Differences In Hematologic Toxicity Research Articles

Randomized Double-Blind Placebo-Controlled Trial of Thalidomide in Combination With Gemcitabine and Carboplatin in Advanced Non–Small-Cell Lung Cancer

Cancers rely on angiogenesis for their growth and dissemination. We hypothesized that thalidomide, an oral antiangiogenic agent, when combined with chemotherapy, and as maintenance treatment, would improve survival in patients with advanced non-small-cell lung cancer (NSCLC). Seven hundred twenty-two patients were randomly assigned to receive placebo or thalidomide capsules 100 to 200 mg daily for up to 2 years. All patients received gemcitabine and carboplatin every 3 weeks for up to four cycles. End points were overall survival (OS), progression-free survival (PFS), response rate, grade 3/4 toxicity, and quality of life (QoL). The median OS rates were 8.9 months (placebo) and 8.5 months (thalidomide). The hazard ratio (HR) was 1.13 (95% CI, 0.97 to 1.32; P = .12). The 2-year survival rate was 16% and 12% in the placebo and thalidomide arms, respectively. The PFS results were consistent with those for OS. The risk of having a thrombotic event was increased by 74% in the thalidomide group: HR of 1.74 (95% CI, 1.20 to 2.52; P = .003). There were no differences in hematologic toxicities, but a slight excess of rash and neuropathy in the thalidomide group. QoL scores were similar but thalidomide was associated with less insomnia, and more constipation and peripheral neuropathy. In a retrospective analysis, patients with nonsquamous histology in the thalidomide group had a poorer survival: 2-year risk difference of 10% (95% CI, 4% to 16%; P < .001). In this large trial of patients with NSCLC, thalidomide in combination with chemotherapy did not improve survival overall, but increased the risk of thrombotic events. Unexpectedly, survival was significantly worse in patients with nonsquamous histology.

8039 Weekly cisplatin (wCDDP) with concurrent radiotherapy (cRT) in locally advanced cervical cancer (LACC) patients (pts): a monoinstitutional experience

Although peritoneal carcinomatosis (PC) from colorectal and appendiceal tumors is consistent with metastatic disease, complete cytoreduction with hyperthermic intraperitoneal chemotherapy (HIPEC) using mitomycin C (MMC) can improve survival. A recent phase I study by our group using hyperthermic intraperitoneal oxaliplatin has demonstrated its safety and appropriate dose. Our goal in this study is to present a single institution’s experience with the hematologic toxicities of the two agents.We performed a retrospective review of 187 patients with PC of colorectal or appendiceal origin who underwent HIPEC with MMC or oxaliplatin between October 2006 and September 2009. Hematologic toxicities were graded according to the NCI Common Terminology Criteria for Adverse Events Version 4.0.Of the 187 patients, 55 had oxaliplatin-based HIPEC while 132 patients received MMC. Splenectomy was performed in 95 patients (50.8%) due to disease involvement. When comparing hematologic toxicity for MMC and oxaliplatin among the cohort of patients who underwent splenectomy, a statistically significant difference was noted in the incidence of platelet (P = .02) and neutrophil (P = .05) toxicity, with oxaliplatin having a higher incidence of grade 3 and grade 4 platelet and neutrophil toxicity respectively. However, no statistically significant difference in hematologic toxicity was noted between the two agents in patients who did not undergo splenectomy during cytoreductive surgery.Oxaliplatin-based HIPEC for PC of colorectal and appendiceal origin is associated with similar white blood cell toxicity and higher platelet and neutrophil toxicity compared to MMC-based HIPEC.

Recent progress in the treatment of multiple myeloma: updates and highlights from ASH 2008

Recent progress in the treatment of multiple myeloma: updates and highlights from ASH 2008

Toxicity of fludarabine and cyclophosphamide with or without rituximab as initial therapy for patients with previously untreated mantle cell lymphoma: results of a randomised phase II study

The National Cancer Research Network (NCRN) is currently coordinating a Phase III randomised study (LY05) comparing fludarabine and cyclophosphamide (FC) with or without rituximab (R) for previously untreated mantle cell lymphoma (MCL). The combination of FC is well-recognised as significantly immunosuppressive and there are concerns that adding rituximab may increase infection risk further. The impact of rituximab on other markers of toxicity is also unclear. We analysed the toxicity data on 139 patients treated within the NCRN LY05 trial. Non-hematological toxicity was similar between the two treatment arms. The only difference in hematological toxicity was a higher rate of lymphocytopenia with fludarabine cyclophosphamide and rituximab (FCR), which did not translate into increased febrile episodes or infections. In conclusion, the addition of rituximab to FC for previously untreated MCL has no significant impact on toxicity.

Differences in hematotoxicity between male and female patients with Hodgkin lymphoma and other malignancies

With improved treatment strategies and prognosis for patients with Hodgkin lymphoma (HL), interest has increasingly focused on high-risk groups. These groups include a small proportion of patients who experience relapse or who have primary refractory disease despite state-of-the-art treatment. Although many research efforts have been made in this field, specific biological markers that reliably predict unfavorable outcome during first-line treatment are lacking. Recent analyses in HL and other malignancies, however, have demonstrated an important impact of patient-related factors, such as individual differences in hematologic toxicity and drug metabolism, on disease outcome. A different cytochrome enzyme status and slower drug clearance in female patients, resulting in higher systemic toxicity and effectiveness of treatment, indicate that sex-specific aspects are important. In this Review, we discuss the current data on hematotoxicity among male and female patients with HL and other malignancies. In addition, we highlight the potential causes of hematotoxicity and its impact on treatment outcome and the role of future strategies.

Comparison of Results from a Phase 1/2 Study of Lumiliximab (Anti-CD23) in Combination with FCR for Patients with Relapsed CLL with Published FCR Results.

Lumiliximab is a PRIMATIZED® anti-CD23 monoclonal antibody with human IgG1 constant regions and macaque variable regions. Preclinical data demonstrated that lumiliximab enhanced both fludarabine- and rituximab- mediated apoptosis in CLL cells. Thus, a Phase 1/2, open-label, dose-escalation, multicenter study (Study 152–30) evaluating lumiliximab + fludarabine, cyclophosphamide, and rituximab (L + FCR) for relapsed CD23+ B-cell CLL was initiated. Treatment has been completed and follow-up is ongoing. Thirty-one patients (pts) received either 375 mg/m2 (n=3) or 500 mg/m2 (n=28) of lumiliximab in combination with a 28-day cycle of FCR for up to 6 cycles. Median age at study entry was 58 yrs. The majority of pts (74%) were Rai Stage I/II. The most common adverse events included nausea (77%), pyrexia (61%), chills (55%), neutropenia (55%), and fatigue (48%). Twenty pts (65%) experienced a Grade 3 or 4 event. An overall response rate of 71% was demonstrated: 48% complete response (CR), 10% partial response (PR), and 13% unconfirmed PR. Currently, baseline cytogenetic data is available for 21 pts who received 500 mg/m2 of lumiliximab. Although preliminary, 1 of the 4 pts with del(17p13.1) responded; of the 6 pts with del(11q22.3), 5 responded with 4 attaining a CR. A comparison with published data from a study of FCR alone in 177 pts with relapsed or refractory CLL conducted at the M.D. Anderson Cancer Center (MDACC) (Wierda W, O'Brien S, Wen S, et al. J Clin Oncol. 2005; 23:4070–4078) demonstrated that L + FCR has an acceptable safety profile, does not appear to increase the toxicity (including myelosuppression) of the FCR regimen, and compares favorably with the CR rate of the FCR regimen alone, as displayed in Table 1. Most pt characteristics (age, gender, median number of prior therapies, and WHO performance status) were similar between the 2 studies; however, more pts in the MDACC study were Rai Stage III-IV (50% vs 22%) and were rituximab-naïve (88% vs 40%). Furthermore, there were no obvious differences in hematologic toxicity between the 2 studies and the tolerability of L + FCR was similar to that of FCR, with approximately 50% percent of pts completing 6 cycles of treatment in both studies. These data suggest that L + FCR may produce a higher complete response rate than FCR without additional toxicity. Based upon this data, a multicenter, global, randomized study of L + FCR vs. FCR alone is being initiated.Table 1Comparison of Responses in Study 152–30 and the MDACC StudyStudy 152–30, L + FCR (N=31), n (%)MDACC, FCR (N =177), n (%)Overall Response22 (71%)130 (73%)Complete Response115 (48%)45 (25%)Partial Response13 (10%)85 (48%)Unconfirmed Partial Response24 (13%)1CR and PR response criteria were the same in both studies.2PRu is included in the OR.

A prospective pharmacogenetic study of 5FU/LV in high-risk stage II and III colon cancer patients

2067 Background: The promoter of thymidylate synthase (TS) has a variable number of tandem repeats (VNTR) polymorphism and a single nucleotide polymorphism (SNP) within the VNTR region. The VNTR have been associated with toxicity of TS inhibitors in retrospective studies. The TS SNP has not been studied with respect to toxicity from TS inhibitors. The TS SNP has been suggested to abolish activity of the USF-1 enhancer located in the 2nd tandem repeat of the VNTR. The combined effect of the VNTR and SNP means that pts will have 2, 3 or 4 USF-1 enhancers in the TS promoter. We hypothesized that the number of enhancers would predict pts at risk for Gr 3/4 mucositis and diarrhea and have undertaken a prospective pharmacogenetic study of TS polymorphisms in colon cancer pts treated with 5-fluoruracil (5FU)/leucovorin (LV). Methods: Pts were treated with 5FU/LV (425mg/m2/20mg/m2) daily for 5 ds every 4 wks. Pts had blood drawn wkly for hematologic toxicity in cycle 1. Pts were assessed for mucositis and diarrhea according NCI CTC 2.0. Blood for genotyping was obtained prior to treatment. Results: Thus far 56 out of 104 pts have been enrolled, 28 pts have been genotyped and 27 are evaluable for toxicity. Patient characteristics: median age 60.5 yrs (range 39–76), 11F/16M, Stage III 23, Stage II 4. The observed toxicities were: diarrhea (37%, Gr 1; 22%, Gr 2; 11%, Gr 3; 4%, Gr 4) and mucositis (59%, Gr 1; 22%, Gr 2; 4%, Gr 3). Frequencies of 2 tandem repeat (TSER*2) and 3 tandem repeat (TSER*3) polymorphisms were respectively 0.38 and 0.62. Patients were genotyped for the C to G SNP at position 12 in the 2ndrepeat of TSER*3, 38% of TSER*3 had a G at position 12 (TSER*3G), and 62% of TSER*3 had a C at position 12 (TSER*3C). The frequency of Gr 3/4 mucositis/diarrhea was 4/12 (33%) in pts with 2 enhancers (TSER*2/TSER*2 or TSER*3G/TSER*3G) vs. 1/15 (7%) in patients with 3 or 4 enhancers (TSER*3C/TSER*3C, TSER*3C/TSER*3G, TSER*3C/TSER*2), (p=0.14, Fisher's exact test). There was no difference in hematologic toxicity between the two groups. Conclusions: Our early results suggest the TS SNP may be a critical determinant of toxicity in pts treated with 5FU/LV. No significant financial relationships to disclose.

FEASIBILITY AND TOLERANCE OF CISPLATIN AND FLUOROURACIL INFUSION IN ELDERLY PATIENTS WITH SQUAMOUS-CELL CARCINOMA

Many head and neck and esophageal cancers are diagnosed in patients over 65 years old, but limited data are available on the tolerance of elderly patients to chemotherapy protocols designed for adults. We therefore retrospectively evaluated tolerance of cisplatin (100 mg/m(2) day 1) plus fluorouracil (1,000 mg/m(2)/day as a 120 h infusion) in a group of patients over 65 years of age with squamous cell carcinoma (n=20, group A) and compared it with a second group of younger patients (n=20, group B). Baseline patient characteristics were well balanced between the 2 groups. The median age was 69 years (range, 66-76) in group A and 47 years (range, 19-61) in group B. A total of 54 cycles (range, 1-6) and 65 cycles (range, 1-7) were delivered respectively in group A and B. Dose reductions were required in 9% (group A) and in 10% (group B) of the cycles. No toxic death was recorded in either group. No statistical difference in hematological toxicity was observed between the 2 groups of patients. Although the incidence of grade 1-2 renal toxicity was higher in elderly patients (5 vs 1), the difference was not significant (p=0.09). A similar incidence of mucositis (25%), nausea/vomiting (40%) and diarrhea (5%) was observed for each group. In conclusion, selected elderly patients with good performance status and adequate organ function can be safely treated with CDDP and FU without significantly increased toxicity.