Christopher H. Crane

Adjuvant chemotherapy in rectal cancer: Defining subgroups who may benefit after neoadjuvant chemoradiation and resection: A pooled analysis of 3,313 patients.

Recent literature suggests that the benefit of adjuvant chemotherapy (aCT) for rectal cancer patients might depend on the response to neoadjuvant chemoradiation (CRT). Aim was to evaluate whether the effect of aCT in rectal cancer is modified by response to CRT and to identify which patients benefit from aCT after CRT, by means of a pooled analysis of individual patient data from 13 datasets. Patients were categorized into three groups: pCR (ypT0N0), ypT1‐2 tumour and ypT3‐4 tumour. Hazard ratios (HR) for the effect of aCT were derived from multivariable Cox regression analyses. Primary outcome measure was recurrence‐free survival (RFS). One thousand seven hundred and twenty three (1723) (52%) of 3,313 included patients received aCT. Eight hundred and ninety eight (898) patients had a pCR, 966 had a ypT1‐2 tumour and 1,302 had a ypT3‐4 tumour. For 122 patients response, category was missing and 25 patients had ypT0N+. Median follow‐up for all patients was 51 (0–219) months. HR for RFS with 95% CI for patients treated with aCT were 1.25(0.68–2.29), 0.58(0.37–0.89) and 0.83(0.66–1.10) for patients with pCR, ypT1‐2 and ypT3‐4 tumours, respectively. The effect of aCT in rectal cancer patients treated with CRT differs between subgroups. Patients with a pCR after CRT may not benefit from aCT, whereas patients with residual tumour had superior outcomes when aCT was administered. The test for interaction did not reach statistical significance, but the results support further investigation of a more individualized approach to administer aCT after CRT and surgery based on pathologic staging.

Proton beam radiation as salvage therapy for bilateral colorectal liver metastases not amenable to second-stage hepatectomy.

Background: Bilobar colorectal liver metastases (CRLM), are now aggressively managed in a multidisciplinary fashion with a two‐stage hepatectomy; however, up to 30% of patients are not candidates for second stage hepatectomy. In this report, we describe a novel technique of delivering ablative radiation to the entire right hemiliver by using proton therapy in a series of patients. Methods: A data base of patients undergoing entire right hemiliver ablative radiation was maintained prospectively. Clinical, pathologic and treatment characteristics were collected for these patients. Survival duration was calculated from end of radiation. Radiation was delivered with proton therapy using deep inspiratory breath hold (DIBH) and a phase contrast simulation CT scan. Results: All five patients tolerated radiation treatment well. All four patients treated with biologic equivalent dose (BED) >89.6 Gy achieved partial or complete radiographic response and in‐field local control at last follow up. Two patients are alive and without evidence of disease. Two patients experienced disease progression outside of the liver. Conclusion: These results suggest that the use of stereotactic proton therapy as a salvage therapy for patients with CRLM not amenable to second stage hepatectomy may achieve good local control and permit an opportunity for long term survival.

Adoption of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer

Importance Treatment of locally advanced rectal (LARC) cancer involves chemoradiation, surgery, and chemotherapy. The concept of total neoadjuvant therapy (TNT), in which chemoradiation and chemotherapy are administered prior to surgery, has been developed to optimize delivery of effective systemic therapy aimed at micrometastases. Objective To compare the traditional approach of preoperative chemoradiation (chemoRT) followed by postoperative adjuvant chemotherapy with the more recent TNT approach for LARC. Design, Setting, and Participants A retrospective cohort analysis using Memorial Sloan Kettering Cancer Center (MSK) records from 2009 to 2015 was carried out. A total of 811 patients who presented with LARC (T3/4 or node-positive) were identified. Exposures Of the 811 patients, 320 received chemoRT with planned adjuvant chemotherapy and 308 received TNT (induction fluorouracil- and oxaliplatin-based chemotherapy followed by chemoRT). Main Outcomes and Measures Treatment and outcome data for the 2 cohorts were compared. Dosing and completion of prescribed chemotherapy were assessed on the subset of patients who received all therapy at MSK. Results Of the 628 patients overall, 373 (59%) were men and 255 (41%) were women, with a mean (SD) age of 56.7 (12.9) years. Of the 308 patients in the TNT cohort, 181 (49%) were men and 127 (49%) were women. Of the 320 patients in the chemoRT with planned adjuvant chemotherapy cohort, 192 (60%) were men and 128 (40%) were women. Patients in the TNT cohort received greater percentages of the planned oxaliplatin and fluorouracil prescribed dose than those in the chemoRT with planned adjuvant chemotherapy cohort. The complete response (CR) rate, including both pathologic CR (pCR) in those who underwent surgery and sustained clinical CR (cCR) for at least 12 months posttreatment in those who did not undergo surgery, was 36% in the TNT cohort compared with 21% in the chemoRT with planned adjuvant chemotherapy cohort. Conclusions and Relevance Our findings provide additional support for the National Comprehensive Cancer Network (NCCN) guidelines that categorize TNT as a viable treatment strategy for rectal cancer. Our data suggest that TNT facilitates delivery of planned systemic therapy. Long-term follow-up will determine if this finding translates into improved survival. In addition, given its high CR rate, TNT may facilitate nonoperative treatment strategies aimed at organ preservation.

Dose escalation with an IMRT technique in 15 to 28 fractions is better tolerated than standard doses of 3DCRT for LAPC

Purpose To review acute and late toxicities after chemoradiation for locally advanced pancreatic ductal adenocarcinoma in patients who were treated with escalated dose radiation (EDR). Methods and materials Maximum Common Terminology Criteria for Adverse Events Version 4.0 acute toxicities (AT) during radiation and within 60 days after radiation were recorded for both acute gastrointestinal toxicity and overall toxicity (OT). Late toxicities were also recorded. EDR was generally delivered with daily image guidance and breath-hold techniques using intensity modulated radiation therapy (IMRT) planning. These were compared with patients who received standard dose radiation (SDR) delivered as 50.4 Gy in 28 fractions using 3-dimensional chemoradiation therapy planning. Results A total of 59 of 154 patients (39%) received EDR with biologically equivalent doses >70 Gy. The most frequent schedules were 63 Gy in 28 fractions (19 of 154 patients), 67.5 Gy in 15 fractions (10 of 154 patients), and 70 Gy in 28 fractions (15 of 154 patients). No grade 4 or grade 5 OT or late toxicities were reported. Rates of grade 3 acute gastrointestinal toxicity were significantly lower in patients who received EDR compared with SDR (1% vs 14%; P < .001). Similarly, rates of grade 3 OT were also lower for EDR compared with SDR (4% vs 16%; P = .004). The proportion of patients who experienced no AT was higher in the EDR group than the SDR group (36% vs 15%; P = .001). For EDR patients treated with IMRT, a lower risk of AT was associated with a later treatment year (P = .007), nonpancreatic head tumor location (P = .01), breath-hold (P = .002), 4-dimensional computed tomography (P = .003), computed tomography on rails (P = .002), and lower stomach V40 (P = .03). With a median time of 12 months (range, 1-79 months) from the start of radiation therapy to the last known follow-up in the EDR group, 51 of 59 patients (86%) had no late toxicity. Six of 59 EDR patients (10%) had either strictures or gastrointestinal bleeding that required intervention. No significant predictors of late toxicity were identified. Conclusion Overall acute and late toxicity rates were low with EDR using an IMRT technique with image guidance and respiratory gating.

Stereotactic body radiation vs. intensity-modulated radiation for unresectable pancreatic cancer

Abstract Background: Stereotactic body radiation therapy (SBRT) is an emerging treatment option for unresectable pancreatic cancer, and is postulated to be more effective and less toxic than conventionally fractionated intensity modulated radiation therapy (IMRT). Material and methods: We retrospectively reviewed unresectable stage I–III pancreatic adenocarcinoma treated from 2008 to 2016 at our institution with SBRT (five fractions, 30–33 Gy) or IMRT (25–28 fractions, 45–56 Gy with concurrent chemotherapy). Groups were compared with respect to overall survival (OS), local and distant failure, and toxicity. Log-rank test and Cox proportional hazards regression model, and competing risks methods were used for univariate and multivariate analysis. Results: SBRT patients (n = 44) were older than IMRT (n = 226) patients; otherwise there was no significant difference in baseline characteristics. There was no significant difference in OS or local or distant failure. There was no significant difference in rates of subsequent resection (IMRT =17%, SBRT =7%, p = .11). IMRT was associated with more acute grade 2+ gastrointestinal toxicity, grade 2+ fatigue, and grade 3+ hematologic toxicity (p = .008, p < .0001, p = .001, respectively). Conclusions: In this analysis, SBRT achieves similar disease control outcomes as IMRT, with less acute toxicity. This suggests SBRT is an attractive technique for pancreatic radiotherapy because of improved convenience and tolerability with equivalent efficacy. However, the lack of observed advantages in disease control with this moderate-dose SBRT regimen may suggest a role for increasing SBRT dose, if this can be accomplished without significant increase in toxicity.

Trends in intensity modulated radiation therapy use for locally advanced rectal cancer at National Comprehensive Cancer Network centers

Purpose Intensity modulated radiation therapy (IMRT) has been rapidly incorporated into clinical practice because of its technological advantages over 3-dimensional conformal radiation therapy (CRT). We characterized trends in IMRT utilization in trimodality treatment of locally advanced rectal cancer at National Comprehensive Cancer Network cancer centers between 2005 and 2011. Methods and materials Using the prospective National Comprehensive Cancer Network Colorectal Cancer Database, we determined treatment patterns for 976 patients with stage II-III rectal cancer who received pelvic radiation therapy at contributing centers between 2005 and 2011. Multivariable logistic regression was used to identify factors associated with IMRT versus 3-dimensional CRT. Radiation therapy compliance and time to completion were used to compare acute toxicity. Results A total of 947 patients (97%) received 3-dimensional CRT (80%) or IMRT (17%). Ninety-eight percent of these patients received radiation therapy preoperatively, and 81% underwent definitive resection. IMRT use increased from <13% pre-2009 to >30% in 2010 and thereafter, with significant variability among institutions (range, 0%-43%). Other factors associated with IMRT use included age ≥65 years, dose >50.4 Gy, African-American race, and no transabdominal surgery. Rates of and time to radiation therapy completion were similar between the groups. Conclusions Although most patients with stage II-III rectal cancer at queried National Cancer Institute–designated cancer centers between 2005 and 2011 received 3-dimensional CRT, significant and increasing numbers received IMRT. IMRT utilization is highly variable among institutions and not uniform among sociodemographic groups but may be more consistently embraced in specific clinical settings. Given this trend, comparative-effectiveness research is needed to evaluate the benefits of IMRT for rectal cancer.

Conformal Radiation Therapy in Pancreatic Cancer

We are still learning how to best combine radiation with chemotherapy. Concurrent regimens with newer sensitizers have led to increased toxicity. One way of improving the therapeutic ratio is to reduce the toxicity of treatment. New radiation techniques allow improved localization of the radiation dose and a reduction in the volume of normal tissue irradiated. This could lead to reduced toxicity of treatment and possibly to radiation-dose escalation. The appropriate volume of irradiation with the concurrent use of newer, more toxic radiosensitizers in pancreatic cancer is controversial. Treatment of the regional lymphatics increases toxicity, but may be important. Concerns of toxicity have led some investigators to use smaller fields and to rely on chemotherapy for high-risk nodal areas. Newer radiotherapy techniques, such as 3DCRT and IMRT, improve the radiation-dose distribution and thus offer a theoretical advantage that may translate into a clinical benefit in this new era of more toxic combinations of radiation and chemotherapy Improved radiation targeting may have a role in reducing toxicity and may allow escalation of the radiation dose, or the inclusion of additional cytotoxic agents into current regimens.

Pretreatment plasma HGF as potential biomarker for susceptibility to radiation-induced liver dysfunction after radiotherapy

Radiotherapy shows excellent local control in liver cancers but carries the risk of radiation-induced liver dysfunction and liver failure. We conducted a study of plasma hepatocyte growth factor (HGF) in a clinical trial of proton radiotherapy in patients with unresectable liver cancers (NCT00976898), and in an observational study for liver cancer patients undergoing surgical treatments. Liver dysfunction within 3 months after radiotherapy—a Childs−Turcotte−Pugh (CTP) score increase of 1 point or more—occurred in 9/34 (26%) of patients. Patients with no increase in CTP score had lower pretreatment plasma HGF level (p = 0.015). Both the increase in CTP score (p = 0.034) and the pretreatment plasma HGF (p = 0.017) were associated with OS. Plasma HGF was significantly associated with presence of cirrhosis (p = 0.0027) and with Model for End-stage Liver Disease (MELD) score (p < 0.0001), but not with OS in surgical liver cancer patients. Pretreatment plasma HGF is a candidate biomarker for patient selection for radiotherapy.

Role of Radiation Therapy in Hepatocellular Carcinoma

The toxicities of radiation to the liver have previously limited the feasibility and utility of radiation therapy in the treatment of hepatocellular carcinoma. Traditional treatment techniques did not allow for high, curative doses of radiation to be delivered while sparing the surrounding functional liver, bowel, and other critical organs. However, due to advances in technology, long-term tumor control rates appear to be comparable to ablation and surgical resection when curative doses can be administered. Similarly, toxicity rates from modern series are acceptable, particularly given the common comorbidity profile of this patient population. This may due to advances in radiation delivery techniques which allow for higher doses to be given more precisely with a lower risk of toxicity to the uninvolved liver and other nearby critical structures. More conformal techniques using IMRT or proton therapy can help to achieve this goal. SBRT and hypofractionated regimens also appear promising and allow shorter courses without compromising safety or efficacy.

Dose escalation of radiotherapy in unresectable extrahepatic cholangiocarcinoma

To evaluate the effect of escalated dose radiation therapy (EDR, defined as doses >50.4 Gy in 28 fractions [59.5 Gy BED]) on overall survival (OS), freedom from local progression (FFLP), and freedom from distant progression (FFDP) of patients with unresectable extrahepatic cholangiocarcinoma (EHCC).