Higher Gastrointestinal Toxicity Research Articles

Gastrointestinal Toxicity Following Proton and Photon Radiation for Prostate Cancer in Patients with Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) has been considered a relative contraindication for radiation for prostate cancer (PC) due to concern for gastrointestinal (GI) toxicity. Modern radiation planning techniques such as intensity modulated radiation therapy (IMRT) have resulted in a significant decrease in GI toxicity in the general PC population. Several published case series have suggested overall excellent outcomes using IMRT in PC patients with IBD. Proton therapy (PT) with improved dosimetric sparing of bowel and rectum may offer additional benefit, but to our knowledge, there is no published data assessing outcomes after PT in PC patients with IBD. We report our institutional experience treating PC patients with IBD with both PT and IMRT. We identified patients with an IBD diagnosis treated for PC at our institution from 2012-2022 with either IMRT or PT. Baseline clinical characteristics were captured, along with radiation parameters, including dose, fractionation, inclusion of pelvic nodes, and use of a rectal spacer. IBD specifics captured included type of IBD, use of IBD medication, and pre radiation colonoscopy findings when available. Early and late GI toxicities were captured via retrospective chart review and graded per the Common Terminology Criteria for Adverse Events (CTCAE) version 5. Eighteen patients with IBD were treated with RT for PC at our institution, including 10 with ulcerative colitis, 7 with Crohn's disease, and 1 with IBD NOS. Nine of these patients were treated with PT and 9 with IMRT. Most were treated with conventional fractionation (n = 14) and the rest with moderate hypofractionation. Fourteen received primary RT to an intact prostate, and the rest received salvage RT. In four patients, the pelvic nodes were also treated. Rectal spacers were used for 8 patients. Nine of the patients were on IBD medications, and of the 15 patients with records of pre-RT colonoscopy, only 1 demonstrated inflammatory findings, which were noted in the ileum. Median follow-up was 3.5 years (1-6) Acute grade (Gr)1 GI toxicity was seen in 6(33%) patients with diarrhea and proctitis. No patients developed acute Gr 2 GI toxicity, and 1 patient developed acute Gr 3 diarrhea and proctitis. This patient had asymptomatic Crohn's disease prior to IMRT, not on medication, and was treated to the prostate and pelvic nodes. Late Gr 1 GI toxicity was seen in 4 (22%) patients. Median time to late GI toxicity was 9.5 months. No patients developed late Gr 2 or higher GI toxicity. Modern radiation techniques including IMRT and PT are well tolerated in PC patients with well-controlled IBD. Larger studies with longer follow up would be helpful to further characterize these patients' outcomes. In the meantime, IMRT and PT should be considered as treatment options in patients with well-controlled IBD.

Conventional vs. Hypo-Fractionated, Radiotherapy for High-Risk Prostate Cancer (PCS5), Randomized, Non-Inferiority, Phase 3 Trial: Posthoc Analysis of IMRT vs. 3D-CRT Radiation Therapy Associated Toxicities

The Prostate Cancer Study number 5 (PCS5), is a multi-centric non-inferiority, phase 3, randomized controlled trial of high-risk prostate cancer patients of treated with either conventionally fractionated radiotherapy (CFRT) or hypofractionated radiotherapy (HFRT). The 7 years' pre-planned analysis showed that HFRT (68 Gy in 25 fractions) was as effective and well tolerated as CFRT (76 Gy in 38 fractions). In this posthoc analysis we aim to report the genitourinary (GU) and gastrointestinal (GI) toxicities associated with radiation therapy techniques: intensity-modulated radiotherapy (IMRT) and 3D-conformal radiotherapy (3D-CRT). PCS5 randomized patients in a 1:1 ratio to receive either CFRT or HFRT. All patients received long term neoadjuvant, concurrent and adjuvant androgen suppression, with a median duration of 24 months. The toxicities were reported as per the Common Terminology Criteria for Adverse Events version 4. Acute toxicities were defined as presenting ≤ 180 days post-RT start and delayed > 180 days. The cumulative acute and delayed GI and GU toxicities were classified in grade groups: grade 1 or higher (G1+), G2+, and G3+. For each grade group, acute and delayed, we performed multivariable logistic regression analyses, adjusting for age, CTV volume, diabetes, fractionation (CRFT or HFRT), hypertension, and stage < T3b or ≥ T3b. For efficacy analyses cox-regression was utilized. A p-value < 0.05 was considered significant. Three hundred twenty of the 329 patients enrolled in the trial were included in this posthoc analyses. The mean age was 71.4 ± 6.1 years, and the mean CTV volume (n = 219) was 47.25 ± 19.9 cc. IMRT was used in 195 (60.6%) patients and 3D-CRT in 125 (39.1%) patients. Multivariable logistic regression showed a significant difference in favor of IMRT for GI G2+ acute toxicity (OR = 0.285 [0.14-0.59]; CI: 95%; p<0.001) and GI G2+ delayed toxicity (OR = 0.202 [0.60-0.69]; CI: 95%; p = 0.01). There were no differences in G3+ GI or GU toxicities and there were no grade 4 toxicities. There were no differences in efficacy at 7 years between the two treatment technics. Outcomes for IMRT vs. 3D-CRT respectively, overall survival (81.5% vs 79.2%; HR: 0.92 [0.55-1.53]; CI: 95%; p-value: 0.74), distant metastasis free survival (90,7% vs 92.8%; HR: 1.4 [0.63-3.1]; CI: 95%; p-value: 0.42), prostate cancer mortality (95.8% vs. 92.2%; HR: 0.93 [0.32-2.67]; CI: 95%; p-value: 0.89), and biochemical failure (85.1% vs 88%; HR: 1.35 [0.72-2.52]; CI: 95%; p-value: 0.35). This is the first phase 3 randomized controlled trial assessing the use of HFRT vs. CFRT, exclusively in high-risk prostate cancer patients. Given that our efficacy data at 7 years follow-up establishes moderate HFRT as a new standard of care and no difference between IMRT and 3D-CRT, we strongly recommend that patients who are treated with EBRT should receive IMRT, given the reduced acute and delayed grade 2 or higher GI toxicities.

NALIRIFOX vs FOLFIRINOX vs gemcitabine plus nab-paclitaxel as first-line treatment of advanced pancreatic cancer: An individual patient data pooled analysis of phase 3 registration trials.

e16262 Background: The NAPOLI-3 trial showed the superiority of the NALIRIFOX regimen over the combination of gemcitabine and nab-Paclitaxel (GemNabP) as first-line treatment (1LTx) of advanced pancreatic cancer (PDAC), thus being candidate as a reference regimen in this setting. However, a comparison with the FOLFIRINOX regimen has not yet been performed. Methods: We performed a pooled analysis of phase III trials that defined FOLFIRINOX, NALIRIFOX and GemNabP as optimal 1LTx options in advanced PDAC. Individual patient outcomes were retrieved from Kaplan Meier plots of each trial, and analysed after assessment of data reconstruction accuracy. Progression free survival (PFS) and overall survival (OS) were compared between the three different arms, using Cox proportional hazard models including each trial as a random effect variable to account for inter-trial variability. Overall response rates (ORR) and Grade 3 or 4 (G3/4) toxicity rates were also compared. Results: A total of 1372 patients treated with FOLFIRINOX (n=171, 12), NALIRIFOX (n=383, 28) and GemNabP (n=818, 60) were included. Median PFS was significantly longer in patients treated with NALIRIFOX (7.4 months) as compared to FOLFIRINOX [6.4 months, HR 1.48 (95% CI 1.21 - 1.82), p&lt;.001] and GemNabP [5.6 months, HR 1.45 (95% CI 1.24 - 1.70), p = p&lt;.001]. NALIRIFOX also provided significantly higher ORR [42% vs 32% (FOLFIRINOX) vs 29% (GemNabP), p&lt;.001]. GemNabP was associated with poorer OS [9.2 months, HR 1.25 (95% CI 1.07 - 1.46), p=0.005], while no significant difference was observed between FOLFIRINOX [11.1 months, HR 1.12, (95% CI 0.88 - 1.43), p=0.344] and NALIRIFOX (11.1 months). Among G3/4 events, NALIRIFOX was associated with higher rates of diarrhea [p&lt;.001] and lower rates of peripheral neuropathy, thrombocytopenia and neutropenia [p&lt;.001], though with no difference in febrile neutropenia occurrence [p=0.158]. Conclusions: NALIRIFOX may provide superior ORR and PFS as compared to FOLFIRINOX and GemNabP as 1LTx of advanced PDAC, though with higher gastrointestinal toxicities and no difference in OS compared to FOLFIRINOX. Careful patient selection, drug costs consideration and direct comparison between FOLFIRINOX and NALIRIFOX is warranted. [Table: see text]

The comparative analysis of gastrointestinal toxicity of azithromycin and 3′-decladinosyl azithromycin on zebrafish larvae

The most commonly reported side effect of azithromycin is gastrointestinal (GI) disorders, and the main acid degradation product is 3’-Decladinosyl azithromycin (impurity J). We aimed to compare the GI toxicity of azithromycin and impurity J on zebrafish larvae and investigate the mechanism causing the differential GI toxicity. Results of our study showed that the GI toxicity induced by impurity J was higher than that of azithromycin in zebrafish larvae, and the effects of impurity J on transcription in the digestive system of zebrafish larvae were significantly stronger than those of azithromycin. Additionally, impurity J exerts stronger cytotoxic effects on GES-1 cells than azithromycin. Simultaneously, impurity J significantly increased ghsrb levels in the zebrafish intestinal tract and ghsr levels in human GES-1 cells compared to azithromycin, and ghsr overexpression significantly reduced cell viability, indicating that GI toxicity induced by azithromycin and impurity J may be correlated with ghsr overexpression induced by the two compounds. Meanwhile, molecular docking analysis showed that the highest -CDOCKER interaction energy scores with the zebrafish GHSRb or human GHSR protein might reflect the effect of azithromycin and impurity J on the expression of zebrafish ghsrb or human ghsr. Thus, our results suggest that impurity J has higher GI toxicity than azithromycin due to its greater ability to elevate ghsrb expression in zebrafish intestinal tract.

Comparison of toxicities between ultrahypofractionated radiotherapy versus brachytherapy with or without external beam radiotherapy for clinically localized prostate cancer

To compare gastrointestinal (GI) and genitourinary (GU) toxicities in patients with localized prostate cancer treated with ultrahypofractionated radiotherapy (UHF) or brachytherapy [BT; low dose rate, LDR or high dose rate (HDR) with or without external beam radiotherapy (EBRT)]. We compared 253 UHF and 1664 BT ± EBRT groups. The main outcomes were the incidence and severity of acute and late GU and GI toxicities. The secondary endpoint was biochemical control rate. Cumulative late actuarial GU toxicity did not differ for grade ≥ 2 (8.6% at 5-years in UHF and 13.3% in BT ± EBRT, hazard ratio [HR], 0.7066; 95% CI, 0.4093–1.22, p = 0.2127). Actuarial grade ≥ 2 late GI toxicity was higher in UHF (5.8% at 5-years, HR: 3.619; 95% CI, 1.774–7.383, p < 0.001) than in BT ± EBRT (1.1%). In detailed subgroup analyses, the high-dose UHF group (H-UHF) using BED ≥ 226 Gy1.5, showed higher GI toxicity profiles than the other subgroups (HDR + EBRT, LDR + EBRT, and LDR monotherapy, and L-UHF BED < 226 Gy1.5) with equivalent GU toxicity to other modalities. With a median follow-up period of 32 months and 75 months, the actuarial biochemical control rates were equivalent between the UHF and BT ± EBRT groups. UHF showed equivalent efficacy, higher GI and equivalent GU accumulated toxicity to BT ± EBRT, and the toxicity of UHF was largely dependent on the UHF schedule.

Postoperative or Salvage Proton Radiotherapy for Prostate Cancer After Radical Prostatectomy.

PurposePostprostatectomy radiation improves disease control, but limited data exist regarding outcomes, toxicities, and patient-reported quality of life with proton therapy.Method and MaterialsThe first 102 patients who were enrolled on an outcome tracking protocol between 2006 and 2017 and treated with double-scattered proton therapy after prostatectomy were retrospectively reviewed. Eleven (11%) received adjuvant radiation, while 91 (89%) received salvage radiation. Seventy-four received double-scattered proton therapy to the prostate bed only. Twenty-eight received a double-scattered proton therapy prostate-bed boost after prostate-bed and pelvic-node treatment. Eleven adjuvant patients received a median dose of 66.6 GyRBE (range, 66.0-70.2). Ninety-one salvage patients received a median dose of 70.2 GyRBE (range, 66.0-78.0). Forty-five patients received androgen deprivation therapy for a median 9 months (range, 1-30). Toxicities were scored using Common Terminology Criteria for Adverse Events v4.0 criteria, and patient-reported quality-of-life data were reviewed.ResultsThe median follow-up was 5.5 years (range, 0.8-11.4 years). Five-year biochemical relapse-free and distant metastases-free survival rates were 72% and 91% for adjuvant patients, 57% and 97% for salvage patients, and 57% and 97% overall. Acute and late grade 3 or higher genitourinary toxicity rates were 1% and 7%. No patients had grade 3 or higher gastrointestinal toxicity. Acute and late grade 2 gastrointestinal toxicities were 5% and 2%. The mean values and SDs of the International Prostate Symptom Score, International Index of Erectile Function, and Expanded Prostate Cancer Index Composite bowel function and bother were 7.5 (SD = 5.9), 10.2 (SD = 8.3), 92.8 (SD = 11.1), and 91.2 (SD = 6.4), respectively, at baseline, and 12.1 (SD = 9.1), 10.1 (SD = 6.7), 87.3 (SD = 18), and 86.7 (SD = 13.8) at the 5-year follow-up.ConclusionHigh-dose postprostatectomy proton therapy provides effective long-term biochemical control and freedom from metastasis, with low acute and long-term gastrointestinal and genitourinary toxicity.

Randomized study of prevention of gastrointestinal toxicities by nutritional support using an amino acid-rich elemental diet during chemotherapy in patients with esophageal cancer (KDOG 1101).

This randomized study was designed to evaluate the clinical effect of an elemental diet during chemotherapy in patients with esophageal cancer. The inclusion criteria were as follows: (1) esophageal squamous cell carcinoma, (2) stage IB-IV, (3) schedule to receive docetaxel, cisplatin, and 5-fluorouracil (DCF chemotherapy), (4) 20-80years old, (5) performance status of 0-2, (6) oral intake ability, and (7) written informed consent. Patients were divided into two groups: the elemental supplementary group and the non-supplementary group. Patients received ELENTAL® (160g/day) orally 9weeks after the start of chemotherapy. Primary endpoint was the incidence of grade 2 or higher gastrointestinal toxicity according to the Common Terminology Criteria for Adverse Events, version 4.0. Secondary endpoints were the incidence of all adverse events and the evaluation of nutritional status. Thirty-six patients in the elemental supplementary group and 35 patients in the non-supplementary group were included in the analysis. The incidence of grade 2 or higher gastrointestinal toxicity and all grade 3 or 4 adverse events did not differ significantly between the groups. In the elemental supplementary group, the body weight (p = 0.057), muscle mass (p = 0.056), and blood levels of transferrin (p = 0.009), total amino acids (p = 0.019), and essential amino acids (p = 0.006) tended to be maintained after chemotherapy. Nutritional support provided by an amino acid-rich elemental diet was ineffective for reducing the incidence of adverse events caused by DCF chemotherapy in patients with esophageal cancer.

Pelvic bone marrow sparing intensity modulated radiotherapy reduces the incidence of the hematologic toxicity of patients with cervical cancer receiving concurrent chemoradiotherapy: a single-center prospective randomized controlled trial

PurposeTo test the efficacy and feasibility of pelvic bone marrow sparing intensity modulated radiotherapy (PBMS-IMRT) in reducing grade 2 or higher hematological toxicity (HT2+) for patients with cervical cancer treated with concurrent chemoradiotherapy.Methods and materialsA total of 164 patients with Stage Ib2–IIIb cervical cancer were prospectively enrolled from March 2018 to March 2019 at a single center and were randomly allocated into the PBMS group or the control group. The control group received weekly cisplatin concurrently with IMRT, followed by intracavitary brachytherapy. The PBMS group additionally received PBM dose constraint. The dosimetric parameters of the pelvic bone (PB) and the subsites including hip bone (HIP) and lumbosacral spine (LSS) and the corresponding bone marrow were recorded. The endpoint of the trial was acute hematologic or gastrointestinal toxicity. Receiver operating characteristic curves were used to derive optimal dosimetric planning constraints.ResultsEighty-two patients in the PBMS group and 82 in the control group were enrolled for statistical analysis. The incidence of HT2+ in the PBMS group was 50.0%, significantly lower than the 69.5% incidence in the control group (P = 0.02). Patients with PB V40 ≥ 28% were more likely to experience HT2+ (OR = 2.85, P = 0.006), while the incidence of grade 2 or higher gastrointestinal toxicity (GT2+) events did not differ significantly between the two groups (P > 0.05). Dosimetric parameters of LSS showed stronger associations with HT2+ than other subsites. The patients with LSS V10 ≥ 87% and LSS mean ≥ 39 Gy were more likely to experience HT2+ (OR = 3.13, P = 0.001;OR = 3.03, P = 0.002, respectively).ConclusionPBMS-IMRT reduced HT compared with IMRT alone. Efforts to maintain LSS V10 < 87%, LSS mean < 39 Gy and PB V40 < 28% simultaneously may reduce the risk of HT2 +.Trial registrationThe trial was registered with Chinese clinical trial registry (ChiCTR1800015069).

Single-Dose Focal Salvage High Dose Rate Brachytherapy for Locally Recurrent Prostate Cancer

AimsTo evaluate focal high dose rate (HDR) brachytherapy in locally recurrent prostate cancer. Materials and methodsPatients with biochemical relapse after non-surgical primary treatment for localised prostate cancer were selected after a negative screen for metastatic disease. Template mapping biopsies combined with multiparametric magnetic resonance imaging were used to identify the location of the tumour and the focal clinical target volume. The planning aim dose prescription was 19 Gy. Outcome measures were biochemical relapse-free survival and toxicity using International Prostate Symptom Score and Common Terminology Criteria for Adverse Events (version 4.0) scores. ResultsBetween March 2013 and December 2018, 50 patients underwent salvage HDR brachytherapy. The median follow-up was 21 months (range 1–53). Biochemical progression-free survival at 2 and 3 years was 63% and 46%, respectively. On multivariate analysis, only prostate-specific antigen nadir ≤0.5 ng/ml post-salvage (P = 0.03, hazard ratio 0.04) was associated with biochemical progression-free survival. Relapse was associated with distant metastases in 11/13 patients in whom this was investigated. Late grade 3 genitourinary toxicities were gross haematuria (three patients), severe lower urinary tract symptoms (two patients), erectile dysfunction (one patient) and urethral stricture requiring surgery (four patients). No acute and late grade 4 or 5 genitourinary and no grade 3 or higher gastrointestinal toxicities were recorded. ConclusionsFocal salvage HDR monotherapy achieves biochemical control in 46% of patients at 3 years with acceptable toxicity rates in selected patients. Biochemical relapse was related to a post-salvage prostate-specific antigen nadir of ≥0.5 ng/ml. Long-term outcomes are needed to assess the impact on the natural history of prostate cancer in these patients.

Can Chemotherapy be Integrated with Brachytherapy in Locally Advanced Carcinoma Cervix- A Proof of Principle Study.

Introduction:Cancer of the cervix is the second most common cancer in women in India. Chemoradiotherapy is the standard treatment for locally advanced carcinoma cervix. Chemotherapy is not given on days of brachytherapy due to the fear of increased toxicity though studies supporting or refuting it are limited. We intended to study feasibility of adding chemotherapy to brachytherapy with assessment of acute toxicity and response rates.Methods:29 patients of locally advanced carcinoma cervix (FIGO IIB to IIIB) were assigned to receive either three sessions of high dose rate (HDR) brachytherapy alone or HDR brachytherapy with concurrent chemotherapy of Paclitaxel and Carboplatin after completion of external beam radiation with concurrent Cisplatin. Patients were assessed for compliance of treatment, toxicity and response rates at three and six months. The p-value less than 0.05 was considered statistically significant. Fischer’s exact test was used for statistical analysis.Results:15 patients were assigned to the standard of care arm and 14 patients to the experimental chemo-brachytherapy arm. The median number of cycles of chemotherapy possible with brachytherapy was two (Range: 1 -3). At three months after treatment all patients except one patient in each arm had a complete response. There was two acute grade 3 hematological toxicity and two acute grade 3 or higher gastrointestinal toxicity in the experimental arm but none in the standard arm. The experimental arm had a statistically higher incidence of acute grade 3 and 4 toxicity than the standard arm (p=0.042). Conclusions:Chemo-brachytherapy is associated with higher acute toxicity with comparable response rates. Small patient numbers and short follow up impedes us from providing conclusive evidence.

Hypofractionated Proton Therapy in Early Prostate Cancer: Results of a Phase I/II Trial at Loma Linda University.

To determine whether a hypofractionated proton therapy regimen will control early-stage disease and maintain low rates of side effects similar to results obtained using standard-fraction proton therapy at our institution. A cohort of 146 patients with low-risk prostate cancer according to National Comprehensive Cancer Network guidelines (Gleason score <7, prostate-specific antigen [PSA] <10, tumor stage of T1-T2a) received 60 Gy (cobalt Gy equivalent) of proton therapy (20 fractions of 3.0 Gy per fraction) in 4 weeks, a dose biologically equivalent to standard fractionation (44-45 fractions of 1.8 Gy to a total of 79.2 to 81 Gy in 0 weeks). Patients were evaluated at least weekly during treatment, at which time documentation of treatment tolerance and acute reactions was obtained. Follow-up visits were conducted every 3 months for the first 1 years, every 6 months for the next 3 years, then annually. Follow-up visits consisted of history and physical examination, PSA measurements, and evaluation of toxicity. The median follow-up time was 42 months (range, 3-96 months). Acute grade 2 urinary toxicity occurred in 16% (20/120) of the patients; acute grade 2 or higher gastrointestinal toxicity was seen in 1.7% (2/120). At 9 months, 1 patient had late grade 3 urinary toxicity, which resolved by 12 months; no grade 3 gastrointestinal toxicities occurred. The 3-year biochemical survival rate was 99.3% (144/145). The median time to PSA nadir was 30 months. Hypofractionated proton therapy of 60 Gy in 20 fractions was safe and effective for patients with low-risk prostate cancer.

Impact of GSTM1, GSTT1 and GSTP1 genes polymorphisms on clinical toxicities and response to concomitant chemoradiotherapy in cervical cancer

ABSTRACTBackground: Certain forms of chemoradiotherapy generate toxic reactive oxygen species, which may be ameliorated by antioxidant enzymes such as glutathione S-transferase (GST). Genetic polymorphisms of GST may predict treatment outcomes and can be used as genetic marker to screen patients before treatment. We hypothesised an effect of GST polymorphisms on the response and toxicities produced by chemoradiation therapy.Materials and methods: GST polymorphisms were determined by multiplex polymerase chain reaction and PCR-restriction fragment length polymorphism (PCR-RFLP) in 227 women with cervical cancer receiving cisplatin based chemoradiotherapy. Treatment response and toxicities were evaluated by standard internationally recognised criteria (RECIST and RTOG).Results: Severe (grade 3–4) gastrointestinal and haematological toxicities were present in 22 (9.4%) and 16 (7.0%) patients, respectively. GSTM1 null, GSTT1 null and GSTP1 AG genotypes brought marginally better non-significant associations. In single locus analysis GSTP1 AG and GG was linked to greatest risk of severe (grade 3–4) gastrointestinal toxicity (OR = 3.12, P = 0.035 and OR = 6.99, P = 0.01, respectively). In gene–gene interaction analysis, GSTM1 null-GSTP1 GG showed 4.2-fold higher risk of severe gastrointestinal toxicity (P = 0.014). GSTT1 null-GSTP1 AG reached statistical significance with a 3.9-fold higher risk of high grade gastrointestinal toxicity (P = 0.038).Conclusions: Although no significant links were found between GST polymorphism and treatment response, null genotypes of GSTM1, GSTT1 and ‘G’ allele of GSTP1 bring a higher risk of severe gastrointestinal toxicity due to chemoradiation therapy in cervical cancer.

Salvage reirradiation for local failure of prostate cancer after curative radiation therapy: Association of rectal toxicity with dose distribution and normal-tissue complication probability models

PurposeThis study aimed to assess the impact of radiation dose on rectal toxicity after salvage external beam radiation therapy (EBRT) with or without a brachytherapy boost for exclusive local failures after the primary EBRT for prostate cancer. Methods and materialsFourteen patients with no severe residual late toxicity after primary EBRT ± brachytherapy were reirradiated after a median time interval of 6.1 years. The median normalized total dose in 2 Gy fractions (NTD2Gy, α/β ratio = 1.5 Gy for prostate cancer cells) was 74 Gy at primary EBRT and 85.1 Gy at reirradiation. Rectal dose-volume histograms (converted to NTD2Gy_alpha/beta = 3 Gy) and the corresponding normal-tissue complication probability (NTCP) values for gastrointestinal (GI) toxicity were evaluated for 2 groups: High GI toxicity (grade ≥3) and low GI toxicity (grade ≤2). ResultsThe 5-year grade ≥3 GI toxicity-free survival rate was 57.1%. The median rectal V70Gy and maximum dose to 1 cm3 (D1ccrect) at primary EBRT were both predictive for grade ≥3 GI toxicity (9% vs 0%; P = .04 and 72.2 Gy vs 66.8 Gy; P < .01, respectively). When adding primary radiation therapy (RT) and reirradiation plans, the median D1ccrect was 139.8 Gy versus 126.7 Gy (P < .01) for high and low GI toxicity groups. NTCP >10% at primary RT was predictive for high GI toxicity at reirradiation (P < .05). ConclusionsEven in the absence of residual toxicity after primary RT, rectal doses >70 Gy and NTCP >10% calculated for a first irradiation may be associated with a higher risk of developing high GI toxicity at reirradiation with a possible D1ccrect threshold of 130 Gy.

Phase I study of dose escalation to dominant intraprostatic lesions using high-dose-rate brachytherapy.

PurposeRadiation dose escalation for prostate cancer improves biochemical control but is limited by toxicity. Magnetic resonance spectroscopic imaging (MRSI) can define dominant intraprostatic lesions (DIL). This phase I study evaluated dose escalation to MRSI-defined DIL using high-dose-rate (HDR) brachytherapy.Material and methodsEnrollment was closed early due to low accrual. Ten patients with prostate cancer (T2a-3b, Gleason 6-9, PSA < 20) underwent pre-treatment MRSI, and eight patients had one to three DIL identified. The eight enrolled patients received external beam radiation therapy to 45 Gy and HDR brachytherapy boost to the prostate of 19 Gy in 2 fractions. MRSI images were registered to planning CT images and DIL dose-escalated up to 150% of prescription dose while maintaining normal tissue constraints. The primary endpoint was genitourinary (GU) toxicity.ResultsThe median total DIL volume was 1.31 ml (range, 0.67-6.33 ml). Median DIL boost was 130% of prescription dose (range, 110-150%). Median urethra V120 was 0.15 ml (range, 0-0.4 ml) and median rectum V75 was 0.74 ml (range, 0.1-1.0 ml). Three patients had acute grade 2 GU toxicity, and two patients had late grade 2 GU toxicity. No patients had grade 2 or higher gastrointestinal toxicity, and no grade 3 or higher toxicities were noted. There were no biochemical failures with median follow-up of 4.9 years (range, 2-8.5 years).ConclusionsDose escalation to MRSI-defined DIL is feasible. Toxicity was low but incompletely assessed due to limited patients’ enrollment.

Safety and toxicity of axitinib and sorafenib monotherapy for patients with renal cell carcinoma: a meta-analysis.

We sought to investigate safety of axitinib or sorafenib in renal cell carcinoma (RCC) patients receiving and compare toxicity of these two vascular endothelial growth factor receptor inhibitors. Databases of PubMed and Embase were searched. Studies enrolled were phase II and III prospective trials, as well as retrospective studies, in which patients diagnosed with RCC were treated with axitinib or sorafenib monotherapy at a starting dose of 5 mg and 400 mg twice daily, respectively. The overall incidence of high grade hypertension, fatigue, gastrointestinal toxicity and hand-foot syndrome, along with their 95% confidence intervals (CI), were calculated using fixed or random effects model according to heterogeneity test results. A total of 26 trials, including 4790 patients, were included in our meta-analysis. Among them, 6 arms were related to axitinib and another 22 were associated with sorafenib. The incidences of hypertension (24.9% vs. 7.9%), fatigue (8.2% vs. 6.6%), gastrointestinal toxicity (17.6% vs. 11.3%) were higher in patients receiving axitinib versus those receiving sorafenib, while the incidence of hand-foot syndrome was lower n patients receiving axitinib versus those receiving sorafenib (9.5% vs. 13.3%). In conclusion, axitinib showed noticeably higher risks of toxicity versus sorafenib. Close monitoring and effective measures for adverse events are recommended during therapy.

Clinical outcomes of salvage chemoradiotherapy for locally recurrent biliary tract cancer.

The purpose of this study was to investigate the clinical outcomes and prognostic factors of concurrent chemoradiotherapy (CCRT) for locally recurrent biliary tract cancer (BTC) after curative surgical resection. We performed a retrospective cohort study of patients with locally recurrent BTC treated with CCRT between October 2004 and December 2013. The study included and analyzed 42 patients with a history of curative-intent surgical resection of confirmed adenocarcinoma originating from the biliary tract. The median time to recurrence after surgery was 16.1 months (range, 4.5-77.8 months). Median follow-up after CCRT was 26.9 months (range, 5.2-81.9) with no grade 3 or higher gastrointestinal toxicities. Analysis of the first site of failure showed local progression (LP) developed in 20 patients (47.6%); among these, 16 (38.1%) had isolated LP. The median values were 15.8 months (range, 1.7-81.7) for LP-free survival (LPFS), 10.6 months (range, 1.7 - 81.7) for progression-free survival (PFS) and 41.2 months (range, 5.2-81.9) for overall survival (OS). Multivariate analysis showed that the level of pre-CCRT carbohydrate antigen (CA) 19-9 and the chemotherapy regimen were significant prognostic factors for LPFS and PFS; pT stage was the only significant prognostic factor for OS. CCRT for locally recurrent BTC showed promising outcomes as a salvage modality, but LP was still frequent. The pre-CCRT CA 19-9 level and the chemotherapy regimen were prognostic factors for LPFS and PFS.

Reduced toxicity with equivalent outcomes using three-dimensional volumetric (3DV) image–based versus nonvolumetric point–based (NV) brachytherapy in a cervical cancer population

PurposeBrachytherapy (BT) techniques have historically used a two-dimensional nonvolumetric (NV) system involving dose prescribed to a point fixed in space. We compared dosimetric, toxicity, and oncologic outcomes for volumetric planning (3DV) versus CT point-based planning. Methods and MaterialsPatients treated with external beam radiation therapy and high dose rate (HDR) intracavitary BT were included (n = 71). Patients planned with NV BT treated from 2009 to 2011 (n = 37) were compared to patients planned with 3DV BT treated from 2012 to 2014 (n = 34). Investigators delineated volumes for organs at risk clinical target volumes for the 2009–2011 NV cohort. Acute and chronic toxicity data were graded. ResultsThe mean HDR clinical target volume D90 received in the NV and 3DV cohorts were significantly different (p < 0.001). The mean dose to point A was significantly higher in the NV cohort than in the 3DV cohort (p < 0.001). There were significantly more Grade 3 or higher gastrointestinal toxicities in the NV cohort (p = 0.048). There was a nonsignificant trend toward improved oncologic outcomes for patients undergoing CT-based planning. Conclusions3DV BT allows for a significant reduction of dose to critical structures, resulting in decreased gastrointestinal toxicity, while delivering noninferior doses to the high-risk clinical target volume. Outcomes were improved in the 3D cohort trending toward statistical significance.

Effectiveness of a nutritional intervention in the reduction of gastrointestinal toxicity during teletherapy in women with gynaecological tumours

ObjectiveTo evaluate whether nutritional intervention through a diet low in oligosaccharides, disaccharides, monosaccharides and fermentable polyols reduces acute gastrointestinal toxicity by pelvic teletherapy in patients with gynaecological tumours. Material and methodsA prospective unicentric randomised clinical trial comparing patients on a diet low in oligosaccharides, disaccharides, monosaccharides and fermentable polyols versus a standard Mexican diet, designed to detect a decrease from 80% of grade 1–2 acute gastrointestinal toxicity in the normal diet group versus a 25% of acute gastrointestinal toxicity grade 1–2 in patients assigned to a diet low in oligosaccharides, disaccharides, monosaccharides and fermentable polyols. ResultsThirteen patients were recruited per group, with a higher gastrointestinal toxicity in the normal diet group, grade 1–2 (85% vs 77%) and 3 (23% vs 0%) compared to the diet low in oligosaccharides, disaccharides, monosaccharides and fermentable polyols (p 0.16). The diet low in oligosaccharides, disaccharides, monosaccharides and fermentable polyols group had a lower symptom score at the end of treatment in the quality of life questionnaire of patients with cervical cancer (1.41 vs 1.85, p 0.01) and a lower mean deterioration in performance status (0.61 of 0.5 vs 0.23 of 0.43, p 0.049). 85% of the patients had an excellent attachment to the diet. No significant factors associated with the presence of grade 3 gastrointestinal toxicity were found. ConclusionThe implementation of a diet low in oligosaccharides, disaccharides, monosaccharides and fermentable polyols during treatment with pelvic teletherapy is a low cost and high attachment intervention, which decreases the deterioration of functional status and symptomatology at the end of treatment in patients with cervical cancer.

Does Race Influence Health-related Quality of Life and Toxicity Following Proton Therapy for Prostate Cancer?

Objective:This matched-paired analysis explores disparities in health-related quality of life (QOL) and common toxicities between African American (AA) and white patients following proton therapy for prostate cancer at our institution.Materials and Methods:A total of 1536 men with clinically localized prostate cancer were treated from 2006 to 2009 with definitive proton therapy to a median dose of 78 Gy +/− androgen deprivation therapy. A cohort of 92 consecutively treated AA men was matched to a cohort of 92 white men on the basis of National Comprehensive Cancer Network risk category and age. The 2 groups were compared with regard to comorbidities, demographics, and treatment regimen. Differences in genitourinary and gastrointestinal (GI) toxicity according to the Common Terminology Criteria for Adverse Events scale and QOL data from the Expanded Prostate Index Composite 26-question questionnaire were reported.Results:Median follow-up was 2.1 years. Baseline patient and treatment characteristics were similar between the 2 groups with the exception of prostate-specific antigen ≥10 (32% for AAs vs. 20% for whites; P=0.068) and use of androgen deprivation therapy (26% for AAs vs. 21% for whites; P=0.38). No difference in Expanded Prostate Index Composite 26-question sexual summary, urinary incontinence, urinary obstruction, or bowel summary scores was detected between the 2 groups, nor was there a difference in grade 2 or higher GI toxicity (P=0.45). AAs had a statistically nonsignificant higher absolute incidence of late grade 3 genitourinary toxicity (4.4% vs. 0%; P=0.12).Conclusions:After 2 years, there were no disparities in health-related QOL, physician-reported Common Terminology Criteria for Adverse Events GI toxicity, or biochemical relapse. Longer follow-up is needed to confirm these findings.

Predictive dosimetric parameters for gastrointestinal toxicity with hypofractioned radiotherapy in pancreatic adenocarcinoma.

To better guide the development and optimization of radiotherapy planning, to reduce the incidence of radiation reactions, and to improve the quality of life of the patients with pancreatic cancer using radiotherapy, we conducted this study to explore the dosimetric parameters that predict the risk of gastrointestinal (GI) toxicity with hypofractioned radiotherapy for pancreatic cancer. Between January 2014 and January 2015, the medical records of 68 patients with pancreatic cancer who underwent helical tomotherapy at the Air Force General Hospital were analyzed. The doses delivered to the planning target volume, clinical target volume, and gross tumor volume–internal gross tumor volume of the primary pancreatic lesions were 50, 60, and 70–80 Gy in 15–20 fractions, respectively. GI toxicity was scored according to version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events. The stomach and duodenum were contoured separately to determine the dose–volume histogram parameters. Univariate and multivariate analyses were adopted to identify clinical and physical risk factors associated with GI toxicity. The median follow-up was 9 months (range: 4–16 months). Eighteen patients had grade II acute GI toxicity, one patient had grade III acute GI toxicity, 17 patients had grade II late GI toxicity, and one patient had grade III late GI toxicity. On univariate analysis, the volume, the average dose Dmean, the maximum dose to 1, 3, 5, and 10 cm3 of the stomach and duodenum (D1, D3, D5, and D10), and the relative volumes receiving 5–40 Gy (V5–V40), and the absolute volumes receiving 5–45 Gy (aV5–aV45) of the duodenum were significantly associated with grade II or higher GI toxicity (P<0.05). On multivariate analysis, aV45 of the duodenum was an independent predictor for grade II or higher GI toxicity (P=0.031). The receiver operating characteristic analysis also showed that an aV45 of 0.5 cm3 was the optimal threshold to predict GI toxicity for the entire cohort. Our findings indicate that many dosimetric parameters of the duodenum correlate with grade II or higher GI toxicity. To reduce GI toxicity, the absolute volume of the irradiated duodenum should be reduced.