Window of opportunity with PD1 blockade before chemoradiotherapy for an advanced stage clear cell carcinoma of the cervix.

Clear cell carcinoma is a rare and very aggressive subset of cervical cancer, with poor outcome if diagnosed at advanced stage. There are few data available on the optimal management of this histotype, and treatment recommendations that include surgery and chemoradiotherapy, are essentially based on those for squamous cell carcinoma. Here we report the case of a young patient newly diagnosed with advanced stage (FIGO IIB) clear cell carcinoma of the uterine cervix who received a window of opportunity one injection of nivolumab followed by standard chemoradiotherapy. She showed a persistent complete remission after 28 months of follow-up, but developed hypothyroidism, as a consequence of immunotherapy, and required lifelong thyroid hormone replacement.

Prone versus supine free-breathing for right-sided whole breast radiotherapy.

Prone setup has been advocated to improve organ sparing in whole breast radiotherapy without impairing breast coverage. We evaluate the dosimetric advantage of prone setup for the right breast and look for predictors of the gain. Right breast cancer patients treated in 2010-2013 who had a dual supine and prone planning were retrospectively identified. A penalty score was computed from the mean absolute dose deviation to heart, lungs, breasts, and tumor bed for each patient's supine and prone plan. Dosimetric advantage of prone was assessed by the reduction of penalty score from supine to prone. The effect of patients' characteristics on the reduction of penalty was analyzed using robust linear regression. A total of 146 patients with right breast dual plans were identified. Prone compared to supine reduced the penalty score in 119 patients (81.5%). Lung doses were reduced by 70.8%, from 4.8 Gy supine to 1.4 Gy prone. Among patient's characteristics, the only significant predictors were the breast volumes, but no cutoff could identify when prone would be less advantageous than supine. Prone was associated with a dosimetric advantage in most patients. It sets a benchmark of achievable lung dose reduction.Trial registration: ClinicalTrials.gov NCT02237469, HUGProne, September 11, 2014, retrospectively registered.

Combining Clinical and Dosimetric Features in a PBS Proton Therapy Cohort to Develop a NTCP Model for Radiation-Induced Optic Neuropathy.

PURPOSE: Radiation-induced optic neuropathy (RION) is a rare, yet severe complication following radiation therapy for brain, head and neck, or skull-base tumors. Although several risk factors, such as age, metabolic syndrome, and delivered dose, have been identified, we aimed at expanding the understanding of the mechanisms of interplay regarding dosimetry and patient variables leading to the onset of RION with a focus on proton therapy. METHODS AND MATERIALS: In this retrospective study, we have investigated proton-specific risk factors by comparing common phenomenological normal tissue complication probability models with a multivariate analysis that includes clinical features on a cohort of patients with skull-base and head and neck cancer treated with pencil beam scanning. RESULTS: Although predictive power of the Lyman-Kutcher-Burman and Poisson models was limited for this data set, the addition of clinical variables such as age, tumor involvement, hypertension, or sex remarkably increased model performance. CONCLUSIONS: Based on our assessment, the maximum dose in the optical apparatus is confirmed the most intuitive risk factor. However, above a certain dose threshold, clinical patient characteristics are the deciding factors for the onset of RION. We observed a tendency toward a volume effect that, if confirmed, would imply a benefit for high precision radiation therapy techniques such as proton therapy for the treatment of patients with high clinical risk for RION.

Is prone free breathing better than supine deep inspiration breath-hold for left whole-breast radiotherapy? A dosimetric analysis.

PURPOSE: The advantage of prone setup compared with supine for left-breast radiotherapy is controversial. We evaluate the dosimetric gain of prone setup and aim to identify predictors of the gain. METHODS: Left-sided breast cancer patients who had dual computed tomography (CT) planning in prone free breathing (FB) and supine deep inspiration breath-hold (DiBH) were retrospectively identified. Radiation doses to heart, lungs, breasts, and tumor bed were evaluated using the recently developed mean absolute dose deviation (MADD). MADD measures how widely the dose delivered to a structure deviates from a reference dose specified for the structure. A penalty score was computed for every treatment plan as a weighted sum of the MADDs normalized to the breast prescribed dose. Changes in penalty scores when switching from supine to prone were assessed by paired t-tests and by the number of patients with a reduction of the penalty score (i.e., gain). Robust linear regression and fractional polynomials were used to correlate patients' characteristics and their respective penalty scores. RESULTS: Among 116 patients identified with dual CT planning, the prone setup, compared with supine, was associated with a dosimetric gain in 72 (62.1%, 95% CI: 52.6-70.9%). The most significant predictors of a gain with the prone setup were the breast depth prone/supine ratio (>1.6), breast depth difference (>31 mm), prone breast depth (>77 mm), and breast volume (>282 mL). CONCLUSION: Prone compared with supine DiBH was associated with a dosimetric gain in 62.1% of our left-sided breast cancer patients. High pendulousness and moderately large breast predicted for the gain.

Dose-escalated volumetric modulated arc therapy for total marrow irradiation: A feasibility dosimetric study with 4DCT planning and simultaneous integrated boost.

PURPOSE: To evaluate the planning feasibility of dose-escalated total marrow irradiation (TMI) with simultaneous integrated boost (SIB) to the active bone marrow (ABM) using volumetric modulated arc therapy (VMAT), and to assess the impact of using planning organs at risk (OAR) volumes (PRV) accounting for breathing motion in the optimization. METHODS: Five patients underwent whole-body CT and thoraco-abdominal 4DCT. A planning target volume (PTV) including all bones and ABM was contoured on each whole-body CT. PRV of selected OAR (liver, heart, kidneys, lungs, spleen, stomach) were determined with 4DCT. Planning consisted of 9-10 full 6 MV photon VMAT arcs. Four plans were created for each patient with 12 Gy prescribed to the PTV, with or without an additional 4 Gy SIB to the ABM. Planning dose constraints were set on the OAR or on the PRV. Planning objective was a PTV Dmean < 110% of the prescribed dose, a PTV V110% < 50%, and OAR Dmean ≤ 50-60%. RESULTS: PTV Dmean < 110% was accomplished for most plans (n = 18/20), while all achieved V110%<50%. SIB plans succeeded to optimally cover the boost volume (median ABM Dmean = 16.3 Gy) and resulted in similar OAR sparing compared to plans without SIB (median OAR Dmean = 40-54% of the ABM prescribed dose). No statistically significant differences between plans optimized with constraints on OAR or PRV were found. CONCLUSIONS: Adding a 4 Gy SIB to the ABM for TMI is feasible with VMAT technique, and results in OAR sparing similar to plans without SIB. Setting dose constraints on PRV does not impair PTV dosimetric parameters.

Radiation-induced optic neuropathy after pencil beam scanning proton therapy for skull-base and head and neck tumours.

OBJECTIVE: To assess the radiation-induced optic neuropathy (RION) prevalence, following high dose pencil beam scanning proton therapy (PBSPT) to skull base and head and neck (H&N) tumours. METHODS: Between 1999 and 2014, 216 adult patients, median age 47 years (range, 18-77), were treated with PBS PT for skull base or H&N malignancies, delivering ≥45 GyRBE to the optic nerve(s) (ON) and/or optic chiasma (OC). The median administered dose to the planning target volume was 74.0 GyRBE (range, 54.0-77.4). The median follow-up was 5.3 years (range, 0.8-15.9). RESULTS: RION was observed in 14 (6.5%) patients at a median time of 13.2 months (range, 4.8-42.6) following PBSPT. Most (92.9%) of RION were symptomatic. Most affected patients (11/14; 79%) developed unilateral toxicity. Grade 4, 3, 2 and 1 toxicity was observed in 10, 2, 1 and 1 patients, respectively. On univariate analyses, age (<70 vs ≥70 years; p < 0.0001), hypertension (p = 0.0007) and tumour abutting the optic apparatus (p = 0.012) were associated with RION. OC's V60 GyRBE was of border line significance (p = 0.06). None of the other evaluated OC-ON dose/volume metrics (Dmax, Dmean, V40-60) were significantly associated with this complication. CONCLUSION: These data suggest that high-dose PBS PT for skull base and H&N tumours is associated with a low prevalence of RION. Caution should be however exercised when treating elderly/hypertensive patients with tumours abutting the optic apparatus. ADVANCES IN KNOWLEDGE: This is the first study reporting the risk of developing RION following proton therapy with PBS technique, demonstrating the safety of this treatment.

Endoscopic resection with adjuvant chemo-radiotherapy for superficial esophageal squamous cell carcinoma: A critical review.

Radical esophagectomy with extended lymph node dissection is considered the standard of care in treatment of squamous cell carcinoma of esophagus with deep mucosal invasion (pT1a m3) or submucosal involvement (pT1b). However, despite the increasing use of minimally invasive approaches, it remains a major surgery associated with significant morbidities and even mortality risk. Endoscopic resection (ER) results in excellent local control in early superficial mucosal (pT1a) disease yet there is substantial risk of lymph node metastases in T1b disease. Therefore, ER followed by combined with chemo-radiotherapy (CRT) would potentially improve the outcome in pT1a m3 or pT1b disease and would be an attractive conservative alternative to esophagectomy. Retrospective series published so far have shown promising results for this combined treatment. Herein the current literature of the indications, treatment outcome and toxicities of this treatment strategy are discussed and critically reviewed.

[Sexual health after radiotherapy]. / La santé sexuelle après radiothérapie.

The impact of locoregional toxicity after radiotherapy on sexual function is the objective of this review. We explore those organs affected by cancer that are obviously implied in patients' intimate lives : cancers of the breast, prostate, pelvic region, and ENT region. However, we strongly believe that any patient diagnosed with cancer, and treated for one, could by all means be exposed to psychological and somatic changes leading to deterioration of their sexuality.

L'évaluation de l'impact locorégional après un traitement de radiothérapie sur la fonction sexuelle est l'objectif de cet article. Nous passerons en revue les organes atteints de cancer dont l'implication dans la vie intime des patients nous a semblé la plus parlante : les cancers du sein, de la prostate, de la région pelvienne et de la sphère ORL. Néanmoins, nous sommes convaincus que tout patient avec un diagnostic de cancer, et traité pour celui-ci, peut être exposé à des séquelles psychologiques et somatiques entraînant une baisse de sa sexualité.

Modern intensity-modulated radiotherapy with image guidance allows low toxicity rates and good local control in chemoradiotherapy for anal cancer patients.

PURPOSE: To report outcomes of a population of anal cancer patients treated with modern intensity-modulated radiotherapy and daily image-guided radiotherapy techniques. METHODS: We analyzed data of 155 patients consecutively treated with intensity-modulated radiotherapy +/- chemotherapy in three radiotherapy departments. One hundred twenty-two patients presented a stage II-IIIA disease. Chemotherapy was administered in 138 patients, mainly using mitomycin C and 5-fluorouracil (n = 81). All patients received 36 Gy (1.8 Gy/fraction) on the pelvic and inguinal nodes, on the rectum, on the mesorectum and on the anal canal, and a sequential boost up to a total dose of 59.4 Gy (1.8 Gy/fraction) on the anal canal and on the nodal gross tumor volumes. RESULTS: Median follow-up was 38 months (interquartile range 12-51). Toxicity data were available for 143 patients: 22% of them presented a G3+ acute toxicity, mainly as moist desquamation (n = 25 patients) or diarrhea (n = 10). Three patients presented a late grade 3 gastrointestinal toxicity (anal incontinence). No grade 4 acute or late toxicity was recorded. Patients treated with fixed-gantry IMRT delivered with a sliding window technique presented a significantly higher risk of acute grade 3 (or more) toxicity compared to those treated with VMAT or helical tomotherapy (38.5 vs 15.3%, p = 0.049). Actuarial 4-year local control rate was 82% (95% CI 76-91%). CONCLUSIONS: Modern intensity-modulated radiotherapy with daily image-guided radiotherapy is effective and safe in treating anal cancer patients and should be considered the standard of care in this clinical setting.

Prognostic value of biochemical response to neoadjuvant androgen deprivation before external beam radiotherapy for prostate cancer: A systematic review of the literature.

External beam radiation therapy (EBRT) in combination with androgen deprivation therapy (ADT) is considered a standard treatment option for patients with aggressive localized and locally-advanced prostate cancer. Randomized phase III trials have provided evidence for combining EBRT to short-term ADT for intermediate-risk disease and to long-term ADT for patients harboring high-risk tumors. Even if several improvements and developments have been made in the last years in terms of radiotherapy delivery techniques, image-guided radiotherapy, and better sparing of the organs at risk the current use of ADT remains still linked to a therapeutic algorithm based on the prostate cancer risk classification as proposed by clinical trials. Emerging literature has recently shown that the biochemical response to a course of neoadjuvant ADT before EBRT, called the "prostate-specific antigen (PSA) nadir" (lowest value after treatment), may influence the long-term biochemical tumor-control outcomes of prostate cancer patients. An individualized approach adapting the duration of hormonal treatment according to the PSA response during the neoadjuvant phase, as well using new generation hormonal agents, may represent a new therapeutic strategy and a future way to improve the therapeutic ratio for prostate cancer patients. In this systematic review of the literature we explored the prognostic value of the PSA response to the neoadjuvant ADT phase and the rationale to adjust the use of ADT and EBRT in patients with intermediate- and high-risk prostate cancer based on the biochemical response to the neoadjuvant androgen ablation phase.

Moderate Hypofractionated Protracted Radiation Therapy and Dose Escalation for Prostate Cancer: Do Dose and Overall Treatment Time Matter?

PURPOSE: This was a retrospective study of 2 sequential dose escalation regimens of twice-weekly 4 Gy/fractions hypofractionated intensity modulated radiation therapy (IMRT): 56 Gy and 60 Gy delivered within a protracted overall treatment time (OTT) of 6.5 and 7 weeks, respectively. METHODS AND MATERIALS: 163 prostate cancer patients with cT1c-T3a disease and nodal involvement risk ≤20% (Roach index) were treated twice weekly to the prostate ± seminal vesicles with 2 sequential dose-escalated IMRT schedules: 56 Gy (14 × 4 Gy, n=81) from 2003 to 2007 and 60 Gy (15 × 4 Gy, n=82) from 2006 to 2010. Patient repositioning was made with bone matching on portal images. Gastrointestinal (GI) and genitourinary (GU) toxicities were scored according to the Common Terminology Criteria for Adverse Events version 3.0 grading scale. RESULTS: There were no significant differences regarding the acute GU and GI toxicities in the 2 dose groups. The median follow-up times were 80.2 months (range, 4.5-121 months) and 56.5 months (range, 1.4-91.2 months) for patients treated to 56 and 60 Gy, respectively. The 5-year grade ≥2 late GU toxicity-free survivals with 56 Gy and 60 Gy were 96 ± 2.3% and 78.2 ± 5.1% (P=.001), respectively. The 5-year grade ≥2 late GI toxicity-free survivals with 56 Gy and 60 Gy were 98.6 ± 1.3% and 85.1 ± 4.5% (P=.005), respectively. Patients treated with 56 Gy showed a 5-year biochemical progression-free survival (bPFS) of 80.8 ± 4.7%, worse than patients treated with 60 Gy (93.2 ± 3.9%, P=.007). A trend for a better 5-year distant metastasis-free survival was observed among patients treated in the high-dose group (95.3 ± 2.7% vs 100%, P=.073, respectively). On multivariate analysis, only the 60-Gy group predicted for a better bPFS (P=.016, hazard ratio = 4.58). CONCLUSIONS: A single 4-Gy additional fraction in patients treated with a hypofractionated protracted IMRT schedule of 14 × 4 Gy resulted in a similar and minimal acute toxicity, in worse moderate to severe urinary and GI late effects, but a significantly better biochemical control.

Impact of hydrogel spacer injections on interfraction prostate motion during prostate cancer radiotherapy.

Background The dosimetric advantage of prostate-rectum spacers to displace the anterior rectal wall outside of the high-dose radiation regions has been clearly established in prostate cancer radiotherapy (RT). The aim of this study was to assess the impact of hydrogel spacer (HS) in the interfraction prostate motion in patients undergoing RT for prostate cancer. Material and methods Twenty prostate cancer patients implanted with three fiducial markers (FM) with (n = 10) or without (n = 10) HS were analyzed. Displacements between the prostate isocenter based on the FM's position and the bony anatomy were quantified in the left-right (LR), anterior-posterior (AP), superior-inferior (SI) axes by offline analyses of 122 cone beam computed tomography scans. Group systematic (M), systematic (Σ) and random (σ) setup errors were determined. Results In patients with or without HS, the overall mean interfraction prostate displacements were 0.4 versus -0.4 mm (p = 0.0001), 0.6 versus 0.6 mm (p = 0.85), and -0.6 mm versus -0.3 mm (p = 0.48) for the LR, AP, and SI axes, respectively. Prostate displacements >5 mm in the AP and SI directions were similar for both groups. No differences in M, Σ and σ setup errors were observed in the three axes between HS + or HS- patients. Conclusions HS implantation does not significantly influence the interfraction prostate motion in patients treated with RT for prostate cancer. The major expected benefit of HS is a reduction of the high-dose levels to the rectal wall without influence in prostate immobilization.

Serum free light chain measurement aids the diagnosis of myeloma in patients with severe renal failure.

BACKGROUND: Monoclonal free light chains (FLCs) frequently cause rapidly progressive renal failure in patients with multiple myeloma. Immunoassays which provide quantitative measurement of FLCs in serum, have now been adopted into screening algorithms for multiple myeloma and other lymphoproliferative disorders. The assays indicate monoclonal FLC production by the presence of an abnormal kappa to lambda FLC ratio (reference range 0.26-1.65). Previous work, however, has demonstrated that in patients with renal failure the FLC ratio can be increased above normal with no other evidence of monoclonal proteins suggesting that in this population the range should be extended (reference range 0.37-3.1). This study evaluated the diagnostic sensitivity and specificity of the immunoassays in patients with severe renal failure. METHODS: Sera from 142 patients with new dialysis-dependent renal failure were assessed by serum protein electrophoresis (SPE), FLC immunoassays and immunofixation electrophoresis. The sensitivity and specificity of the FLC ratio's published reference range was compared with the modified renal reference range for identifying patients with multiple myeloma; by receiver operating characteristic curve analysis. RESULTS: Forty one patients had a clinical diagnosis of multiple myeloma; all of these patients had abnormal serum FLC ratios. The modified FLC ratio range increased the specificity of the assays (from 93% to 99%), with no loss of sensitivity. Monoclonal FLCs were identified in the urine from 23 of 24 patients assessed. CONCLUSION: Measurement of serum FLC concentrations and calculation of the serum kappa/lambda ratio is a convenient, sensitive and specific method for identifying monoclonal FLC production in patients with multiple myeloma and acute renal failure. Rapid diagnosis in these patients will allow early initiation of disease specific treatment, such as chemotherapy plus or minus therapies for direct removal of FLCs.

Lifestyle or life-saving medicines? A primary healthcare professional and consumer opinion survey on over-the-counter statins.

BACKGROUND: Over-the-counter (OTC) simvastatin 10 mg became available in the UK in July 2004 with the aim of improving primary prevention of ischemic heart disease. OBJECTIVE: To document the views of the main stakeholders (general practitioners [GPs], community pharmacists, and consumers) on issues pertaining to the reclassification of simvastatin to OTC availability, highlight differences between stakeholder groups, and identify factors likely to influence consumer behavior. METHODS: A self-administered questionnaire survey of GPs, community pharmacists, and potentially eligible consumers was carried out 8 months after the UK launch of OTC simvastatin. Participants were asked about their awareness of the drug, their willingness to use such medicines, and their views on relevant management practices. RESULTS: Awareness of OTC simvastatin was high among GPs but limited among consumers. Although OTC availability was favored by pharmacists, consumers and GPs generally thought it was not a good idea. GPs and pharmacists cited increased consumer choice as the most important likely benefit; consumers thought potential savings to the National Health Service were equally important. Medication misuse and neglect of lifestyle risk factors were unanimously considered to be the most important likely risks. Unlike the majority of pharmacists, most GPs thought that current dosing guidelines were inappropriate, but there was consensus that long-term nonadherence would probably curtail any treatment benefit. Most respondents agreed that GPs should be informed if their patients were using OTC statins but disagreed as to the best way to communicate this information. CONCLUSIONS: OTC availability of statins did not appear to be considered a popular public health intervention by consumers and GPs, as the drugs were widely perceived as being prone to misuse. However, OTC availability was favored by pharmacists, who saw this as empowering both for consumers and themselves. Key issues in dispensing, managing, and evaluating the public health impact of this intervention remain outstanding.

Skull base growth in children with Chiari malformation Type I.

OBJECT: The goal of this study was to establish whether children with Chiari malformation Type I (CM-I) have abnormal skull base geometry. METHODS: Distances and angles between skull base landmarks were measured on preoperative magnetic resonance images obtained in 30 children (age range 36-204 months) with symptomatic isolated CM-I; 16 of them (53%) had syringomyelia. Comparisons were made with 42 children of similar age who comprised the control group by using one-way analysis of variance. RESULTS: The angle formed by the crista galli (CG), dorsum sellae (DS), and foramen magnum (FM) was larger than normal in individuals with CM-I than in those without (145 degrees in patients with CM-I but no syringomyelia and 151 degrees in those with CM-I and syringomyelia compared with 135 degrees in controls; p = 0.000). The angle formed by the left internal auditory meatus (IAM), FM, and right IAM was also larger than normal in the patients (122 degrees in patients with CM-I but no syringomyelia and 123 degrees in those with CM-I and syringomyelia compared with 110 degrees in controls; p = 0.001). The angle formed by the anterior clinoid process (ACP), CG, and right ACP was smaller than normal (29 degrees in all patients with CM-I compared with 34 degrees in controls; p = 0.000). The distance between the two IAMs was longer than normal (75 mm in patients with CM-I but no syringomyelia and 63 mm in those with CM-I and syringomyelia compared with 58 mm in controls; p = 0.000). The distance between the two ACPs was shorter than normal in the syringomyelia group (31 mm in patients with CM-I but no syringomyelia and 27 mm in those with CM-I and syrinx compared with 32 mm in controls; p = 0.001). Within the group of patients with CM-I, the DS-FM and left ACP-right ACP distances were smaller in the syringomyelia group (p = 0.009 and p = 0.037, respectively). CONCLUSIONS: Children with CM-I have abnormal geometrical measurements of their entire skull base, not only the posterior fossa, irrespective of presence of syringomyelia. This may indicate a mesodermal defect as a possible cause of the malformation.

Posterior fossa volume in children with Chiari malformation Type I.

OBJECT: The authors sought to establish whether the volume of the posterior fossa in children suffering from Chiari malformation Type I (CM-I) is smaller than normal, as has been suggested previously. They also investigated the role of syringomyelia in posterior fossa development. METHODS: Both posterior fossa volume (PFV) and intracranial volume (ICV) were measured using segmentation techniques on preoperative magnetic resonance images obtained in 42 children who underwent surgery for CM-I (mean age 127 months, range 36-204 months); 25 (59%) of the patients had syringomyelia. The PFV/ICV ratio was calculated to eliminate differential supratentorial growth. Patients who had deformities potentially interfering with skull growth or who had undergone a shunt insertion procedure prior to craniovertebral decompression were excluded. The results were compared with measurements of 51 healthy children using one-way analysis of variance. In patients with CM-I only, the mean PFV and PFV/ICV ratios were not statistically different than those for healthy children. In patients with both CM-I and syringomyelia (CM-S), the mean PFV and PFV/ICV ratios were statistically smaller than those for healthy children. The ICV was 1383 cm3 in the healthy group, 1459 cm3 in the CM-I only group, and 1400 cm3 in the CM-S group (p = 0.363); the PFV was 186 cm3 in the healthy group, 196 cm3 in the CM-I only group, and 171 cm3 in the CM-S group (p = 0.036); the PFV/ICV ratio was 0.135 in the healthy group, 0.134 in the CM-I only group, and 0.122 in the CM-S group (p = 0.004). These differences were more prominent in the first 10 years of life. CONCLUSIONS: Children with isolated CM-I do not have a PFV smaller than normal, whereas children with both CM-I and syringomyelia have a PFV significantly smaller than normal. This result indicates that the two subgroups may represent different phenotypic expression or even a different pathogenesis.