scholarly journals Efficacy, Safety, and Biomarkers of Neoadjuvant Bevacizumab, Radiation Therapy, and Fluorouracil in Rectal Cancer: A Multidisciplinary Phase II Study

2009 ◽  
Vol 27 (18) ◽  
pp. 3020-3026 ◽  
Author(s):  
Christopher G. Willett ◽  
Dan G. Duda ◽  
Emmanuelle di Tomaso ◽  
Yves Boucher ◽  
Marek Ancukiewicz ◽  
...  

Purpose To assess the safety and efficacy of neoadjuvant bevacizumab with standard chemoradiotherapy in locally advanced rectal cancer and explore biomarkers for response. Patients and Methods In a phase I/II study, 32 patients received four cycles of therapy consisting of: bevacizumab infusion (5 or 10 mg/kg) on day 1 of each cycle; fluorouracil infusion (225 mg/m2/24 hours) during cycles 2 to 4; external-beam irradiation (50.4 Gy in 28 fractions over 5.5 weeks); and surgery 7 to 10 weeks after completion of all therapies. We measured molecular, cellular, and physiologic biomarkers before treatment, during bevacizumab monotherapy, and during and after combination therapy. Results Tumors regressed from a mass with mean size of 5 cm (range, 3 to 12 cm) to an ulcer/scar with mean size of 2.4 cm (range, 0.7 to 6.0 cm) in all 32 patients. Histologic examination revealed either no cancer or varying numbers of scattered cancer cells in a bed of fibrosis at the primary site. This treatment resulted in an actuarial 5-year local control and overall survival of 100%. Actuarial 5-year disease-free survival was 75% and five patients developed metastases postsurgery. Bevacizumab with chemoradiotherapy showed acceptable toxicity. Bevacizumab decreased tumor interstitial fluid pressure and blood flow. Baseline plasma soluble vascular endothelial growth factor receptor 1 (sVEGFR1), plasma vascular endothelial growth factor (VEGF), placental-derived growth factor (PlGF), and interleukin 6 (IL-6) during treatment, and circulating endothelial cells (CECs) after treatment showed significant correlations with outcome. Conclusion Bevacizumab with chemoradiotherapy appears safe and active and yields promising survival results in locally advanced rectal cancer. Plasma VEGF, PlGF, sVEGFR1, and IL-6 and CECs should be further evaluated as candidate biomarkers of response for this regimen.

2004 ◽  
Vol 21 (5-6) ◽  
pp. 455-457 ◽  
Author(s):  
Ken Taniguchi ◽  
Hikaru Fujioka ◽  
Yasuhiro Torashima ◽  
Junzo Yamaguchi ◽  
Kunihide Izawa ◽  
...  

2006 ◽  
Vol 33 ◽  
pp. S35-S40 ◽  
Author(s):  
Christopher G. Willett ◽  
Sergey V. Kozin ◽  
Dan G. Duda ◽  
Emmanuelle di Tomaso ◽  
Kevin R. Kozak ◽  
...  

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4106-4106
Author(s):  
L. S. Blaszkowsky ◽  
T. S. Hong ◽  
A. X. Zhu ◽  
E. L. Kwak ◽  
H. J. Mamon ◽  
...  

4106 Background: The German Rectal Cancer Study Group established neoadjuvant therapy as a standard of care in patients with T3/T4 rectal cancer. Beva, a vascular endothelial growth factor (VEGF) inhibitor with demonstrated activity in colorectal cancer, and erl, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor may both serve as radiation sensitizers. Methods: Twenty one pts with LARC, defined as T3 or T4 disease by MRI or endorectal ultrasound, were enrolled from May 2006-December 2008. Pts had adequate hepatic, renal and hematopoietic function, and an ECOG performance status of ≤2. Treatment consisted of 5-FU 225 mg/M2/day by continuous infusion for the duration of radiation (50.4 Gy). Beva 5 mg/kg was administered on days 1, 15 and 29. The first cohort received erl 50 mg, the second cohort 100 mg, and third cohort 150 mg daily until completion of radiation. Pts underwent surgery 6–9 weeks following the radiation. The primary endpoints were determination of the maximally tolerated dose (MTD) and pathologic complete response (pCR). Secondary endpoints included toxicity (TOX), local control (LC), progression free survival and median survival. A total of 25 pts will be treated at the MTD. Results: Twenty-one pts began study therapy: 2 withdrew consent prior to completing study therapy, and 2 pts were removed prior to completion for clostridium difficile colitis and cardiac ischemia. No dose limiting toxicities were achieved. Erl 100 mg was chosen as the MTD. Two pts have not yet completed study treatment. Fifteen pts have completed study therapy and have undergone surgery, of whom 7 (47%) have demonstrated a pCR. At a median follow-up of 7 months, there have been no local recurrences in patients who completed study therapy. Grade 3–4 treatment related TOX included: lymphopenia 6 (59%), diarrhea 4 (24%), rash 2(12%), cardiac ischemia 1(6%), transaminitis 1(6%), mucositis 1(6%). One pt developed an anastomotic leak. Conclusions: Beva and erl in combination with infusional 5-FU and RT appears to be a highly active preoperative regimen for locally advanced rectal cancer. [Table: see text]


2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 125-125
Author(s):  
Ankita Tandon ◽  
Jessica Frakes ◽  
Rutika Mehta ◽  
Sarah E. Hoffe ◽  
Maria E Martinez Jimenez ◽  
...  

125 Background: Neoadjuvant chemo-radiation is a standard of care for locally advanced rectal cancer. Patients with pathologic complete response (pCR) have improved outcomes with less local and systemic failure. Dual targeting with platelet derived growth factor (PDGF) and vascular endothelial growth factor receptor (VEGFR) in combination with radiation can escalate tumor response with radiation. Lenvatinib is an oral multi-kinase inhibitor and had shown potent anti-tumor activity in xenograft models cultured with human colorectal cancer (CRC) lines. Methods: Patients with stage II or III rectal cancer, confirmed by endoscopic ultrasound or MRI, were recruited in 3 cohorts of 3 patients per dose level, with an expansion cohort at the MTD. Lenvatinib oral daily dose started at 14 mg (cohort 1) and was escalated to 20 mg (cohort 2) followed by 24 mg (cohort 3). In this 3+3 design, patients received dose escalation of lenvatinib with standard doses of capecitabine (850 mg/m2 PO BID) concurrent with external beam radiation on days 1-5 weekly for 28 treatments. Following completion patients underwent surgery in 6-10 weeks. Results: Twenty patients with median age of 55 were enrolled in 3 cohorts (1 patient was ineligible). There were no dose limiting toxicity at the maximum tested dose of lenvatinib (24 mg). Two patients are still awaiting surgery. 12 patients have undergone low anterior resection and 5 patients have had abdominoperineal resection. Therefore, out of 17 patients, 29.4% (5/17) showed pCR, and downstaging was observed in 71% of the patients (12/17). The mean neoadjuvant rectal cancer score (NAR) was 11.4 and median NAR was 8.43. Six patients had grade 3 adverse events (AEs) (1 rectal pain,1 transaminitis, 2 lymphopenia, 1 HTN, 1 with both leukocytosis and hyponatremia). No grade 4 AEs were noted. Most common AEs were hypertension, rectal pain, nausea, diarrhea, fatigue and dermatitis. No peri operative complications were observed. Conclusions: The study shows that the combination of lenvatinib and capecitabine with radiation is well tolerated in locally advanced rectal cancer with promising mean NAR score. The encouraging results will need to be validated in a randomized study. Clinical trial information: NCT02935309.


Sign in / Sign up

Export Citation Format

Share Document