Higher Hematologic Toxicity Research Articles

Treatment outcomes of extended-field radiation therapy and the effect of concurrent chemotherapy on uterine cervical cancer with para-aortic lymph node metastasis.

PurposeTo review the clinical outcomes of extended-field radiation therapy (EFRT) and to analyze prognostic factors significant for survival in patients receiving EFRT for uterine cervical carcinoma with para-aortic node (PAN) metastasis.Patients and methodsWe retrospectively reviewed 90 patients with stage IB-IVA cervical cancer and PAN metastasis between 1987 and 2012. Median age was 50 (range, 24–77). Patients received median 70.2 Gy (range, 56–93) to point A and median 50.4 Gy (range, 45–60.4) to PAN over median 69 elapsed days (range, 43–182). Forty-six patients (51.1%) received concurrent chemotherapy. Survival was calculated using the Kaplan–Meier method. We analyzed prognostic factors for overall actuarial survival (OS) and progression-free survival (PFS) using a Cox regression method.ResultsThe median follow-up period for surviving patients was 55 months (range, 3–252). Seventy patients (77.8%) had complete remission. Forty-six patients experienced treatment failure as follows: 11 patients (12.2%) as local recurrence, 19 (21%) as regional recurrence and 33 (36.7%) as distant metastasis. The 5-yr OS and PFS were 62.6% and 43.9%, respectively. Treatment response was the only statistically independent prognostic factors for OS (p= 0.04) and PFS (p< 0.001) on multivariate analysis. Grade 3 or 4 hematologic gastrointestinal and urogenital toxicities were observed in about 10% of patients.ConclusionsOur institutional experiences showed that EFRT was an effective treatment for cervical cancer patients with PAN metastasis. The addition of chemotherapy to EFRT seems to have uncertain survival benefit with higher hematologic toxicity.Electronic supplementary materialThe online version of this article (doi:10.1186/s13014-014-0320-5) contains supplementary material, which is available to authorized users.

Chemotherapy for Adults with Malignant Glioma: A Systematic Review and Network Meta-Analysis.

Malignant glioma is the most common primary brain tumor in adults and the survival rate has remained very low. Thus, determining the optimal treatment for patients can be challenging. To compare the efficacy of common therapies, we performed network meta-analysis to estimate the efficacy and safety among procarbazine, lomustine, vincristine, temozolomide, bevacizumab plus temozolomide, and placebo for patients with malignant glioma. Relevant studies (as of March, 2014) were identified by searching PubMed, Embase, and Central databases. The primary endpoint of the analysis was the overall survival (OS) and progression-free survival (PFS) of glioma patients. Nine trials with a total of 3472 patients were included in our network meta-analyses. Compared with placebo, bevacizumab plus temozolomide was associated with the highest estimates of OS and PFS for 12 and 24 months (12 month OS odds ratio [OR]: 2.44; 95% credibility interval [CrIs]: 0.76-9.69; 24 month OS OR: 2.56; 95% CrIs: 1.12?5.24; 12 month PFS OR: 6.76; 95% CrIs: 2.80?17.34; 24 month PFS OR: 3.69; 95% CrIs: 0.62?28.63). However, bevacizumab plus temozolomide did not significantly improve OS or PFS compared to temozolomide alone. Bevacizumab plus temozolomide combination therapy is not significantly more effective than temozolomide alone in improving survival of glioma patients. Moreover, bevacizumab was associated with higher hematologic toxicities. Bevacizumab should be used with caution in glioma patients. Additional randomized controlled trials are required to confirm this finding.

Feasibility of Concurrent Chemoradiation in Cervical Cancer Patients From Rural Background

BackgroundConcurrent chemoradiation causes toxicities such as enteritis, hematologic toxicities which may lead to treatment interruptions, and therefore inferior outcomes. Adequate supportive care is very important to complete the scheduled protocol. Most of our patients are from rural background with a heterogeneous social background (nutrition and social support). There is paucity of literature to evaluate the tolerance of this intense treatment in these groups of patients, and hence, this study was undertaken. MethodsIn this observational study, 30 rural women having carcinoma cervix treated with concurrent chemoradiation between January and July 2013 were reviewed retrospectively. They were assessed weekly for dyselectrolytemia, enteritis, and hematologic toxicity using Radiation Therapy Oncology Group Acute Radiation Morbidity Scoring Criteria. Treatment gaps along with reasons were recorded and correlated. ResultsMedian age of patients was 54 years. Of the patients, 43.3% were International Federation of Gynecology and Obstetrics stage II and 46.7% stage III. Grade 3 enteritis was seen in 7 of 30 patients (23.3%). None (0%) had grade 3 or higher hematologic toxicity. Dyselectrolytemia–hyponatremia (46.66%), hypokalemia (26.66%), hypocalcemia (6.66%), and hypomagnesemia (10%) were noted. Two of thirty patients (6.66%) received the planned 5 cycles, cisplatin 40 mg/m2 weekly. There were treatment interruptions in radiation in 6 (20%) and treatment delays in chemotherapy in 10 (33.33%) patients. ConclusionConcurrent chemoradiation for patients from rural areas is associated with higher acute toxicities. Regular monitoring for enteritis and dyselectrolytemias and timely intervention can help improve compliance and decrease treatment interruptions and thereby achieve the optimum treatment outcome.

Novel Association Between CD74 Polymorphisms and Hematologic Toxicity in Patients With NSCLC After Platinum-Based Chemotherapy

BackgroundPlatinum-based chemotherapy regimens can cause DNA damage. Macrophage migration inhibitory factor (MIF) plays an important role in the regulation of the cell cycle by either controlling the activity of the SKP1-Cullin/Cdc53-F-box protein ubiquitin ligase (SCF) complex or activating its receptor, CD74. Patients and MethodsWe used a pathway-based approach to investigate the association between genetic polymorphisms in MIF-pathway genes and the outcomes of platinum-based chemotherapy in advanced non–small-cell lung cancer (NSCLC). We used iSelect 24×1 HD BeadChip (Illumina, Inc, San Diego, CA) to genotype 32 tag and potentially functional single nucleotide polymorphisms (SNPs) of 8 selected genes and evaluated their associations with different outcomes for 1004 patients with advanced NSCLC treated with platinum-based chemotherapy. In particular, gastrointestinal toxicity and hematologic toxicity were analyzed for associations with specific genotypes, alleles, and haplotypes. ResultsTwo polymorphisms of CD74, rs2748249 (C/A) and rs1560661 (A/G), were significantly associated with hematologic toxicity. Carrying an A allele in rs2748249 was associated with higher hematologic toxicity (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.24-2.39; P = .001) and carrying a G allele in rs1560661 was associated with lower hematologic toxicity (OR, 0.42; 95% CI, 0.25-0.70; P = .00099) compared with the wild type. Haplotype analysis revealed that the patients with the CG haplotype (consisting of rs2748249 and rs1560661) had reduced hematologic toxicity compared with patients with other haplotypes (OR, 0.70; 95% CI, 0.56-0.87; P = .0013). The binding domain shared by 3 transcription factors (activator protein-2α [AP-2α], progesterone response A/B, and TFII-I) comprised the 2 SNPs that may be involved in the regulation of CD74-related B-cell survival. ConclusionOur study is the first to suggest, to our knowledge, that polymorphisms in CD74 might be a marker of lower hematologic toxicity for patients with advanced NSCLC receiving platinum-based chemotherapy.

Pilot study assessing a seven-day continuous intrathecal topotecan infusion for recurrent or progressive leptomeningeal metastatic cancer

To determine the feasibility and toxicity profile of topotecan administered as a seven-day continuous intrathecal infusion for patients with leptomeningeal metastasis secondary to recurrent or progressive central nervous system cancer. Two patients with central nervous system leptomeningeal metastasis were treated with a seven-day continuous infusion of topotecan (0.2 mg/day) administered via continuous intrathecal/intraventricular infusion at a rate of 0.6 mL/h, totaling 1.4 mg/course. CSF and plasma concentrations of topotecan closed lactone (the active metabolite) were quantified at various points during topotecan infusion. Patients were monitored for neurologic and systemic toxicities according to NCI common toxicity criteria. Both patients tolerated the seven-day continuous topotecan without any significant adverse events. One patient received a second course 21 days after treatment initiation. CSF concentration of topotecan closed lactone ranged from 3.73 to 312 ng/mL (median = 131 ng/mL) and plasma topotecan closed lactone ranged from 0.44 to 1.78 ng/mL (median = 0.92 ng/mL). The median CSF topotecan concentration was greater than the median serum topotecan concentration by a 44-fold magnitude when samples were obtained at the same time point. None of the patients experienced any grade 3 or higher hematological toxicities or signs of arachnoiditis. A seven-day continuous intrathecal infusion of topotecan is well tolerated and has the potential of maximizing central nervous system drug exposure.

Phase I trial of the combination of the Akt inhibitor nelfinavir and chemoradiation for locally advanced rectal cancer

PurposeTo investigate the toxicity of nelfinavir, administered during preoperative chemoradiotherapy (CRT) in patients with locally advanced rectal cancer. Material and methodsTwelve patients were treated with chemoradiotherapy to 50.4Gy combined with capecitabine 825mg/m2 BID. Three dose levels (DL) of nelfinavir were tested: 750mg BID (DL1), 1250mg BID (DL2) and an intermediate level of 1000mg BID (DL3). Surgery was performed between 8 and 10weeks after completion of CRT. Primary endpoint was dose-limiting toxicity (DLT), defined as any grade 3 or higher non-hematological or grade 4 or higher hematological toxicity. ResultsEleven patients could be analyzed: 5 were treated in DL1, 3 in DL2 and 3 in DL3. The first 3 patients in DL1 did not develop a DLT. In DL2 one patient developed gr 3 diarrhea, 1 patient had gr 3 transaminase elevation and 1 patient had a gr 3 cholangitis with unknown cause. An intermediate dose level was tested in DL3. In this group 2 patients developed gr 3 diarrhea and 1 patient gr 3 transaminase elevation and gr 4 post-operative wound complication. Three patients achieved a pathological complete response (pCR). ConclusionsNelfinavir 750mg BID was defined as the recommended phase II dose in combination with capecitabine and 50.4Gy pre-operative radiotherapy in rectal cancer. First tumor response evaluations are promising, but a further phase II study is needed to get more information about efficacy of this treatment regimen.

Characteristics of patients with colo-rectal cancer and comorbid dementia

panitumumab in this patient population, we conducted a retrospective review of elderly patients treated with these agents at Fox Chase Cancer Center (FCCC) between 2004 and 2010. Methods: Patients aged ≥65 with confirmed metastatic adenocarcinoma of the colon or rectum treated with cetuximab or panitumumab were included in the analysis. Patient demographics, disease characteristics, treatment drugs and duration, KRAS status and overall survival were recorded. Toxicity evaluation included review of common hematologic and non-hematologic toxicities seen with these agents. Results: A total of 117 patients were included; 99 received cetuximab and 18 received panitumumab therapy. The majority of patients were males (58.9%) with colon cancer (82%) and stage IV disease at presentation (50.5%). The median age at treatment initiation was 73 years (range: 65–86). Median overall survival was 2.64 years, and the median time on treatment was 70 days. Overall survival was similar among the different age groups evaluated (65–69, 69–73, 73–80, 80–90) and no correlation was found between increasing age at treatment initiation and treatment duration. Worse performance status at treatment initiation was associated with a shorter overall survival (p=0.013) and with shorter treatment duration (p=0.01). Most patients were treated prior to the incorporation of routine KRAS testing. Thus, KRAS status was available for 35 patients (29.7%), of whom 5 had KRAS mutant tumors. 65% of cetuximab and 44% of panitumumab treatments were given in combination with chemotherapy (i.e. irinotecan). Advanced age was associated with higher use of single agent anti-EGFR antibody therapy (p=0.0009). Most patients received these agents in the second line (35%) or third line (39%) setting. No correlation was found between age or performance status at treatment initiation and the line of therapy in which the drug was used. The incidence of any grade 3 or higher non-hematologic toxicity was 36% (34% for single agent and 38.3% for combination therapy). Common grade 3 or higher non-hematologic toxicities were hypomagnesemia— 17.1%, diarrhea—10.2%, and rash—9.4%. The incidence of any grade 3 or higher hematologic toxicity was 15.3% (6.8% for single agent and 20.5% for combination therapy) with anemia being the most common heme toxicity in both groups. Longer treatment duration and poor performance status at treatment initiation were associated with increased rates of grade 3 or higher hematologic or non-hematologic toxicity (pb0.0001 and p=0.011 respectively). Conclusions: Our data demonstrate that anti-EGFR agents can be safely used for treatment of older adults with mCRC, with toxicity profiles similar to those reported in large phase III studies of generally younger patients. Poor performance status at treatment initiation was associated with decreased overall survival and increased incidence of ≥grade 3 adverse events.

Comparison of 2 Contouring Methods of Bone Marrow on CT and Correlation With Hematological Toxicities in Non–Bone Marrow–Sparing Pelvic Intensity-Modulated Radiotherapy With Concurrent Cisplatin for Cervical Cancer

To compare volumes and dose volume histogram (DVH) parameters for bone marrow contours using 2 methods on computed tomography (CT) and correlation with grade 2 or higher hematological toxicity (HT) in patients with cervical cancer treated with non-bone marrow-sparing intensity-modulated radiotherapy (IMRT) with concurrent cisplatin. The planning CT scans of 47 patients prospectively enrolled and treated with IMRT arm of a phase 2 trial (NCT00193804) contoured for pelvic bone marrow in 2 sets; whole bone (WB), and freehand (FH) inner cavity of bone. Various subvolumes were made in each set--sacrum, ilium, ischium, lower pelvis, lumbosacral spine, sacrum, and whole pelvis--and compared for volume and DVH parameters (V(10), V(20), V(30), and V(40)) using paired t test. The hematological parameters during RT compiled from electronic database analyzed for higher than grade 2 (Radiation Therapy Oncology Group) HT and correlated with DVH parameters using log regression analysis (P < 0.05 significant). The FH subvolumes were 25% to 30% of WB. The mean DVH parameters V(10), V(20), V(30), and V(40) for whole-pelvis FH and WB were 86.5%, 77.5%, 62.5%, and 40.5%; and 88%, 79.6%, 62.9%, and 40%, respectively. There was significant difference between the DVH parameters of 2 sets (P < 0.05) for all subvolumes except ischium V(20), sacrum V(10), and lumbosacral spine V(10). The leukopenia, neutropenia, anemia, and thrombocytopenia higher than grade 2 was seen in 53%, 29.8%, 65.9%, and 10.6%, respectively. The mean V(10) for whole pelvis was less than 90% for both sets. On both univariate and multivariate analyses, only FH whole pelvis V(40) more than or equal to 40% correlated with higher than grade 2 leukopenia (Mann-Whitney U test, P = 0.026) and neutropenia (P = 0.05) with odds ratio, 4 (95% confidence interval, 1.166-13.728; P = 0.028). The FH bone marrow cavity volume is a better surrogate of active bone marrow on CT images and correlated with higher than grade 2 HT (V(40) >40%). Further prospective studies validating significance of high-dose effects and identifying correlation of bioimaging with CT contouring are warranted.

Phase II Trial of Adjuvant Chemotherapy with S-1 for Colorectal Liver Metastasis

This phase II trial was designed to evaluate the safety and efficacy of adjuvant chemotherapy with S-1 in patients with curatively resected liver metastasis from colorectal cancer. Results of an interim analysis of safety and short-term outcomes are reported. Patients who underwent curative resection of liver metastasis from colorectal cancer received S-1 monotherapy (on days 1-28, followed by 14 days' rest, 8 cycles) as adjuvant chemotherapy. Among 62 patients enrolled between October 2008 and August 2010, a total of 60 patients were eligible for analysis. The most frequent grade 3 or higher hematologic toxicity involved neutropenia in three patients (5.0 %). Nonhematologic toxicities of grade 3 or higher were fatigue in 6.7 % of patients. Grade 4 enteritis occurred in one patient, but resolved promptly after withdrawal of S-1 therapy. The completion rate of the eight scheduled cycles of chemotherapy was 58.3 %. The most common reasons for withdrawal of treatment was the detection of early relapse in 16 patients (64 %). When the 16 patients who had recurrence during adjuvant treatment were excluded from analysis, 79.5 % of the remaining 44 patients completed the scheduled treatment. Early recurrence within 1 year after curative liver resection occurred in 21 patients (35 %). The most common site was the remnant liver in 14 patients. Orally administered S-1 after curative liver resection has an acceptable toxicity profile and a high rate of completion of the therapy. S-1 can be safely used and might be a viable treatment option in an adjuvant setting.

Phase II multi-institutional prospective randomised trial comparing S-1+paclitaxel with S-1+cisplatin in patients with unresectable and/or recurrent advanced gastric cancer

Background:A combination of S-1 and cisplatin has been shown to be effective with acceptable safety for the first-line treatment of far-advanced gastric cancer in Japan. This is the first randomised phase II trial to compare S-1+paclitaxel with S-1+cisplatin in this setting.Methods:Patients with unresectable and/or recurrent advanced gastric cancer were randomly assigned to receive one of the two regimens: S-1 (40 mg m−2 twice daily) on days 1–14 plus paclitaxel (60 mg m−2) on days 1, 8, and 15 of a 4-week cycle (S-1+paclitaxel) or S-1 (40 mg m−2 twice daily) on days 1–21 plus cisplatin (60 mg m−2) on day 8 of a 5-week cycle (S-1+cisplatin). The primary end point was the response rate (RR). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety.Results:A total of 83 patients were eligible for safety and efficacy analyses. In the S-1+paclitaxel and S-1+cisplatin groups, RRs (52.3% vs 48.7% P=0.74) and median PFS (9 vs 6 months; P=0.50) were similar. The median OS was similar in the S-1+paclitaxel and S-1+cisplatin groups (16 vs 17 months; P=0.84). The incidence of grade 3 or higher haematological toxicity was 19.0% with S-1+paclitaxel and 19.5% with S-1+cisplatin. The incidence of grade 3 or higher non-haematological toxicity was 14.2% with S-1+paclitaxel and 17.1% with S-1+cisplatin.Conclusion:S-1+paclitaxel was suggested to be a feasible and effective non-platinum-based regimen for chemotherapy in patients with advanced gastric cancer. Our results should be confirmed in multicenter, phase III-controlled clinical trials.

Feasibility and toxicity of docetaxel before or after fluorouracil, epirubicin and cyclophosphamide as adjuvant chemotherapy for early breast cancer

The tolerance and safety associated with the administration order of the anthracycline and taxane drugs have not been evaluated. Breast cancer patients with node-positive or high-risk patients with node-negative were eligible. The feasibility and toxicity were evaluated in the following regimens--arm A, 3 courses of fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2) and cyclophosphamide 500 mg/m(2) (FEC) followed by 3 courses of docetaxel 100 mg/m(2) (DOC); arm B, 3 courses of DOC followed by 3 courses of FEC. Forty-two patients were registered. The relative dose intensity was 94.2 % for FEC and 97.8 % for DOC in arm A, and 98.9 % for DOC and 95.2 % for FEC in arm B. In arm A, grade 3 or higher hematological toxicity was observed in nine patients, and febrile neutropenia developed in three patients with FEC. In arm B, grade 3 or higher hematological toxicity was observed in seven patients, but febrile neutropenia was not noted in any patient. The regimens in both arms A and B were safe regarding adjuvant chemotherapy for early breast cancer. However, DOC followed by FEC might be more tolerable. Further studies will maximize the results obtained with DOC followed by FEC.

Maintenance Therapy with Bortezomib Plus Thalidomide (VT) or Bortezomib Plus Prednisone (VP) In Elderly Myeloma Patients Included In the GEM2005MAS65 Spanish Randomized Trial

Abstract 477In 2005, Spanish Myeloma Group (GEM/Pethema) activated a two-stage, randomized trial including 260 elderly untreated myeloma patients. In the first stage, patients received induction therapy based mainly on a once per week dosing of bortezomib in combination with prednisone plus either melphalan (VMP) or thalidomide (VTP). The results of this first stage were already published (Mateos et al. Lancet Oncology 2010) and among all the 260 patients included in the trial, VMP and VTP as induction regimens yielded similar overall responses rate (80% and 81%, respectively). Patients completing the six induction cycles, in absence of disease progression or toxicity, moved to the second stage, in which each of the arms were equally randomly assigned to maintenance therapy with bortezomib plus prednisone (VP) or bortezomib plus thalidomide (VT). Maintenance consisted of one conventional cycle of bortezomib (1.3 mg/m2 on days 1, 4, 8 and 11) every 3 months, plus either oral prednisone 50 mg every other day or oral thalidomide 50 mg daily, for up to 3 years. We report the results of this second stage of the trial comparing VT with VP for up to three years as maintenance following induction with VMP or VTP.178 out of 260 patients were randomized to receive VT or VP. Concerning baseline characteristics, both groups were well balanced, including the response status at the moment of randomization to maintenance (23% of patients were in CR in VT arm and 20% in VP arm). Median follow-up after randomization to maintenance therapy was 34 months (8–54). Overall, maintenance therapy resulted in an improvement of the depth of response and the IF-CR rate was increased from 24% after induction up to 42%. Although no significant differences were observed between VT and VP, the IF-CR rate was slightly higher for VT versus VP (46% versus 39%). For all patients receiving maintenance therapy, the median progression free survival (PFS) from initiation of treatment was 35 months (95% CI 29–39) and the median overall survival (OS) 60 months (95%C CI 51–69). From the randomization to maintenance therapy, the median PFS was 30 months (95% CI 21–39) for patients receiving VT and 24 months (95% CI 15–33) for those receiving VP (p=0·1). The slight benefit of VT versus VP as maintenance was independent of the type of induction therapy (VMP or VTP) (p=0·9). No differences in overall survival from this timepoint for VT and VP arms were observed (HR 1·4, 95% CI 0·8–2·4). Concerning safety profile, grade 3 or higher hematological toxicity was recorded only as neutropenia in one patient (1%) in each arm and grade 1–2 occurred in less than 5% of patients (3% and 2% of patients in VT arm developped neutropenia and thrombocytopenia, respectively; and 1% of anemia in VP arm). Concerning non-hematological toxicity, although more of the side effects were of grade 1–2 in both arms, their incidence was superior for VT as compared with VP arm (p=0·0001). Of note, seven patients (7%) in VT arm developped cardiac events, consisting on bradycardia (2 pts), tachycardia (2 pts), heart attack (2 pts) and cardiac failure (1 pt), while only one patient in VP arm. Gastrointestinal toxicity, as constipation or paralitic ileus, was reported in 11 patients (11%) in VT and 3 patients (3%) in VP arm. Grade 3–4 peripheral neuropathy was observed in 9 patients (9%) in VT and 3 (3%) in VP arm.In summary, VT or VP as maintenance therapy resulted in a substantial increase in complete response rate, from 24% after induction to 42%, which can not be attributed to thalidomide or prednisone single agents but to their combination with bortezomib. In terms of CR, PFS and OS, although no significant differences between VT and VP were observed, a trend to better outcome for VT patients was observed, with a PFS that is one of the longest so far reported for elderly MM patients (39 months from diagnosis). However, VT arm was also associated with a higher incidence of non-hematological toxicity. These regimens, including bortezomib-based induction schemes that use weekly dosing of bortezomib, followed by bortezomib-maintenance schemes represent a platform for further optimisation of the treatment for elderly patients with multiple myeloma through use of lenalidomide instead of thalidomide by reducing adverse events and potentially improving the efficacy. Disclosures:Mateos:Celgene: Honoraria; Janssen-Cilag: Honoraria. Off Label Use: BORTEZOMIB, THALIDOMIDE AND PREDNISONE ARE NOT APPROVED FOR THE MAINTENANCE THERAPY.

Helical TomoTherapy in the Treatment of Anal Cancer: Treatment Planning and Acute Toxicity Data

Helical TomoTherapy in the Treatment of Anal Cancer: Treatment Planning and Acute Toxicity Data

Phase II study of topotecan and bevacizumab in advanced refractory non-small cell lung cancer (NSCLC).

7563 Background: Bevacizumab in combination with carboplatin and paclitaxel improves survival of patients with NSCLC in a first-line setting. We hypothesized that non-cross-resistant, second-line salvage therapy with the topoisomerase 1 inhibitor, topotecan, in combination with bevacizumab would have activity in NSCLC. Methods: Forty-two patients were enrolled between 10/2006-9/2010. Patients received topotecan 4.0 mg/m2 on days 1, 8 and 15 and bevacizumab 10 mg/kg on days 1 and 15 as IV infusions. Treatment was repeated every 28 days in the absence of disease progression or unacceptable toxicity. Eligibility criteria included age older than 18 years, ECOG PS of 0-1, and adequate organ function. Patients with treated brain metastases were permitted to enter this study. Response assessment (using RECIST) was performed every two cycles. Primary endpoint of this study was progression-free survival (PFS). Results: Forty-two patients were enrolled in the study. Median age was 60.6 years (range = 36-81). Patients had a median of 3 prior treatment regimens (range 1-7), and 93% had prior platinum therapy. The primary objective of PFS was 238 days (95% CI, 117-332 days). Overall survival (OS) was 345 days (95% CI, 213-464 days). Response rates were as follows: 14.3% partial response (PR), 54.8% stable disease (SD), 28.6% progressive disease (PD). Grade 3 hematologic toxicities seen in participants included thrombocytopenia (16.7%), neutropenia (9.5 %), and anemia (4.8%). There was no grade 4 or higher hematologic toxicities. Only one toxic death, due to pulmonary hemorrhage, occurred during the study. The only grade 4 toxicity was a pulmonary embolism in one patient. Grade 3 non-hematologic adverse events were minimal (<8%) and included: hyperglycemia, bone pain, gastroesophageal reflux, diarrhea, infection, shortness of breath, bowel obstruction, DVT, abdominal pain, pseudogout, and SVC thrombosis. Conclusions: The combination of bevacizumab and topotecan as a salvage therapy for metastatic NSCLC appears to be well tolerated and provides significant progression-free survival. A randomized trial should be performed to compare this combination with other NSCLC regimens.

Pentostatin and rituximab therapy for previously untreated patients with B‐cell chronic lymphocytic leukemia

The combination of pentostatin (P), cyclophosphamide (C), and rituximab (R) achieved an overall response (OR) rate >90%, with >40% complete responses (CRs) in patients with untreated chronic lymphocytic leukemia (CLL). To evaluate whether the tolerability of this regimen could be enhanced without sacrificing efficacy, a phase 2 trial was conducted of P and R without C, using a higher P dose (4 mg/m(2)). Among the 33 patients enrolled, 82% were male, the median age was 65 years (9 patients were aged >or=70 years), and 64% were classified as having Rai stage III to IV disease. The OR rate was 76%, with 9 CRs (27%), 5 nodular partial responses, and 11 partial responses (PRs) reported. At the time of last follow-up, 29 of 33 patients were still alive at a median follow-up of 14 months (range, 1-34.8 months). Four (12%) patients experienced grade 3 or higher hematologic toxicity, and 5 (15%) experienced grade 3 or higher nonhematologic toxicity. Comparison of this trial with the previous PCR trial demonstrated that patients treated with PCR had a higher OR rate (91% vs 76%) and CR rate (41% vs 27%) compared with patients treated with PR. The median treatment-free survival for all accrued patients was notably longer in patients treated with PCR compared with PR (30 months vs 16 months). The findings of the current study suggest that increasing the dose of the purine nucleoside analogue does not eliminate the need for cyclophosphamide in chemoimmunotherapy for the treatment of CLL.

Clinical Experience of Decitabine in Elderly Patients with Myelodysplastic Syndromes (MDS).

Abstract 2792 Poster Board II-768 Background: Decitabine, a potent DNA hypomethylating agent, has demonstrated efficacy in MDS patients. The incidence of MDS increases with age, with limited treatment options for these patients. With advancing age, patients are generally less tolerant of treatment and suffer from more comorbidities. Important goals of therapy are to improve transfusion dependence and to delay progression of disease, with favorable toxicity. This subgroup analysis evaluated the effect of decitabine on overall response rate (ORR), duration of response, time to response, transfusion independence, and tolerability in subgroups of older patients (65-75 and &gt;75 years of age). Methods: Data used in these analyses were from two previously published clinical trials (Steensma et al. J Clin Oncol, 2009 [DACO-020] and Kantarjian et al. Cancer 2006 [DACO-007]). In both trials, eligible patients were ≥18 years of age and had MDS (de novo or secondary) of any French-American-British subtype and an International Prognostic Scoring System score ≥0.5. In DACO-020, patients were treated with decitabine 20 mg/m2 IV daily for 5 consecutive days every 4 weeks. Response rate was assessed with the International Working Group (IWG 2006) criteria in DACO-020. In DACO-007, patients were treated with decitabine 15 mg/m2 IV over 3 hours every 8 hours for 3 consecutive days every 6 weeks. Response rate was assessed with the IWG 2000 criteria in DACO-007. Results: In DACO-020, baseline disease characteristics were generally similar between groups, except more patients in the 65-75 age group (n = 58) had RARS (19% vs. 4%) or RAEB (50% vs. 38%) and fewer had RA (12% vs. 38%) compared to patients in the &gt;75 age group (n = 26). Further, more patients in the &gt;75 group were transfusion dependent at baseline (77% vs. 57%). Grade 3-4 anemia, leukopenia, neutropenia, and thrombocytopenia were less frequent (22, 5, 35, and 22%, respectively) in patients in the 65-75 age group versus patients in the &gt;75 age group (27, 8, 46, and 35%, respectively). Remarkably, however, there were no reports of febrile neutropenia in &gt;75 age group (26% in the 65-75 age group). Conclusions: In this subgroup analysis, decitabine is an effective and generally well tolerated treatment strategy, even in elderly patients with MDS. Despite the advanced age, responses were more rapid and more durable in the mature elderly than younger patients. The slightly higher hematological toxicity did not translate into increased infectious risk, with no febrile neutropenic episodes in patients over age 75 in these studies. These data suggest that the goals of therapy do not need to be stratified by age, and support future trials of decitabine in elderly and other at-risk populations with MDS. Disclosures: Geils: Eisai Inc. : Speakers Bureau.

Feasibility and toxicity of docetaxel before or after fluorouracil, epirubicin, and cyclophosphamide as adjuvant chemotherapy for early-stage breast cancer

604 Background: As adjuvant chemotherapy for breast cancer, the addition of docetaxel to regimens containing anthracyline has been shown to be effective. However, tolerance and safety associated with the administration order of the two drugs have not been evaluated. Methods: Breast cancer patients with node-positive or high-risk patients with node-negative were eligible. The treatment completion rate and toxicity were evaluated in 2 arms who underwent a total of 6 courses of the following regimens: Arm A: 3 courses of fluorouracil 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 (FEC100: q3w) followed by 3 courses of docetaxel (DOC100: 100 mg/m2, q3w); and Arm B: 3 courses of DOC100 (q3w) followed by 3 courses of FEC100 (q3w). Results: June 2006 to April 2008, 42 patients were registered. To the present, analysis has been completed in 21 patients in arm A and 21 in arm B. The mean age of patients was 49.1 years and 53.8 years, respectively. In arm A, the stage of cancer was 1 in 4 patients, 2a in 10, and 2b in 7, in arm B, the stage of cancer was 1 in 3 patients, 2a in 9, and 2b in 9. The adjuvant chemotherapy completion rate was 100 % for arm A and 95.2 % for arm B. The relative dose intensity (RDI) was 94.2 % for FEC100 and 97.8 % for DOC100 in arm A, and 98.9 % for DOC100 and 95.2 % for FEC100 in arm B. In arm A, grade 3 or higher hematological toxicity was observed in 9 patients, and febrile neutropenia developed in 3 patients with FEC100. In arm B, grade 3 or higher hematological toxicity was observed in 7 patients, but febrile neutropenia was not noted in any patients. Grade 3 or higher non-hematological toxicity was observed with FEC100 in 2 patients each in the two arms. Grade 1 or 2 edema developed in 11 patients with DOC100 in the two arms. Conclusions: In both arm A and B, adverse events associated with FEC100 were frequently observed but spontaneously recovered, or adequate management was possible by supportive therapy. Adverse events associated with DOC100 were mild. The regimens in both arms A and B were safe regarding adjuvant chemotherapy for early stage breast cancer. However, DOC100 followed by FEC100 may be more tolerable and effective. No significant financial relationships to disclose.

A phase II, randomized trial of neo-adjuvant chemotherapy comparing a three-drug combination of paclitaxel, ifosfamide, and cisplatin (TIP) versus paclitaxel and cisplatin (TP) followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: the Snap-02 Italian Collaborative Study

BackgroundThe efficacy and tolerability of the regimen containing paclitaxel and cisplatin (TP) in the neo-adjuvant treatment of locally advanced squamous cell cervical cancer are unknown. The TIP regimen (TP plus ifosfamide) showed high efficacy but high toxicity and it is used as an internal control. Patients and methodsIn all, 154 patients were randomized to TP (paclitaxel 175 mg/m2 + cisplatin 75 mg/m2; n = 80) or TIP (TP + ifosfamide 5 g/m2; n = 74), three cycles, followed by radical surgery. Pathological response to chemotherapy was classified as optimal [no residual tumor (complete response) or residual disease with ≤3 mm stromal invasion (PR1)] or suboptimal response. ResultsPatient characteristics (TP/TIP): stage IB2 (56%/64%), IIA (18%/14%), IIB (20%/19%), III–IVA (5%/4%) and median age (42 years/45 years). The optimal response rate in the TP group was 25%, 95% confidence interval (CI) = 16% to 37% and 43%, 95% CI = 31% to 55% in the TIP group. Grades 3–4 leukopenia (6%/53%) and neutropenia (26%/76%) were significantly more frequent on TIP. ConclusionTP performance was below expectation since the lower 95% confidence limit of the optimal response rate failed to reach the prespecified minimum requirement of efficacy, i.e. 22%. The TIP regimen confirmed its activity but was associated with higher haematological toxicity than TP.

N9986: a phase II trial of thalidomide in patients with relapsed chronic lymphocytic leukemia

We enrolled 28 eligible patients with relapsed chronic lymphocytic leukemia (CLL) to a phase II study of single agent thalidomide (200 mg/d, with dose escalation up to 1000 mg/d over 60 days). The median age was 66 years and 71% were males. Study participants received a median of 2 (range 1–7) prior treatment regimens and 61% had Rai stage 3–4 disease at enrollment. Grade 3 or higher hematologic toxicity was observed in 13 (46%) and 16 (57%) had grade 3 or higher non-hematologic toxicity. Grade 3–4 tumor flare was observed in five (18%) patients. The overall response rate was 11% (3 of 28) with one (4%) complete remission and two (7%) partial remissions. Duration of response for these three responders was 3, 14 and 15 months. Fourteen (50%) patients had stabilisation of disease for a median duration of 8 months (95% CI: 7–16 months). Median time to progression for all 28 patients was 7.3 months. Although thalidomide appears to have modest clinical activity in pretreated/relapsed CLL primarily based on reduction of the absolute lymphocyte count, in our opinion the toxicity profile precludes it from more active investigation in CLL.

Treatment outcomes and prognostic factors in uterine cervical cancer patients treated with postoperative extended field radiation therapy

To evaluate treatment outcomes and prognostic factors in uterine cervical cancer patients treated with postoperative extended field radiation therapy (POEFRT) with or without chemotherapy. Between 1983 and 2006, 35 patients with a pathologically confirmed positive para-aortic node (PAN) or common iliac node (CIN) who underwent a radical hysterectomy with bilateral pelvic lymph node dissection and PAN dissection received POEFRT with (N=23) or without (N=12) chemotherapy. Prognostic factors such as age, stage, size, parametrium invasion, lymphovascular space invasion, nodal station, depth of stromal invasion and use of chemotherapy were analyzed. With a median follow-up of 44 months, the 5-year overall survival (OS), disease-free survival (DFS), distant failure-free survival (DFFS) and loco-regional failure-free survival rates were 51%, 51%, 59% and 93%, respectively. The use of chemotherapy significantly improved the 5-year OS rate (61% vs. 48%, p=0.004), the 5-year DFS rate (54% vs. 38%, p=0.004) and the 5-year DFFS rate (57% vs. 48%, p=0.009). PAN involvement resulted in a compromised 5-year DFS rate (42% vs. 73%, p=0.002) and 5-year DFFS rate (47% vs. 82%, p=0.004) as compared to CIN involvement. Grade 3 or higher hematological toxicity was observed more frequently in patients who received POEFRT combined with chemotherapy as compared to patients who received POEFRT alone (52% vs. 17%, p=0.04). The use of POEFRT resulted in an excellent loco-regional control rate. The addition of chemotherapy may improve outcome in patients who have received POEFRT, but with higher manageable toxicity.