Dose Reduction Of Chemotherapeutic Agents Research Articles

Treatment strategy for myeloid leukemia with Down syndrome

Myeloid leukemia with Down syndrome (ML-DS) demonstrates unique characteristics such as the predominance of FAB M7, an age predilection during the first 4 years of life, and higher sensitivity to chemotherapeutic agents, which translate into a good treatment response as well as increased treatment-related toxicities. Consequently, patients with ML-DS have traditionally been treated separately from non-DS acute myeloid leukemia (AML) children. The 3-year event-free survival rates in recent clinical studies in the Western countries and Japan are all more than 85%. In Japan, two studies (AML-D05 and AML-D11) were conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group. The efficacy of risk-oriented therapy according to morphological response was evaluated in the AML-D05 study. Despite that a dose reduction of chemotherapeutic agents could be performed in many cases, the overall outcome was comparable with those of previous Japanese studies. In the subsequent AML-D11 study, the role of minimal residual disease (MRD) was evaluated. MRD by flow cytometry (FCM) and targeted deep sequencing of GATA1 following the initial induction therapy were significant prognostic factors for predicting relapse. Dose modification according to the end-of-induction FCM-MRD is being attempted in the ongoing JCCG AML-D16 study.

Risk-Oriented Therapy for Myeloid Leukemia of Down Syndrome: A Nationwide Prospective Study By the Japanese Pediatric Leukemia / Lymphoma Study Group (JPLSG)

Introduction: Asmyeloid leukemia in Down syndrome patients (ML-DS) is known to have higher sensitivity against cytotoxic agents, children with ML-DS are treated with less intensive ML-DS-oriented protocol in recent clinical studies. On the basis of results of previous Japanese trials for ML-DS, we have evaluated an efficacy of the risk-oriented therapy in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-D05 study.Patients and Methods: Between January 2008 and December 2010, seventy-four patients with newly diagnosed ML-DS from 122 hospitals in Japan were enrolled in this study. All patients received induction chemotherapy consisted of pirarubicin (25 mg/m2/d for 2 days), cytarabine (100 mg/m2/d for 7 days), and etoposide (150 mg/m2/d for 3 days). Patients who achieved complete remission (CR) after initial induction therapy were stratified to the Standard Risk (SR) and received four courses of reduced dose intensification therapy. Patients who did not achieve CR were stratified to the High Risk (HR) and received intensfied therapy consisted of continuous and high-dose cytarabine. Prophylaxis for CNS leukemia was not included throughout the therapy.Results: Out of 74 patients registered in this study, two patients were excluded (one because of uncontrolled cardiac failure, another of non-Down syndrome), and 72 were eligible and were evaluated. Male/Female ratio was 40/32. The median age at diagnosis was 19 months (range, 10 months and 17 years old). Median follow-up period was 3.64 years (range, 0.05 -5.96 years. One patient died of sepsis during initial induction therapy. Sixty-nine patients were stratified to SR and 2 patients to HR. Both of the two HR patients achieved CR but one relapsed. No therapy-related death was observed during intensification therapy. The 3-year event free and overall survival rate was 83.3% ± 4.4% and 87.5% ± 3.9 %, respectively. Age at diagnosis less than 2 years old was significant favorable prognostic factor for relapse (p=0.009). Sex, history of TAM, and chromosomal abnormalities (Normal karyotype or monosomy 7) did not influence the risk of relapse.Conclusion: This study succeeded the previous Japanese strategy with very low-intensive chemotherapy regimen for ML-DS, and despite the dose reduction of chemotherapeutic agents compared to the previous studies, the overall outcome was good and further dose reduction might be possible for specific subgroups. However, considering that most relapse occurred in the SR group defined by morphological treatment response and that relapsed cases are rarely salvageable, more accurate method for identification of the poor prognostic subgroup is needed.This trial is registered with UMIN Clinical Trials Registry (UMIN-CTR, URL: http://www.umin.ac.jp/ctr/index.htm), number UMIN000000989. DisclosuresNo relevant conflicts of interest to declare.

IJU this issue

Kazunori Kihara M.D., Ph.D. Associate Editor This issue, which covers a wide variety of meaningful topics, contains two Perspectives, one Review Article, seven Original Articles, two Short Communications, one Procedure and two Letters to the Editor. The Perspective, by Oya (Tokyo, Japan), concerns the eradication of cancer cells in advanced renal cell carcinoma. It emphasizes that elucidating the molecular phenotype of the resistant cancer cells is important in determining the molecules to be targeted, and that molecules involved in the epithelial-mesenchymal transition are candidates for targeting. The Perspective by Tanaka (Fukuoka, Japan) gives us a serious warning on the wide dissemination of multidrug-resistant Neisseria gonorrhoeae strains of sequence types 1407 and 2958. The effect of population-based screening on the incidence of prostate cancer, cancer stage and grade, cancer-specific mortality, and overall mortality remains controversial. The review by Lumen et al. (Ghent, Belgium) consists of an overview of available studies and a meta-analysis on population screening for prostate cancer, and they conclude that by excluding the main shortcomings in screening studies, screening is able to reduce prostate cancer mortality. Hinotsu (Kyoto, Japan) makes an Editorial Comment in response to this. In the first of seven Original Articles, Maru et al. (Sapporo, Japan) investigated the influence of baseline renal function and dose reduction of chemotherapeutic agents on the outcome of metastatic urothelial carcinoma patients with renal impairment. The data show that “unfit (baseline 24-h creatinine clearance <60 mL/min/1.48 m2)” is a poor prognostic factor and that dose reduction contributed to continuous treatment in the unfit group, although its contribution to the prognosis is uncertain. Canter (Atlanta, USA) makes an Editorial Comment on this article. Urinary proteome analysis for prostate cancer diagnosis, carried out by Schiffer et al. (Hannover, Germany), shows that it is a cost-effective application for use in routine clinical practice. The interesting finding that combined histoarchitectural and cytological biopsy grading improves grading accuracy in low-grade prostate cancer is reported by Helpap et al. (Singen, Germany). Liu et al. (Hangzhou, China) show through a meta-analysis that cruciferous vegetables intake is related to a decreased risk of prostate cancer, and Hori (Cambridge, UK) makes an Editorial Comment on this. The relationship between alcohol consumption and female urinary incontinence is investigated by Lee et al. (Perth, Australia), who observed only a weak association in middle-aged and older Japanese women. Hsieh (Taipei, Taiwan) makes an Editorial Comment in response to this. Li et al. (Kobe, Japan) report, based on a meta-analysis, that surgical varicocele repair significantly increases testosterone production and improves testicular Leydig cell function. Yamamoto et al. (Osaka, Japan) report that water avoidance stress induces frequency through cyclooxygenase-2 expression in a rat bladder model. In a Short Communication, the applicability of five published criteria for active surveillance for prostate cancer to Japanese patients was evaluated by Goto et al. (Yokohama, Japan), who concluded that they appear to be appropriate. An Editorial Comment on this is given by Suzuki (Tokyo, Japan). The additive effect of zoledronic acid on serum prostate-specific antigen changes was reported by Kamiya et al. (Chiba, Japan) in hormone-sensitive prostate cancer patients with bone metastasis treated by combined androgen blockade, which suggests a potential antitumor effect of zoledronic acid. In the Procedure, Furubayashi et al. (Fukuoka, Japan) describe cutaneous ureterostomy using the transverse mesocolon. In one Letter to the Editor, Guo et al. (Beijing, China) present clinical characteristics of malignant solitary fibrous tumors of the kidney with thoracic vertebral metastasis. In the other, Ito et al. (Yokosuka, Japan) show a case of struma testis with seminoma arising from an undescended testis, on which an Editorial Comment by Chen (Suzhou, China) is given. None declared.

Influence of baseline renal function and dose reduction of nephrotoxic chemotherapeutic agents on the outcome of metastatic urothelial carcinoma: A retrospective study

To investigate the influence of baseline renal function and dose reduction of chemotherapeutic agents on the outcome of metastatic urothelial carcinoma patients with renal impairment. A total of 57 patients with metastatic urothelial carcinoma treated by systemic chemotherapy were included in the present study. The 24 h-creatinine clearance was measured before each cycle and dose reduction was carried out according to our guidelines. Patients were divided into two groups according to baseline 24 h-creatinine clearance: fit group (60 mL/min/1.48 m(2) ≤) and unfit group (60 mL/min/1.48 m(2) >). Clinical characteristics and final outcomes were compared between the two groups. There was no significant difference in the total number of chemotherapy cycles of each patient between the two groups (fit group: median 5; unfit group: median 4; P=0.7466), although dose reduction was carried out significantly more often in the unfit group than in the fit group during treatment (fit group: median 0 cycles; unfit group: median 3.5 cycles; P=0.0016). Overall, the median survival was 16 months. There was a significant survival difference between the two groups (fit group: median 17 months; unfit group: median 10 months; P=0.0419). On multivariate analyses, impaired renal function at the baseline remained an adverse factor (HR 2.27, P=0.01). "Unfit" was a poor prognostic factor for metastatic urothelial carcinoma. The dose reduction strategy contributed to continuous treatment in the unfit group. However, its contribution to the prognosis of unfit patients is uncertain.

Dose reduction of chemotherapeutic agents after weight loss.

The aim of dose reduction of chemotherapeutic agents following weight loss is to avoid excessive toxicity while maintaining an equivalent therapeutic effect. Several methods of calculating this dose reduction are currently in use, including dose reduction in proportion to the reduction in body surface area (BSA) or the amount of weight lost and no dose reduction unless significant toxicity occurs. Each of these methods results in the administration of a different dose and therefore different drug exposure, as measured by the area under the time versus concentration curve (AUC). We have used pharmacokinetic modeling software and normative data on the pharmacokinetics of high-dose methotrexate to determine the change in AUC resulting from dose reduction by each of the methods cited for patients with weight loss. Dose reduction in proportion to the reduction in weight results in the same AUC and therefore equivalent drug exposure as before weight loss. In contrast, the more common practice of dose reduction in proportion to the decrease in BSA (as determined by recalculating BSA) results in a higher AUC than before weight loss. This results in increased drug exposure and potentially increased toxicity, which may be avoided if dose reduction is carried out in proportion to the decrease in weight rather than in BSA. The same principles are applicable to other drugs, particularly those associated with dose-dependent toxicity.

Variation in the practice of dose reduction of chemotherapeutic agents after weight loss or amputation.

Dose reduction of chemotherapeutic agents in response to weight loss or amputation is important in avoiding excessive therapy-related toxicity. Several methods of calculating this dose reduction are currently in use, including dose reduction in proportion to (a) the reduction in body surface area (BSA), (b) the amount of weight lost, and (c) no dose reduction unless toxicity is observed. Each of these methods results in the administration of a different dose, and few guidelines exist as to the preferred method. We conducted a survey of a large group of pediatric oncologists, pediatric oncology nurses, and data managers to determine the methods of dose reduction currently in use for patients (a) with weight loss, (b) after amputation, and (c) with further weight loss after amputation. Responses were obtained from 237 of 294 individuals surveyed (80.6%). The most popular method was to dose reduce in proportion to the reduction in BSA in patients with weight loss alone (88%), amputees (60%), and amputees with ongoing weight loss (66%). Other methods were chosen by 7%, 31%, and 24% of participants in each of these clinical settings, respectively. The chosen methods result in a discrepancy of administered doses of up to 37%. Our results highlight the need for the standardization of practice, and the determination of the optimal method of dose reduction after weight loss or amputation.