287 OUTCOMES OF DEFINITIVE CHEMORADIOTHERAPY IN LONG SEGMENT ESOPHAGEAL CANCERS FROM A TERTIARY CANCER CENTRE IN INDIA

2021 ◽  
Vol 34 (Supplement_1) ◽  
Author(s):  
Jaiprakash Agarwal ◽  
Anil Tibdewal ◽  
Carlton Johnny ◽  
Pradnya Chopade ◽  
Naveen Mummudi ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Dose Reduction ◽  
Dose Group ◽  
Standard Dose ◽  
Organs At Risk ◽  
Treatment Strategies ◽  
Squamous Carcinoma ◽  
Definitive Chemoradiotherapy ◽  
Esophageal Cancers

Abstract   Definitive chemoradiotherapy (CTRT) is the standard of care for unresectable esophageal cancer. Long segment esophageal primary disease makes it challenging to deliver radiation doses needed to achieve good local control without exceeding normal tissue tolerance to the surrounding organs at risk (OAR). We report our experience and outcomes of such patients where the RT doses were reduced from our institutional standard of 63Gy to 50.4Gy. Methods Between Jan 2017 and Dec 2019, 30/232 consecutive esophageal cancer patients were identified with long segment disease that required dose reduction from 63 to 50.4Gy and were included in this analysis. For this study, we divided nodal regions by their location into cervical, mediastinal, and gastro-hepatic. We generated and compared dosimetric parameters of the standard dose (63Gy) plan with that of treated low-dose plan (50.4Gy) using paired t-test. We also evaluated the patterns of recurrence and have reported them as local relapse (LR), loco-regional relapse (LRR), and distant metastases (DM). Results The median age was 55.5 years; 16 (53.3%) were males and 28 (93.3%) had squamous carcinoma. Single nodal site was involved in 6(20%), 2 sites in 20(66.7%) and 3 sites in 4 (13.3%). Median GTV and PTV length were 7.9 cm (IQR:6.4–9.7 cm) and 18.8 cm (IQR:14.08–22.31 cm) respectively. Median OAR doses with standard Vs treated plan achieved were: Total lung V20 and V5:28 Vs 22.14% (p = 0.00), and 81 Vs 70.5% (p = 0.005) respectively, and heart V20:70.92% Vs 64.7% (p = 0.000). No patients experienced ≥grade2 lung toxicity. After a median follow up of 8.4 months, 3 patients experienced LRR and 1 developed DM. Conclusion Treatment of long segment esophageal cancers warrants dose reduction to avoid higher doses to OAR like lung and heart. Early loco-regional and distant failures suggest need for improved treatment strategies or dose escalation with more conformal techniques like proton therapy. Longer follow-up is necessary to assess the median LR, LRR rates and overall survival for this reduced dose group as compared to the standard dose group.

Which Should be Pursued, Cumulative Dose or Dose Intensity: A Real-World Effectiveness Analysis of Bortezomib-Based First Line Treatment for Untreated Multiple Myeloma Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4247-4247
Author(s):  
Shenmiao Yang ◽  
Aijun Liu ◽  
Yuping Zhong ◽  
Xiaojun Huang ◽  
Wenming Chen ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Cumulative Dose ◽  
Dose Group ◽  
Standard Dose ◽  
Dose Intensity ◽  
Fixed Dose ◽  
First Line ◽  
Reduced Dose ◽  
First Line Treatment

Abstract Background: The higher cumulative dose of bortezomib associated with better OS was demonstrated by some prospective studies of bortezomib continuing therapy. A cutoff of cumulative bortezomib dose of 39mg/m2 was found in the treatment of multiple myeloma (MM) with VISTA trial recently. However, dose reduction due to adverse events was common. Moreover, many Chinese patients accepted bortezomib injections at a fixed dose of 1.75mg, the half volume of a vial because of economic problems. To clarify if a reasonable cumulative bortezomib dose achieved by prolonged treatment duration with reduced dose intensity can do the same work, we conducted a multicenter retrospective analysis in previously untreated MM patients with the initial treatment of bortezomib-based regimens. Method: From March 2005 to December 2014, 579 previously untreated MM patients received the bortezomib-based chemotherapy with informed consents in three hematologic centers of Beijing. Median age at the diagnosis was 59 years (range: 27~89). Initial chemotherapeutic regimens included BD, PAD, BCD and VMP. After median of 4 cycles (range: 0.25~13.00) of treatment, the median cumulative dose of bortezomib was 28mg (range: 1.75~124.80). The median follow-up of surviving patients was 26.0 months (2.0-123.0). Seventy nine patients recieved autologous hematopoietic cell transplantation (ASCT) according to the eligibility and patients' desire. Results: To overcome confounding effects of early discontinuations/deaths on the cumulative dose, a landmark analysis was conducted at 6 months, eliminating patients who died before this time from the analysis. Among the patients survived the initial 6-month treatment, 450 treated with chemotherapy alone and 78 received ASCT. ROC analysis showed the cumulative bortezomib dose predicted survival in chemotherapy group with the AUC of 0.617 (95%CI: 0.565~0.670, P<0.001). A cutoff value of cumulative bortezomib dose was 20.75mg with optimal sensitivity and specificity of 0.831 and 0.373, respectively. The patients' characteristics of both low (<20.75mg) and high (≥20.75mg) cumulative bortezomib dose groups were comparative. The high cumulative dose group had superior OS than the low cumulative dose group (median OS: 51.0 months (95%CI: 44.66-57.34) vs. 42.0 months (95%CI: 33.24-50.76), P=0.015). However, PFS was not significantly different between the two groups (P=0.994). Two hundred and forty eight (65.3%) patients initiated treatment of bortezomib with the fixed dose of 1.75mg, and 202 (34.7%) patients had the standard dose of 1.3 mg/m2. Bortezomib dose reduction occured in 50 patients. Twenty nine (11.7%) patients of the standard dose intensity group and 2(1.0%) of the fixed dose intensity group had the dose reduction due to adverse events. And the other 19 patients reduced bortezomib dose for other reasons. PFS and OS of the patients with reduced dose intensity were not significantly different from the patients with the standard dose intensity of 1.3 mg/m2 (P=0.183 and 0.482, respectively). However, in the patients with the cumulative bortezomib dose of ≥20.75mg and the standard dose intensity of 1.3mg/m2 was associated with superior survival (P=0.05). Median OS of these patients was 57.0 months (95%CI: 50.62-63.38), while median OS of other patients treated with the cumulative bortezomib dose of <20.75mg or reduced dose intensity was 45.0 months (95%CI: 41.45-48.55). In the ASCT group, we could not find any association between bortezomib dose and the survival. Conclusion: For previously untreated MM patients intend to be treated with chemotherapy alone, we suppose cumulative bortezomib dose ≥20.75mg in the first line treatment should be administered for better OS. Despite reasonable cumulative bortezomib dose, any reduction of the dose intensity from 1.3mg/m2 is associated with inferior OS. For patients treated with ASCT, the association between the bortezomib dose and the survival needs to be elucidated with a long term follow-up. Disclosures No relevant conflicts of interest to declare.

scholarly journals Standard-dose versus high-dose radiotherapy with concurrent chemotherapy in esophageal cancer: A prospective randomized study

2018 ◽  
Vol 07 (01) ◽  
pp. 27-30 ◽  
Author(s):  
Navin Nayan ◽  
M. Bhattacharyya ◽  
Vikas K. Jagtap ◽  
A. K. Kalita ◽  
R. Sunku ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Total Dose ◽  
Standard Dose ◽  
Randomized Study ◽  
Complete Response ◽  
Concurrent Chemotherapy ◽  
Prospective Randomized Study ◽  
High Dose ◽  
Large Sample Size

Abstract Objective: The objective of this study is comparision of local and distant control rates with high-dose versus standard-dose radiotherapy along with concurrent chemotherapy in esophageal cancer – a prospective randomized study. Materials and Methods: Histologically proven Stage I–III patients with carcinoma esophagus were randomized into two groups. One group has been treated with standard-dose radiotherapy, i.e., a total dose of 50.4 Gy (1.8 Gy/day, 28#, 5 days/week). The other group (study arm) has received high-dose radiotherapy, i.e. a total dose of 64.8 Gy (1.8 Gy/day, 36#, 5 days/week). Both groups have received 2 cycles of 3 weekly concurrent chemotherapy (cisplatin 75 mg/m[2] on day 1 and 5-fluorouracil 750 mg/m[2] continuous intravenous infusion over 24 h on day 1–4). Follow-up response evaluation was done by both endoscopy and computed tomography scan after 6–8 weeks and after 2 months thereafter. Results: Out of a total of 28 patients, 68% showed a complete response, 14% showed partial response, and 18% patients developed progressive disease at first and subsequent follow up (median follow-up of 21 months). Among the complete response patients, rates were higher in high-dose group compared to standard-dose radiotherapy group (71% vs. 64%, P = 0.38). Treatment-related toxicities were acceptable in both groups. Conclusion: High-dose radiotherapy with concurrent chemotherapy seems to be more effective with acceptable toxicity in our study. However, further follow-up and large sample size may be required to validate the current study conclusion.

scholarly journals Management of Secondary Prevention in Venous Thromboembolism: Use of Reduced Doses of Rivaroxaban and Apixaban in Extended Therapy

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 16-17
Author(s):  
Desiree Campoy ◽  
Katia Flores ◽  
Gonzalo Artaza ◽  
César A Velasquez ◽  
Tania Canals ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Secondary Prevention ◽  
Board Of Directors ◽  
Dose Reduction ◽  
Standard Dose ◽  
Control Group ◽  
Advisory Committees ◽  
The Mean ◽  
D Dimer

BACKGROUND After a standard anticoagulation period (3-6 months), the risk of venous thromboembolism recurrence (RVTER) needs to be considered. Such risk is higher in unprovoked events and patients with persistent risk factor. The increase of D-dimer (DD) levels during the therapy seems to be strongly associated to RVTER. The use of rivaroxaban 10 mg/day and apixaban 2.5mg/12h as an extended therapy (ET) after the standard anticoagulation period has been proven to be an effective strategy to prevent recurrence without increasing bleeding events. AIM To assess the effectiveness and safety of reduced doses of rivaroxaban and apixaban as ET in patients with RVTER and to compare their DD levels with those of a control group on anticoagulant therapy at a standard dose. METHODS From April 2016 to June 2020, we included patients with venous thromboembolism (VTE) who received ET with rivaroxaban and apixaban with/at reduced doses. Dose reduction was performed following the clinical algorithm of our unit (Fig. 1). The DD values were determined using HemosIl D-Dimer HS-500 and the cut-off value was established at 500 µg/L DD levels were compared with a control group of 235 patients with VTE who received ET with standard doses of anticoagulation. DD levels were measured at the time of diagnosis (D1), initiation of treatment (D2) and 3 months after treatment (D3). RESULTS From a total of 116 patients (65.5% women), 77.6% (n=90) received rivaroxaban 10 mg/24h and 22.4% received apixaban 2.5 mg/12h as an ET. The mean duration of the initial anticoagulant therapy was 12 +/- 8.8 months. The mean DD value prior to the ET was 388 µg/L. In this group, 63.8% (n=74) was an unprovoked VTE and 17.2% (20) had hereditary thrombophilia. The mean of follow-up time was 6.9 +/- 8.3 months. No recurrences of VTE were observed during the follow-up and only one major bleeding event was reported in a high-bleeding risk patient. We observed a progressive decrease of DD levels from the VTE diagnosis to the last visit, with D1, D2, and D3 values of 987 µg/L ± 324, 388 µg/L ± 134, and 288 µg/L ± 98, respectively. There were no differences in d-dimer concentrations between patients with reduce doses of rivaroxaban or apixaban and the control group with standard doses (D1: 85.6% vs 81%, p =0.22; D2: 10.2% vs 8.0%, p =0.14; and D3: 9.1% vs 9.5%, p =0.18). CONCLUSIONS Our data indicated that an ET strategy with reduced doses of rivaroxaban or apixaban is effective and safe. We did not observe significant differences in DD levels at follow-up compared to the control group receiving a standard dose of anticoagulation. Further studies are needed in order to select and standardize dose reduction criteria in secondary prevention. Figure 1 Disclosures Campoy: boehringer ingelheim: Consultancy; Daiichi Sankyo: Speakers Bureau. Sierra:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Research Funding; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead-Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Olivera:Daiichi Sankyo: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Boehringer Ingelheim: Consultancy, Speakers Bureau; BAYER: Consultancy.

PS02.204: GASTRIC TUBE CANCER AFTER ESOPHAGECTOMY FOR ESOPHAGEAL CANCER: A SYSTEMATIC REVIEW

2018 ◽  
Vol 31 (Supplement_1) ◽  
pp. 180-180
Author(s):  
Damiano Gentile ◽  
Pietro Riva ◽  
Anna Da Roit ◽  
Silvia Basato ◽  
Salvatore Marano ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Gastric Tube ◽  
Conflicts Of Interest ◽  
Case Reports ◽  
Treatment Strategies ◽  
Vocal Cord Palsy ◽  
Review Literature ◽  
Gastric Tube Cancer ◽  
Publication Number

Abstract Background Gastric conduit used for reconstruction after esophagectomy for esophageal cancer (EC) has the potential to develop a metachronous cancer known as gastric tube cancer (GTC). The aim of our study was to review literature and evaluate outcomes and possible treatment strategies for GTC. Methods A comprehensive systematic literature search was conducted using PubMed. No restriction was set for type of publication, number, age and sex of patients. Study language was limited to English. Characteristics of EC and its treatment and GTC and its treatment were analyzed. Results A total of 26 studies were analyzed, 10 retrospective analysis and 16 case reports, involving 170 patients, 17 patients (10%) were affected by multifocal GTC. 143 ECs (84,1%) were squamous cell carcinomas. In 95 patients (55,9%) a posterior-mediastinal reconstructive route was used at the time of esophagectomy for EC. Mean interval between esophagectomy and diagnosis of GTC was 67,18 months (4–236 months). 184 GTCs were metachronous lesions (98,4%). 164 GTCs were adenocarcinomas (98,2%). 84 GTCs were located in the lower part of the gastric tube. 88 patients were endoscopically treated. 63 patients underwent surgery. 30 total gastrectomies + limphoadenectomy with colon or jejunal interposition were performed. 27 subtotal gastrectomies and 6 wedge resections were performed. Main reported post-operative complications were: anastomotic leak, vocal cord palsy and respiratory failure. 19 patients were treated with chemoradiotherapy and palliative care. 68,2% of endoscopically treated patients, 63,5% of surgically resected patients and 5,2% of patients who underwent chemoradiotherapy were alive at a mean follow-up of 25,5 months. Feasibility of endoscopic resections in patients diagnosed with superficial GTC has been established. Surgical treatment represents the preferred treatment modality in operable patients with locally invasive tumor. Patients treated with conservative therapy have a scarce prognosis. Conclusion Yearly endoscopic follow-up is of paramount importance in patients who underwent esophagectomy for EC with gastric tube reconstruction. At least, a 10-year endoscopic surveillance is recommended. Disclosure All authors have declared no conflicts of interest.

scholarly journals Esophageal Cancer: Genomic and Molecular Characterization, Stem Cell Compartment and Clonal Evolution

Medicines ◽  
2017 ◽  
Vol 4 (3) ◽  
pp. 67 ◽  
Author(s):  
◽  
◽  
Keyword(s):  
Stem Cells ◽  
Esophageal Cancer ◽  
Clonal Evolution ◽  
Basal Layer ◽  
Treatment Strategies ◽  
Squamous Carcinoma ◽  
Cellular Origin ◽  
Genetic Abnormalities ◽  
Genetic Landscape ◽  
New Treatment

Esophageal cancer (EC) is the eighth most common cancer and is the sixth leading cause of death worldwide. The incidence of histologic subtypes of EC, esophageal adenocarcinoma (EAC) and esophageal squamous carcinoma (ESCC), display considerable geographic variation. EAC arises from metaplastic Barrett’s esophagus (BE) in the context of chronic inflammation secondary to exposure to acid and bile. The main risk factors for developing ESCC are cigarette smoking and alcohol consumption. The main somatic genetic abnormalities showed a different genetic landscape in EAC compared to ESCC. EAC is a heterogeneous cancer dominated by copy number alterations, a high mutational burden, co-amplification of receptor tyrosine kinase, frequent TP53 mutations. The cellular origins of BE and EAC are still not understood: animal models supported a cellular origin either from stem cells located in the basal layer of esophageal epithelium or from progenitors present in the cardia region. Many studies support the existence of cancer stem cells (CSCs) able to initiate and maintain EAC or ESCC. The exact identification of these CSCs, as well as their role in the pathogenesis of EAC and ESCC remain still to be demonstrated. The reviewed studies suggest that current molecular and cellular characterization of EAC and ESCC should serve as background for development of new treatment strategies.

Combined Carbimazole-131I Treatment for Thyrotoxicosis

1972 ◽  
Vol 17 (2) ◽  
pp. 57-61 ◽  
Author(s):  
J. R. McDougall ◽  
W. R. Greig
Keyword(s):  
Dose Group ◽  
Low Dose ◽  
Radioactive Iodine ◽  
Standard Dose ◽  
Antithyroid Drugs ◽  
131I Treatment ◽  
Therapeutic Regime ◽  
The Individual ◽  
To Receive

A sequential therapeutic regime was prescribed for 74 thyrotoxic patients. Every patient received carbimazole in conventional doses for 20 weeks; the average time to obtain control was 10.2 weeks. The patients although older than those usually treated with antithyroid drugs (range 38–68 years) showed no difference in the expected rate of control or in the recognised incidence of side effects. Following the carbimazole therapy the patients were alternatively allotted to receive standard or low (50% of standard) doses of 131I, the individual doses being calculated from simple formulae. After the radio-iodine all of the patients were treated with carbimazole for a further 20 weeks. Review of the patients after completion of the trial and subsequent follow up without therapy shows that 42.1 per cent of the standard dose group remain euthyroid after one therapy dose of 131I, 36.8 per cent have relapsed and 21.1 per cent have become hypothyroid. In the low dose group 44.4 per cent are euthyroid, 47.2 per cent have had a recurrence and 8.4 per cent have become hypothyroid. The results are discussed in the light of current views about the treatment of thyrotoxicosis with drugs and with radioactive iodine.

scholarly journals Esophageal Cancer After Bariatric Surgery: Increasing Prevalence and Treatment Strategies

2021 ◽  
Author(s):  
Victor D. Plat ◽  
Anne Kasteleijn ◽  
Jan Willem M. Greve ◽  
Misha D. P. Luyer ◽  
Suzanne S. Gisbertz ◽  
...  
Keyword(s):  
Bariatric Surgery ◽  
Esophageal Cancer ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Loss To Follow Up ◽  
Multicenter Cohort ◽  
Incidence And Mortality ◽  
Individualized Approach ◽  
Post Bariatric Surgery

Abstract Purpose The number of bariatric procedures has increased exponentially over the last 20 years. On the background of ever-increasing incidence of esophageal malignancies, the altered anatomy after bariatric surgery poses challenges in treatment of these cancers. In this study, an epidemiological estimate is presented for the future magnitude of this problem and treatment options are described in a retrospective multicenter cohort. Methods The number of bariatric procedures, esophageal cancer incidence, and mortality rates of the general population were used for epidemiological estimates. A retrospective multicenter cohort was composed; patients were treated in three large oncological centers with a high upper gastrointestinal cancer caseload. Consecutive patients with preceding bariatric surgery who developed esophageal cancer between 2014 and 2019 were included. Results Approximately 3200 out of 6.4 million post bariatric surgery patients are estimated to have developed esophageal cancer between 1998 and 2018 worldwide. In a multicenter cohort, 15 patients with esophageal cancer or Barrett’s esophagus and preceding bariatric surgery were identified. The majority of patients had a history of Roux-en-Y gastric bypass (46.7%) and had an adenocarcinoma of the distal esophagus (60%). Seven patients received curative surgical treatment, five of whom are still alive at last follow-up (median follow-up 2 years, no loss to follow-up). Conclusion Based on worldwide data, esophageal cancer development following bariatric surgery has increased over the past decades. Treatment of patients with esophageal cancer after bariatric surgery is challenging and requires a highly individualized approach in which optimal treatment and anatomical limitations are carefully balanced. Graphical abstract

PS02.039: SERUM CRP LEVEL IS A PROGNOSTIC FACTOR OF ESOPHAGEAL CANCER TREATED WITH DEFINITIVE CHEMORADIOTHERAPY

2018 ◽  
Vol 31 (Supplement_1) ◽  
pp. 131-131
Author(s):  
Daisuke Ishioka ◽  
Masaaki Saito ◽  
Jun Takahashi ◽  
Tamotsu Obitsu ◽  
Hirokazu Kiyozaki ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Conflicts Of Interest ◽  
Standard Dose ◽  
Clinical Stage ◽  
Univariate Analysis ◽  
Complete Response ◽  
Advanced Esophageal Cancer ◽  
Definitive Chemoradiotherapy ◽  
History Of ◽  
Serum Crp

Abstract Background In advanced esophageal cancer, definitive combined chemoradiotherapy (d-CRT) is considered to be one of standard therapy in Japan. However, there have been few studies of the correlation of clinical factors and response to chemoradiotherapy. The aim of this study is to clarify the correlation of serum CRP level and response to definitive chemoradiotherapy for advanced esophageal cancer. Methods A total of 78 patients with clinical stage II/III esophageal cancer who were treated with d-CRT at our institute from 2002 to 2014 were retrospectively reviewed. 57 patients received chemotherapy using low-dose 5-FU and cisplatin, and remaining 19 patients received chemotherapy using standard-dose 5-FU and cisplatin according to the protocol described in the RTOG trial combined with radiation therapy. The patients were stratified by response to chemoradiotherapy by two groups. 60 patients (54 patients had a complete response and 6 had a partial response) were in Responder group, and 18 patients (7 patients had a stable disease and 11 had a progressive disease) were in Non- responder group. The correlation of survival rate and serum CRP level before d-CRT was evaluated. Results At the time of analysis, the median follow-up period was 32 months (range 3–124 months). The overall survival of the Responder group was significantly better than that of Non- responder group (P < 0.001). Univariate analysis showed that white blood cell > 8000/m3 (P = 0.036), CRP > 1.0mg/dl (P = 0.002), adventitia invasion (P = 0.04) and history of the smoking (P = 0.037) were predictive for response of d-CRT. Multivariate analyses identified serum CRP level (P = 0.002) as independent prognostic factors for response of d-CRT. Conclusion Our findings suggest that serum CRP level may be a useful marker to predict a response to definitive chemoradiotherapy. However, further examinations in the future will be necessary to determine its efficacy. Disclosure All authors have declared no conflicts of interest.

scholarly journals Dose Reductions in Ibrutinib Therapy Are Not Associated with Inferior Outcomes in Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5567-5567 ◽  
Author(s):  
Othman S. Akhtar ◽  
Kris Attwood ◽  
Ian Lund ◽  
Ryan Hare ◽  
Francisco J. Hernandez-Ilizaliturri ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Treatment Initiation ◽  
Standard Dose ◽  
Comprehensive Cancer Center ◽  
Fixed Dose ◽  
Significant Difference ◽  
Baseline Characteristics ◽  
Dose Modifications ◽  
Dose Reductions

Abstract Introduction: Ibrutinib is a first-in-class small molecule inhibitor that binds irreversibly to Bruton's Tyrosine Kinase (BTK) and has shown remarkable efficacy in the treatment of CLL. Current guidelines recommend life-long therapy with administration at a fixed daily dose of 420 mg. However, lower doses of ibrutinib have been demonstrated to adequately abrogate kinase function. Limited clinical data suggests that dose reductions are not associated with inferior outcomes. Hypothetically, judicious dose reductions to manage toxicities could result in improved tolerance and decreased discontinuation rates. Our objective was to study the impact of dose reductions on outcomes in CLL patients treated with ibrutinib in a real-world setting. Methods: We conducted a retrospective chart review of all CLL patients treated with ibrutinib at Roswell Park Comprehensive Cancer Center between January 2014 and June 2017. Patients who underwent ibrutinib dose reduction were identified. Baseline characteristics and outcomes were compared between patients who underwent dose reductions vs those who did not. Reason and timing of dose reduction was also elucidated. Mann-Whitney U and Fisher's Chi Square test were used to compare groups, Kaplan Meier methods were used for time to event analysis, and Cox regression was used to obtain hazard ratios (HR). Overall survival (OS) was calculated as time from start of ibrutinib until death or last follow-up, freedom from progression (PFS) was taken as time from start of ibrutinib until progression or last follow-up. All analyses were performed in SAS v9.4 (Cary, NC). Results: A total of 70 CLL patients treated with ibrutinib were followed for a median period of 21.9 months. Most patients had RR disease (n = 63) and 7 received ibrutinib as frontline therapy. All patients received a fixed dose regimen with the standard dose of 420 mg once daily. Twenty-three (31.3%) patients required dose reductions and received ibrutinib at a median dose of 140 mg . Eleven (47.8%) of these had dose reductions within 3 months of treatment initiation. There was no statistically significant difference in baseline characteristics including age, number of prior lines of treatment, WBC count, hemoglobin or LDH level in the dose reduced group (DRG) and standard dose group (SDG). Patients in the DRG had a lower median platelet count at initiation of ibrutinib than patients in the SDG (86 x 103/mm3 vs 145 x 103/mm3, p<0.05). The most frequent reasons for dose reductions included cytopenia (n=8), fatigue (n=5), infections (n=4) and atrial fibrillation (n=3) with 2 patients requiring dose reduction due to simultaneous CYP inhibitor administration. There was no statistically significant difference in the overall response rate (ORR) (p=0.25) and clinical benefit rate (CBR) (p=1.00) between the DRG (ORR- 65.2%, CBR- 91.4%) and SDG (ORR 78.7%, CBR 91.5%). Median PFS and OS was not reached in both groups. PFS at 12 months was 86% (95% CI 63-95%) and 87% (95% CI 71- 94%) in the DRG and SDG respectively (p=0.92). OS at 12 months was 83% (95% CI 60-93%) and 84% (95% CI 69-92%) in the DRG and SDG respectively (p=0.53). We noticed no statistically significant difference in the median PFS and OS between the two groups (Figure 1). In a subgroup analysis, we compared outcomes in patients in the SDG with those who had dose modifications within 3 months of initiating therapy or later and found no statistically significant differences in OS and PFS between the groups (p=0.15 and p=0.46 respectively). Of the 23 patients requiring dose modifications, 11 (47.8%) had to eventually discontinue therapy as compared to 17 (36.2%) patients in the SDG and we noticed similar 1-year discontinuation rates in the DRG and SDG groups (22% vs 21% respectively, p=0.91). Conclusion: In CLL patients treated with ibrutinib, reductions in the dose of ibrutinib were not associated with worse outcomes. These results extended to all patients with dose modifications, irrespective of whether the modification was made within 3 months of treatment initiation, or later in the course of treatment. Disclosures No relevant conflicts of interest to declare.

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