The standard of care for the definitive treatment of locoregionally advanced cervical cancer is external beam radiation therapy (EBRT) with concurrent chemotherapy followed by a brachytherapy boost. ...Historically, EBRT was delivered via a two-dimensional technique based primarily on bony landmarks. This gave way to three-dimensional conformal radiation therapy, which allows for dose calculation and adjustment based on individual tumour and patient anatomy. Further technological advances have established intensity-modulated radiation therapy (IMRT) as a standard treatment modality, given the ability to maintain tumoricidal doses to target volumes while reducing unwanted radiation dose to nearby critical structures, thereby reducing toxicity. Routine image guidance allows for increased confidence in patient alignment prior to treatment, and the ability to visualise the daily position of the targets and organs at risk has been instrumental in allowing safe reductions in treated volumes. Additional EBRT technologies, including proton therapy and stereotactic body radiation therapy, may further improve the therapeutic index. In the realm of brachytherapy, a shift from point-based dose planning to image-guided brachytherapy has been associated with improved local control and reduced toxicity, with additional refinement ongoing. Here we will discuss these advances, the supporting data and future directions.
Previous studies have found that overestimating treatment effects (i.e. ‘optimism bias’) leads to underpowered clinical trials. The prevalence of ‘optimism bias’ in contemporary National Clinical ...Trials Network (NCTN) cancer clinical trials is unknown.
We conducted a systematic review of NCTN phase III randomized trials published from January 2007 to January 2017. We compared the hypothesized versus observed treatment effects in each trial, and examined whether trial-related factors were correlated with the study results. We also reviewed the methods of each protocol to assess whether a rationale for the hypothesized effect size was provided.
We identified 161 clinical trials, of which 130 were eligible for analysis. Original protocols could not be located for 8 trials (5.0%). Twenty-eight trials (21.5%) observed a statistically significant difference in the primary end point favoring the experimental treatment. The median ratio of observed-to-expected hazard ratios among trials that observed a statistically significant effect on the primary end point was 1.07 (range: 0.33–1.28) versus 1.32 (range: 0.86–2.02) for trials that did not, compared with 1.34 and 1.86, respectively, for National Cancer Institute (NCI) trials published between 1955 and 2006. An effect size at least as large as the one projected in the protocol trials was observed in 9.8% of trials, compared with 17% of NCI trials published from 1955 to 2006. Most trials (64.6%) provided no rationale to support the magnitude of the proposed treatment effect in the protocol.
Despite a reduction in ‘optimism bias’ compared with previous eras, most contemporary NCTN phase III trials failed to establish statistically significant benefits of new cancer therapies. Better rationalization of proposed effect sizes in research protocols is needed.
To provide a preliminary analysis of chronic gastrointestinal (GI) toxicity in gynecology patients treated with intensity-modulated whole pelvic radiation therapy (IM-WPRT).
Between February 2000 and ...August 2001, 36 gynecology patients received IM-WPRT. All patients underwent a contrast-enhanced computed tomography scan, and a clinical target volume (CTV) was contoured consisting of the upper vagina, parametria, uterus (if present), and presacral and pelvic lymph node regions. The CTV was expanded by 1 cm to create a planning target volume (PTV). Seven or 9-field IM-WPRT plans were generated. IM-WPRT plans were highly conformal, providing excellent coverage of the PTV and considerable sparing of normal tissues, including the small bowel and rectum. Chronic GI toxicity was scored: 0 (no symptoms), 1 (mild symptoms, no medications required), 2 (moderate symptoms, medications required), and 3 (severe symptoms, hospitalization, surgery required). Chronic GI toxicity in 30 gynecology patients treated with conventional WPRT patients before the implementation of IM-WPRT was also evaluated. Median follow-up in the IM-WPRT and WPRT groups were 19.6 and 30.2 months, respectively.
The IM-WPRT and WPRT groups were well balanced in terms of most patient and treatment factors, including age, site, stage, chemotherapy, WPRT dose, and brachytherapy, except for a higher frequency of surgery (75 vs. 54%,
p = 0.02) in the IM-WPRT group. Overall, IM-WPRT patients had a lower rate of chronic GI toxicity (11.1 vs. 50.0%,
p = 0.001) than WPRT patients. The percentage of IM-WPRT patients with Grade 1, 2, and 3 toxicity were 8.3%, 2.8%, and 0%, respectively. Corresponding percentages in the WPRT group were 30.0%, 16.7%, and 3.3%, respectively. The only other factor correlated with chronic GI toxicity was age (
p = 0.02). On multivariate (logistic regression) analysis controlling for age and other clinical factors, IM-WPRT retained its statistical significance (
p = 0.01; odds ratio 0.16; 95% confidence interval 0.04, 0.67)
Our results suggest that IM-WPRT is associated with less chronic GI toxicity than conventional WPRT in patients with gynecologic malignancies. However, longer follow-up and more patients are clearly needed to ascertain whether the benefits of IM-WPRT treatment seen here translate into true long-term reductions in chronic GI toxicity.
Reports have suggested that streptococcal infection may be etiologically related to pediatric autoimmune neuropsychiatric disorders (PANDAS), but there are few good epidemiologic studies to support ...this theory. Using population-based data from a large West-Coast health maintenance organization, we assessed whether streptococcal infection was associated with increased risk for obsessive-compulsive disorder (OCD), Tourette's syndrome (TS), or tic disorder.
This is a case-control study of children 4 to 13 years old receiving their first diagnosis of OCD, TS, or tic disorder between January 1992 and December 1999 at Group Health Cooperative outpatient facilities. Cases were matched to controls by birth date, gender, primary physician, and propensity to seek health care.
Patients with OCD, TS, or tic disorder were more likely than controls to have had prior streptococcal infection (OR: 2.22; 95% CI: 1.05, 4.69) in the 3 months before onset date. The risk was higher among children with multiple streptococcal infections within 12 months (OR: 3.10; 95% CI: 1.77, 8.96). Having multiple infections with group A beta-hemolytic streptococcus within a 12-month period was associated with an increased risk for TS (OR: 13.6; 95% CI: 1.93, 51.0). These associations did not change appreciably when limited to cases with a clear date of onset of symptoms or with tighter matching on health care behavior.
These findings lend epidemiologic evidence that PANDAS may arise as a result of a postinfectious autoimmune phenomenon induced by childhood streptococcal infection.
Purpose: To identify dosimetric factors correlated with acute gastrointestinal (GI) toxicity in gynecology patients undergoing intensity-modulated whole pelvic radiation therapy (IM-WPRT).
Material ...and methods: Fifty gynecology patients received IM-WPRT (45–1.8
Gy/fraction) between 2/00 and 3/02. All patients were treated to a clinical target volume (CTV) consisting of the upper vagina, parametria, uterus, presacral region and pelvic lymph nodes. Grade 2 acute GI toxicity requiring frequent medications and grade 3–5 toxicities were designated as clinically significant and analyzed as a function of patient and dosimetric variables. The most significant volumetric factors were fit to a normal tissue complication probability (NTCP) function.
Results: Fourteen women (28%) developed clinically significant acute GI toxicity. None of the patient factors were correlated with acute GI toxicity. In addition, the volume of rectum receiving 25, 50, 75, 90, 100 and 110% of the prescription dose did not reach statistical significance. In contrast, a correlation was observed between the volume of small bowel (SB) irradiated and acute GI toxicity, particularly the SB volumes receiving 90 and 100% of the prescription dose (
p=0.009 and
p=0.009, respectively). Controlling for patient and other dosimetric factors, the SB volume receiving the 100% (Vol
SB,100) of the prescription dose remained the sole significant factor on multivariate analysis (
p=0.012). Subsequently, a NTCP curve, quantifying the risk of acute GI toxicity, was generated based on the Vol
SB,100.
Conclusions: The most significant factor correlated acute GI toxicity in gynecology patients undergoing IM-WPRT is Vol
SB,100.
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