Survival outcomes used to generate version 9 American Joint Committee on Cancer staging system for anal cancer.

The American Joint Committee on Cancer (AJCC) staging system for all cancer sites, including anal cancer, is the standard for cancer staging in the United States. The AJCC staging criteria are dynamic, and periodic updates are conducted to optimize AJCC staging definitions through a panel of experts charged with evaluating new evidence to implement changes. With greater availability of large data sets, the AJCC has since restructured and updated its processes, incorporating prospectively collected data to validate stage group revisions in the version 9 AJCC staging system, including anal cancer. Survival analysis using AJCC eighth edition staging guidelines revealed a lack of hierarchical order in which stage IIIA anal cancer was associated with a better prognosis than stage IIB disease, suggesting that, for anal cancer, tumor (T) category has a greater effect on survival than lymph node (N) category. Accordingly, version 9 stage groups have been appropriately adjusted to reflect contemporary long-term outcomes. This article highlights the changes to the now published AJCC staging system for anal cancer, which: (1) redefined stage IIB as T1-T2N1M0 disease, (2) redefined stage IIIA as T3N0-N1M0 disease, and (3) eliminated stage 0 disease from its guidelines altogether.

Preoperative Treatment of Locally Advanced Rectal Cancer.

BACKGROUND: Pelvic radiation plus sensitizing chemotherapy with a fluoropyrimidine (chemoradiotherapy) before surgery is standard care for locally advanced rectal cancer in North America. Whether neoadjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) can be used in lieu of chemoradiotherapy is uncertain. METHODS: We conducted a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX (with chemoradiotherapy given only if the primary tumor decreased in size by <20% or if FOLFOX was discontinued because of side effects) as compared with chemoradiotherapy. Adults with rectal cancer that had been clinically staged as T2 node-positive, T3 node-negative, or T3 node-positive who were candidates for sphincter-sparing surgery were eligible to participate. The primary end point was disease-free survival. Noninferiority would be claimed if the upper limit of the two-sided 90.2% confidence interval of the hazard ratio for disease recurrence or death did not exceed 1.29. Secondary end points included overall survival, local recurrence (in a time-to-event analysis), complete pathological resection, complete response, and toxic effects. RESULTS: From June 2012 through December 2018, a total of 1194 patients underwent randomization and 1128 started treatment; among those who started treatment, 585 were in the FOLFOX group and 543 in the chemoradiotherapy group. At a median follow-up of 58 months, FOLFOX was noninferior to chemoradiotherapy for disease-free survival (hazard ratio for disease recurrence or death, 0.92; 90.2% confidence interval [CI], 0.74 to 1.14; P = 0.005 for noninferiority). Five-year disease-free survival was 80.8% (95% CI, 77.9 to 83.7) in the FOLFOX group and 78.6% (95% CI, 75.4 to 81.8) in the chemoradiotherapy group. The groups were similar with respect to overall survival (hazard ratio for death, 1.04; 95% CI, 0.74 to 1.44) and local recurrence (hazard ratio, 1.18; 95% CI, 0.44 to 3.16). In the FOLFOX group, 53 patients (9.1%) received preoperative chemoradiotherapy and 8 (1.4%) received postoperative chemoradiotherapy. CONCLUSIONS: In patients with locally advanced rectal cancer who were eligible for sphincter-sparing surgery, preoperative FOLFOX was noninferior to preoperative chemoradiotherapy with respect to disease-free survival. (Funded by the National Cancer Institute; PROSPECT ClinicalTrials.gov number, NCT01515787.).

Data-driven optimization of version 9 American Joint Committee on Cancer staging system for anal cancer.

INTRODUCTION: The American Joint Committee on Cancer (AJCC) staging system undergoes periodic revisions to maintain contemporary survival outcomes related to stage. Recently, the AJCC has developed a novel, systematic approach incorporating survival data to refine stage groupings. The objective of this study was to demonstrate data-driven optimization of the version 9 AJCC staging system for anal cancer assessed through a defined validation approach. METHODS: The National Cancer Database was queried for patients diagnosed with anal cancer in 2012 through 2017. Kaplan-Meier methods analyzed 5-year survival by individual clinical T category, N category, M category, and overall stage. Cox proportional hazards models validated overall survival of the revised TNM stage groupings. RESULTS: Overall, 24,328 cases of anal cancer were included. Evaluation of the 8th edition AJCC stage groups demonstrated a lack of hierarchical prognostic order. Survival at 5 years for stage I was 84.4%, 77.4% for stage IIA, and 63.7% for stage IIB; however, stage IIIA disease demonstrated a 73.0% survival, followed by 58.4% for stage IIIB, 59.9% for stage IIIC, and 22.5% for stage IV (p <.001). Thus, stage IIB was redefined as T1-2N1M0, whereas Stage IIIA was redefined as T3N0-1M0. Reevaluation of 5-year survival based on data-informed stage groupings now demonstrates hierarchical prognostic order and validated via Cox proportional hazards models. CONCLUSION: The 8th edition AJCC survival data demonstrated a lack of hierarchical prognostic order and informed revised stage groupings in the version 9 AJCC staging system for anal cancer. Thus, a validated data-driven optimization approach can be implemented for staging revisions across all disease sites moving forward.

Cardiac metabolic changes on 18 F-positron emission tomography after thoracic radiotherapy predict for overall survival in esophageal cancer patients.

PURPOSE: Heart doses have been shown to be predictive of cardiac toxicity and overall survival (OS) for esophageal cancer patients. There is potential for functional imaging to provide valuable cardiac information. The purpose of this study was to evaluate the cardiac metabolic dose-response using 18 F-deoxyglucose (FDG)-PET and to assess whether standard uptake value (SUV) changes in the heart were predictive of OS. METHODS: Fifty-one patients with esophageal cancer treated with radiation who underwent pre- and post-treatment FDG-PET scans were retrospectively evaluated. Pre- and post-treatment PET-scans were rigidly registered to the planning CT for each patient. Pre-treatment to post-treatment absolute mean SUV (SUVmean) changes in the heart were calculated to assess dose-response. A dose-response curve was generated by binning each voxel in the heart into 10 Gy dose-bins and analyzing the SUVmean changes in each dose-bin. Multivariate cox proportional hazard models were used to assess whether pre-to-post treatment cardiac SUVmean changes predicted for OS. RESULTS: The cardiac dose-response curve demonstrated a trend of increasing cardiac SUV changes as a function of dose with an average increase of 0.044 SUV for every 10 Gy dose bin. In multivariate analysis, disease stage and SUVmean change in the heart were predictive (p < 0.05) for OS. CONCLUSIONS: Changes in pre- to post-treatment cardiac SUV were predictive of OS with patients having a higher pre- to post-treatment cardiac SUV change surviving longer.

Response to radiotherapy in pancreatic ductal adenocarcinoma is enhanced by inhibition of myeloid-derived suppressor cells using STAT3 anti-sense oligonucleotide.

Pancreatic ductal adenocarcinoma (PDAC) has a heterogeneous tumor microenvironment (TME) comprised of myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, neutrophils, regulatory T cells, and myofibroblasts. The precise mechanisms that regulate the composition of the TME and how they contribute to radiotherapy (RT) response remain poorly understood. In this study, we analyze changes in immune cell populations and circulating chemokines in patient samples and animal models of pancreatic cancer to characterize the immune response to radiotherapy. Further, we identify STAT3 as a key mediator of immunosuppression post-RT. We found granulocytic MDSCs (G-MDSCs) and neutrophils to be increased in response to RT in murine and human PDAC samples. We also found that RT-induced STAT3 phosphorylation correlated with increased MDSC infiltration and proliferation. Targeting STAT3 using an anti-sense oligonucleotide in combination with RT circumvented RT-induced MDSC infiltration, enhanced the proportion of effector T cells, and improved response to RT. In addition, STAT3 inhibition contributed to the remodeling of the PDAC extracellular matrix when combined with RT, resulting in decreased collagen deposition and fibrotic tissue formation. Collectively, our data provide evidence that targeting STAT3 in combination with RT can mitigate the pro-tumorigenic effects of RT and improve tumor response.

Induction Chemotherapy Plus Neoadjuvant Chemoradiation for Esophageal and Gastroesophageal Junction Adenocarcinoma.

BACKGROUND: Neoadjuvant chemotherapy with concurrent radiotherapy (nCRT) is an accepted treatment regimen for patients with potentially curable esophageal and gastroesophageal junction (GEJ) adenocarcinoma. The purpose of this study is to evaluate whether induction chemotherapy (IC) before nCRT is associated with improved pathologic complete response (pCR) and overall survival (OS) when compared with patients who received nCRT alone for esophageal and GEJ adenocarcinoma. METHODS: Using the National Cancer Database (NCDB), patients who received nCRT and curative-intent esophagectomy for esophageal or GEJ adenocarcinoma from 2006 to 2015 were included. Chemotherapy and radiation therapy start dates were used to define cohorts who received IC before nCRT (IC + nCRT) versus those who only received concurrent nCRT before surgery. Propensity weighting was conducted to balance patient, disease, and facility covariates between groups. RESULTS: 12,460 patients met inclusion criteria, of whom 11,880 (95%) received nCRT and 580 (5%) received IC + nCRT. Following propensity weighting, OS was significantly improved among patients who received IC + nCRT versus nCRT (HR 0.82; 95% CI 0.74-0.92; p < 0.001) with median OS for the IC + nCRT cohort of 3.38 years versus 2.45 years for nCRT. For patients diagnosed from 2013 to 2015, IC + nCRT was also associated with higher odds of pCR compared with nCRT (OR 1.59; 95% CI 1.14-2.21; p = 0.007). CONCLUSION: IC + nCRT was associated with a significant OS benefit as well as higher pCR rate in the more modern patient cohort. These results merit consideration of a sufficiently powered prospective multiinstitutional trial to further evaluate these observed differences.

Controversies in radiotherapy for pancreas cancer.

The management of pancreatic adenocarcinoma remains an area of controversy and ongoing discovery. Despite advances in surgical and radiation techniques, as well as chemotherapeutic agents, outcomes of patients diagnosed with this devastating malignancy remain poor. This article aims to review the available literature evaluating the efficacy of adjuvant, neoadjuvant, and definitive radiation therapy. We will also highlight areas of ongoing research efforts being carried out to improve outcomes in this patient population.

Impact of neoadjuvant chemotherapy and stereotactic body radiation therapy (SBRT) on R0 resection rate for borderline resectable and locally advanced pancreatic cancer.

BACKGROUND: The role of neoadjuvant stereotactic body radiation therapy (SBRT) in patients with borderline resectable pancreas cancer (BRPC) and locally advanced pancreas cancer (LAPC) remains controversial. METHODS: We retrospectively evaluated BRPC and LAPC patients treated at our institution who underwent 2-3 months of chemotherapy followed by SBRT to a dose of 30-33 Gy. Overall survival (OS) and recurrence-free survival (RFS) were estimated and compared by Kaplan-Meier and log-rank methods. RESULTS: We identified 103 (85 BRPC and 18 LAPC) patients treated per our neoadjuvant paradigm between 2011 and 2018, with resectability based on NCCN definitions. Median follow up was 25 months. Of patients completing neoadjuvant therapy, 73 (71%) underwent definitive resection. Seventy-one (97%) patients with definitively resected tumors had R0 resection and 5 (7%) had a complete pathologic response CR to neoadjuvant therapy. The median overall survival (OS) of the cohort was 24 months. Those with a complete or marked pathologic response had significantly better OS than those with a moderate response (41 vs 24 months, p < 0.02) and patients unable to undergo definitive surgery (17 months, p < 0.0003). Six resected patients experienced grade ≥3 surgical complications. CONCLUSIONS: Neoadjuvant chemotherapy and SBRT are associated with promising pathologic response rates and R0 resection rates, with acceptable perioperative morbidity.

Endoscopic Ultrasound Placement of Preloaded Fiducial Markers Shortens Procedure Time Compared to Back-Loaded Markers.

BACKGROUND & AIMS: Fiducial markers are inert radiopaque gold or carbon markers implanted in or near pancreatic tumor to demarcate areas for image-guided radiation therapy. Endoscopic ultrasound (EUS) pre-loaded fiducial needles (PLNs) have been developed to circumvent technical issues associated with traditional back-loaded fiducials (BLNs). We performed a randomized controlled trial to compare procedure times in patients with pancreatic adenocarcinoma undergoing EUS-guided placement of BLNs vs PLNs. METHODS: In a prospective study, 44 patients with pancreatic adenocarcinoma referred for fiducial marker placement at 2 tertiary care centers were assigned to groups that received PLNs (n = 22) or BLNs (n = 22); each group had the same proportion of patients with tumors of different locations (head or neck vs body or tail).The procedure was standardized among all endoscopists and placement of a minimum of 3 markers inside the tumor was defined as technical success. The times for procedure and fiducial placement were recorded, total number of fiducial markers used documented, and grade of procedure difficulty ranked by passing the needle or deploying the fiducials. Other recorded variables included tumor characteristics, fluoroscopy use, and the number of fiducials clearly seen by EUS and fluoroscopy. The primary aim was to compare the duration of EUS-guided fiducial insertion of BLNs vs PLNs. RESULTS: The median placement time was significantly shorter in the PLN group (9 min) than the BLN group (16 min) (P < .001). However, the 44% reduction in time did not reach pre-specified levels (≥60%). Similar results were found after stratifying by tumor location. Deployment of BLNs was easier than deployment of PLNs (P = .03). There was no significant difference between groups in technical success, number of fiducials placed, EUS or fluoroscopic visualization, or adverse events. During simulation computed tomography and image-guided radiation therapy, there was no difference between groups in visualization of fiducials, migration rate, or accuracy of placement. CONCLUSIONS: In a randomized controlled trial of 44 patients with pancreatic adenocarcinoma, we found EUS-guided placement of PLNs to require less time and produce similar results compared with BLNs. Further refinements in PLN delivery system are needed to increase the ease of deployment. Clinicaltrials.gov no: NCT02332863.

Impact of Surgical Resection on Survival Outcomes After Chemoradiotherapy in Anal Adenocarcinoma.

BACKGROUND: Anal adenocarcinoma is a rare malignancy with a poor prognosis, and no randomized data are available to guide management. Prior retrospective analyses offer differing conclusions on the benefit of surgical resection after chemoradiotherapy (CRT) in these patients. We used the National Cancer Database (NCDB) to analyze survival outcomes in patients undergoing CRT with and without subsequent surgical resection. METHODS: Patients with adenocarcinoma of the anus diagnosed in 2004 through 2015 were identified using the NCDB. Patients with metastatic disease and survival <90 days were excluded. We analyzed patients receiving CRT and stratified by receipt of surgical resection. Logistic regression was used to evaluate predictors of use of surgery and to form a propensity score-matched cohort. Overall survival (OS) was compared between treatment strategies using Cox proportional hazards regression. RESULTS: We identified 1,747 patients with anal adenocarcinoma receiving CRT, of whom 1,005 (58%) received surgery. Predictors of increased receipt of surgery included age <65 years, private insurance, overlapping involvement of the anus and rectum, N0 disease, and external-beam radiation dose ≥4,000 cGy. With a median follow-up of 3.5 years, 5-year OS was 61.1% in patients receiving CRT plus surgery compared with 39.8% in patients receiving CRT alone (log-rank P<.001). In multivariate analysis, surgery was associated with significantly improved OS (hazard ratio, -0.59; 95% CI, 0.50-0.68; P<.001). This survival benefit persisted in a propensity score-matched cohort (log-rank P<.001). CONCLUSIONS: In the largest series of anal adenocarcinoma cases to date, treatment with CRT followed by surgery was associated with a significant survival benefit compared with CRT alone in propensity score-matching analysis. Our findings support national guideline recommendations of neoadjuvant CRT followed by resection for patients with anal adenocarcinoma.

Improved survival in rectal cancer patients who are treated with long-course versus short-course neoadjuvant radiotherapy: A propensity-matched analysis of the NCDB.

BACKGROUND: Randomized controlled trials have demonstrated comparable survival outcomes for short-course (SCRT) and long-course neoadjuvant radiotherapy (LCRT) in patients with rectal cancer. METHODS: Using the National Cancer Data Base (2004-2015), a propensity score was used to match 188 patients with rectal cancer receiving SCRT to 376 patients receiving LCRT. Perioperative, oncologic, and survival outcomes were compared. RESULTS: Patient and clinical tumor characteristics were similar between groups. Patients in the LCRT were more likely to undergo surgery (91% vs 85%; P = 0.03). The LCRT group were more likely to have tumor (T) (56% vs 43%) and nodal (N) (25% vs 19%) downstaging, and a complete pathological response (15% vs 6%) compared with the SCRT group (all P < 0.05). Length of stay (6 vs 8 days), 30-day (1% vs 5%) mortality, and 90-day mortality (1% vs 10%) were significantly lower in the LCRT group (all P < 0.05). After adjusting for patient and tumor-related characteristics, LCRT was associated with a 50% reduction in the risk of mortality compared with SCRT (hazard ratios, 0.50; 95% confidence interval, 0.35-0.70). CONCLUSIONS: In this analysis, LCRT was superior to SCRT in terms of tumor response to neoadjuvant therapy, perioperative mortality, and overall survival. These findings provide evidence for the use of LCRT when neoadjuvant therapy is indicated.

Risk factors for paclitaxel-induced peripheral neuropathy in patients with breast cancer.

BACKGROUND: Paclitaxel induced peripheral neuropathy (PIPN) is a major debilitating side effect of paclitaxel in patients with breast cancer with no fully known mechanisms. The aim of the study was to find out the possible risk factors for PIPN. METHODS: Eligible patients with node positive breast cancer undergoing chemotherapy with paclitaxel were assessed. They belonged to an initial randomized controlled trial in which the effectiveness of omega-3 fatty acids in preventing and reducing severity of PIPN was evaluated (protocol ID: NCT01049295). Reduced total neuropathy score (r-TNS) was used for measuring PIPN. All analyses were performed adjusting for intervention effect. The association between age, BMI, BSA, pathological grade, molecular biomarkers and PIPN was evaluated. RESULTS: Fifty-seven patients with breast cancer were investigated. Age was significantly associated with risk of PIPN (RR:1.50, P value = .024). Body mass index and BSA had significant association with severity of PIPN (B:1.28, P = .025; and B: 3.88, P = .010 respectively). Also, BSA showed a significant association with the risk of PIPN (RR: 2.28, P = .035; B: 3.88, P = .035). Incidence and severity of PIPN were much more pronounced in progesterone receptor positive (PR+) patients (RR:1.88, P = .015 and B:1.54, P = .012). Multivariate analysis showed that age and the status of PR+ were independent risk factor for incidence and the status of PR+ was the only independent risk factor for severity of PIPN. CONCLUSION: Age, BSA and the status of PR+, should be considered as the risk factors for PIPN before commencement of chemotherapy with paclitaxel in patients with breast cancer. Older patients, those with greater BSA and PR+ patients may need closer follow up and more medical attention due to greater incidence and severity of PIPN.

Perioperative outcomes and survival following neoadjuvant stereotactic body radiation therapy (SBRT) versus intensity-modulated radiation therapy (IMRT) in pancreatic adenocarcinoma.

BACKGROUND AND OBJECTIVES: To compare outcomes in patients receiving neoadjuvant stereotactic body radiation therapy (SBRT) with those receiving intensity-modulated radiation therapy (IMRT) for pancreatic adenocarcinoma. METHODS: We analyzed patients receiving neoadjuvant SBRT for borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC) (2012-2016). Differences in baseline characteristics, perioperative outcomes, progression-free survival (PFS), and overall survival (OS) were compared. RESULTS: Seventy-five (82.4%) patients received SBRT and 16 (17.6%) received IMRT. There were no differences in surgical resection rates in the SBRT (n = 38, 50.7%) and IMRT (n = 11, 68.8%) groups (P = 0.188). Among resected patients, there was no difference in postoperative outcomes or pathologic outcomes including lymph node status, margin status, lymphovascular and perineural invasion, or pathologic response to neoadjuvant treatment (P > 0.05). Among all patients, median PFS and OS were 9.9 and 23.5 months in the SBRT group, respectively, and 15.3 and 21.8 months in the IMRT group, respectively (P > 0.05). Similarly, there was no difference in PFS or OS between groups when stratified by BRPC, LAPC, and surgically resected patients (P > 0.05). CONCLUSIONS: In the neoadjuvant setting, SBRT and IMRT appear to have similar rates of resection, perioperative outcomes, and survival outcomes, but additional studies with increased sample size and longer follow up are needed.

Evaluation of respiratory motion-corrected cone-beam CT at end expiration in abdominal radiotherapy sites: a prospective study.

BACKGROUND: Cone beam computed tomography (CBCT) for radiotherapy image guidance suffers from respiratory motion artifacts. This limits soft tissue visualization and localization accuracy, particularly in abdominal sites. We report on a prospective study of respiratory motion-corrected (RMC)-CBCT to evaluate its efficacy in localizing abdominal organs and improving soft tissue visibility at end expiration. MATERIAL AND METHODS: In an IRB approved study, 11 patients with gastroesophageal junction (GEJ) cancer and five with pancreatic cancer underwent a respiration-correlated CT (4DCT), a respiration-gated CBCT (G-CBCT) near end expiration and a one-minute free-breathing CBCT scan on a single treatment day. Respiration was recorded with an external monitor. An RMC-CBCT and an uncorrected CBCT (NC-CBCT) were computed from the free-breathing scan, based on a respiratory model of deformations derived from the 4DCT. Localization discrepancy was computed as the 3D displacement of the GEJ region (GEJ patients), or gross tumor volume (GTV) and kidneys (pancreas patients) in the NC-CBCT and RMC-CBCT relative to their positions in the G-CBCT. Similarity of soft-tissue features was measured using a normalized cross correlation (NCC) function. RESULTS: Localization discrepancy from the end-expiration G-CBCT was reduced for RMC-CBCT compared to NC-CBCT in eight of eleven GEJ cases (mean ± standard deviation, respectively, 0.21 ± 0.11 and 0.43 ± 0.28 cm), in all five pancreatic GTVs (0.26 ± 0.21 and 0.42 ± 0.29 cm) and all ten kidneys (0.19 ± 0.13 and 0.51 ± 0.25 cm). Soft-tissue feature similarity around GEJ was higher with RMC-CBCT in nine of eleven cases (NCC =0.48 ± 0.20 and 0.43 ± 0.21), and eight of ten kidneys (0.44 ± 0.16 and 0.40 ± 0.17). CONCLUSIONS: In a prospective study of motion-corrected CBCT in GEJ and pancreas, RMC-CBCT yielded improved organ visibility and localization accuracy for gated treatment at end expiration in the majority of cases.

Quality Control of Radiation Delivery for Lower Gastrointestinal Cancers.

OPINION STATEMENT: Assessing the quality of health care delivered is a priority across medical specialties, but it is particularly critical for radiation oncology, a field with rapid introduction of new technologies and treatment paradigms. Deviation from acceptable standards can lead to delivery of inferior therapies and medical errors that can directly compromise patient clinical outcome, thus leading to disparities in quality of care. Professional oncologic specialty societies often take ownership of standardizing best practices by issuing evidence-based disease-specific consensus guidelines. They also inform quality indicators that are set as requirements for accreditation, maintenance of certification, and reimbursement. Cooperative groups also create benchmarks for quality radiation therapy through design of clinical protocols that set standard-of-care treatment practices. Pelvic radiotherapy for colorectal and anal cancers has undergone a significant transformation in radiation planning and delivery including increased complexity in contour segmentation with a transition from three-dimensional to intensity-modulated radiation therapy (IMRT). Compliance with quality metrics proposed in national consensus guidelines and participation in clinical trials help keep practicing radiation oncologists up-to-date with advances in our field and well-trained to provide safe and effective high-value care.

Intensity-modulated radiotherapy versus three-dimensional conformal radiotherapy in rectal cancer treated with neoadjuvant concurrent chemoradiation: a meta-analysis and pooled-analysis of acute toxicity.

BACKGROUND: To compare the acute gastrointestinal (GI) and genitourinary (GU) toxicity profiles between intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3DCRT) in rectal cancer patients treated with neoadjuvant chemoradiation (NCRT) using meta-analysis and pooled-analysis from published articles. METHODS: Literature search was performed in PubMed and EMBASE from inception to March 2017. The odd ratios (ORs) were calculated and random effects model was used for meta-analysis. Chi-square or Fisher's exact test was performed for the pooled-analysis. RESULTS: Six studies including a total of 859 patients met the inclusion criteria. Most patients (98.7%) received NCRT. In the meta-analysis, IMRT reduced grade ≥ 2 acute overall GI toxicity, diarrhea and proctitis with ORs of 0.38, 0.32 and 0.60, respectively (all P < 0.05), compared to 3DCRT. IMRT also reduced acute grade ≥ 3 proctitis compared to 3D-CRT (OR, 0.24; P = 0.03). No significant heterogeneity or publication bias was detected. In the pooled-analysis, IMRT reduced the incidence of grade ≥ 2 acute overall GI toxicity, diarrhea, proctitis and GU toxicity (all P < 0.05). Moreover, lower incidence of grade ≥ 3 acute overall GI toxicity, diarrhea and proctitis were observed in the patients treated with IMRT (all P < 0.05). CONCLUSIONS: IMRT significantly reduced acute toxicity in locally advanced rectal cancer patients treated with NCRT compared to 3DCRT.

Prevalence of patient-reported gastrointestinal symptoms and agreement with clinician toxicity assessments in radiation therapy for anal cancer.

PURPOSE: Gastrointestinal (GI) symptoms pose a significant burden to patients receiving chemoradiation therapy (CRT) for anal cancer; however, the impact of symptoms from the patient perspective has not been quantified. This retrospective study examined and compared patient and clinician reports of acute GI toxicity during CRT. MATERIALS AND METHODS: Patients treated with definitive RT using intensity-modulated radiation therapy for anal cancer between 9/09 and 11/12 were reviewed. Median RT dose was 56 Gy (range 45-56), and 76 patients (97%) received concurrent 5-fluorouracil-based chemotherapy. During RT, patients completed the 7-item Bowel Problem Scale (BPS) weekly. Clinicians assessed toxicity separately using CTCAE v. 3.0. Scores of BPS ≥ 3 and CTCAE ≥ 1 were considered to be clinically meaningful. Agreement of the two assessments was evaluated by Cohen's kappa coefficient. RESULTS: Seventy-eight patients completed at least one BPS and had a corresponding clinician assessment. Patients reporting scores of ≥3 was highest at week 5 (n = 68) for diarrhea (44.1%), proctitis (57.4%), and mucus (48.4%), while urgency (47.6%), tenesmus (31.7%), and cramping (27%) were highest at week 4 (n = 63). Baseline bleeding scores (26.7%; score ≥3) improved during treatment (13.4% at week 5). "Poor" agreement was observed between patient- and clinician-reported proctitis (Cohen's k = 0.11; n = 58); however, there was "good" agreement for diarrhea (Cohen's k = 0.68; n = 58). CONCLUSIONS: Acute GI toxicity during definitive CRT for anal cancer was most significant during weeks 4-5, while rectal bleeding improved during treatment. Discrepancies in patient- and clinician-reported symptoms demonstrate the potential for patient-reported outcomes to be useful tools for anal cancer clinical assessments.

Risk of second cancers in the era of modern radiation therapy: does the risk/benefit analysis overcome theoretical models?

In the era of modern radiation therapy, the compromise between the reductions in deterministic radiation-induced toxicities through highly conformal devices may be impacting the stochastic risk of second malignancies. We reviewed the clinical literature and evolving theoretical models evaluating the impact of intensity-modulated radiation therapy (IMRT) on the risk of second cancers, as a consequence of the increase in volumes of normal tissues receiving low doses. The risk increase (if any) is not as high as theoretical models have predicted in adults. Moreover, the increase in out-of-field radiation doses with IMRT could be counterbalanced by the decrease in volumes receiving high doses. Clinical studies with short follow-up have not corroborated the hypothesis that IMRT would drastically increase the incidence of second cancers. In children, the risk of radiation-induced carcinogenesis increases from low doses and consequently the relative risk of second cancers after IMRT could be higher than in adults, justifying current developments of proton therapy with priority given to this population. Although only longer follow-up will allow a true assessment of the real impact of these modern techniques on radiation-induced carcinogenesis, a comprehensive risk-adapted strategy will help minimize the probability of second cancers.