastases
Estimated 2year-DFS is 78%
Table 1, Patients characteristics
Flow chart
Enrolled patients: 48
Patients evaluable for induction CT: 48 (100%)
Patients who have completed induction CT: 46 (96%)
Patients evaluable for CRT: 45 (94%)
Patients who have completed CRT: 45 (94%)
Patients evaluable for surgery: 44 (92%)
Available histopathological report: 43 (90%), 1 ongoing
Conclusions
Induction CT with FOLFOXIRI and BV is feasible and highly active
A protocol amendment was needed due to toxicities during CRT
The rate of early post-surgical complications is not negligible
A longer follow up is needed for DFS
Table 2, Induction toxicities
Table 3, Chemo-radiotherapy toxicities after protocol amendment ca