paywalled: Hematological Toxicity After Robotic Stereotactic Body Radiosurgery for Treatment of Metastatic Gynecologic Malignancies

Hematological Toxicity After Robotic Stereotactic Body Radiosurgery for Treatment of Metastatic Gynecologic Malignancies

published online 30 April 2012.

Corrected Proof

• Abstract

Purpose

To evaluate hematological toxicity after robotic stereotactic body radiosurgery (SBRT) for treatment of women with metastatic abdominopelvic gynecologic malignancies.

Methods and Materials

A total of 61 women with stage IV gynecologic malignancies treated with abdominopelvic SBRT were analyzed after ablative radiation (2400 cGy/3 divided consecutive daily doses) delivered by a robotic-armed Cyberknife SBRT system. Abdominopelvic bone marrow was identified using computed tomography-guided contouring. Fatigue and hematologic toxicities were graded by retrospective assignment of common toxicity criteria for adverse events (version 4.0). Bone marrow volume receiving 1000 cGy (V10) was tested for association with post-therapy (median 32 days [25%-75% quartile, 28-45 days]) white- or red-cell counts, hemoglobin levels, and platelet counts as marrow toxicity surrogates.

Results

In all, 61 women undergoing abdominopelvic SBRT had a median bone marrow V10 of 2% (25%-75% quartile: 0%-8%). Fifty-seven (93%) of 61 women had received at least 1 pre-SBRT marrow-taxing chemotherapy regimen for metastatic disease. Bone marrow V10 did not associate with hematological adverse events. In all, 15 grade 2 (25%) and 2 grade 3 (3%) fatigue symptoms were self-reported among the 61 women within the first 10 days post-therapy, with fatigue resolved spontaneously in all 17 women by 30 days post-therapy. Neutropenia was not observed. Three (5%) women had a grade 1 drop in hemoglobin level to <10.0 g/dL. Single grade 1, 2, and 3 thrombocytopenias were documented in 3 women.

Conclusions

Abdominopelvic SBRT provided ablative radiation dose to cancer targets without increased bone marrow toxicity. Abdominopelvic SBRT for metastatic gynecologic malignancies warrants further study.

abstract: Effects on the immune system and toxicity of carboplatin/paclitaxel combination chemotherapy in patients with stage III-IV ovarian and non small cell lung cancer and its role in survival and toxicity.

 
Effects on the immune system and toxicity of carboplatin/paclitaxel combination chemotherapy in patients with stage III-IV ovarian and non small cell lung cancer and its role in survival and toxicity.


Abstract
 
Purpose:
To examine the impact of paclitaxel and carboplatin combination chemotherapy on the parameters of the immune system in patients with non small cell lung cancer (NSCLC) and with ovarian cancer before, during and after chemotherapy, and the effect of this combination on the overall patient survival.

Methods:
24 patients with NSCLC and 20 with ovarian cancer (all in stage IIIb-IV) treated with 6 courses of paclitaxel and carboplatin combination chemotherapy were separated into two groups according to their survival group A: long survival (> 12 months for NSCLC; > 30 months for ovarian cancer) group B: short survival (<12 months for NSCLC; <30 months for ovarian cancer).

At the same time we studied some immunological parameters (CD3, CD4, CD8, CD56, CD34, IL-3, IFN-γ) in relation with the induced toxicity during chemotherapy. The results were analysed using the ANOVA method.

Results: 
We observed a statistically significant difference of CD4 and CD4/CD8 after chemotherapy between groups A and B (p<0.001 and p< 0.006 respectively), implying that the further increase of T-helper cells after chemotherapy had a positive impact on survival. In addition, statistically interesting was the difference in values of IFN-γ between patients of groups A and B before and after chemotherapy (p< 0.039 and p< 0.027, respectively). Patients with high IL-3 had little chance of toxicity.

Conclusion:
Our findings support that with carboplatin/ paclitaxel combination chemotherapy, important parameters of the immune system (IFN-γ, CD4, CD4/CD8) can be used as prognostic factors for survival, while others (IL-3) as indicators of toxicity.

abstract: Progression-free and overall survival of a modified outpatient regimen of primary intravenous/intraperitoneal paclitaxel and intraperitoneal cisplatin in ovarian, fallopian tube, and primary peritoneal cancer

Progression-free and overall survival of a modified outpatient regime... [Gynecol Oncol. 2012] - PubMed - NCBI

Abstract

OBJECTIVE:

GOG study 172 demonstrated improved progression-free (PFS) and overall (OS) survival for patients with stage III optimally debulked ovarian and peritoneal carcinoma treated with IV/IP paclitaxel and IP cisplatin compared to standard IV therapy. The inpatient administration, toxicity profile, and limited completion rate have been blamed for the lack of acceptance and widespread use of this regimen. We sought to evaluate the PFS, OS, toxicity, and completion rate of a modified outpatient IP regimen.


 CONCLUSIONS:
By modifying the GOG 172 treatment regimen, convenience, toxicity, and tolerability appear improved, with survival outcomes similar to those of GOG 172. This modified IV/IP regimen warrants further study.

Phase I Study of the Vascular-Disrupting Agent OXi4503

Phase I Study of the Vascular-Disrupting Agent OXi4503:

Purpose:
Preclinical studies show that OXi4503 (combretastatin A1 diphosphate, CA1P) is more potent than other clinically evaluated vascular-disrupting agents.

Experimental Design:
Escalating doses of OXi4503 were given intravenously over 10 minutes on days 1, 8, and 15 every 28 days to patients with advanced solid tumors.

Results:
Doses were escalated in single-patient cohorts from 0.06 to 1.92 mg/m², then expanded cohorts to 15.4 mg/m² in 43 patients. Common adverse drug reactions were hypertension, tumor pain, anemia, lymphopenia, and easily controllable nausea/vomiting and fatigue. Five patients experienced different drug-related dose-limiting toxicities, atrial fibrillation, increased troponin, blurred vision, diplopia, and tumor lysis. Prophylactic amlodipine failed to prevent adverse events. Pharmacokinetics showed dose-dependent linear increases in peak plasma concentrations and area under the curve value of OXi4503. One partial response was seen in a heavily pretreated patient with ovarian cancer. Dynamic contrast-enhanced MRI confirmed a dose effect and showed significant antivascular effects in 10 of 13 patients treated at doses of 11 mg/m² or higher.

Conclusions:
The maximum tolerated dose was 8.5 mg/m² but escalation to 14 mg/m² was possible with only temporary reversible cerebrovascular toxicity by excluding hypertensive patients. As a tumor response was seen at 14 mg/m² and maximum tumor perfusion reductions were seen at doses of 11 mg/m² or higher, the recommended phase II dose is from 11 to 14 mg/m². Clin Cancer Res; 18(5); 1415–25. ©2012 AACR.

Amlodipine (Brand name: Norvasc)

www.nlm.nih.gov

Amlodipine is used alone or in combination with other medications to treat high blood pressure and chest pain (angina). Amlodipine is in a class of medications called calcium channel blockers. It lowers blood pressure by relaxing the blood vessels so the heart does not have to pump as hard. It controls chest pain ...

Side effects - How to take - Precautions - Dietary Instructions - Missed a dose

Call for Changes in Clinical Trial Reporting of Older Patients With Cancer [Correspondence] opens in pdf file

"In studies in which older patients make up a significant proportion
(>15%) of the study population, an analysis of the possible
interaction between outcome, toxicity, and age should be provided in
detail according to specific patient characteristics (comorbidity, function,
and so on). Toxicity should include a reporting of grade 2 toxicities,
when appropriate, given that grade 2 toxicity can be significant in
a patient age 75 years."


"In sum, clinical trials currently fail to address the issues involved
in treating an aging patient with cancer. Designers of clinical cancer
trials must begin to incorporate statistical analyses related to aging, so
that clinicians can optimize their treatment of the older patient
with cancer."

open access: Pharmaceutical care for patients with breast and ovarian cancer - adverse drug events

Blogger's Note:  'tag' line includes breast cancer only; study included few ovarian cancer patients

Conclusions

 

In conclusion, our results suggest that pharmaceutical care for patients with breast and ovarian cancer is feasible and may have an impact on PROs as particularly indicated by significant improvements of the antiemetic response and patient satisfaction. 

Although there is no doubt that a higher awareness of drug-related problems is beneficial, final conclusions on the effectiveness of a new health care intervention can only be drawn when studied in a randomized trial. Therefore, our data may serve as a valuable basis for planning a large randomized multicenter trial.

abstract: Antiangiogenic Agents in Combination With Chemotherapy for the Treatment of Epithelial Ovarian Cancer

Objective: The purpose of this review was to provide an overview of angiogenesis, including the rationale for targeting angiogenesis as a treatment strategy for epithelial ovarian cancer (EOC) and to discuss available clinical trial data with antiangiogenic agents in EOC, with a focus on combinations with chemotherapy.

Methods: This was a literature review of clinical studies evaluating select antiangiogenic agents in combination with traditional cytotoxic chemotherapy for the treatment of EOC.

Results: Several therapies that target angiogenesis-specific pathways are undergoing clinical development for EOC. Although some of these agents have demonstrated single-agent activity for EOC, there is considerable interest in combining this treatment strategy with chemotherapy in an effort to potentially improve treatment benefits in this patient population. Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, is the most studied antiangiogenic agent in EOC and has shown efficacy as monotherapy and combined with chemotherapy in both the relapsed/recurrent and first-line settings. However, results from recent phase 3 trials raise questions regarding patient selection and optimal dose, schedule, and duration of bevacizumab therapy. Other agents in various phases of testing include aflibercept (VEGF Trap), a fusion protein that binds all isoforms of VEGF; multitargeted antiangiogenic tyrosine kinase inhibitors (eg, BIBF 1120, cediranib, pazopanib, sorafenib); and AMG 386, a selective angiopoietin inhibitor. Toxicities associated with VEGF inhibition are also a concern with antiangiogenic therapy, including hypertension, proteinuria, thromboses, and gastrointestinal perforation.

Conclusions: Results from recently completed and ongoing clinical trials combining antiangiogenic agents with chemotherapy are awaited in hopes of expanding therapeutic options for patients with EOC.

abstract: Recommendations on management of EGFR inhibitor-induced skin toxicity: A systematic review

"Due to the small number of randomized controlled trials conducted in the field of EGFR inhibitor-induced skin toxicity so far, it is not possible yet to generate evidence based guidelines on its management. Here, we review and discuss ($$$ requires subscription) available trials and case studies reporting on the management of EGFR inhibitor-induced skin toxicity."

Letter to the Editor: Unexpected gastrointestinal toxicity from Docetaxel/Carboplatin/Erlotinib followed by maintenance Erlotinib treatment for newly diagnosed stage III/IV ovarian cancer, primary peritoneal, or fallopian tube cancer

Note: no abstract/pay-per-view (subscription req'd $$$)

abstract: Factors for Hematopoietic Toxicity of Carboplatin: Refining the Targeting of Carboplatin Systemic Exposure — JCO

Purpose Area under the curve (AUC) dosing is routinely carried out for carboplatin, but the chosen target AUC values remain largely empirical. This multicenter pharmacokinetic-pharmacodynamic (PK-PD) study was performed to determine the covariates involved in the interindividual variability of carboplatin hematotoxicity that should be considered when choosing individual target AUCs. 

Patients and Methods Three hundred eighty-three patients received carboplatin as part of established regimens. A semi-physiologic population PK-PD model was applied to describe separately the time course of absolute neutrophil and platelet counts using NONMEM software. The plasma ultrafiltrable carboplatin concentration (C_Carbo) was assumed to inhibit the proliferation of blood cell precursors through a linear model: drug effect = slope × C_Carbo. The slope corresponds to the patients' sensitivity to carboplatin hematotoxicity. The relationships between the patients' sensitivity to the neutropenic or thrombopenic effects of carboplatin and various covariates, including associated chemotherapies, demographic, biologic, and pharmacogenetic data, were studied. 

Results The sensitivity of carboplatin-induced thrombocytopenia decreased in the case of concomitant paclitaxel chemotherapy (slope decreased by 24%), whereas it increased with coadministration of etoposide and gemcitabine (slope increased by 45% and 133%, respectively). For neutropenia, the sensitivity increased when carboplatin was combined with other cytotoxics (slope increased by 76%). 

Conclusion This study provides useful information to clinicians to better estimate the hematopoietic toxicity of carboplatin and thus choose more rationally carboplatin target AUCs as a function of pretreatment or concomitantly administered chemotherapies. For example, an AUC of 5 mg/mL · min is associated with a risk of grade 3 or 4 thrombocytopenia of 2% in combination with paclitaxel versus 38% with gemcitabine in a non-pretreated patient.

(abstract) From randomized trial to practice: single institution experience using the GOG 172 i.p. chemotherapy regimen for ovarian cancer — Ann Oncol

Background: The objective of the study was to evaluate completion rates and toxic effects of an i.p. chemotherapy regimen in a cross-section of nonselected patients with ovarian cancer (OC).

Overcoming TRAIL resistance in ovarian carcinoma

CONCLUSION: Continued efforts with combination therapy designed to target multiple steps in apoptotic pathways may not only improve the efficacy of TRAIL-mediated therapies, but may also improve quality of life for ovarian cancer patients by reducing toxicity associated with cancer therapy.

Abstract/full acess: Hypertension and hand-foot skin reactions related to VEGFR2 genotype and improved clinical outcome following bevacizumab and sorafenib

Background: Hypertension (HT) and hand-foot skin reactions (HFSR) may be related to the activity of bevacizumab and sorafenib. We hypothesized that these toxicities would correspond to favorable outcome in these drugs, that HT and HFSR would coincide, and that VEGFR2 genotypic variation would be related to toxicity and clinical outcomes.

METHODS
Patients and treatment
The analyses were performed on genomic DNA from 178 patients (143 males and 35 females) with solid tumors who received sorafenib (VEGFR2 inhibitor) and/or bevacizumab (anti-VEGF) with or without other agents....cont'd (excerpt from pdf file)

Conclusions: This study suggests that HT and HFSR may be markers for favorable clinical outcome, HT development may be a marker for HFSR, and VEGFR2 alleles may be related to the development of toxicities during therapy with bevacizumab and/or sorafenib.

Oncologist preferences for health States associated with the treatment of advanced ovarian cancer - (interview with 34 oncologists) - abstract

Objective:
"To explore oncologists' preferences for hypothetical outcome scenarios (i.e. health states) resulting from various treatment options."
Conclusions:
"These data suggest that oncologists may choose treatments that maximize clinical efficacy only when not associated with severe toxicities or low emotional well-being unless associated with a large improvement in efficacy. Physicians may prefer a more toxic chemotherapy regimen that improves survival, and are more willing to compromise emotional well-being for a large survival advantage in the setting of newly diagnosed disease. Slight improvements in clinical efficacy may not be acceptable to oncologists unless associated with higher emotional well-being for the patient."

2010: Collateral damage: toxic effects of targeted antiangiogenic therapies in ovarian cancer : The Lancet Oncology (abstract only)

Note: abstract/full access is by subscription/$$

commentary/Japanese study - Carbo/Taxol - Dose-Dense Chemotherapy for Ovarian Cancer - National Cancer Institute

"...Women with advanced ovarian cancer lived longer and without their tumors growing after receiving a modified regimen of a standard chemotherapy drug combination, Japanese researchers have reported. In a large phase III clinical trial, the researchers randomly assigned women to receive six cycles of carboplatin and paclitaxel (Taxol) every 3 weeks (standard regimen) or six cycles of carboplatin every 3 weeks and a lower dose of paclitaxel (Taxol) once a week (dose-dense regimen). Women in the dose-dense group had a 29 percent reduction in the risk of progression and a 25 percent reduction in the risk of death after 3 years of follow-up. The results were published online September 18, 2009, in The Lancet (see the journal abstract).
Although the dose-dense regimen had more toxic effects than the standard regimen, survival benefits of this magnitude "have been rare in women with advanced ovarian cancer," wrote. Noriyuki Katsumata, M.D., and colleagues from the Japanese Gynecologic Oncology Group (JGOG).
The results, explained Ted Trimble, M.D., M.P.H., from NCI's Division of Cancer Treatment and Diagnosis, are consistent with what has been seen in breast cancer using a dose-dense chemotherapy regimen. The idea, he continued, is "to balance efficacy and toxicity by using a weekly schedule rather than every 3 weeks."...."

Guidelines for the management of ovarian cancer during pregnancy.

"If chemotherapy is indicated, we recommend delaying administration, if possible, until after the delivery or at least after 20 weeks in order to minimize the potential fetal toxicity".