Mean Dose Intensity Research Articles

Prospective analysis of quality of life in elderly patients treated with adjuvant chemotherapy for non-small-cell lung cancer

BackgroundGiven the more comorbidities with a decline in physiologic reserve, it can be challenging to make appropriate treatment decisions in the elderly. Patients and methodsHere, we prospectively evaluated and compared the health-related quality of life (HRQOL) of patients aged ≥65 with aged <65 who were treated with a postoperative chemotherapy for completely resected stage Ib, II or IIIa non-small-cell lung cancer (NSCLC). Either four cycles of paclitaxel (Taxol)–carboplatin (PC) or vinorelbine–cisplatin (NP) was used. The HRQOL was assessed with EORTC QLQ-C30 and EORTC QLQ-LC13. ResultsBetween October 2008 and October 2011, a total of 139 patients (aged <65, n = 73; ≥65, n = 66) were enrolled, and 127 (91.4%) completed the questionnaire. Overall, the quality of life (QOL) in elderly patients did not significantly deteriorate with adjuvant chemotherapy and the time trend of QOL in elderly patients was similar to that of younger patients. Although the elderly suffered from increased treatment-related adverse events involving sore mouth, peripheral neuropathy and alopecia compared with the baseline, the same time trends were also observed in younger group. The mean dose intensities (MDIs) for PC and NP regimen were not significantly different between the two age groups. ConclusionsPostoperative chemotherapy did not substantially reduce HRQOL in elderly NSCLC patients, and HRQOL during and after adjuvant chemotherapy did not significantly differ by age.

Phase II study of weekly cabazitaxel for "unfit" metastatic castration resistant prostate cancer patients progressing after docetaxel treatment: Preliminary toxicity analysis—SOGUG-CABASEM trial.

e16014 Background: Docetaxel (D) is standard first-line chemotherapy in patients (pts) with metastatic castration-resistant prostate cancer (CRPC). Cabazitaxel (C), a novel taxane developed to overcome D resistance, showed an overall survival improvement in second line CRPC in a three-weekly dose schedule. Its main toxicity is hematological with a risk of febrile neutropenia, especially in unfit patients. We aimed to evaluate efficacy and safety of weekly C/prednisone in "unfit" metastatic CRPC previously treated with D. Methods: Unfit pts (ECOG 2, dose reduction due to febrile neutropenia during treatment with D or radiation therapy affecting more than 25% of bone marrow reserve) with advanced CRPC progressing after D treatment with ECOG &lt;=2 and adequate bone marrow, liver and kidney functions were included. C 10 mg/m2 was administered on days 1, 8, 15 and 22 of 5-week cycles with daily prednisone 5 mg b.i.d. Radiological and PSA response was evaluated according to the PCCTWG II criteria and toxicity according NCI-CTC AE. Results: To date 28 pts have been enrolled and data are available for 21. Median age was 74 y (range 60-83), 13 (62%) pts had ECOG 2, 16 (76%) had bone metastases. Sixty-one cycles were administered (median: 3; range: 1-6) and 225 weekly administrations (median 10; range 1-24). Mean dose intensity was 94%. Most frequent related adverse events (AEs) of all grades as % of cycles were: asthenia (40%), anemia (34%), leukopenia (11%), thrombocytopenia (13%), diarrhea (10%), rash (8%), nauseas (8%), dysgeusia (8%), xerostomia (8%), anorexia (7%), mucositis (5%) and neuropathy (3%). Grade 3-4 AEs as % of cycles were: thrombocytopenia (8%), asthenia (7%), mucositis (2%), nausea (2%) and vomiting (2%). One patient discontinued the study due to asthenia G3. No grade III/IV diarrhea, neutropenia or febrile neutropenia were observed. Conclusions: Administration of weekly C (10 mg/m2) to unfit pts seems to be safe with no grade ≥3 neutropenia, diarrhea and febrile neutropenia reported. If confirmed in a larger scale, weekly C may represent an attractive option for unfit pts with mCRPC progressing after D treatment. Clinical trial information: NCT01518283.

A phase II trial of a cremophor-free, polymeric micelle formulation of paclitaxel and gemcitabine in patients with advanced non-small cell lung cancer.

e19129 Background: Non-platinum doublet paclitaxel and gemcitabine has shown efficacy on par with platinum-based doublet regimens as first-line chemotherapy in advanced non-small cell lung cancer patients. Genexol-PM is a Cremorphor EL(CrEL)-free polymeric micelle formulation of paclitaxel. This study was designed to evaluate the efficacy and safety of Genexol-PM and gemcitabine combination in advanced non-small cell lung cancer patients. Methods: This is a single-arm, single-center phase II study. Patients with advanced NSCLC received Genexol-PM at 230mg/m2 on day 1 and gemcitabine 1000mg/m2 on day 1 and day 8 of a 3-week cycle as first-line chemotherapy. Six cycles of chemotherapy were administered unless there is a disease progression. The primary endpoint was response rate. Results: Forty-three patients received the study drugs with median of 4 cycles per patient (range, 1-6). Among 35 patients who received more than one cycle, mean dose intensity of CrEL-free paclitaxel and gemcitabine was 209 mg/m2/3-week and 1,853 mg/m2/3-week respectively. Overall response rate was 46.5%. The median progression free survival was 4.0 months (95% CI 2.0-6.0 months) and median overall survival was 14.8 months (95% CI 9.1-20.5 months). 18 patients (51%) experienced grade 3/4 adverse events, including neutropenia or febrile neutropenia (n=7), pneumonia (n=3), asthenia (n=3), peripheral neuropathy (n=2), diarrhea (n=1), skin rash (n=1), myalgia (n=1), pulmonary thromboembolism (n=1), LV dysfunction (n=1), and dyspnea with sudden death (n=1). Adverse events leading to drug discontinuation were occurred in 9 patients, among which 2 patients were died of adverse events (pneumonia, dyspnea with sudden death). Conclusions: CrEL-free paclitaxel in combination with gemcitabine demonstrated comparable antitumor activity with less emetogenicities in non-small cell lung cancer patients. Clinical trial information: NCT01770795.

Abstract P1-12-05: First-line chemotherapy with pegylated liposomal doxorubicin versus capecitabine in elderly patients with metastatic breast cancer: results of the phase III OMEGA study of the Dutch Breast Cancer Trialists' Group (BOOG)

Abstract Background The efficacy and feasibility of chemotherapy in elderly metastatic breast cancer (MBC) patients (pts) have been studied in various phase II studies. However, results of prospective randomized studies in elderly MBC pts are scarce. Methods In this phase III multicenter study, MBC pts ≥ 65 years eligible for first-line chemotherapy were randomized between pegylated liposomal doxorubicin (PEGdoxo) (45mg/m2, IV, q 4 wks) or capecitabine (Cape) (1000 mg/m2 PO bid, days 1–14, q 3 wks). Other eligibility criteria were ECOG performance status (PS) ≤ 2 (3 allowed if due to pain or pre existing comorbidity), adequate bone marrow and organ functions. Stratification factors were PS (0–1 vs 2–3), HER2 status, visceral/non-visceral disease, adjuvant hormonal therapy (HTx), and HTx for MBC. Baseline geriatric assessment (GA) included functional status, instrumental activities of daily living, cognition, mood, comorbidity, polypharmacy and nutritional status. Chemotherapy was continued for 24 wks in the absence of progressive disease (PD) or unacceptable toxicity. Primary endpoint was progression-free survival (PFS), secondary endpoints were response rate, overall survival (OS), toxicity (CTC criteria) and compliance. Results Between April 2007 and August 2011, 78 pts were randomized to PEGdoxo (n = 40) or Cape (n = 38). The study was prematurely closed due to slow accrual and supply problems with PEGdoxo. Mean age was 74 years (range 65–86; 75+ 54%; 80+ 13%). Pt characteristics were balanced between the two arms: PS 0–1 77%, ER+ 68%, HER2+ 5%, visceral/non-visceral disease 76%/24%, adjuvant HTx 46%, HTx for MBC 56%, ≥ 3 metastatic sites 50%. Only 22 out of 75 pts with a baseline GA had no geriatric condition (29%), while 32 pts (43%) and 21 pts (28%) had one or ≥ 2 geriatric conditions, respectively. Chemotherapy was given for 6 months in 38%, with a mean dose intensity of 84% in both arms. Reasons for early treatment discontinuation were: PD (31%), toxicity (28%), pt withdrawal (3%). After a median follow up of 32 months, 74 pts had PD and 56 pts had died. The median PFS was 5.7 and 7.7 months with PEGdoxo and Cape (HR 0.68, 95% CI: 0.42–1.11, p = 0.12) and the median OS was 13.8 and 16.8 months, respectively (HR 0.84, 95% CI: 0.49–1.42, p = 0.51). Response was evaluable in 64 pts, with a partial response (PR) in 7 (21%) and 6 pts (19%), and stable disease in 21 (64%) and 17 pts (55%) for PEGdoxo and Cape, respectively. Toxicity was acceptable, mainly being grade 1–2, with for PEGdoxo/Cape grade 1 alopecia in 14/4 pts (grade 2 in 1 PEGdoxo pt), grade 3 fatigue in 5/5 pts, grade 3 HFS in 4/6 pts and grade 3 mucositis in 4/1 pts, respectively. Pts with ≥ 1 geriatric condition more frequently experienced grade 3–4 toxicity, after correcting for type of chemotherapy, age and PS (HR 2.24, 95% CI: 1.21–4.16). Pts aged 75+ had a twofold higher risk of dying, irrespective of treatment arm (HR 2.31, 95% CI: 1.31–4.07). Conclusions First-line chemotherapy with either PEGdoxo or Cape was feasible in elderly MBC pts, with adequate dose intensity and acceptable toxicity, even in non-fit pts or pts aged 75+. Baseline GA correlated with toxicity. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-12-05.

1040P - The Impact of Induction Chemotherapy on Cisplation Dose Intensity During Chemo-Radiotherapy (CTRT) in Oropharyngeal Squamous Cell Cancer (OPC)

ABSTRACT Background Induction (IC) with TPF (Taxotere, Cisplatin, 5-FU) has been associated with improved outcome in advanced head and neck squamous cell cancer patients (pts). Full dose of cisplatin (300 mg/m2) during CTRT has been demonstrated to impact on patients' outcome. The aim of the current study is to investigate whether the IC could impact on cisplatin dose intensity during CTRT in a homogeneous population of OPC. Materials and methods The study population consisted of 101 pts with stage III-IV OPC treated from 07/2004 to 12/2011 with IC (n = 53) plus CTRT or CTRT alone (n= 48). IC consisted of TPF, while weekly 50 mg/m2 or 3-weekly 100 mg/m2 cisplatin was administered concurrently with RT (planned chemotherapy dose = 300 mg/m2; planned RT dose = 66-70 Gy, 3DRT or IMRT with a conventional or accelerated fractionation). Carboplatin substituted cisplatin in case of creatinine clearance less than 60 mL/min. HPV status, concurrent cisplatin dose intensity and RT overall treatment time (OTT) were analyzed. Results Stage IV pts were 100% in the IC group and 83% in CTRT, while HPV positive OPCs were detected in 58% and 63% of the cases respectively. TPF median number of cycles was 3, with induction cisplatin median dose administered of 200 mg/ m2. RT median total dose administered was 70 Gy in both group. Accelerated fractionated RT was adopted in 65% of CTRT alone group and in 21% of IC group. Two pts (1 in each group) did not complete CTRT because of cardiovascular events. Mean and median dose intensity of cisplatin concurrent to RT in the IC group was 77.7% and 75% (35%-100%) while in CTRT group was 86% and 91.7% (33%-100%), with a p value = 0.014. In 11 pts (21%) treated with IC and only in 1 pts (2%) treated with CTRT alone cisplatin was substituted with carboplatin. No different cisplatin dose intensity was identified in HPV positive versus HPV negative cases. Prolonged OTT (longer than 5 days) was observed in two patients in IC group due to sepsis and severe mucositis as well as in one patient in CTRT group due to machine failure. Conclusions Concurrent cisplatin dose intensity was significantly reduced in pts receiving IC compared to CTRT alone, irrespective of HPV status. Whether this has an impact on the results of IC followed by full dose CT/RT has to be clarified. Disclosure All authors have declared no conflicts of interest.

A multicenter randomized controlled trial (RCT) of adjuvant chemotherapy (CT) in nasopharyngeal carcinoma (NPC) with residual plasma EBV DNA (EBV DNA) following primary radiotherapy (RT) or chemoradiotherapy (CRT).

5511 Background: The benefit of adjuvant CT in NPC is unclear. Administering CT after full-dose CRT presents challenges in treatment compliance and toxicity. Post-RT EBV DNA predicts poor survival and may be a biomarker of subclinical residual disease. We conducted a biomarker driven RCT using EBV DNA to select high risk NPC patients (pts) for adjuvant CT while sparing low risk pts from unnecessary toxicity. Methods: Biopsy proven NPC, AJCC stage IIB-IVB, detectable EBV DNA at 6-8 wks post-RT, no persistent locoregional disease or distant metastasis, ECOG 0 or 1, adequate organ function. Randomised with stratification for primary therapy (RT Vs CRT) and tumor stage (II/III Vs IV) to arm A (adjuvant cisplatin 40 mg/m2 and gemcitabine 1000mg/m2, both given on D1+8 q3w x 6 cycles) or arm B (clinical follow-up). EBV DNA and PET scan were performed before and 6 months after randomization. Primary endpoint was relapse free survival and secondary endpoints included toxicity of adjuvant CT. With a hazard ratio of 2, 100 pts were required with a power of 0.8 and an alpha at 0.05. This safety analysis was approved by DMSC. Results: From 9/2006 to 12/2011, 514 pts consented for EBV DNA screening, 95 with detectable EBV DNA consented for adjuvant study. After work-up, 74 were eligible for randomization (37 to arm A; 37 to arm B). The two arms were well balanced in baseline characteristics. 80% received prior neoadjuvant and/or concurrent CT. Staging: IIB (36.5%), III (29.7%), IVA (18.9%), IVB (14.8%). Five pts refused adjuvant CT after randomization. Overall 65% and 57% completed 5 and 6 cycles respectively. Mean dose intensity (DI): 84% for cisplatin (22.5 mg/m2/wk, range 0.0-26.7), 92% for gemcitabine (612.8 mg/m2/wk, range 333.3-777.8). Treatment related adverse events above CTC G2 were summarized in Table. Conclusions: Delivery of 6 cycles of adjuvant CT is feasible with acceptable toxicity after full dose RT or CRT. [Table: see text]

Abstract 5754: Temozolomide therapy for progressive metastatic paraganglioma/pheochromocytoma: SDHB mutation as a prognosis biomarker for efficacy

Abstract Malignant pheochromocytoma and paraganglioma (PPGLs) are rare diseases with a heterogeneous behaviour. Nowadays systemic therapies, including 131I-MIBG therapy and the cyclophosphamide-dacarbazine-vincristine chemotherapy regimen (CVD), constitute the most popular options in case of aggressive tumors. We have investigated the antitumor effect of temozolomide (TMZ), in patients with metastatic PPGLs. All patients were assessed for TMZ efficacy, with CT scan and PET scan performed every 3 months. Safety and identification for prognosis factors of response were secondary endpoints. Fifteen consecutive patients with progressive (n=14) or symptomatic (n=1) metastatic PPGLs began TMZ therapy at our institution between November 2007 and January 2011. There were 12 men (80%); median age was 43 years, with a functioning tumor in 73% of the cases. Germline mutations were screened: 10 patients harbored SDH B mutation and 5 patients had no mutation among SDH A, SDH C, SDH D, NF1, RET or VHL genes. Primary was located in the adrenal gland for 53% of the patients, thorax for 40 % and neck for 7%. TMZ was given at a dose of 150 mg/m2/d for five days of a 28-days cycle for the first cycle and then at 200 mg/m2 for five days each subsequent cycle. Seven patients received TMZ as first line therapy, 2 patients as second line and 6 patients as third line. Median number of cycle administered was 7, mean dose intensity was 171 mg/m2 (95% CI 160.7-181) for each treatment cycle. TMZ was well tolerated: the most frequent all grade toxicities included asthenia, nausea and anemia. Grade 3 toxicities were lymphopenia (n=2) and hypertension (n=1). According to RECIST 1.1 criteria, 11 patients were evaluable: 4 patients experienced a partial response, 6 a stable disease, 1 patient a progressive disease. With a median follow up of 29 months (range 6.4-37.9), median overall survival was not reached and median progression free survival (PFS) was 9.6 months. Partial response was observed in 4 out of 10 SDHB mutated patients but no sporadic case. Patients with SDH B mutations or with no mutation had a median PFS of 16.7 months or 2.6 months, respectively (log-rank, p=0.013); Patients with SDH B mutations or with no mutation had a 12-month PFS of 60% or 0%, respectively. Expression of Methyl Guanine Methyl Transferase (MGMT) by immunohistochemistry (IHC) was analyzed in 4 patients, including 3 responders and, was found negative. MGMT IHC is ongoing in the remaining patients This study demonstrates for the first time the antitumor efficacy of TMZ in a large series of metastatic PPGLs as well as the potential role for SDH B mutation as a prognosis biomarker of response of response. Loss of MGMT expression in SDH B mutated patients could explain these results. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5754. doi:1538-7445.AM2012-5754

Initial safety report of ACTS-CC trial (TRICC0706): A randomized phase III trial of UFT/LV versus S-1 as adjuvant therapy for stage III colon cancer.

3561 Background: The ACTS-CC trial is a phase III trial designed to validate non-inferiority of S-1 to UFT/ LV, a standard treatment in Japan as adjuvant chemotherapy for stage III colon cancer. We report the results of an interim analysis of safety of these treatments in this trial. Methods: Patients with stage III colon cancer and a PS of 0-1 who underwent curative surgery were randomly assigned to receive UFT/LV (UFT: 300 to 600 mg/day according to BSA and, LV: 75 mg/day on days 1 to 28, followed by 7 days rest, 5 courses) or S-1 (80, 100, or 120 mg/day according to BSA on days 1 to 28, followed by 14 days rest, 4 courses). We analyzed clinicopathological features, treatment status and safety. Results: Among 1,535 enrolled patients between Apr. 2009 and Jun. 2010, we excluded 31 patients who had duplicate registration, withdrew informed consent, or did not receive the assigned treatment. 1,504 patients (756 in S-1 group, 748 in UFT/LV group) were included in this analysis. Totally, the mean age at enrollment was 64.5 years, the male:female ratio was 1.2:1, wide lymph node dissection (D3) was done in 80% and the median number of dissected lymph nodes was 17. The completion rate of the protocol treatment was 75% (77% in S-1 group, 73% in UFT/LV group), and 18% of patients discontinued treatment within 2 courses. Treatment was discontinued because of adverse events (AEs) in 18% (18% in S-1 group, 18% in UFT/LV group). The mean dose intensity (actual cumulative dose received/total dose according to the protocol) was 82% in S-1 group and 81% in UFT/LV group, including the patients who discontinued treatment because of recurrence. The overall incidences of AEs in S-1 group and UFT/LV group were 80% and 74%: 33% and 27% for anemia, 32% and 25% for anorexia, 27% and 13% for pigmentation, 26% and 23% for hyperbilirubinemia, 23% and 24% for diarrhea, 19% and 14% for stomatitis, 15% and 20% for AST, and 13% and 21% for ALT, respectively. Conclusions: Although AE profiles differed between S-1 group and UFT/LV group in this trial, AEs were acceptable, and the completion rate of the protocol treatment was high. Both S-1 and UFT/LV could be safely used as adjuvant therapy.

The impact of dose intensity on the efficacy of gemcitabine plus carboplatin (GC) therapy for recurrent platinum-sensitive ovarian cancer (PSOC): A retrospective analysis of AGO-OVAR 2.5.

5088 Background: The gemcitabine plus carboplatin combination (GC) is known to provide a clinical advantage compared to single-agent C for patients (pts) with recurrent PSOC. Dose reductions and delays for toxicity are common during standard GC therapy. To evaluate the potential impact of G and C dose adjustments on clinical outcomes in pts with PSOC, we retrospectively analyzed dose intensity (DI) data from the phase III trial AGO-OVAR 2.5. Methods: Data analyses were performed for 175 GC-treated pts. G and C weekly DIs were calculated as the mean dose of drug received divided by the planned weekly dose for each pt through each cycle of treatment. Progression-free survival (PFS) and response rate (RR) were compared across G DI groups for pts who received 6 cycles using the log-rank test and Fisher’s exact test, respectively To reduce the bias of time dependence, we examined subsequent PFS after cycle 2 stratified by G DI within the first 2 cycles (in pts who received >2 cycles). Results: A total of 99 pts (56.6%) completed 6 cycles. The mean weekly G DI ranged from 89.5% at cycle 1 to 73.0% at cycle 6; the mean weekly C DI ranged from 99.5% at cycle 1 to 91.5% at cycle 6. Results for pts receiving either 6 cycles or >2 cycles are shown in the table. There were no significant differences across G DI groups for either PFS (P=0.199) or RR (P=0.537) for pts receiving 6 cycles or for subsequent PFS (P=0.249) when pts were grouped by G DI within the first 2 cycles. Comparisons of G and C DI based on the numbers of cycles completed (up to 8) also showed no significant differences in PFS or RR. Conclusions: Differences in DI of both G and C for pts receiving from 2 to 8 cycles of standard GC chemotherapy had no impact on either PFS or RR in the AGO-OVAR 2.5 trial. Protocol-specified dose adjustments do not appear to impact the efficacy of GC therapy for pts with PSOC. Patients receiving 6 cycles (n=99) Patients receiving >2 cycles (n=158) Mean DI of G by quartile N RR P Median PFS (months) P N Median PFS (months) P DI <25th percentile 25 64% 0.537 11.5 0.199 39 9.1 0.249 25th percentile ≤ DI < median 24 50% 8.9 39 8.4 Median ≤ DI <75th percentile 25 64% 10.0 40 6.4 DI ≥75th percentile 25 48% 7.6 40 7.7

Pemetrexed Safety and Pharmacokinetics in Patients with Third-Space Fluid

Pemetrexed is established as first-line treatment with cisplatin for malignant pleural mesothelioma and advanced nonsquamous non-small-cell lung cancer (NSCLC) and as single-agent second-line treatment for nonsquamous NSCLC. Because the structure and pharmacokinetics of pemetrexed are similar to those of methotrexate, and methotrexate is associated with severe toxicity in patients with third-space fluid (TSF), the safety of pemetrexed in patients with TSF was evaluated. Patients with TSF (pleural effusions, ascites) and relapsed, stage III/IV NSCLC or malignant pleural/peritoneal mesothelioma were treated with pemetrexed (500 mg/m2) on day 1 of each 21-day cycle. TSF was drained at any time only if clinically indicated. Plasma samples were collected during cycles 1 and 2 to compare pemetrexed concentrations with reference data from patients without TSF. Thirty-one patients with TSF received 123 pemetrexed doses (median, 4 cycles per patient; range, 1-11; mean dose intensity, 97.5%). Seven grade 3/4 drug-related toxicities, including four hematologic, were reported; there were no treatment-related deaths. There was no correlation between TSF amount and type, number, and sequelae of toxicities. Pemetrexed plasma concentrations were within the range of those in patients without TSF. Pemetrexed clearance and central volume of distribution were not statistically different between patients with and without TSF. No clinically relevant alterations of pemetrexed pharmacokinetics occurred in patients with TSF. Pemetrexed was well tolerated; toxicities were expected and manageable. The standard pemetrexed dose recommendations were adequate for patients with TSF in this study. These data suggest that draining TSF before administering pemetrexed is unnecessary.

Comprehensive IMRT plus weekly cisplatin for advanced head and neck cancer: The University of Wisconsin experience

We retrospectively examined the treatment efficacy and toxicity profile of intensity-modulated radiotherapy (IMRT) plus concurrent weekly cisplatin chemotherapy in patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC). A total of 57 patients with stage III or IV HNSCC were treated with IMRT and concurrent weekly cisplatin (dosed at 30 mg/m(2)) between November 2001 and May 2007. The median prescription dose to the gross tumor volume was 70 Gy (using 2.0-2.2 Gy daily fractions). In-field tumor control at 2 years was 89.1%, locoregional control was 85.5%, and overall survival was 86.9%. The median radiation dose delivered was 70 Gy. The mean dose intensity of cisplatin administered was 25.7 mg/m(2)/week. Comprehensive head and neck IMRT to 70 Gy delivered with weekly cisplatin chemotherapy (30 mg/m(2)) is feasible and generally well tolerated.

Efficacy and safety of capecitabine in combination with docetaxel and mitomycin C in patients with pre-treated pancreatic, gallbladder, and bile duct carcinoma

Preclinical data indicate the improvement of the antitumor activity of capecitabine by mitomycin C and docetaxel through upregulation of thymidine phosphorylase activity. Therefore, we have established a combination regimen of these drugs (DocMitoCape), which demonstrated preliminary activity especially in bile duct and pancreatic carcinoma. Here we report the safety and efficacy of the DocMitoCape regimen in pre-treated patients with gallbladder, bile duct, or pancreatic carcinoma. Treatment consisted of capecitabine (2,000 mg/m(2) days 1-14) in combination with docetaxel (40 mg/m(2) day 1) and mitomycin C (4 mg/m(2) day 1). Cycles were repeated on day 22. Toxicity was graded according to NCI-CTC criteria, and the antitumor activity was assessed by RECIST criteria. Twenty-eight pre-treated patients with a median age of 59 suffering from pancreatic, gallbladder, intra- (IHCCC) or extrahepatic (EHCCC) bile duct carcinoma were included. Eleven patients had received ≥2 lines of prior chemotherapy. A total of 183 and a median of six cycles were administered (range 1-21). The mean dose intensity was as follows (cycles 1-2/3-4; %): capecitabine 97/92, docetaxel 100/100, mitomycin C 99/100. Main adverse events grades 2/3/4 were (n): leukocytopenia 3/2/2, anemia 13/4/0, thrombocytopenia 3/1/0, nausea/vomiting 2/1/0, diarrhea 5/1/0, hand-foot-skin reaction 7/0/0. Six patients achieved partial and seven patients minor remissions, while six patients had stable disease adding to a tumor control rate of 68%. Median progression-free and overall survival was 4.5 (range 1.0-44.9) and 6.8 months (range 1.5-44.9), respectively, calculated from the start of treatment. In all, the DocMitoCape regimen exhibited a favorable safety profile and a high rate of tumor stabilizations in patients with pre-treated gallbladder, bile duct and pancreatic carcinoma. It might be considered after failure of standard regimens in these types of cancer.

Preliminary Toxicity Results of a Phase II Randomized Trial of Weekly or Every 3-Week Ixabepilone in Metastatic Breast Cancer (MBC).

Abstract Background: Epothilones, including ixabepilone, have demonstrated antitumor activity in a wide range of chemonaïve and chemo-resistant cancer models. This study was conducted to determine efficacy and toxicity of the weekly schedule (weekly x 3 w/ no dosing in Week 4) compared to the every 3-week schedule in MBC patients.Patients and Methods: Patients with HER2-negative MBC that was measurable, or nonmeasurable with serum CA27.29 (or CA15.3) ≥50, performance status (ECOG 0-2) with no limit on prior chemotherapy were enrolled. Any existing peripheral neuropathy must have been ≤Grade 1. Treatment: Patients were randomly assigned to receive ixabepilone 16 mg/m2 IV over 1-hour on Days 1, 8, and 15 of each 28-day cycle (Arm 1), or 40 mg/m2 IV over 3-hours on Day 1 of each 21-day cycle (Arm 2). Toxicity was assessed and graded at every visit using the NCI CTCAE v3. Disease was assessed every 12 weeks during treatment.Results: 173 patients enrolled to date out of a planned accrual of 176 patients (85 in Arm 1 and 88 in Arm 2); median follow-up was 3.8 and 3.48 months, respectively. Median age [range] was 60 [37-79] in Arm 1 and 57 [39-80] in Arm 2, respectively. ECOG PS 2 was ∼7% in both treatment arms, all others were 0 or 1. Most patients had received prior chemotherapy for MBC (Arm 1/Arm 2: 1 or more prior regimens 74%/73%), and/or hormonal therapy. Prior adjuvant/neoadjuvant therapy had been received by 53% and 73% of patients in Arms 1 and 2, respectively. Prior anthracyclines had been administered to 61% and 76% in Arms 1 and 2, respectively, while taxanes had been administered to 69% and 75%, respectively. Hormone receptor status ER/PR Arm 1/Arm 2: +/+ 56.5%/44%, +/- 15%/18%, and -/- 20%/24%. Dosing: Arm 1 received a mean dose of 14.8 mg/m2, whereas Arm 2 received 37.2 mg/m2 over a median of 3 28-day cycles and 4 21-day cycles, respectively. Mean dose intensity was 93% in both arms. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 22% (Arm 1) and 57% (Arm 2) of patients; serious adverse events occurred in 28% and 36% of Arm 1 and Arm 2 patients, respectively. Grade 3-4 TR neutropenia occurred in only 5% of Arm 1 patients, but was 33% in Arm 2; febrile neutropenia was limited to 1 patient in Arm 2 (Grade 3). Other Grade 3-4 TRAEs in &amp;gt;5% of patients (Arm 1/Arm 2) were: fatigue (5%/16%), neuropathy (5% [4% Grade 3, 1% Grade 4]/14% [∼13% Grade 3, 1% Grade 4]), dehydration (1%/10%), and vomiting (0%/6%). Discontinuations due to TRAEs were 7% in Arm 1 and 14% in Arm 2. Growth factor use was limited to 2 patients (2%) in Arm 2, due to anemia. Most deaths were due to PD.Conclusion: Both schedules have an acceptable safety profile. Preliminary safety results show the every 3-week ixabepilone schedule resulted in more adverse events than the weekly schedule and Grade 3-4 neuropathy occurred less frequently with the weekly dosing. Preliminary ORR, PFS, and OS will be reported.Supported, in part, a research grant from Bristol-Myers Squibb, Princeton, NJ. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6099.

Lenalidomide plus Dexamethasone Has Similar Tolerability and Efficacy in Treatment of Relapsed/Refractory Multiple Myeloma Patients with or without History of Neuropathy.

Abstract 3873Poster Board III-809 BACKGROUNDNeuropathy in multiple myeloma, related either to the disease itself or as a result of anti-myeloma treatment, may limit patients' therapeutic options. AIMSTo assess efficacy and safety of lenalidomide + dexamethasone treatment in relapsed/refractory multiple myeloma patients depending on reported neuropathy history. METHODSThis subanalysis is based on pooled data from two large multi-center randomized placebo-controlled phase-3 trials (MM-009, MM-010), for patients who had received at least one prior therapy of multiple myeloma. Patients were randomized to receive either 25 mg of lenalidomide or placebo on Days 1-21 of a 28-day cycle. Both groups also received 40mg of oral dexamethasone on Days 1-4, 9-12, and 17-20 for the first four cycles, after which dexamethasone was administered only on Days 1-4. All patients who received lenalidomide + dexamethasone during the study period were included in this subanalysis (n=353). Patients with a reported history of neuropathy between time of first multiple myeloma diagnosis and date of study randomization (n=70) were compared to patients without a reported history of neuropathy (n=283). Adverse event terms included were: non-specified neuropathy, peripheral motor neuropathy, non-specified peripheral neuropathy, peripheral sensory neuropathy and non-specified polyneuropathy. Lenalidomide mean and median daily dose intensity, duration of treatment and efficacy [including complete response (CR), very good partial response (VGPR), time to progression (TTP) and overall survival (OS)] were assessed. RESULTSLenalidomide mean daily dose intensity (excluding treatment breaks on Days 22-28 of each 28-day cycle) was not significantly different between patients with or without history of neuropathy (21.6 mg vs. 22.6 mg; p=0.1479). In addition, the median daily dose intensity was equivalent to the planned daily dose of 25mg (p=0.3857). Mean and median treatment duration were also not significantly different between the two groups (10.1 vs. 10.7 months, p = 0.5307, respectively 9.6 vs. 10.2 months, p=0.5473). Response rates were not significantly different for patients with or without history of neuropathy, with CR/VGPR of 40% vs. 33% (p=0.3116) and overall response rates of 68% vs. 64% (p=0.6174), respectively. Time to progression was not significantly different between the two groups (median TTP 14.8 vs. 12.3 months, p=0.6488), and neither was overall survival (median OS not yet reached vs. 30.6 months, p=0.7848). CONCLUSIONSWith median daily dose intensities both at 25mg and a comparable mean daily dose intensity at 21.6 and 22.6 mg, lenalidomide is well tolerated in both patients with and without history of neuropathy. With a favorable tolerability profile, patients are able to continue therapy for longer, achieving desired response, longer TTP, and ultimately longer overall survival. The results of these data demonstrated that lenalidomide + dexamethasone is an optimal therapeutic choice in relapsed or refractory multiple myeloma irrespective of a patient's history of neuropathy. Disclosures:Delforge:Celgene: Honoraria, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria. Facon:Janssen Cilag: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bravo:Celgene: Employment. Dimopoulos:Celgene: Honoraria.

Long-term outcome of mesna, ifosfamide, mitoxantrone, etoposide (MINE) regimen as a consolidation in patients with aggressive non-Hodgkin lymphoma responding to CHOP

In aggressive non-Hodgkin lymphoma (NHL), CHOP (cyclophosphamide, vincristine, doxorubicin, prednisolone) regimen has been standard for decades, and rituximab has increased response rates and survival in CD20 positive patients, recently. The aim of this prospective trial was to evaluate the long-term efficacy and toxicity of MINE as a consolidation treatment in aggressive NHL patients who had achieved CR or unproven CR after six cycles of CHOP in the first line setting. The primary end-point was disease-free-survival (DFS). Thirty-eight patients were enrolled between February 1992 and May 2000. All of the patients received two cycles of MINE (mesna 1.3 g/m(2), ifosfamide 1.3 g/m(2), etoposide 65 mg/m(2) on days 1-3, and mitoxantrone 12 mg/m(2) on day 1, every 3 weeks) following response to CHOP. Initial bulky disease sites were also applied radiotherapy. Male/female ratio was 1.53(23/15). Median age was 49(30-73). Most of the patients had advanced stage (84.2% for stage >3) and high IPI score (79% for IPI score >2). Sixty percent had diffuse large cell histology. Median follow-up time was 118 months (9-195). Actual mean dose intensity was 88%. There were seven febrile neutropenia episodes. Two patients had grade two neuropathy, one had grade three mucositis and another one had non-neutropenic pneumonia. There was no early toxic death. No serious late toxicity was observed during long-term follow-up. Five- and 10-year DFS rates were both 65.3%. DFS rate in the patients with more than two poor prognostic factors according to IPI score is remarkably high (88%). Five- and 10-year OS was 62.5 and 59%, respectively. MINE regimen seems to be effective as a consolidation regimen, especially, in intermediate/high risk patients and has low early and late toxicities, and it warrants to be evaluated in phase III randomised trials with rituximab in CD20 positive aggressive NHL patients.

3051 Health-related quality of life (HRQL) correlation between family members and cancer patients undergoing chemotherapy

Few data are available to help predict which older cancer patient is at risk of developing chemotherapy-related toxicity. This study was a pilot for a project designing a predictive risk score. Chemotherapy patients aged 70 years and older were prospectively enrolled. Chemotherapies were adjusted for their published toxicity. 60 patients were enrolled, 59 were evaluable. Mean dose-intensity was 90.3%, range 33.3–129.0%. 47% of the patients experienced grade 4 haematological and/or grade 3-4 non-haematological toxicity. Published toxicity (MAX2), diastolic blood pressure, marrow invasion and lactate dehydrogenase (LDH) were all associated with toxicity (P<0.1); Body Mass Index, previous chemotherapy, red blood cells, platelets, polymedication with dose-intensity; and polymedication with FACT-G change. After adjustment for the published toxicity, the variables retained their significance, except for LDH and polymedication (for dose-intensity). Although the size of this pilot study imposes a cautious interpretation, patient-related and chemotherapy-related variables correlated independently with toxicity. Designing a composite predictive score to use in assessing the toxicity of multiple chemotherapy regimens therefore appears to be a valid undertaking.

Effect of race on the safety and efficacy outcomes of gemcitabine plus paclitaxel treated patients with metastatic breast cancer (MBC): Analyses from a phase III trial

1070 Background: Population-based studies often attribute racial disparities in breast cancer outcomes to differences in access to treatment, quality of care, or other socioeconomic factors. In a controlled clinical trial setting, these systemic differences between races should be minimal. To evaluate the potential impact of race on outcomes in a controlled clinical setting, we retrospectively analyzed data from a phase III trial (B9E-MC-JHQG; NCT00006459 ) of patients (pts) with MBC. Methods: Analyses were performed on the JHQG trial database after 440 total pt deaths for both study arms. Demographics, safety, and efficacy were analyzed using safety population data from 3 racial groups: Caucasian (CA), Asian (AS), and Hispanic (HP). CA was the reference for all pair-wise comparisons. The logistic model was used to calculate odds ratios for tumor response and the Cox model was used to calculate hazard ratios for time-to-event parameters, adjusting for significant prognostic factors. Results: We report analyses of the gemcitabine (G) + paclitaxel (T) treatment arm. Demographics were balanced across the 3 groups with the exception that ER+/PR+ status was lower for AS compared to CA and HP; unknown ER/PR status was higher for AS. AS had significantly less neutropenia, fatigue, and nausea, but more anemia compared to CA and HP. Median number of treatment cycles completed was lower, but mean dose intensities for G and T were slightly higher, for AS. Response rate and progression-free survival were similar in the 3 groups. Overall survival (OS) and post-study chemotherapy (PSC) were significantly reduced for AS. Conclusions: Our analysis suggests that AS pts were better able to tolerate GT therapy compared to CA and HP pts. However, AS pts had the poorest OS outcome of the 3 racial groups, potentially due to reduced participation in PSC. [Table: see text] [Table: see text]

Chemotherapy dose adjustment after severe toxicity in older cancer patients

9627 Background: About 60% of older cancer patients experience a grade 4 hematologic (G4H) toxicity and/or a grade 3–4 non- hematologic (G3–4NH) toxicity from chemotherapy. Yet, the mean dose intensity of their treatment is 90% (Extermann et al., 2002). This suggests that oncologists might use alternative strategies to dose reduction. No data exist as to the safety of these alternative strategies. Methods: We reviewed the data from 2 prospective studies of tolerance to chemotherapy in older patients. The dose modifications were left at the discretion of the physicians. Toxicity data were prospectively collected for up to 6 months and rated with CTC 3.0. We assessed whether the treatment was modified in response to G4H, G3–4NH, or either (severe toxicity). We assessed what the modification was, whether patients experienced subsequent severe toxicity, and the reason for stopping treatment. Results: In our sample of 205 patients (age 70- 92, median 75), 72% had a severe toxicity: 35% G4H, 59% G3–4NH, and 24% both. Treatment was modified in 59% of patients with G4H, 56% with G3–4NH, and 57% with both. A modification was made for 85 patients: 22 interruptions of treatment, 25 dose reductions, 13 delays without dose reduction, 21 modified regimens, 3 additional anti-emetics, 2 prophylactic anti-infectious agents, 1 addition of G-CSF, and 1 potassium replacement. Subsequently, 37% of patients who had a modification experienced further severe toxicity, versus 14% of the patients who did not have a modification (p<0.002). Baseline age, sex, BMI, tumor stage, comorbidity, depression, and functional, nutritional, or cognitive status had little or no correlation with the decision to modify the treatment. Conclusions: Most older cancer patients experience a severe toxicity from their chemotherapy. Yet, 2 out of 5 do not undergo chemotherapy modification after it. Oncologists appeared able to effectively identify patients in whom it was safe to continue a full-dose regimen, although this study could not identify clear explanatory mediators. Therefore, requiring a systematic dose reduction for severe toxicity in therapeutic trials and practice might lead to undertreatment of older cancer patients. Research to establish more nuanced treatment modification guidelines needs to be conducted. No significant financial relationships to disclose.

Adjuvant Vinorelbine and Cisplatin in Elderly Patients: National Cancer Institute of Canada and Intergroup Study JBR.10

Recent trials have shown significant survival benefit from adjuvant chemotherapy for non-small-cell lung cancer (NSCLC). Whether elderly patients tolerate platinum-based adjuvant chemotherapy and derive the same survival advantage is unknown. This retrospective study evaluated the influence of age on survival, adjuvant chemotherapy delivery, and toxicity in National Cancer Institute of Canada (NCIC) Clinical Trials Group study JBR.10. Pretreatment characteristics and survival were compared for 327 young (< or = 65 years) and 155 elderly (> 65 years) patients. Chemotherapy delivery and toxicity were compared for 213 treated patients (63 elderly, 150 young). Baseline demographics by age were similar with the exception of histology (adenocarcinoma: 58% young, 43% elderly; squamous: 32% young, 49% elderly; P = .001) and performance status (PS; PS 0: 53% young, 41% elderly; P = .01). Chemotherapy significantly prolonged overall survival for elderly patients (hazard ratio, 0.61; 95% CI, 0.38 to 0.98; P = .04). This benefit is similar to the effect for all patients in JBR.10. Mean dose-intensities of vinorelbine and cisplatin were 13.2 and 18.0 mg/m2/wk in young, respectively, and 9.9 and 14.1 mg/m2/wk in elderly patients (vinorelbine, P = .0004; cisplatin, P = .001), respectively. The elderly received significantly fewer doses of vinorelbine (P = .014) and cisplatin (P = .006). Fewer elderly patients completed treatment and more refused treatment (P = .03). There were no significant differences in toxicities, hospitalization, or treatment-related death by age group. Fifteen (11.9%) of 126 deaths in the young resulted from nonmalignant causes, and 15 (21.1%) of 71 in the elderly (P = .13). Despite elderly patients' receiving less chemotherapy, adjuvant vinorelbine and cisplatin improves survival in patients older than 65 years with acceptable toxicity. Adjuvant chemotherapy should not be withheld from elderly patients.

Phase II trial of nolatrexed dihydrochloride [ThymitaqTM, AG 337] in patients with advanced hepatocellular carcinoma

To evaluate the tolerability and efficacy of nolatrexed in patients with advanced hepatocellular carcinoma. Forty-eight patients were entered onto this study. Nolatrexed was administered every 3 weeks as a 24-h continuous intravenous infusion of 725 mg/m(2)/day for 5 days. Doses were adjusted to maintain a dose level that produced > or = grade 2 toxicity. Response was assessed after every two cycles. Plasma pharmacokinetic samples were assayed using a validated high performance liquid chromatography ultraviolet method. Thirty-nine (81%) patients were evaluable for response. The mean number of cycles received was 2.8 (range 1-12). The mean dose intensity was 700 mg/m(2)/day (SD of 71). One patient had a partial response (2.6%) for 7 months. Eighteen (46%) patients had SD, 20 (51%) patients had progressive disease. The median duration of SD was 93 days. The median overall survival was 32 weeks [95% CI (22-37)]. The most frequent Grade 3 or 4 adverse events were stomatitis (25%), dehydration (23%) and asthenia (21%). There was no evidence of cumulative toxicity. The overall median plasma concentration (C (max)) was 14.20 microg/mL (range 1.41 to 119 microg /mL) with no accumulation observed between cycles 1-6. This phase II study of nolatrexed in advanced HCC patients, demonstrated minimal activity and significant stomatitis. Hence, it does not warrant further study as a single agent for this disease.