Carla Hajj

Role of radiation therapy in the management of pancreatic cancer

Local failure remains a major issue for patients with both resectable and locally advanced pancreatic cancer. The role of radiation therapy in the management of this disease is less clear and represents an area of some controversy. The objective of this review is to present the rationale for radiation therapy in pancreatic cancer, as well as to discuss the potential limitations and caveats of the currently available studies. J. Surg. Oncol. 2013;107:86–96.

Role of Radiotherapy and Newer Techniques in the Treatment of GI Cancers

The role of radiotherapy in multidisciplinary treatment of GI malignancies is well established. Recent advances in imaging as well as radiotherapy planning and delivery techniques have made it possible to target tumors more accurately while sparing normal tissues. Intensity-modulated radiotherapy is an advanced method of delivering radiation using cutting-edge technology to manipulate beams of radiation. The role of intensity-modulated radiotherapy is growing for many GI malignancies, such as cancers of the stomach, pancreas, esophagus, liver, and anus. Stereotactic body radiotherapy is an emerging treatment option for some GI tumors such as locally advanced pancreatic cancer and primary or metastatic tumors of the liver. Stereotactic body radiotherapy requires a high degree of confidence in tumor location and subcentimeter accuracy of the delivered dose. New image-guided techniques have been developed to overcome setup uncertainties at the time of treatment, including real-time imaging on the linear accelerator. Modern imaging techniques have also allowed for more accurate pretreatment staging and delineation of the primary tumor and involved sites. In particular, magnetic resonance imaging and positron emission tomography scans can be particularly useful in radiotherapy planning and assessing treatment response. Molecular biomarkers are being investigated as predictors of response to radiotherapy with the intent of ultimately moving toward using genomic and proteomic determinants of therapeutic strategies. The role of all of these new approaches in the radiotherapeutic management of GI cancers and the evolving role of radiotherapy in these tumor sites will be highlighted in this review.

Novel mechanisms of action of classical chemotherapeutic agents on sphingolipid pathways.

Abstract The prevailing mechanisms of action of traditional chemotherapeutic agents have been challenged by sphingolipid cancer research. Many studies have shown that ceramide generation in response to cytotoxic agents is central to tumor cell death. Ceramide can be generated either via hydrolysis of cell-membrane sphingomyelin by sphingomyelinases, hydrolysis of cerebrosides, or via de novo synthesis by ceramide synthases. Ceramide can act as a second messenger for apoptosis, senescence or autophagy. Inherent or acquired alterations in the sphingolipid pathway can account for resistance to the classic chemotherapeutic agents. In particular, it has been shown that activation of the acid ceramidase can lead to the formation of sphingosine 1-phosphate, which then antagonizes ceramide signaling by initiating a pro-survival signaling pathway. Furthermore, ceramide glycosylation catalyzed by glucosylceramide synthase converts ceramide to glucosylceramide, thus eliminating ceramide and consequently protecting cancer cells from apoptosis. In this review, we describe the effects of some of the most commonly used chemotherapeutic agents on ceramide generation, with a particular emphasis on strategies used to enhance the efficacy of these agents.

Acute toxicity with intensity modulated radiotherapy versus 3-dimensional conformal radiotherapy during preoperative chemoradiation for locally advanced rectal cancer.

BACKGROUND AND PURPOSE We examined acute toxicity profiles and outcomes among rectal cancer patients treated with pre-operative chemoradiation using intensity modulated radiotherapy (IMRT) or 3-dimensional conformal radiotherapy (3DCRT) to identify predictive clinical factors associated with increased acute toxicity. MATERIAL AND METHODS We retrospectively reviewed records of 301 consecutive rectal cancer patients treated with pre-operative chemotherapy and radiotherapy (median dose 5000cGy) at our institution between 2007 and 2014. RESULTS Of the 301 patients, 203 (67.4%) were treated with IMRT and 98 (32.6%) with 3DCRT. Significantly more patients experienced ⩾grade 2 diarrhea in the 3DCRT group compared to the IMRT group (22% vs 10%, p=0.004), and those who received 3DCRT had 2.7 times greater odds of a higher diarrhea score than those on IMRT, even after adjusting for patient characteristics and chemotherapy (OR 2.71, p=0.01) Fewer patients experienced grade 2 genitourinary toxicity in the IMRT group (6% vs 13% 3DCRT, p=0.04) and there was a trend toward decreased grade 2 proctitis in the IMRT group (22% vs 32% 3DCRT, p=0.07). Patients over the age of 55 had 45% lower odds of proctitis than patients younger than 55. CONCLUSION The use of IMRT significantly reduced grade ⩾2 diarrhea and GU toxicity during chemoradiation. Younger patients were more likely to report grade 2 or higher proctitis.

Chemotherapy and intensity-modulated radiation therapy for locally advanced pancreatic cancer achieves a high rate of R0 resection.

Abstract Background: To assess local control, survival and conversion to resectability among locally advanced pancreatic cancer (LAPC) patients treated with induction chemotherapy (ICT) followed by chemoradiotherapy treatment using intensity-modulated radiation therapy (IMRT). Material and methods: Between 2007 and 2012, 134 LAPC patients were treated with ICT followed by IMRT. After chemoradiotherapy, 40 patients received maintenance chemotherapy. Results: With a median follow-up of 20 months, median overall survival (OS) was 23 months. One- and two-year OS was 85% and 47%, respectively. On multivariate analysis, progression of disease after IMRT was associated with worse OS. Cumulative incidence of local failure was 10% at one year and 36% at two years. Twenty-six patients (19%) underwent resection after chemoradiotherapy including 22 patients (85%) with negative margins. On multivariate analysis, response to IMRT was associated with surgery (p = .01). Acute grade 3-4 hematologic and non-hematologic toxicity rates were 26% and 4.5%, respectively. Conclusion: IMRT is safe in patients with LAPC. Patients with non-progressive LAPC after ICT and who received IMRT had high rates of local control and prolonged survival.

A Combination of Radiation and the Hypoxia-Activated Prodrug Evofosfamide (TH-302) is Efficacious against a Human Orthotopic Pancreatic Tumor Model

This study was designed to investigate the effect of single-dose radiation therapy (RT) in combination with evofosfamide (TH-302), a hypoxia-activated prodrug, in a pre-clinical model of pancreatic cancer. AsPC1 tumors were implanted orthotopically in the pancreas of nude mice. Tumors were treated with 15 Gy of RT, using a 1 cm diameter field, and delivered as a continuous arc. Image-guidance to center the field on the tumor was based on CT imaging with intraperitoneal contrast. Evofosfamide (100 mg/kg, i.p.) was administered 3 hours before RT. Tumor volumes were measured using ultrasound, and regrowth curves were plotted. Tumor hypoxia and cell proliferation were measured using pimonidazole and the thymidine analog EdU, respectively. In vitro clonogenic assays were performed. Tumors were shown to contain substantial areas of hypoxia, as calculated by percent pimonidazole staining. Evofosfamide was active in these tumors, as demonstrated by a significant reduction in uptake of the thymidine analog EdU. This effect was visible in oxygenated tissue, consistent with the previously reported bystander effects of evofosfamide. RT produced significant regrowth delay, as did evofosfamide. The combination of both agents produced a growth delay that was at least equal to the sum of the two treatments given separately. The improvement in tumor response when evofosfamide is combined with RT supports the hypothesis that hypoxia is a cause of radioresistance in high dose RT for pancreatic cancer. Assessing the efficacy and safety of stereotactic radiation treatment and evofosfamide is warranted in patients with locally advanced pancreatic cancer.

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.

Sphingolipids’ Role in Radiotherapy for Prostate Cancer

There are several well-established mechanisms involved in radiation-induced cell death in mammalian cell systems. The p53-mediated apoptotic pathway is the most widely recognized mechanism (Lowe et al. Nature 362:847-849, 1993), although apoptosis has long been considered a less relevant mechanism of radiation-induced cell death (Steel, Acta Oncol 40:968-975, 2001; Brown and Wouters, Cancer Res 59:1391-1399, 1999; Olive and Durand, Int J Radiat Biol 71:695-707, 1997). We and others have recently focused instead on the emerging links between radiation, apoptosis, and ceramide and showed that ceramide is a sphingolipid-derived second messenger capable of initiating apoptotic cascades in response to various stress stimuli, including radiation.Ceramide, the backbone of all sphingolipids, is synthesized by a family of ceramide synthases (CerS), each using acyl-CoAs of defined chain length for N-acylation of the sphingoid long-chain base. Six mammalian CerS homologs have been cloned that demonstrated high selectivity towards acyl-CoAs (Lahiri et al. FEBS Lett 581:5289-5294, 2007), and more recently, it was shown that their activity can be modulated by dimer formation (Mesicek et al. Cell Signal 22:1300-1307, 2010; Laviad et al. J Biol Chem 283:5677-5684, 2008).This de novo ceramide synthesis has been observed in irradiated cells through a pathway normally suppressed by ataxia telangiectasia-mutated (ATM) protein, a key component of the cellular response to DNA double-strand breaks (Liao et al. J Biol Chem 274:17908-17917, 1999). ATM is not the sole factor known to affect apoptotic potential by modulating CerS activity. Recent work has also implicated protein kinase Cα (PKCα) as a potential CerS activator (Truman et al. Cancer Biol Ther 8:54-63, 2009).In this review, we summarize involvement of CerS in sphingolipid-mediated apoptosis in irradiated human prostate cancer cells and discuss future directions in this field.

Impact of postoperative intensity-modulated radiation therapy (IMRT) on the rate of bowel obstruction in gynecologic malignancy

OBJECTIVE The purpose was to determine the potential impact of IMRT on the rate of bowel obstruction (BO), in patients with gynecologic malignancies undergoing postoperative pelvic RT. METHODS We performed a retrospective review of all patients with endometrial or cervical cancer who received postoperative pelvic RT at our institution from 2000 to 2012. Patients who received definitive or palliative RT, or those with BO due to disease progression, were excluded. Standard two-sided statistical tests were used to evaluate for associated risk factors. Kaplan-Meier, Log rank and Cox proportional hazards regression analysis tests were performed for actuarial analysis. RESULTS A total of 224 patients were identified, 120 (54%) received postoperative pelvic IMRT and 104 (46%) 3-dimentional (3-D) RT. Median follow-up time was 67months. BO was grade 1 (asymptomatic) in 2/228 (0.9%), grade 2 (conservative management) in 4 (1.8%), and grade 3≥ in 4 (1.8%). Overall, the 5-year actuarial rate of BO was 4.8%. The 5-year rate of BO in the IMRT group was 0.9% compared to 9.3% for 3-D RT (p=0.006). Patients with BMI≥30kg/m(2) were less likely to develop BO (2.6% vs. 8.3; p=0.03). On multivariate analysis, only IMRT retained its significance as an independent predictor of less BO (p=0.022). CONCLUSIONS The use of postoperative IMRT for cervical and endometrial cancer was associated with significant reduction in the rate of bowel obstruction. This difference maintained its statistical significance on multivariate analysis. Such finding if confirmed by others will help further solidify the benefit of IMRT in gynecologic cancers.

Radiation Treatment for Gastric Cancer

Locoregional recurrence in the gastric or tumor bed, the anastomosis, or regional lymph nodes occurs in 40–65 % of patients after gastric resection with curative intent. Nearly every combination of adjuvant therapy to surgery can be justified. Two large randomized control studies have evaluated postoperative chemoradiation treatment in surgically resectable locally advanced gastric cancer. The Gastric Surgical Adjuvant Trial (INT-0116) assigned patients to surgery plus postoperative chemoradiotherapy or surgery alone and established postoperative chemoradiation as a standard of care for patients with resected stage IB through intravenous (IV) (M0), gastric or gastroesophageal junction adenocarcinoma. The Adjuvant Chemoradiation Therapy in Stomach Cancer (ARTIST) trial showed that in the subgroup of patients with pathologic lymph node metastases at the time of surgery, adjuvant chemoradiotherapy improves disease-free survival (DFS) compared with chemotherapy alone. Preoperative chemoradiation may also be a promising approach with a 26 % pathologic complete response rate demonstrated in the RTOG 99-04 phase II study. Perioperative chemotherapy with or without radiation treatment is currently being studied in the ongoing Chemoradiotherapy After Induction Chemotherapy of Cancer in the Stomach (CRITICS) and TOPGEAR trials. Radiation treatment for gastric cancer can be technically challenging and associated with significant toxicities. The clinical target volume for adjuvant radiation treatment for gastric cancer depends on the location of the primary disease as well as the status of the lymph nodes involved by disease. Intensity-modulated radiation therapy and respiratory gating allow selective delivery of high doses of radiation to the region of interest while lowering the doses to adjacent normal tissues such as the heart, lungs, kidneys, and liver.