Acute Hematologic Toxicity Research Articles

Iodine-131 metaiodobenzylguanidine (131I-mIBG) treatment in relapsed/refractory neuroblastoma

I-meta-iodo-benzylguanidine (I-mIBG) therapy has been used in treatment of for advanced neuroblastoma for many years with promising results. There are several studies regarding predictors and outcomes of I-mIBG therapies in relapsed/refractory neuroblastoma patients. To identify the predictors and outcomes of I-mIBG treatment in relapsed/refractory neuroblastoma. This study was a retrospective review of 22 patients with high risk stage IV relapsed/refractory neuroblastoma who received at least one cycle of I-mIBG therapy. Patient' characteristics, hematologic toxicity, scintigraphic semi-quantitative scoring, and overall survival were recorded. Factors predicting survival were analyzed. Twenty-two patients (50% male) with mean age of 3.7 years (4.8 months to 8.3 years) received I-mIBG therapies at an average of 3.8 and mean dose of 136 mCi (5032 MBq) per treatment. Most common acute hematologic toxicity was thrombocytopenia. Overall 5-year survival rate was 37% (95% confidence interval: 16.3-58.0) and median survival time was 2.8 year (95% confidence interval: 1.38-6.34). Patients with rising Curie score of ≥25% upon the second therapy were major determinants of overall survival with poorer response to treatment. At least three treatments of I-mIBG were needed to identify some degrees of survival prolongation (crude hazard ratio: P-value = 0.003). Age, sex, metastatic status, and baseline Curie scoring system were good predictors associated with survival. Seven patients (32%) demonstrated objective responses. Despite multimodality therapy, high risk neuroblastoma had a propensity of treatment failure in terms of relapsed or refractory, with some objective responses after I-mIBG treatments. The declined or non-rising Curie score upon second post-treatment total body scan was an important predictor of survival and aided a decision whether or not to proceed with bone marrow transplantation.

Abstract P6-10-03: Germline (g)BRCA1/2 mutations (m) and hematological toxicities in patients (pts) with triple negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NACT)

Abstract Background: BRCA1/2 genes play a central role in DNA repair. Therefore, pts harboring gBRCA1/2m treated with chemotherapy might be at higher risk of acute hematological toxicities due to the lower level of functional BRCA1/2 protein potentially resulting in more toxicity. Published results are discordant, further data are needed. Methods: Pts with early TNBC and known gBRCA1/2m treated with anthracycline-taxane based NACT in the GeparQuinto (n=487), GeparSixto (n=291) and GeparOcto (n=393) studies were included. Primary G-CSF prophylaxis was foreseen only for the iddETC arm in GeparOcto. Primary objective was the rate of neutropenia grade (G)3-4 after cycle 1; secondary objectives were the rate of other hematological toxicities G3-4 and the overall toxicity rate after cycle 1 as well as hematological toxicities in gBRCA1/2 pts during the taxane part of chemotherapy. Results: 209/1171 evaluated pts (17.8%) had a gBRCA1/2m (177 gBRCA1m, 33 gBRCA2m). Median age was 48yrs [21-78]. The rate of neutropenia G3-4 after cycle 1 in gBRCA1/2 wildtype (wt) pts was 35.7% vs 37.4% in gBRCA1/2m (p=0.683), 35.9% in gBRCA1m (p=1.000), 44.8% in gBRCA2m (p=0.330). gBRCA1/2 mutational status did not predict neutropenia G3-4 at univariate (OR=1.08, 95%CI 0.78-1.48 p=0.658) or multivariate analysis adjusted for age, BMI and treatment (OR=1.26, 95%CI 0.87-1.82 p=0.226). The overall rate and the rates of other hematological toxicities are shown in the table. gBRCA1/2 mutational status did also not predict for any other hematological toxicities G3-4 (univariate OR=0.94, 95%CI 0.64-1.40 p=0.773; multivariate OR=0.94, 95%CI 0.62-1.43 p=0.779). gBRCA1/2 mutational status predicted for hematological toxicities G3-4 under taxane treatment (univariate OR=1.94, 95%CI 1.35-2.77 p<0.001; multivariate OR=2.91, 95%CI 1.55-5.45 p=0.001). During taxane treatment, the overall rate of hematological toxicities G3-4 in wt pts was 43.1% (n=270) vs 59.5% (n=91) in gBRCA1/2m, p<0.001; anemia G3-4 2.6% (n=16) vs 3.3% (n=5), p=0.584; leucopenia G3-4 32.7% (n=203) vs 47.1% (n=72), p=0.001; neutropenia G3-4 35.8% (n=219) vs 49.3% (n=73), p=0.003; thrombopenia G3-4 1.4% (n=9) vs 4.6% (n=7), p=0.024; febrile neutropenia 5.9% (n=37) vs 4.6% (n=7), p=0.696. Conclusions: Overall, gBRCA1/2 mutation is not associated with a significantly higher risk of severe hematological toxicities. Under taxane therapy, pts with gBRCA1/2 demonstrate a higher rate of hematological toxicities G3-4, especially neutropenia, compared to wildtype pts, and should therefore be carefully monitored. Hematological toxicities after cycle 1wildtypegBRCA1/2mp-valuegBRCA1mp-valuegBRCA2mp-valueN%N%N%N%neutropenia G3-432635.77437.40.6836135.91.0001344.80.330febrile neutropenia171.831.41.00010.60.33726.10.130leucopenia G3-424425.83818.20.0212815.80.0041030.30.548anemia G3-420.200.01.00000.01.00000.01.000thrombopenia G3-4111.210.50.70510.60.70400.01.000any hematological toxicities G1-477782.617081.70.76314180.10.4533090.90.344any hematological toxicities G3-442846.38843.60.5337241.90.3171651.60.587 Citation Format: Jenny Furlanetto, Volker Möbus, Andreas Schneeweiss, Kerstin Rhiem, Hans Tesch, Jens-Uwe Blohmer, Kristina Lübbe, Michael Untch, Christoph Salat, Jens Huober, Peter Klare, Rita Schmutzler, Fergus J Couch, Bianca Lederer, Bernd Gerber, Dirk-Michael Zahm, Ingo Bauerfeind, Valentina Nekljudova, Claus Hanusch, Christian Jackisch, Theresa Link, Sibylle Loibl, Peter A Fasching. Germline (g)BRCA1/2 mutations (m) and hematological toxicities in patients (pts) with triple negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NACT) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-03.

A prospective comparative study between concurrent chemoradiation with brachytherapy boost with concurrent chemoradiation alone in locally advanced cancer esophagus.

Context:Carcinoma esophagus is a highly malignant disease with very low cure rate. Concurrent chemoradiation is the standard of care in patients deemed unfit for surgery. Intraluminal brachytherapy (ILRT) is effective for palliation of dysphagia and is also used as a boost to external beam radiotherapy (EBRT) in curative intent.Aims:The aim of the study was to compare the clinical outcome of definitive concurrent chemoradiation followed by ILRT boost with concurrent chemoradiation alone in locally advanced carcinoma esophagus in terms of tumor response and toxicities.Settings and Design:A single institutional prospective study was carried out between January 2014 and June 2015.Subjects and Methods:Fifty-seven patients of locally advanced carcinoma esophagus were allocated to study and control arms. Both groups were treated with definitive concurrent chemoradiation with 44 Gy of EBRT. The chemotherapy consisted of injection cisplatin 70 mg/m2 intravenous on day 1 with capecitabine 800 mg/m2 b.i.d. daily from day 1 to 4 orally on days 1 and 22 of EBRT. After 2 weeks, the control group was treated with EBRT boost of 10 Gy in 5 fractions, while the study group received intraluminal high-dose rate (HDR) brachytherapy boost of 10 Gy in 2 fractions. No concurrent chemotherapy was administered during ILRT. The treatment outcome was assessed in terms of tumor response and toxicities using the CTCAE version 4.0 criteria.Results:At a median follow-up of 10 months, the overall response rate was 89.2% in the control group (25/28) and 93.10% in the study group (27/29). Acute hematological and gastrointestinal toxicities were noted.Conclusions:HDR ILRT in combination with EBRT is effective for treating dysphagia in cancer esophagus with low incidence of severe complications.

Neoadjuvant chemoradiotherapy or radiotherapy in patients aged 75 years or older with locally advanced rectal cancer.

Background: To evaluate the efficacy and treatment related morbidity of neoadjuvant chemoradiotherapy or radiotherapy in elderly patients (aged 75 years or older) with locally advanced rectal cancer (LARC).Methods: We reviewed clinical records of elderly patients with LARC treated with neoadjuvant chemoradiotherapy or radiotherapy between January 2008 and June 2017 at our institute. A dose of 45-50Gy in 25 fractions was delivered to pelvis. The primary tumor received a dose of 55Gy concomitantly for patients receiving intensity modulated radiotherapy (IMRT). The concurrent chemotherapy included capecitabine alone and capecitabine plus oxaliplatin (Xelox). Surgery was performed for suitable patients at least 6 weeks after neoadjuvant treatment. Overall survival (OS), disease specific survival (DSS), disease free survival (DFS) and local control (LC) were calculated with Kaplan-Meier method.Results: A total of 85 patients were enrolled in this study, the median age was 80 years old (range: 75-90 years). After neoadjuvant treatment, surgery was performed in 56 patients (65.9%). Downstaging rate was 85.7% (48/56) with T downstaging in 35 patients (62.5%) and N downstaging in 36 patients (64.3%). Twelve patients (21.4%) obtained pathological complete response (pCR). The incidence of grade 3 or greater acute hematological, gastrointestinal and genitourinary toxicities were 10.7%, 5.2% and 1.8%, respectively. Seven patients (12.5%) experienced postoperative complications. The median follow-up duration was 35.7 months (range: 4.3-100.3 months), The 3-year and 5-year OS, DSS, DFS, LC were 68.9% and 47.2%, 75.8% and 60.4%, 68.2% and 56.1%, 83.9% and 78.3%, respectively.Conclusion: In patients aged 75 years or older with LARC, neoadjuvant chemoradiotherapy followed by surgery was well tolerated with promising survival outcomes, which should be strongly suggested if medically suitable.

212Pb-NNV003 as a Novel Targeted Alpha Therapy for CD37 Positive B-cell Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin Lymphoma (NHL)

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in western countries, accounting for approximately one quarter of all leukemias and Non-Hodgkin lymphoma (NHL) caused an estimated 200,000 cancer deaths worldwide in 2014. More than 90,000 cases of chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) are expected in the US each year. Immuno-chemotherapy using anti-CD20 monoclonal antibodies (mAb) in combination with DNA alkylating agents is the front-line therapy of CLL and NHL. Despite promising initial results, relapses after repeated administration of immuno-chemotherapy are frequent and relapsed/refractory patients show poor prognosis. As CD37 is strongly and selectively expressed on the surface of mature B lymphocytes and B-cell malignancies, the development of new therapies targeting CD37 expressing cells may prove useful for relapsed or refractory patients as an alternative to CD20 targeting agents. We have developed a targeted alpha therapy (TAT) where the CD37-specific antibody NNV003 is coupled to the in-vivo alpha-particle-generator, 212Pb. When treated with alpha radiation, targeted cancer cells are exposed to high linear energy transfer (LET). LET acts over a short range (50–100 μm), causing double strand breaks in the DNA of targeted cells while sparing adjacent normal tissues. The efficacy of a single escalating 212Pb-NNV003 administration was evaluated on disseminated models of human Burkitt’s lymphoma (Daudi) and CLL (MEC-2). 10 million Daudi cells or 2.5 million MEC-2 cells were intravenously injected in CB17-SCID or R2G2 mice and 212Pb-NNV003 was given two days later. Unspecific, 212Pb-labeled antibody was used as control. Dose range finding and tolerability studies were performed in CB17-SCID and R2G2 tumor-free mice to define the maximum tolerated dose prior to the efficacy studies. 212Pb-NNV003 displays a favorable toxicity profile after a single intravenous injection in tumor-free mice. No acute hematological toxicity was observed, and animals presented only a slight initial reduction in their platelets (PLT) counts which was fully recovered 4-weeks after injection. A single intravenous dose of 10, 15 or 20 μCi of 212Pb-NNV003 led to 70%, 90% and 100% of mice injected with MEC-2 cells being tumor free 20 weeks post cell injection. Control animals that received saline, cold antibody or 212Pb-cetuximab presented a median survival of 4.9, 5.4 and 9.3 weeks, respectively. A single intravenous dose of 2.5, 5 and 7.5 μCi 212Pb-NNV003 led to over 80% tumor-free mice injected with Daudi cells 15 weeks post cell injection. Control animals that received saline, cold antibody or 212Pb-cetuximab presented a median survival of 7, 7.8 and 7.7 weeks, respectively. The results of preclinical studies suggest that TAT using 212Pb-NNV003 may have positive clinical implication for the treatment of CD37 positive CLL and NHL.

Recommended foscarnet dose is not associated with improved outcomes in cytomegalovirus salvage therapy

BackgroundCytomegalovirus (CMV) infection causes significant morbidity and mortality in transplant recipients. Ganciclovir and valganciclovir have proven efficacy but are limited by resistance and toxicity, whereas foscarnet typically retains activity when CMV has become resistant to other antivirals. Foscarnet dosing used in practice may be discordant with what is recommended in product labeling, as the result of an unconventional dosing nomogram or prescriber preference; however, it is unknown how discordant foscarnet dosing affects outcomes. ObjectiveOur purpose was to characterize the relationship between initial foscarnet dosing intensity (relative to product labeling) and key effectiveness and safety endpoints. Study designThis single-center, retrospective study included immunosuppressed adults with CMV viremia who received foscarnet between January 2012–July 2017. Subjects were divided into low dose (LD) and non-low dose (NLD) groups, according to foscarnet dose intensity. The primary endpoint was time-to-CMV eradication. Secondary endpoints included time-to-CMV clearance, acute kidney injury, hematologic toxicity, and mortality. ResultsOf 87 subjects, 38 met inclusion. Primary immunosuppression reasons were solid organ (63%) or hematopoietic cell transplant (29%). Seventeen and 21 subjects were in the LD and NLD groups, respectively. Median time-to-CMV eradication was 17 days (LD group) versus 13 days (NLD group), p = 0.823. Median time-to-CMV clearance was also non-significant (p = 0.505). There was no association between initial foscarnet dosing intensity and acute kidney injury, hematologic toxicity, or mortality (24% in both groups). ConclusionsThese findings suggest outcomes may be sensitive to other factors and underscore the need for further studies to improve understanding of foscarnet dosing in immunosuppressed patients.

Effect of Pelvic Bone Marrow-Sparing on Acute Hematologic Toxicity in Rectal Cancer Patients Undergoing Chemoradiotherapy

To investigate whether pelvic bone marrow sparing (PBMS) could reduce the incidence of acute hematologic toxicity in rectal cancer patients undergoing chemo-radiotherapy. 84 rectal cancer patients were selected and divided into the IMRT Group (42 cases) and the PBMS-IMRT Group (42 cases). All patients underwent concurrent chemo-radiotherapy. The PTV was prescribed with a total dose of 50∼50.4Gy in 1.8∼2Gy fractions. Capecitabine combined was administered concurrently with pelvic radiation. The pelvic bone was contoured both for the PBMS-IMRT and IMRT groups. Only the pelvic bone in PBMS-IMRT group was prescribed by:V10≤85%,V20≤65%,V30≤45%.The mean dose (Dmean) and the volume of each organ at risk (OAR) with dose range from 5 to 50Gy (e.g., V 5, V10, V15, V20, V25, V30, V35, V40, V45, andV50) was calculated for all the patients from the two groups. The patient acute hematologic toxicity (e.g. patient with symptoms of leukopenia, neutropenia, anemia, or thrombocytopenia) was recorded according to RTOG scoring scale. Independent sample t test were applied for the dose-volume parameters, and card square analysis for clinical parameters. In terms of the OAR dose-volume parameters, the V5∼V35 and Dmean for the pelvic bone, left femoral head and the right femoral head significantly (p<0.05) decreased for the PBMS-IMRT Group compared with the IMRT group. There was no significant difference in any dose-volume parameters for the bladder. As for PTV dose distribution, there was a significant (p=0.001) improvement of the target conformity in the PBMS-IMRT group. In addition, the dose homogeneity was also improved by 14.5% for this group, although not significantly (P=0.108). For the following acute hematologic toxicity observation, the numbers of the patients with grade 0, 1, 2, 3, 4 were 12, 6, 14, 10, and 0 respectively for the IMRT group. Meanwhile the corresponding numbers were 10, 19, 12, 1, and 0 for PBMS-IMRT group. The incidence of grade 2 or upper acute hematologic toxicity in the PBMS-IMRT group was significantly reduced (31%, 13/42 vs. 57.1%, 24/42, p=0.027). There was no incidence of grade 2 or upper acute cystitis in both of the two groups. The marrow-sparing of the pelvic bone significantly reduces its dosage as well as the left and right femoral head. Patients with pelvic bone marrow-sparing had lower incidence of the grade 2 or upper acute hematologic toxicity compared with those without marrow-paring. Pelvic bone marrow-sparing can benefit patients with rectal cancer undergoing chemo-radiotherapy.

Three Weekly Versus Weekly Cisplatin Concurrent Radiotherapy in Patients with Post-operation Cervical Cancer: A Retrospective Analysis

To evaluate completion rate and acute treatment-related toxicity of concurrent chemoradiotherapy with cisplatin 40 mg/m2 for one day per week compared to cisplatin 20 mg/m2 for consecutive five days every three weeks in postoperative radiotherapy for cervical cancer. This retrospective study included 59 patients, with postoperative pathology suggesting cervical malignant tumors, FIGO stage IB-IIA, undergoing radiotherapy and concurrent chemotherapy between January 2013 and December 2017. All patients were divided into two groups, weekly group and triweekly group. Patients of weekly group received weekly cisplatin at a dose of 40 mg/m2 for at least 4 to 5 cycles and patients of triweekly group received 20 mg/m2 cisplatin for five days every three weeks for at least 1 or 2 cycles. All patients received concurrent chemotherapy at the beginning of radiotherapy. Main outcome measures included clinical completion rate and acute treatment-related toxicity. The proportion of patients who completed 4 or 5 cycles chemotherapy in weekly group was 66.7%(20/30), and that completed 1 or 2 cycles chemotherapy in triweekly group was 100%(29/29, P＜0.05). Grade 1-2 acute hematological toxicities were similar in the two groups, as follows: grade 1-2 leukopenia (66.7% vs. 51.7%, p＞0.05), grade 1-2 thrombocytopenia (10% and 13.7%, p＞0.05), and grade 1-2 anemia (43.3% and 20.6%, p＞0.05). Most patients in weekly group have no significant gastrointestinal toxicity, while, in triweekly group, 65.5% patients have grade 1-2 nausea or vomiting( p＜0.05), with no grade 3-4 gastrointestinal toxicity. Only 3.3% of weekly group were found having grade 1 hepatotoxicity, and only 3.4% of triweekly group were found having grade 1 nephrotoxicity. No treatment related deaths were encountered. This retrospective study appears to show concurrent chemoradiotherapy with triweekly 20mg/m2 cisplatin for consecutive five days in post-operation cervical cancer gives better completion rate with similar Grade 1-2 acute hematological toxicities, hepatotoxicity, and nephrotoxicity. In addition, the main reason that part of patients in triweekly group did not complete the whole chemotherapy courses was hematological toxicities after the first cycle chemotherapy. Nevertheless, the cumulative hematological toxicity of weekly cisplatin 40 mg/m2 was not lower than that of three weekly 20 mg/m2 because of the high frequency of chemotherapy. Due to the reduction of the frequency of chemotherapy, the time of hospitalization and the simplification of hospitalization procedures, the better compliance, and quality of life of three weekly patients are in line with the situation of the shortage of medical resources in China. We will continue to follow up these patients to assess late treatment related toxicity and long term treatment outcomes.

Anal Cancer Treatment: Significant Reduction of Acute Toxicity Using 4-Fraction-per-Week Approach

The purpose of this study was to compare outcomes in patients with squamous cell carcinoma of the anal canal (SCCA) who were treated with definitive chemo-radiotherapy (CRT) using an alternative approach of 4-fraction-per-week conventional 3D radiotherapy technique. Twenty patients who received definitive chemo-radiotherapy from January 2013 to December 2017 were included in this study. All 20 patients received 5-fluorouracil with mitomycin C (n = 20) as this is our institutional practice, no patients received cisplatin. All 20 patients were treated with conventional radiotherapy technique. The median dose was 5400 cGy (range 5220-5580 cGy). Median follow-up was 24 months. All 20 patients were treated using a modified regimen of 5 fractions only for the first week, followed by 4 fractions per week thereafter (Fridays off starting second week of treatment with no planned break). For the highest dose of 5580 cGy in 31 fractions, this is equivalent to 7.5 weeks or 51 days. Acute skin toxicity was: grade I: 18 patients (90%), grade II: 2 patients (10%), with no grade III or IV skin toxicity. Acute hematologic toxicity: grade I: 14 patients (70%), grade II: 6 patients (30%), with no grade III or IV hematologic toxicity. Acute GI toxicity: grade I: 12 patients (60%), no grade II, III, or IV skin toxicity. No patients required hospitalization from side effects of chemo-radiotherapy treatment. All patients completed treatment as prescribed. Treatment compliance was 100%. The 2-year overall survival in this study is 100%. Since this study was conceived for the purpose of reducing skin toxicity, we were pleasantly surprised to also discover that by having Fridays off, the hematologic and GI toxicity profile was mostly minor in nature and was easily manageable. This innovative approach of 4-fraction-per-week using conventional 3D radiotherapy technique was associated with significantly less acute toxicity (skin, hematologic, and GI), with virtually no need for treatment breaks, and yielded excellent loco-regional control, overall survival when compared with known randomized studies. The acute toxicity profile using this regimen of 4-fraction-per-week 3D conformal technique is better than those reported by similar IMRT studies. This innovative approach of 4-fraction-per-week 3D conformal technique deserves further study by individual investigators or by appropriate clinical trials.

Neoadjuvant Chemoradiotherapy and Surgery in Patients Older Than 75 Years Old with Locally Advanced Mid-Low Rectal Cancer

This study was designed to evaluate the tolerance and clinical outcomes of neoadjuvant chemoradiotherapy and surgery in patients older than 75 years old with LARC. We reviewed clinical records of patients older than 75 years with LARC treated with neoadjuvant chemoradiotherapy in our institute from January 2013 to May 2017. All patients were treated with intensity-modulated radiotherapy (IMRT). A dose of 45-50Gy in 25 fractions was delivered to the pelvis. The primary tumors received a dose of 55Gy with simultaneous integrated boost (SIB). The concurrent chemotherapy included capecitabine alone and capecitabine plus oxaliplatin (Xelox). Surgery was performed for suitable patients at least 6 weeks after chemoradiotherapy. Adjuvant chemotherapy was performed individualized. Overall survival (OS), disease specific survival (DSS), disease free survival (DFS) and local control (LC) were calculated with Kaplan-Meier method. Univariate and multivariate analyses were performed with log-rank test and cox proportional hazards model. A total of 71 patents were enrolled in this study, the median age was 80 years (range: 75-90 years). All patients completed the neoadjuvant treatment procedure. The median follow-up duration was 31.9 months (range: 4.7-65.1 months), the 3-year OS, DSS, DFS and LC were 75.7%, 86.0%, 72.4% and 83.9%, respectively. The incidences of grade 3 or greater acute hematologic (HM), gastrointestinal (GI) and genitourinary (GU) toxicity were 5.6%, 4.2% and 1.4%, respectively. After neoadjuvant chemoradiotherapy, downstaging was observed in 59 patients (83.1%) including 36 patients (50.7%) with T-downstaging and 48 patients (67.6%) with N-downstaging. Forty-three patients (60.6%) underwent surgery including total mesorectal excision (TME) in 35 patients (81.4%) and transanal endoscopic microsurgery (TEM) in eight patients (18.6%), only two patients (5.7%) experienced surgical complications. For patients receiving definitive surgery (TME), pathological complete response (pCR) was obtained in eight patients (22.9%). Multivariate analysis revealed that only surgery was significantly associated with OS, DSS, DFS, and LC. The 3-year OS, DSS, DFS and LC for patients who received surgery or not were 90.1% vs 48.4% (HR=27.0, 95%CI: 2.6-281.8, P=0.006), 90.1% vs 66.2% (HR=13.3, 95%CI: 1.2-148.8, P=0.036), 83.2% vs 50% (HR=3.0, 95%CI: 1.1-8.4, P=0.037) and 90.6% vs 58.3% (HR=3.8, 95%CI: 1.1-13.1, P=0.034), respectively. In patients with LARC older than 75 years old, neoadjuvant chemoradiotherapy was well tolerated with excellent clinical outcomes. Surgery was a significant factor for OS, DSS, DFS, and LC with acceptable complications, which should be strongly suggested for this group of patients.

Reduced Acute Toxicity after Proton Versus Photon Chemoradiation for Anal Cancer: Outcomes from the Proton Collaborative Group REG001-09 Trial

Most anal cancer (AC) patients experience acute grade 2 or higher (G2+) toxicity from definitive chemoradiation (CRT) with intensity modulated radiation therapy (IMRT) as shown in the Radiation Therapy Oncology Group (RTOG) 0529 phase 2 trial. Although normal organ sparing has been shown to favor proton beam therapy (PBT) over IMRT, particularly with respect to small bowel and bone marrow, clinical outcomes of PBT for AC have never been published. The Proton Collaborative Group (PCG) REG001-09 trial (NCT01255748) is a multi-institutional registry study that prospectively captures outcomes for a variety of cancer types in patients receiving PBT and/or photon therapy. We compared prospectively recorded acute toxicity outcomes (genitourinary (GU), gastrointestinal (GI), proctitis, dermatitis, fatigue) of AC patients enrolled on the PCG trial who received definitive CRT with either PBT or IMRT. Hematologic toxicity outcomes were not available for analysis. Acute toxicity was evaluated according to the CTCAE version 4.0 and defined as having occurred during or within 90 days after completion of CRT. Dosimetric outcomes were not recorded in the PCG study and therefore could not be evaluated with regards to toxicity. Fifty-one AC patients received definitive CRT across 5 institutions from 2010-2018; 33 (64.7%) received PBT while 18 (35.3%) received IMRT. Radiation target volumes were designed according to the RTOG anorectal contouring atlas. PBT patients were older (median 69.5 vs. 60.5 years; p=0.079), more often male (48.5% vs. 11.1%; p=0.008), and had less advanced T stage (p=0.063) and N stage (p=0.043). There was no difference in median total prescribed radiation dose (both 54 Gy in 30 fractions) or in the use of concurrent chemotherapy (most received 5-fluorouracil and mitomycin-C). PBT was typically delivered with pencil beam scanning (69.7%) versus passive scattering. There was no difference in acute grade 2+ GU toxicity, dermatitis, proctitis, or fatigue based on radiation modality although there was a trend towards reduced GI toxicity favoring PBT (Table 1). Acute grade 2+ GI toxicity among PBT patients on the PCG study was significantly reduced versus historical IMRT outcomes from the RTOG 0529 trial. These are the first clinical outcomes of PBT for AC. PBT achieves a meaningful reduction in acute GI toxicity compared to IMRT although we were not able to determine whether this was due to a reduction in small bowel dose. Future studies are warranted to compare acute hematologic toxicity, late toxicities, and long-term survival in AC patients receiving definitive CRT with PBT versus IMRT.Abstract 1093; Table 1Acute grade 2 or higher toxicity from definitive chemoradiation for anal cancerPCG PBT (n=33)PCG IMRT (n=18)RTOG IMRT (n=325)PCG PBT vs. PCG IMRT P valuePCG PBT vs. RTOG IMRT P valueGastrointestinal12 (36.4%)11 (61.1%)237 (73%)0.089<0.001Genitourinary3 (9.1%)2 (11.1%)66 (20%)0.8160.119Dermatitis28 (84.8%)16 (88.9%)271 (83%)0.6880.828 Open table in a new tab

Early toxicity and treatment outcomes of extended field-intensity modulated radiotherapy for cervical cancer patients with para-aortic nodal metastasis.

ObjectiveExtended-field radiotherapy (EFRT) with concurrent chemotherapy represents standard treatment in cervical cancer patients with para-aortic lymph nodal (PALN) metastasis. While EFRT with Intensity Modulated RT (IMRT) has been demonstrated to reduce toxicities, the dose thresholds for minimizing acute toxicity is not clear. The present study was undertaken to report the early toxicity with extended-field intensity-modulated radiotherapy (EF-IMRT) for carcinoma of the cervix in our cohort of patients and determine dose-volume parameters that predict ≥grade II haematological toxicity and diarrhoea.MethodologyThis was a retrospective study of consecutive cervical cancer patients with PALN metastasis treated with EF-IMRT. Patients received rotational IMRT +/- neoadjuvant chemotherapy (NACT) and/or concurrent chemotherapy (45–50 Gy/25#/5 weeks) followed by high-dose rate brachytherapy. Acute haematological and gastrointestinal toxicity (diarrhoea and vomiting) was correlated with doses received by bowel and marrow. Receiver operator characteristics curves were used for deriving thresholds that predict for increased toxicity and tested on univariate and multivariate analysis. Finally, disease free and overall survival (DFS and OS) was calculated.ResultsA total of 43 patients were included. One-fourth of the patients (11/43) received NACT and 88% received concurrent chemotherapy. Within the upfront EF-IMRT cohort, 22.6% and 9.7% patients developed grade ≥III haematological (HT) and gastrointestinal (GI) toxicity respectively, with an increase in HT (≥ grade III HT =67%) in patients receiving NACT (p = 0.007). In the entire cohort bone marrow Volume receiving 10 Gy (V10>) 90% correlated with an increase in ≥ grade III HT (p = 0.05). No dose volume thresholds could be validated for GI toxicity. The OS and DFS at 2 years was 56% and 54%, respectively.ConclusionEF-IMRT is a feasible option for cervical cancer patients with PALN involvement and is associated with acceptable grade III toxicity. Future studies need to focus on minimizing HT toxicity.

Impact of different adjuvant radiotherapy modalities on women with early-stage intermediate- to high-risk endometrial cancer

ObjectiveVaginal brachytherapy was recommended for patients with intermediate-risk endometrial cancer, however, optimal radiotherapy modalities for intermediate-high- or high-risk patients remains controversial. Previous studies have mainly focused on survival outcomes and...

Acute hematological toxicity of ivermectin to juvenile Clarias gariepinus

Acute behavioral and hematological toxicity of ivermectin to C. gariepinus juveniles were assessed under static conditions at concentrations of 9 to 25 µg L−1 for up to 4 days. Juveniles were highly sensitive to ivermectin, with an LC50 of 15 µg L−1, culminating in spasms and paralysis. The hematological responses of packed cell volume, hemoglobin and red blood cell count decreased when compared to the control while the white blood cell count showed a biphasic trend. The mean corpuscular volume and mean corpuscular hemoglobin showed a mixed trend, while mean corpuscular hemoglobin concentration increased with increase in the concentration of the drug. Lymphocytes and neutrophils were also significantly (p < .05) increased. Ivermectin did not elicit any significant changes in monocytes, basophils and eosinophils. The observed changes confirm that ivermectin negatively affected the health of the fish. Therefore, real-time monitoring for early warning is recommended.

Correlation between pelvic bone marrow radiation dose and acute hematological toxicity in cervical cancer patients treated with concurrent chemoradiation.

PurposeTo evaluate the association between pelvic bone marrow (BM) dose volume parameters and probability of acute hematological toxicity (HT), a cohort of cervical cancer patients receiving definitive chemoradiation (CRT) was assessed.Materials and methodsMedical records of patients treated by CRT (45 Gy in 25 fractions, without dose constraints applied to the BM) were reviewed. Baseline and weekly hematological parameters were collected. BM was retrospectively delineated and divided into sub-sites: iliac crests, lower pelvis, lumbosacral region. BM volumes (V) receiving 5, 10, 20, 30, 40 Gy (V5, V10, V20, V30, V40, respectively) and mean dose (Dm) were calculated. Logistic regression was used to analyze associations between HT and dose-volume histograms parameters.Results114 patients were included. 75.4% were treated with 3D radiation therapy and 24.6% were receiving intensity modulated radiation therapy (IMRT). Neither age, chemotherapy regimen (cisplatin vs carboplatin), number of chemotherapy cycles, performance status, body mass index, or para-aortic irradiation were associated with HT. In univariate analysis, more frequent grade 3+ leukopenia was found in the IMRT group (odds ratio [OR]: 3.5; 95% CI, 1.4–9.1; p=0.007). In multivariate analysis, grade 4 HT was associated with lower pelvis V5>95% (OR 4.1; 95% CI, 1.6–14. p=0.02), lower pelvis V20>45% (OR 3.5; 95% CI, 1.1–13.4; p=0.05), total pelvic bone V20>65%, and iliac crests Dm >31 Gy (OR 4.5; 95% CI, 1.4–14.7; p=0.02).ConclusionThe following dose constraints could be proposed to decrease acute HT risk: lower pelvis V5<95%, lower pelvis V20≤45%, total pelvic bone V20<65%, and iliac crests Dm <31 Gy.

A prospective randomized study comparing concurrent chemoradiation with weekly and 3 weekly cisplatin in locally advanced oropharyngeal carcinoma.

Introduction:The chemotherapy schedules with cytotoxic dose or weekly regimes are still challenging, weighing the benefits versus toxicities. This prospective randomized study is an attempt to assess the efficacy of two schedules of cisplatin in management of locally advanced HNSCC.Objectives:The objectives of this study was to evaluate tolerance, tumour response and toxicities of concurrent chemoradiation with cisplatin in weekly and three weekly regimes.Methods:Locally advanced oropharyngeal squamous cell carcinoma patients fit for concurrent chemoradiation with cisplatin 40 mg/m2 (weekly) and 100 mg/m2 (3 weekly) were randomized to Arm A and B concurrently with radiotherapy of 70Gy/35frs/7 weeks.Statistical Analysis:Chi-square/ Fisher Exact test has been used to find the significance of study parameters on categorical scale between the groups. The statistical software SPSS 15.0 was used.Results:Between December 2010 and January 2013, 60 patients were enrolled. The median cycles of cisplatin in Arm-A was 5 and 2 in Arm-B. The complete response of 80.9% vs 75% and partial response of 14.3% vs 12.5% was observed in both arms respectively. There was no statistical difference in acute radiation and hematological toxicities between the two groups. With median follow up of 28 months, the 2 and 5 years overall survival was 55% and 58%; 41.6% and 32.3% in arms A and B respectively.Conclusion:In our study of locally advanced oropharyngeal carcinoma treated with radical radiotherapy comparing concurrent chemotherapy with cisplatin weekly vs 3 weekly had no significant difference in overall response, complete response and acute toxicities.

Predictors of acute hematologic toxicity in women receiving extended-field chemoradiation for cervical cancer

Predictors of acute hematologic toxicity in women receiving extended-field chemoradiation for cervical cancer

Clinical experience of craniospinal intensity-modulated spot-scanning proton therapy using large fields for central nervous system medulloblastomas and germ cell tumors in children, adolescents, and young adults.

The outcomes of intensity-modulated proton craniospinal irradiation (ipCSI) are unclear. We evaluated the clinical benefit of our newly developed ipCSI system that incorporates two gantry-mounted orthogonal online X-ray imagers with a robotic six-degrees-of-freedom patient table. Nine patients (7–19 years old) were treated with ipCSI. The prescribed dose for CSI ranged from 23.4 to 36.0 Gy (relative biological effectiveness) in 13–20 fractions. Four adolescent and young adult (AYA) patients (15 years or older) were treated with vertebral-body-sparing ipCSI (VBSipCSI). Myelosuppression following VBSipCSI was compared with that of eight AYA patients treated with photon CSI at the same institution previously. The mean homogeneity index (HI) in the nine patients was 0.056 (95% confidence interval: 0.044–0.068). The mean time from the start to the end of all beam delivery was 37 min 39 s ± 2 min 24 s (minimum to maximum: 22 min 49 s – 42 min 51 s). The nadir white blood cell, hemoglobin, and platelet levels during the 4 weeks following the end of the CSI were significantly higher in the VBSipCSI group than in the photon CSI group (P = 0.0071, 0.0453, 0.0024, respectively). The levels at 4 weeks after the end of CSI were significantly higher in the VBSipCSI group than in the photon CSI group (P = 0.0023, 0.0414, 0.0061). Image-guided ipCSI was deliverable in a reasonable time with sufficient HI. Using VBSipCSI, AYA patients experienced a lower incidence of serious acute hematological toxicity than AYA patients treated with photon CSI.

Nauclea latifolia (Rubiaceae) Stem-bark Hydromethanolic Extract Abrogates a Histone Deacetylase Inhibitor - Induced Multifocal Toxicity in Albino Rats

Objective: Nauclea latifolia (Rubiaceae) stem-bark enjoys wide patronage in ethnomedicine due to multiplicity of usage. Acute and subacute hematological and biochemical toxicity studies are available in literature but none underpins its ameliorative effect with a histone deacetylase inhibitor (HDAC), valproic acid (VPA) which mediates multifocal toxicity in different histological milieu.&#x0D; Methods: Subacute exposure of experimental albino rats with a high dose of valproic acid (500 mg/kg) was executed orally one hour before post-treatment with Nauclea latifolia stem-bark (NLS) extract in three doses (50, 100, 200 mg/kg) and with another group of rats with reference drug, vinpocetine, 25 mg/kg daily for 28 consecutive days after which hematological and biochemical analyses were executed. The liver, kidney and lungs were abstracted for histopathological evaluation.&#x0D; Results: The HDAC inhibitor, Valproic acids induced multifocal biochemical insults on liver function enzymes, lipid profiles, electrolytes and kidney function which were dose- dependently and significantly (P &lt; 0.05 – 0.001) abrogated by the varying doses of administered NLS extract. On the histology the NLS extract effects corroborated the biochemical study in the liver and kidney. The NLS did not demonstrate significant toxicological impingement on the hematology and did not alter VPA-induced histomorphological injury in the lungs cytoarchitecture. The reference drug, vinpocetine was unresponsive to VPA-induced alteration in all the tissues investigated in the administered posology.&#x0D; Conclusion: The NLS extract was effective in abrogating toxicological insults in the liver and kidney but not in the lungs. Further studies are required to understand the mechanism of pharmacological effects of NLS extract and the differential in tissue response.

EP-1395 Radiation Dose to the Thoracic Vertebral Bodies is Associated with Acute Hematologic Toxicities

EP-1395 Radiation Dose to the Thoracic Vertebral Bodies is Associated with Acute Hematologic Toxicities