Dilemma of denosumab therapy: rebound fractures with denosumab cessation or dose delay

5546 Background: The EWOC-1 trial compared Carboplatin monotherapy (C mono) to two different Carboplatin + Paclitaxel (CP) regimens (weekly or 3-weekly) in vulnerable elderly patients treated for advanced ovarian cancers (OC). This study was closed prematurely because of a worse outcome in the C mono group. Both CP regimens were equivalent in terms of feasibility and efficacy with different toxicity profiles. Optimal CP regimen in elderly patient is still unknown. Here we propose a study of another adapted regimen of CP (aCP) performed in elderly patients in our institution. Methods: We retrospectively analyzed OC patients ≥ 70 years who received a Carboplatin AUC 4-5 d1q3week + Paclitaxel 80 mg/m² d1-d8 q3week regimen between 2015 and 2019. Primary endpoint was treatment feasibility according to the EWOC-1 standard: completion of 6 courses of chemotherapy without early stopping for disease progression, death or unacceptable toxicity (adverse event (AE) related to chemotherapy or treatment procedure leading either to early treatment stopping, to an unplanned hospital admission or to death or to a dose delay lasting more than 14 days or more than 2 dose reductions). Results: We identified 36 pts with a median age of 79 years (table). All patient but one had an ONCODAGE-G8 score ≤ 14, 30.6% of patients had a comorbidity Charlson’s index > 4 and 52.5% had an albumin rate < 35 g/L. The feasibility endpoint was met in 58.3% of patients (IC95% = [25.6; 57.8]). Main causes of treatment failure (TF) were early discontinuation because of toxicity in 6 patients (16.7%) and progressive disease in 3 patients (8.33%). Median PFS was 35.3 months (IC95% = [22.7; NR]) and median OS was 62.1 months (IC95% = [31.4.0; NR]). The most frequent AE were asthenia (all grades = 94.4%, grade 3-4 = 13.9%), anemia (all grades = 94.4%, grade 3-4 = 27.8%), neutropenia (all grades = 66.7%, grade 3-4 = 38.9%) and neuropathy sensory (all grades = 61.1%, no grade 3-4). Non high-grade-serous histological type and a poor Charlson’s score were associated with a higher rate of TF (100% and 63.6%, respectively). Conclusions: These results are consistent with the findings of the EWOC-1 trial in both CP regimens and suggest that aCP could be non-inferior with an acceptable toxicity profile. Further prospective and comparative studies are mandatory to confirm this trend and to better identify predictive factors of TF in OC elderly patients.[Table: see text]

Download Full-text

Evaluation of the Hematologic Safety of Same Day Versus Standard Administration (24- to 72-Hour Delay) of Pegfilgrastim in Gynecology Oncology Patients Undergoing Cytotoxic Chemotherapy

International Journal of Gynecological Cancer ◽

10.1097/igc.0000000000000487 ◽

2015 ◽

Vol 25 (7) ◽

pp. 1331-1336 ◽

Cited By ~ 7

Author(s):

Caroline C. Billingsley ◽

Samuel N. Jacobson ◽

Sarah M. Crafton ◽

Aleia K. Crim ◽

Quan Li ◽

...

Keyword(s):

Primary Outcome ◽

Adjusted Relative Risk ◽

Gynecologic Malignancies ◽

Treatment Delays ◽

Dose Modification ◽

Regimen Change ◽

Gynecology Oncology ◽

Grade 3 ◽

Dose Delay ◽

Common Malignancy

ObjectiveWe assessed the safety and efficacy of administration of pegfilgrastim on the same day compared with standard administration 24 to 72 hours after chemotherapy in patients with gynecologic malignancies.MethodsA retrospective review was conducted on patients undergoing pegfilgrastim to mitigate the myelosuppressive consequences of chemotherapy. The primary outcome was incidence of grade 3 to 4 neutropenia following pegfilgrastim for same-day administration (D1) versus standard administration (D2+). Secondary outcomes included dose delay, regimen change, hospitalization due to neutropenia, and incidence of febrile neutropenia.ResultsFour hundred twenty-one patients with 2071 administrations of pegfilgrastim were included. Five hundred six administrations of pegfilgrastim were given on D1 compared with 1565 administrations on D2+. The most common malignancy was ovarian cancer (79.1%), followed by endometrial (14.5%). Comparing the D1 and D2+ cohorts, noninferiority was not established for the incidence of grade 3 to 4 neutropenia (2.6% vs 1.8%, adjusted relative risk [aRR], 1.6; 90% confidence interval [CI], 0.87–3.2) or dose modification (6.5% vs 4.9%; aRR, 1.3; 90% CI, 0.9–1.8). However, the rate of treatment delays (7.3% vs 9.4%; aRR, 0.8; 90% CI, 0.6–1.1) in the D1 and D2+ groups suggested that delays in the D1 group were not more common than in the D2+ group.ConclusionsThe incidence of hematologic toxicities and dose modification in patients receiving same-day pegfilgrastim were not as low as in those undergoing standard administration. However, treatment delays were found to be no more frequent in those receiving same-day pegfilgrastim versus standard administration. Same-day administration of pegfilgrastim is a reasonable option.

Download Full-text

Dose delay, but not dose reduction, in chemotherapy administration is associated with decreased survival in elderly women with ovarian cancer

Gynecologic Oncology ◽

10.1016/j.ygyno.2014.03.100 ◽

2014 ◽

Vol 133 ◽

pp. 32

Author(s):

N. Joseph ◽

R.M. Clark ◽

M. Lee ◽

K. Kopecky ◽

D.S. Dizon ◽

...

Keyword(s):

Ovarian Cancer ◽

Dose Reduction ◽

Elderly Women ◽

Chemotherapy Administration ◽

Dose Delay

Download Full-text

Pegfilgrastim and Daily Granulocyte Colony-Stimulating Factor (G-CSF) Patterns of Use and Neutropenia-Related Outcomes in Cancer Patients in Spain: Results of the Learn Study.

Blood ◽

10.1182/blood.v106.11.4263.4263 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4263-4263

Author(s):

D. Almenar ◽

J. Mayans ◽

O. Juan ◽

J.M. García Bueno ◽

Ji Jalón ◽

...

Keyword(s):

Febrile Neutropenia ◽

Dose Reduction ◽

Cancer Patients ◽

Primary Prophylaxis ◽

Antibiotic Consumption ◽

Secondary Prophylaxis ◽

Duration Of Treatment ◽

Patterns Of Use ◽

Treatment Use ◽

Dose Delay

Abstract Background: Daily G-CSFs(Filgrastim, lenograstim) are widely used to reduce duration of chemotherapy-induced neutropenia(CIN) and incidence of febrile neutropenia(FN) in cancer patients(pts). Data on their patterns of use and effectiveness in routine clinical practice are however limited. The introduction of the once-per-cycle G-CSF pegfilgrastim(Neulasta®) in Spain in 2003 may have changed patterns of use of daily G-CSFs and CIN-related outcomes. Methods: Multicentre, retrospective, observational study of daily G-CSF and pegfilgrastim patterns of use and outcomes in adult subjects with non-myeloid malignancies receiving myelosuppressive chemotherapy(CT). Consecutive patient medical records with documented use of daily G-CSF or pegfilgrastim were abstracted from 10 Spanish centers during 2003. Endpoints: percentage of proactive(primary prophylaxis) vs reactive(secondary prophylaxis/treatment) use of G-CSFs, duration of treatment with G-CSF, and CIN-related outcomes(dose delay, dose reduction, incidence of FN, hospitalization and antibiotic consumption). Results: 248 charts documented pegfilgrastim or daily G-CSF use; 75 pts received pegfilgrastim only; 111 pts received daily G-CSF only(99 Filgrastim, 12 lenograstim); 62 pts received both daily G-CSF and pegfilgrastim during their CT(data not shown). Most common tumor types were lung(25%), breast(20%), malignant lymphomas(20%). Pattern of use (% pts on primary or secondary prophylaxis, or treatment at any time during CT) was:pegfilgrastim(39%,48%,17%, respectively) vs daily G-CSF(40%,48%,30%, respectively). Median number of injections/cycle in the daily G-CSF group was 6 (range 1–13) in primary prophylaxis, and 5 (range 1–11) in secondary prophylaxis and treatment. CIN-related outcomes are shown in the table below. Conclusions: Patterns of use of daily G-CSFs and pegfilgrastim were similar for primary and secondary prophylaxis, but a potential trend to less frequent treatment use in the pegfilgrastim group was observed. CIN-related complications, including incidence of FN, were observed to be lower in pts receiving pegfilgrastim. CT-related complications% pts (95% CI) Pegfilgrastim(n=75) Daily G-CSF(n=111) Dose Delay 44% (33; 55) 46% (36; 55) Dose Reduction 14.7% (8.2; 24.6) 20.7% (14.2; 29.2) Dose Reduction due to Neutropenia 6.7% (2.5; 15.0) 20.7% (14.1; 29.2) Febrile Neutropenia (FN) 10.7% (5.3; 19.9) 24.3% (17.2; 33.1) Hospitalization due to FN 9.3% (4.3; 18.3) 19.8% (13.4; 28.3) Antibiotic Consumption due to FN 8.0% (3.4; 16.7) 17.1% (11.2; 25.3)

Download Full-text

Results of a comprehensive pharmacogenetic analysis of dihydropyrimidine dehydrogenase in patients treated with fluoropyrimidines and patterns of polymorphisms partially related to treatment tolerability.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e13057 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e13057-e13057

Author(s):

Marzia Del Re ◽

Marta Schirripa ◽

Angela Michelucci ◽

Marta Cubelli ◽

Silvia Magagna ◽

...

Keyword(s):

Adverse Reactions ◽

Consensus Sequence ◽

Dihydropyrimidine Dehydrogenase ◽

Cytotoxic Agents ◽

Metabolic Clearance ◽

Good Tolerability ◽

Rate Limiting ◽

Poor Tolerability ◽

Head Neck ◽

Dose Delay

e13057 Background: Metabolic clearance of fluoropyrimidines is highly dependent on the rate-limiting enzyme dihydropyrimidine dehydrogenase (DPD). Deficiency of DPD is associated with drug accumulation and severe toxicities. The DPD gene (DPYD) is highly polymorphic; however, except the G>A mutation in the splicing consensus sequence of intron 14 (IVS14+1G>A), which is responsible of severe enzyme impairment, the association of other variants with adverse reactions is unclear. Therefore, this study was aimed at examining the prevalence of DPYD variants in patients with toxicities and in subjects with good tolerability to fluoropyrimidine-based regimens. Methods: Patients affected by colorectal, breast and head/neck cancers requiring standard treatment with 5-FU or capecitabine in combination with other cytotoxic agents (irinotecan, oxaliplatin, cyclophosphamide or methotrexate) and/or antibodies (cetuximab or bevacizumab) were enrolled: 224 suffered from grade ≥2 non-hematological and ≥3 hematological toxicities (CTCAE v. 4) and 61 control patients developed adverse events to an extent not requiring dose-delay or reduction (i.e., <2 non-hematological and <3 hematological toxicities). DNA was extracted from blood and used to screen patients for known DPD variants (IVS14+1G>A, 496A>G, 1601G>A, 1627A>G, 1896T>C, 2194G>A and 2846T>C) by automatic sequencing. The study was approved by local Ethics Committee. Results: A complex pattern of DPYD variants was identified in both cohorts; the following genotypes were detected in patients with severe toxicities vs controls: 496AG+GG: 24.1 vs 21.3%; 1601GA: 12.5 vs 1.6%; 1627AG+GG: 37.1 vs 32.8%; 1896TC+TT: 6.25 vs 8.2%; IVS14+1GA: 4.9 vs 0%; 2194GA: 25.9 vs 9.8; 2846AT: 1.3 vs 0%. Conclusions: Although there was a higher prevalence of DPYD variants in patients with severe toxicities, their presence also in subjects with good tolerability suggest that their role needs to be re-evaluated, with the exception of IVS14+1GA and 2846AT which were found only in patients with poor tolerability. This study was supported in part by a grant from AIRC to R. Danesi.

Download Full-text

The effect of chemotherapy-induced anemia on dose reduction and dose delay

Supportive Care in Cancer ◽

10.1007/s00520-016-3258-3 ◽

2016 ◽

Vol 24 (10) ◽

pp. 4263-4271 ◽

Cited By ~ 4

Author(s):

Leila Family ◽

Lanfang Xu ◽

Hairong Xu ◽

Kimberly Cannavale ◽

Olivia Sattayapiwat ◽

...

Keyword(s):

Dose Reduction ◽

Dose Delay

Download Full-text

Optimized delay of the second COVID-19 vaccine dose reduces ICU admissions

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2104640118 ◽

2021 ◽

Vol 118 (35) ◽

pp. e2104640118

Author(s):

Paulo J. S. Silva ◽

Claudia Sagastizábal ◽

Luís Gustavo Nonato ◽

Claudio José Struchiner ◽

Tiago Pereira

Keyword(s):

Vaccine Dose ◽

Vaccine Production ◽

Partial Protection ◽

Degree Of Protection ◽

Optimal Delay ◽

Delay Duration ◽

Optimal Duration ◽

Production And Distribution ◽

Number Of Individuals ◽

Dose Delay

Slower than anticipated, COVID-19 vaccine production and distribution have impaired efforts to curtail the current pandemic. The standard administration schedule for most COVID-19 vaccines currently approved is two doses administered 3 to 4 wk apart. To increase the number of individuals with partial protection, some governments are considering delaying the second vaccine dose. However, the delay duration must take into account crucial factors, such as the degree of protection conferred by a single dose, the anticipated vaccine supply pipeline, and the potential emergence of more virulent COVID-19 variants. To help guide decision-making, we propose here an optimization model based on extended susceptible, exposed, infectious, and removed (SEIR) dynamics that determines the optimal delay duration between the first and second COVID-19 vaccine doses. The model assumes lenient social distancing and uses intensive care unit (ICU) admission as a key metric while selecting the optimal duration between doses vs. the standard 4-wk delay. While epistemic uncertainties apply to the interpretation of simulation outputs, we found that the delay is dependent on the vaccine mechanism of action and first-dose efficacy. For infection-blocking vaccines with first-dose efficacy ≥50%, the model predicts that the second dose can be delayed by ≥8 wk (half of the maximal delay), whereas for symptom-alleviating vaccines, the same delay is recommended only if the first-dose efficacy is ≥70%. Our model predicts that a 12-wk second-dose delay of an infection-blocking vaccine with a first-dose efficacy ≥70% could reduce ICU admissions by 400 people per million over 200 d.

Download Full-text

Diffuse Large B Cell Lymphoma in Very Elderly Patients

Blood ◽

10.1182/blood.v124.21.5453.5453 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5453-5453

Author(s):

Ajay Dhakal ◽

Pouyan Gohari ◽

Charalampos Floudas ◽

Sanjay Neupane ◽

Abhinav B Chandra

Keyword(s):

Elderly Patients ◽

Chemotherapy Regimen ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Very Elderly ◽

Large B Cell Lymphoma ◽

Co Morbidity ◽

The Mean ◽

Ecog Ps ◽

Dose Delay

Abstract Background: Incidence of Diffuse Large B-Cell Lymphoma (DLBCL), one of the most common lymphoid malignancies worldwide, increases with age. With improving life expectancy, its incidence among the elderly population is predicted to rise further. Elderly patients pose unique challenges- multiple co-morbidities, variable life expectancy, poor social support systems, and increased risk of therapy-related toxicity. Management decisions in geriatric patients are usually based on data obtained in younger patients. R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) is the standard chemotherapy for younger patients with DLBCL. Unfortunately, among the patients aged 80 or more, data on the use of R-CHOP and its comparison with other treatment regimens are meager. Also, new data on alternate chemotherapy regimens including R with Bendamustine (R-Benda) and R with low dose CHOP (R-miniCHOP) are emerging. Thus, there is a need for development and validation of treatment strategies for DLBCL in this patient population. Objective of this study is to provide a descriptive data including co-morbidity profile, chemotherapy regimen offered, tolerance of chemotherapy, and outcome of the treatment among the DLBCL patients aged 80 or more. Methodology: A retrospective chart review of 33 DLBCL patients (N) aged 80 or more treated in the last 4 years in a tertiary community hospital. Results: Table 1 Age Charlson Co-morbidity Index (CCI) Serum Lactate Dehydrogenase Serum Albumin Serum Beta2 Microglobulin Median Ki67 Valid N 33 30 23 24 9 11 Mean 83.33 2.87 611.91 2.85 6.77 0.70 Median 83.00 2.00 302 2.95 4.85 0.75 Standard Deviation 5.50 1.94 1033.15 0.78 5.79 0.19 Minimum 69 0 84 1.60 1.90 0.40 Maximum 93 9 5038 4.20 19.70 0.95 Table 2 ECOG Performance Score International Prognostic Index (IPI) BMI Hemoglobin Platelets WBC ANC Valid N 25 16 8 31 30 31 28 Mean 2.16 2.56 25.70 11.58 240.73 8.73 5971 Median 2.00 3.00 25.95 11.60 201 8.20 5400 Standard Deviation 1.17 1.03 2.910 1.94 129.64 3.47 2935 Minimum 0 1 20.98 8.20 62 3.60 1400 Maximum 4 4 29.40 15.10 716 16.10 12800 Table 3 Valid N Categories Percentage Sex 33 Male Female 54.5 45.5 Prior Malignancy 33 No Yes 81.8 18.2 Ann Arbor Staging 22 1 2 3 4 22.7 18.2 22.7 36.4 B symptoms 29 No Yes 62.1 37.9 Node Status 33 Nodal Extranodal Nodal and Extranodal 6.1 42.4 51.5 Chemotherapy offered 28 No Yes 17.9 82.1 Intent of Therapy 20 Curative Palliative 85 15 Chemotherapy regimen 22 R-miniCHOP R R-Bendamustine R-CHOP RCVP RCNOP 22.7 9 18.18 36.36 9 4.54 Adverse effect of Chemotherapy 16 No Yes 18.75 81.25 Hospital admission during Chemotherapy 19 No Yes 47.36 52.63 Growth factors required during Chemotherapy 20 No Yes 25 75 Dose delay 17 No Yes 70.58 29.42 Dose modification 17 No Yes 64.70 35.29 Chemotherapy stopped prior to completion 18 No Yes 66.67 33.33 Radiation therapy 19 No Yes 52.63 47.36 Result of chemotherapy 15 Complete Response (CR) Partial Response (PR)Progression 40 40 20 Relapse 7 No Yes 57.14 42.85 Death 10 No Yes 20 80 ANOVA was used for data analysis. A statistically significant difference in mean CCI between those who completed planned chemotherapy course (2.00) and those who did not (4.75) was observed (p= 0.017). Similarly, difference in the mean CCI among those achieving CR (2.00), PR (2.17) and Progression (7.00) was statistically significant (p= 0.005). There were significant differences in the mean pre-chemotherapy ECOG PS between those who completed planned chemotherapy course (1.27) vs. those who did not (2.75), (p= 0. 001) and those achieving CR (1.60), PR (1.00) and progression (3.00), (p=0.012). No significant association was found between CCI or pre-chemotherapy ECOG PS with various factors like type of chemotherapy offered, incidence of adverse effects, and dose delay/modification. Conclusion: Very elderly patients (≥80 years) with DLBCL having good ECOG PS or lower CCI are more likely to complete planned chemotherapy course and achieve remission. CCI might be a good marker for evaluation of co-morbidities in very elderly patients and could serve as a predictive tool for patient outcomes. We intend to analyze data of DLBCL patients aged 65 – 79 years and perform comparative study with existing cohort. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Phase I study of the safety and pharmacokinetics (PK) of paclitaxel or paclitaxel with carboplatin administered in combination with pazopanib (GW786034)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.14118 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 14118-14118 ◽

Cited By ~ 3

Author(s):

B. Suttle ◽

S. Jones ◽

A. Dowlati ◽

A. Tan ◽

C. Mauser ◽

...

Keyword(s):

Dose Escalation ◽

Kinase Inhibitor ◽

Concomitant Administration ◽

Highly Active ◽

Best Response ◽

Ecog Ps ◽

Therapeutic Doses ◽

Dose Delay

14118 Background: Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit. Pazopanib also is a moderate inhibitor of CYP2C8 and CYP3A4 in vitro. Paclitaxel (T), a substrate for CYP2C8 and CYP3A4, administered alone and in combination with carboplatin (Cb) is highly active in breast, NSCLC, and ovarian cancers. The additive benefit of the anti-VEGF agent bevacizumab with T or T-Cb in breast and NSCLC provides strong rationale for use of a multi-targeted TKI with T or T-Cb. Methods: Pts with advanced cancer (ECOG PS 0–1) were eligible. Dose escalation was split into Part 1 [T (15–80 mg/m2) days 1, 8, 15 q 28 days plus pazopanib (400–800 mg) QD starting on day 2 of cycle 1] and Part 2 [T (80- 225 mg/m2) plus Cb AUC 6 q 21 days plus pazopanib 800 mg QD starting on day 2 of cycle 1]. Safety, PK, and clinical response were evaluated. Dose escalation occurred in cohorts of 3–6 pts based on dose-limiting toxicities (DLTs) and PK. Results: 12 pts in Part 1 received the following pazopanib/T doses (n = pts): 400 mg/15 mg/m2 (3), 800 mg/15 mg/m2 (3), 800mg /50 mg/m2 (3), 800mg /80 mg/m2 (3). Preliminary data were available from 9 pts in Part 1. Selected mean PK results for T are shown. 4 pts in Part 2 received 800mg /175 mg/m2/AUC 6 of pazopanib/T/Cb (data not yet available). Most common AEs (>20%) in Part 1 were Gr 1/2 and consisted of fatigue, diarrhea, anorexia, nausea, vomiting, dysgeusia, AST elevation, rash, hypertension, and cough; Gr 3 diarrhea was reported in 1 pt. The 800mg pazopanib/80 mg/m2 T cohort in Part 1 is being expanded to 6 pts due to a DLT (dose delay of > 2 wks due to an abscess). Best response (n=6 pts) in Part 1 was SD (83%) (range 1–5 cycles). Conclusions: Concomitant administration of pazopanib increased paclitaxel mean Cmax and AUC(0–8) approximately 20–35%. Determination of the MTR in Parts 1 and 2 is ongoing. These findings warrant further studies at therapeutic doses of pazopanib, paclitaxel, and carboplatin. [Table: see text] No significant financial relationships to disclose.

Download Full-text