In vivo studies demonstrate that curcumin increases radioresponse of colorectal cancers. To demonstrate efficacy in humans, we performed a randomized double-blind study of locally advanced rectal cancer (LARC) patients receiving pre-operative chemoradiation therapy (CRT) ± curcumin. We used pathologic complete response (pCR) rate as a surrogate for clinical outcome.From 2008-2010, LARC patients were randomized to placebo/curcumin in a 1:2 ratio. Patients received CRT [50.4 gray in 28 fractions; capecitabine (825 mg/m2 twice daily)] followed by surgery. Curcumin (4 grams orally, twice daily) or placebo was given throughout CRT and 6 weeks afterward. Toxicity was monitored weekly. Blood samples taken pre- and 1-hour post-ingestion and tissue biopsies (both collected at CRT week 2) were analyzed for pharmacokinetics. The primary outcome was surgical pCR rate.Of 22 enrolled patients, 15 received curcumin. Median age was 61 years and the majority were male (n=13; 59%). The median serum curcumin concentrations before (3.04 ng/mL; range, 1.24-18.88 ng/mL) and 1 hour after (3.32 ng/mL; range, 0.84-5.36 ng/mL) curcumin intake did not differ significantly (P=0.33). Serum curcumin concentrations both increased and decreased 1-hour post-administration (range as percentage of baseline: 8.8-258.1%). Twelve curcumin patient tissue biopsies had median curcumin concentration of 33.7 ng/mg tissue (range, 0.1-4,765.7 ng/mg). Two placebo and 1 curcumin patient achieved pCRs (P=0.18). One grade 3 toxicity (infection) was experienced.The addition of curcumin to CRT did not increase pCR rates for LARC patients. The unpredictable bioavailability of curcumin contributes to continued uncertainties regarding curcumin efficacy.ClinicalTrials.gov identifier: NCT00745134.
e15230 Background: Early surrogate markers of progression-free survival (PFS) and overall survival (OS) in LAPC patients who receive consolidative chemoradiation therapy (CRT) following induction chemotherapy (CTX) have been poorly studied. The current study was conducted to determine whether Carbohydrate Antigen 19-9 (CA19-9) is an independent prognostic biomarker in LAPC. Methods: LAPC patients treated with CTX followed by CRT at our center from 2007 to 2013 were identified. CA19-9 levels were recorded at baseline, prior to CRT and 1-3 months after CRT. Patients with pre-CRT Ca19-9 levels that were unrecorded, ≤ 50 U/mL or associated with a bilirubin > 2 were excluded from the analysis. 101 patients met the inclusion criteria. Ninety four (93%) underwent induction CTX before consolidative CRT. Median radiation dose was 50.4 Gy, induction CTX was gemcitabine-based (79%), and FOLFIRINOX (21%). Concurrent chemotherapy during CRT was 5-fluorouracil (2%), gemcitabine-based (12%) and capecitabine-based (86%). Univariate and multivariate statistical methods were used to determine significance of the post-treatment changes in CA19-9 on PFS and OS outcomes calculated from start of treatment. Results: Median CA19-9 at baseline was 363 U/mL. After CTX, this dropped to 178 U/mL (p < 0.0001) and further decreased to 108 U/mL post CRT (p < 0.0001, compared to baseline; p = 0.004, compared to pre-CRT). The estimated median OS and PFS were 20.1 months and 11.2 months, respectively. On univariate analysis, patients with post-CRT CA19-9 levels ≤ 90U/mL had an improved OS (25 vs 16.4 months; p < 0.0001) and PFS (13.6 vs 10.3 months; p = 0.001). A reduction in CA19-9 level of ≥ 50% from baseline to post-CRT was associated with improved OS (21.7 vs 16.8 months; p = 0.003) and PFS (12.4 vs 10.3 months; p = 0.02). On multivariate analysis, only post-CRT CA19-9 level ≤ 90 U/mL was associated with improved OS (HR = 0.19; p < 0.0001) and PFS (HR = 0.55; p = 0.049). Conclusions: Post- treatment CA19-9 independently predicts and serves as an early surrogate for OS and PFS in patients with LAPC, offering the potential to tailor subsequent therapy.
354 Background: Lymphopenia is commonly seen following chemoradiation and is associated with a poor prognosis. We conducted this study to determine if the severity of lymphopenia is dependent on the radiation dose and the fractional volume of spleen irradiated unintentionally during definitive chemoradiation in patients with locally advanced pancreatic cancer (LAPC). Methods: 177 patients with LAPC were treated with induction chemotherapy (FOLFIRINOX or gemcitabine- based regimens) followed by chemoradiation (CRT; median 50.4 Gy with concurrent capecitabine) from 1/2006 to 12/2012. Absolute lymphocyte count (ALC) was recorded at baseline, prior to CRT and 2-10 weeks after the end of CRT. Splenic dose-volume histogram (DVH) parameters were reported as mean splenic dose (MSD) and the percentage of splenic volume receiving at least 5 Gy (V5), 10 Gy (V10), 15 Gy (V15) and 20 Gy (V20) dose. Overall survival (OS) was analyzed using Cox model and multivariate logistic regression was used to assess the development of post CRT severe lymphopenia (ALC < 0.5 K/UL) using baseline and treatment factors. Results: Median post-CRT ALC (0.68 K/UL, range 0.13 to 2.72) was significantly lower than both baseline (1.42 K/UL, range 0.34- 3.97; p < 0.0001) and pre-CRT ALC (1.32 K/UL, range 0.36- 4.82; p < 0.0001). Post-CRT ALC < 0.5 K/UL was associated with inferior OS on univariate (16.8 vs. 21.2 months, p = 0.004) and multivariate analysis (HR = 1.9, p = 0.002).The MSD was 8.8 Gy and log MSD showed a significant negative correlation (r = -0.18, p = 0.02) with post-CRT ALC. Median V5, V10, V15 and V20 were 34%, 21%, 13% and 8% respectively. Median V10 (32.6 vs. 16%, p = 0.04), V15 (23.2 vs. 9.5%, p = 0.03) and V20 (15.4 vs. 4.6%, p = 0.02) were significantly higher in patients with severe lymphopenia. On multivariate logistic regression analysis, baseline lymphopenia (ALC < 1 K/UL; p = 0.003, OR = 4.6) and MSD (p = 0.03, OR = 7.3) were independent predictors for the development of severe post-CRT lymphopenia. Conclusions: LAPC patients receiving high MSD during CRT are at increased risk of developing severe lymphopenia, which is an independent predictor of poor OS. Routine assessment of splenic DVHs prior to acceptance of treatment plans may minimize this risk.
Pathologic complete response to neoadjuvant chemoradiation therapy (CRT) is associated with improved outcomes for patients with locally advanced rectal cancer (LARC). Increased response rates have been reported with higher radiation doses, but these studies often lack long-term outcome and/or toxicity data. We conducted a case-control analysis of patients with LARC who underwent definitive CRT to determine the efficacy and safety of intensified treatment with a concomitant boost (CB) approach.
Methods and materials
From 1995 to 2003, a phase 2 protocol examined CRT with 5-fluorouracil and CB radiation therapy (52.5 Gy in 5 weeks) for patients with LARC. Seventy-six protocol patients were matched (case-control approach) for surgery type, tumor (T) stage, and clinical nodal (N) stage with patients who received standard dose (SD) CRT (5-fluorouracil, 45 Gy). A chart review was performed. McNemar's test and Kaplan-Meier analyses were used for statistical analysis.
Results
The SD and CB groups did not differ in tumor circumferential involvement and length, but the tumors of CB patients were closer to the anal verge (4.7 vs 5.7 cm; P = .02). Although tumor downstaging was higher in the CB cohort (76% vs 51%; P < .01), pathologic complete response rates did not differ (CB, 17.1% vs SD, 15.8%, P = 1.00). The incidence of grade ≥3 radiation-related toxicities was low and similar in both groups (CB, 10% vs SD, 3%, P = .22). Postoperative (anastomotic leak, wound complications/abscess, bleeding) and late (small bowel obstruction, stricture) complication rates did not differ between the groups (P > .05). The median follow-up was 11.9 years. The 5-year local control rates were higher for CB (100.0%) compared with SD (90.0%) patients (P = .01). CB patients had higher rates of 10-year progression-free survival (71.9% vs 57.6%, P < .01) and overall survival (71.6% vs 62.4%, P = .01) compared with SD patients.
Conclusions
CRT dose escalation for patients with LARC is safe and effective. The improved T-downstaging and local control observed in CB patients should encourage further dose escalation studies.
