Lower Dose Intensity Research Articles

Reduced Dose-Intensity Subcutaneous Bortezomib Plus Prednisone (VP) Or Plus Cyclophosfamide (VCP) Or Plus Melphalan (VMP) For Newly Diagnosed Multiple Myeloma Patients Older Than 75 Years Of Age

BackgroundFrail patients represent 30% of the myeloma population, and are more susceptible to adverse events (AEs) with subsequent treatment discontinuations that significantly affect efficacy and dose-intensity. This community-based, phase II, multicenter trial aims to assess the efficacy and safety of 3 reduced-dose intensity subcutaneous (sc) bortezomib-based treatments in newly diagnosed elderly multiple (MM) patients. MethodsPatients with symptomatic, measurable MM, older than 75 years were enrolled. No exclusion criteria were planned in the protocol, to avoid patient selection bias. Patients with abnormal cardiac, pulmonary, renal or hepatic function were included.Treatment consisted of nine 28-day cycles with sc bortezomib 1.3 mg/m2 days 1, 8, 15, 22 plus oral prednisone 50 mg every other day (VP) or VP plus oral cyclophosphamide 50 mg every other day (VCP) or oral melphalan 2 mg every other day (VMP) for 28 days, followed by maintenance with sc bortezomib every 2 weeks until progression.A geriatric assessment was performed, including the Charlson index for estimating comorbidities, the Activity of Daily Living (ADL) and the Instrumental Activity of Daily Living (IADL) questionnaires to assess self-care and independence status. Combining these factors with age, patients were classified as fit (<80 years, ADL= 6, IADL=8, Charlson score= 0), unfit (fit patients >80 years or ADL=5, IADL=6-7, Charlson score=1), or frail (unfit patients >80 years or ADL≤4, IADL ≤5 and Charlson score ≥2). ResultsA total of 152 patients were enrolled, including 51 patients in the VP, 51 in the VCP and 50 in the VMP group. Median age was 78 years and 30% of patients were older than 80 years. Overall, 53%, 47% and 32% of the patients had ISS stage III disease, 21%, 20% and 24% had an unfavourable FISH profile [at least one chromosomal abnormality: del17, or t(4;14), or t(14;16)], and 88%, 84% and 78% were defined as unfit/frail in the VP, VCP, and VMP groups, respectively.Patients received a median of 9 treatment cycles and 44% of patients started maintenance. All three induction regimens exhibited substantial activity, with an overall response rate (≥partial response) of 67% in the VP, 63% in the VCP, and 80% in the VMP group. After a median follow-up of 17 months, median progression-free survival (PFS) was 14, 16 and 16 months and 1-year overall survival (OS) estimates were 80%, 82% and 80% in the VP, VCP and VMP group, respectively.The incidence of Serious Adverse Events (SAEs) was 22%, 20% and 30% and the discontinuation rate due to AEs was 14%, 16% and 26% in the VP, VCP and VMP groups, respectively. The most common non hematologic grade ≥3 AEs were infections (12%), cardiovascular events (8%), and neurologic events (7%), including 5% of peripheral neuropathy.According to the geriatric classification, and specifically in the fit, unfit and frail patients, the overall response rate was 92%, 67% and 65%, the 1 year OS was 100%, 88% and 73%, rate of SAEs was 4%, 22%, 30% and discontinuation due to toxicity was 40%, 58% and 67%, respectively. ConclusionsIn this community-based population of elderly newly diagnosed MM patients low-dose intensity VP, VCP and VMP showed similar PFS and OS estimates, while SAEs and discontinuations were higher with VMP, suggesting that a melphalan-free regimen should be preferred in these patients. Geriatric assessment is mandatory, since both efficacy and toxicities are significantly different in fit, unfit and frail patients.Table 1VP (N=51)VCP (N=51)VMP (N=50)Overall response rate67%63%80%At least 1 Serious Adverse Event22%20%30%Discontinuation rate for toxicity14%16%26%Median progression-free survival14 months16 months16 months1-year overall survival80%82%80% Disclosures:Larocca:Janssen and Cilag: Honoraria. Cavallo:Janssen-Cilag: Honoraria. Caravita:Janssen-Cilag: Honoraria. Petrucci:Janssen-Cilag: Honoraria. Sonneveld:Janssen-Cilag: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Research Funding; Millenium: Research Funding; Onyx: Research Funding; Celgene: Research Funding. Boccadoro:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Research Funding; Janssen-Cilag: Consultancy. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.

Phase III trial of a 3-weekly versus 5-weekly schedule of S-1 plus cisplatin (SP) combination chemotherapy for first-line treatment of advanced gastric cancer (AGC): SOS study.

LBA4024 Background: 5-weekly S-1 plus cisplatin (SP5: S-1 80-120 mg/body/day on D1-21, cisplatin 60 mg/m2 on D8, every 5 weeks) has become a standard first-line chemotherapy for AGC in Japan based on the SPIRITS trial (Lancet Oncol. 2008;9:215). To strengthen the low-dose intensity of cisplatin in this SP5 for greater efficacy, a 3-weekly S-1 plus cisplatin (SP3: S-1 80 mg/m2/day on D1-14, cisplatin 60 mg/m2on D1, every 3 weeks) has been developed in Korea (Cancer Chemother Pharmacol. 2008;61:837). Methods: This SOS study was a multicenter, randomized, open-label, phase III study to evaluate whether SP3 was non-inferior/superior to SP5 in terms of progression-free survival (PFS) determined by a blinded central radiology review according to RECIST v1.1. Patients (pts) with metastatic or recurrent gastric or gastroesophageal junction adenocarcinoma and with no prior chemotherapy were randomized 1:1 to receive either SP3 or SP5 until disease progression or unacceptable toxicities. Results: Between February 2009 and January 2012, a total of 625 pts were randomized from 42 sites in Korea and Japan. Median age was 59.6 years. 99% of pts had ECOG performance status 0-1. 16% of pts had prior gastrectomy. 62% of pts had measurable lesions. With a median follow-up of 34.7 months (range, 14.2-48.8) in surviving pts, SP3 was significantly noninferior and superior to SP5 in PFS (median 5.5 months vs. 4.9 months; HR 0.82, 95% CI 0.68-0.99, p=0.0418). Overall response rate (ORR) was also better with SP3 than with SP5 (60% vs. 50%, p=0.029). However, OS of both groups was equivalent (median 14.1 vs. 13.9 months; HR 0.99, 95% CI 0.81-1.21, p=0.9068). Treatment was well tolerated in both arms, while SP3 was associated with more frequent G3/4 anemia (19% vs. 9%) and neutropenia (39% vs. 9%). Dose intensity was higher in SP3 than in SP5 for both agents (median 331 vs. 317 mg/m2/week for S-1, p&lt;0.001; median 18 vs. 12 mg/m2/week for cisplatin, p&lt;0.001). Conclusions: SP3 was noninferior and superior to SP5 in terms of PFS and ORR. However, considering the small benefit in PFS and no difference in OS, both SP3 and SP5 can be recommended for the first-line treatment of AGC. Clinical trial information: NCT00915382.

When less is better: the safety and efficacy of reduced intensity gemcitabine in a difficult patient population with advanced non-small-cell lung cancer

Treatment of elderly or poor performance status (PS) patients with advanced non-small-cell lung cancer (NSCLC) is a debated topic. To evaluate the efficacy of a modified schedule of gemcitabine, 59 patients unfit for platinum were enrolled. Mean age was 75.8 years and 41 % of patients had an ECOG PS 2. Gemcitabine was given at 1000 mg/m(2) on days 1, 8 each 28. Most of patients received gemcitabine as first-line chemotherapy, which was continued as maintenance over 6 cycles in responding and stable patients. Median overall survival (OS) and progression-free survival (PFS) were 7.2 and 5 months. In those 45 evaluable patients, treatment resulted in 1 complete remission (CR), 9 partial remissions (PR), and 20 stable diseases (SDs) with a response rate (CR + PR) of 22 % and a clinical benefit (CR + PR + SD) of 68 %. Gemcitabine was continued over 6 cycles in 16 patients (27 %). These patients were treated until progression with a mean of further 8.6 cycles. Median OS and PFS in these selected patients were 19 and 16 months. The toxicity profile was excellent with only 8 % of overall G3-G4 adverse events. None of the 16 patients under the maintenance phase reported significant toxicity. Gemcitabine given at a lower dose intensity than standard should be considered as valuable therapeutic option in elderly or poor PS patients with advanced NSCLC unfit for platinum. Extending the treatment beyond 6 cycles in responding patients is feasible and may prolong survival.

Impact of Reduced Dose Intensity for Elderly Patients with Diffuse Large B-CELL Lymphoma Receiving R-CHOP Every 14 or 21 Days: An Analysis of the LNH03–6B GELA Study.

AbstractAbstract 2723 Introduction:Elderly patients with diffuse large B-cell lymphoma (DLBCL) frequently receive reduced dose-intensity (DI) chemotherapy (Lyman GH et al. J Clin Oncol 2004) but impact on outcome in the era of classical or dose-dense immunochemotherapy is unknown. Final results of the LNH03–6B did not show any difference in PFS (HR: 0.99 [95%CI: 0.78–1.26]; p=0.90) and OS (HR: 0.96 [95%CI: 0.73–1.26]; p=0.75) between R-CHOP14 and R-CHOP21 (Delarue et al. ASCO 2012). Methods:Patients between 60 and 80 years old with DLBCL and aaIPI≥1 were eligible. They were randomized between R-CHOP14 and R-CHOP21 for 8 cycles. Dose-intensity (DI) was calculated for all patients for cyclophosphamide (CPM), doxorubicin (DOX) and rituximab (RTX) and patients were separated into 4 quartiles for each of these drugs. Outcome (PFS and OS) according to final DI was evaluated for all patients and in R-CHOP14 and R-CHOP21 arms. Results:602 pts were randomized, 600 were evaluable, 304 with R-CHOP14 and 296 with R-CHOP21. Median age was 70 years. Patient characteristics were similar in both arms. The percentage of cycles administered with G-CSF was 89% in R-CHOP14 and 66% in R-CHOP21. Median interval between 2 cycles was 14 d [9–94] in R-CHOP14 arm and 21 d [15–66] in R-CHOP21 arm. Median dose-intensity was 88% in R-CHOP14 and 97% in R-CHOP21 for CPM, and 88% in R-CHOP14 and 96% for R-CHOP21 for DOX. There was no difference of median dose-intensity for CPM and DOX according to G-CSF use at C1 in R-CHOP14 arm. In the R-CHOP14 arm, the increase of DI at the end of treatment, calculated according to 3-week interval as a reference, was 133% for CPM and DOX. When separating patients in 4 quartiles according to final dose intensity, there was no impact for CPM, DOX and RTX for the entire cohort in term of PFS and OS. Moreover, decreased DI for CPM, DOX and RTX did not impact negatively PFS and OS in patients randomized in the R-CHOP14 arm. On the other hand, for patients included in the R-CHOP21 arm, PFS was negatively impacted by lower DI of CPM (p=0.02), DOX (p=0.007) and RTX (p=0.006). OS was also negatively impacted by lower DI of CPM (p=0.0002), DOX (p<0.00001) and RTX (p<0.0001). In the R-CHOP21 arm, the negative impact was pronouncedly marked when comparing patients in the first and the second quartiles with those in the fourth quartile. Conclusion:While low DI has a major impact on PFS and OS in patients who receive conventional dose immunochemotherapy, consequences for patients receiving dose-dense immunochemotherapy seem less pronounced. As a consequence, immunochemotherapy could be safely decreased for elderly patients who receive R-CHOP14 and experienced adverse events. Disclosures:No relevant conflicts of interest to declare.

LBA24 - A Phase 3 Study to Evaluate the Efficacy and Safety of Docetaxel and Prednisone (DP) with or without Lenalidomide (LEN) in Patients with Castrate-Resistant Prostate Cancer (CRPC): The Mainsail Trial

ABSTRACT Introduction LEN, an antiangiogenic and immunomodulatory agent was active and well tolerated as a single agent and in combination with DP in phase 1/2 trials in CRPC. This phase 3, multicenter, randomized, double-blind, placebo (PBO)-controlled study evaluated the efficacy and safety of LEN versus PBO in combination with DP as first-line treatment for CRPC. Methods Chemotherapy-naive patients with progressive metastatic CRPC were randomized to the LEN + DP arm (oral [p.o.] LEN 25 mg/day on days 1–14 of each 21-day cycle) or the PBO + DP arm (PBO in the same schedule). In both arms, docetaxel was administered intravenously at 75 mg/m2 on day 1 of each cycle, and prednisone was dosed 5 mg p.o. twice daily. Primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS), objective response rate, and safety. Patient enrollment was completed in Nov 2011 with a total of 1059 patients randomized. The data analysis results were based on the cut-off date of Jan. 13, 2012. Results 533 patients were randomized in the LEN + DP and 526 patients in the PBO + DP arm. The arms were well balanced; mean age was 69 years and ECOG PS scores were 0 in 48.1% and 1 in 47.5% of patients. Median number of cycles administered was 6 and 8 in the LEN + DP and PBO + DP arms, respectively. The most common grade ≥ 3 adverse events in the LEN + DP arm included neutropenia (22%), febrile neutropenia (12%), neutropenic sepsis (3%). Vascular events grade > 3 were reported in 7.4% of patients in the LEN + DP arm versus 4.4% in the PBO + DP arm. No increased mortality due to toxicity was seen. Median OS and PFS was 77 and 45 weeks in the LEN + DP arm, compared to median not reached (p = 0.0017) and 46 weeks (p = 0.0187), in the PBO + DP arm, respectively. Hazard ratio (LEN over PBO) is 1.53 (95% CI = 1.17 to 2.00) for OS and 1.32 (95% CI = 1.05 to 1.66) for PFS. Conclusions The addition of LEN to DP did not improve OS in patients with CRPC and was associated with greater toxicity. Shorter treatment duration, lower dose intensity and earlier treatment discontinuation might have contributed to this lack of benefit. Studies to explain the poorer outcome of the LEN arm are underway. Disclosure D.P. Petrylak: Advisory board: Amgen, Bayer, Pfizer, Ferring, Millenium, Novartis, Dendreon, Johnson and Johnson, GlaxoSmithKline. Corporate sponsored research: Celgene, Dendreon, Sanofi, Pfizer, AstraZeneca, GlaxoSmithKline, Rogesen institute, Boehringer Ingelheim. K. Fizazi: Participation to advisory boards for Sanofi-Aventis and Celgene C.N. Sternberg: Honoraria: Johnson + Johnson, Astellas, Amgen and Sanofi-Aventis Research funding: Cougar J. Bellmunt: Consultancy and adboard contribution for Cellgene and Sanofi (compensated) D. Barton: Celgene employee and stock owner A. Fandi: Celgene employee and stock owner U. Jungnelius: Celgene Corporation: Company employee S. Li: Statistician working at Celgene. I have Celgene stock options as a regular employee. N. Vogelzang: Member of the MAINSAIL steering committee, did not receive direct funds from Celgene for conducting the research as it was conducted thru US Oncology/McKesson. Honoraria from Celgene for lectures. Salary compensation from US Oncology Research All other authors have declared no conflicts of interest.

Comparison of dose intensity of vincristine, d-actinomycin, and cyclophosphamide chemotherapy for child and adult rhabdomyosarcoma: a retrospective analysis

The prognosis of adult rhabdomyosarcoma (RMS) has been considered dismal. The question is raised that vincristine, d-actinomycin, and cyclophosphamide (VAC) chemotherapy may not be administered as per schedule for adult RMS; consequently, low dose intensity (DI) leads to poor prognosis. Herein, we examined whether the administration of VAC chemotherapy for adults and children with RMS is feasible with regard to the DIs of VAC. Chart review was retrospectively performed for all identified patients. The percentage of relative DI (RDI) was calculated according to the Children's Oncology Group D9803 protocol. Further, we examined the RDI in the first 6 cycles of VAC (induction phase) and the DI after the first 6 cycles of VAC (maintenance phase). We identified a total of 27 adults and 18 children with RMS, respectively. The mean RDIs of vincristine in total phase were significantly lower in adults than that in children (P = 0.04). In induction phase, the mean RDIs of vincristine and cyclophosphamide were similar for both groups; however, they were dropped significantly in adults during maintenance phase (P < 0.05). Mean RDIs of vincristine in elderly patients tended to become low. Low RDI was mainly attributable to hematologic toxicity, infection, and peripheral neuropathy. The prognosis of low versus high RDI was similar. The RDIs of vincristine and cyclophosphamide in the maintenance phase were significantly lower than that in children. VAC chemotherapy for adults was not feasible; these patients require a different regimen.

Everolimus with paclitaxel plus bevacizumab as first-line therapy for HER2-negative metastatic breast cancer (MBC): A randomized, double-blind, placebo-controlled phase II trial of the Sarah Cannon Research Institute (SCRI).

1018 Background: Constitutive activation of mTOR and amplified PI3K/Akt/mTOR signaling are common in MBC, and increase as treatment-resistance is acquired. Everolimus (E), an mTOR inhibitor, has single agent activity, combines well with paclitaxel (P) and bevacizumab (B), and prolonged PFS when added to AI therapy in BOLERO-2. In this randomized phase II trial, E was added to P/B as first-line treatment of HER2-negative MBC. Methods: Women with untreated HER2-negative MBC were randomized (1:1) to P 90mg/m2 IV (days 1, 8, and 15) and B10mg/kg IV (days 1 and 15) q28 days with E 10mg PO (Arm 1) or placebo PO (Arm 2) daily. Response assessment was performed q8 weeks until progression or intolerable toxicity. Primary endpoint was PFS. Secondary endpoints: safety, overall response rate, response duration, overall survival. 110 pts allowed detection of improvement in median PFS from 11 to 16 months with 70% power. Results: Between 8/2009 and 6/2011, 112 pts were randomized (Arm 1=55; Arm 2=57). Median age: 58 years (range: 25-79). 88% were ER+ or PR+. Pts received a median 5 treatment cycles (range: &lt;1- 26+); 18 (16%) pts remain on treatment (Arm1, 9; Arm 2, 9). Median PFS were 8.8 months (Arm 1) and 7.1 months (Arm 2) (95% CIs 7.4-9.6; 5.5-9.1 months, p=0.79, HR 0.94). Complete responses were observed in 5% [Arm1, 4 (7%); Arm 2, 2 (4%)] with partial responses in 49% [Arm1, 29 (53%); Arm 2, 26 (46%)]. Responses rates in taxane pretreated pts Arm 1 22%, Arm 2 12%. Hematologic toxicity was similar in both arms; grade 3 mucositis occurred in 13% of E pts. Dose reductions (47% vs 25%) and interruptions (42% vs 26%) were more frequent with E due to mucositis and rash. Treatment discontinuation rates were similar. Conclusions: The addition of E did not result in a significant improvement in the efficacy of weekly paclitaxel/bevacizumab in the first-line treatment of HER2-negative MBC although response rates and median PFS were better with E. Possible explanation for these results may include lower dose intensity in the E arm, treatment of less resistant pts, or intrinsic differences in E activity when added to antiestrogen vs chemotherapy.

Ifosfamide in the Neoadjuvant Treatment of Osteogenic Sarcoma

Osteogenic sarcoma is the most common primary tumor of bone, with an approximate incidence of three per million. There are two peaks of incidence: one during adolescence, and a later peak in the eighth decade. Despite what can be considered adequate therapy, adults fare worse than children. Nonetheless, the treatment of osteosarcoma represents one of the genuine success stories in oncology. Limb-sparing surgery minimizes the need for physically and psychologically scarring amputations, and newer generations of implants account for bone growth, because these tumors are most common in adolescence. Chemotherapy, administered in both the neoadjuvant and adjuvant settings, has improved the cure rate for osteosarcoma from 5% to 20% in the prechemotherapy era to the 60% to 70% range. On the basis of single-arm phase II studies, single agents and combinations of systemic therapeutics have demonstrated the activity of methotrexate, doxorubicin, and cisplatin (MAP) in metastatic osteosarcoma, leading to two seminal randomized studies confirming the activity of adjuvant chemotherapy. This three-drug combination represents a standard of care for osteogenic sarcoma therapy in the United States. No randomized studies have examined the role of doxorubicin in adjuvant therapy, and randomized studies of cisplatin have been performed based only on patient response to other therapy. However, a methotrexate-free alkylating agent– intensive regimen yielded survival results similar to those of MAP in a single-arm phase II study, and two randomized multicenter clinical trials demonstrated that regimens without methotrexate resulted in overall survival (OS) rates no different than those of more complex combinations containing methotrexate. A separate study examining highversus intermediate-dose methotrexate in the adjuvant setting favored high-dose methotrexate. Criticisms of the negative randomized studies include low dose-intensity and lack of adjustment of methotrexate levels in the experimental arms. Early studies of primary and metastatic osteosarcoma gave rise to other key clinical observations: one, the degree of necrosis observed with neoadjuvantchemotherapypredicts foroverall survival,withaminimum of 90% to 95% tumor necrosis defining a good response; and two, resection of isolated lung metastatic disease may be curative, whereas multifocal disease to bone is generally not curable. Caveats to each observation exist. For example, chondroblastic osteogenic sarcoma may not respond as well to chemotherapy as osteoblastic osteosarcoma, but the poorer response does not portend poorer prognosis; isolated bone metastatic lesions may be resected with curative intent. Dose-intensification and the addition of newer agents have been examined in a variety of single-arm phase II studies, which are inherently difficult to compare. Nonetheless, well-conducted phase III studies performed in pediatric and expert adult sarcoma centers have provided oncologists with strong foundations on which to make clinical decisions. It is in this light that Ferrari et al applied the experience with ifosfamide in the recurrent setting to primary disease. Ifosfamide, in phase I to II combination studies with other agents, has significant activity in recurrent or metastatic osteosarcoma. Thus, it was anticipated that ifosfamide would be useful in primary disease. Supportive data for the adjuvant use of ifosfamide have come from the Istituto Ortopedici Rizzoli, where the authors conducted the present study, and elsewhere. In a study accruing patients with suboptimal necrosis of tumor after neoadjuvant therapy, ifosfamide and etoposide were added to MAP therapy, which had been administered preoperatively. This cohort of high-risk patients had a 56% event-free survival (EFS) rate, which was heartening enough to move ifosfamide into the neoadjuvant setting. In the article that accompanies this editorial, Ferrari et al describe the results of their randomized study of 246 patients with osteosarcoma, younger than age 40 years, who were treated between 2001 and 2006 with neoadjuvant MAP chemotherapy with or without ifosfamide. After surgery, treatment was stratified but not randomized. Patients receiving ifosfamide before surgery continued with it to complete adjuvant treatment, whereas those patients receiving MAP alone received ifosfamide only if they had suboptimal tumor necrosis ( 90%) at time of surgery. The experimental arm demonstrated more hematologic toxicity, as anticipated. However, with a 66-month medianfollow-up, therewasnostatisticallysignificantdifferencebetween the standard and experimental arms in the proportions of patients with at least 90% tumor necrosis (48% v 42%), in EFS (64% v 55%), or in 5-year OS (73% v 74%), the primary end point of the study. The principal conclusion was that ifosfamide did not improve the degree of tumor necrosis significantly and thus was not recommended as part of neoadjuvant chemotherapy. The present study highlights results of the adjuvant osteogenic sarcoma study from the Children’s Cancer Group (CCG) and Pediatric Oncology Group (POG), which was conducted between 1993 and 1997 with 777 eligible patients, 662 without metastases. The CCG/ POG study was hampered in data collection, because the primary end JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 17 JUNE 1

Incidence of reduced chemotherapy relative dose intensity among women with early stage breast cancer in US clinical practice

Chemotherapy is widely used to treat early stage breast cancer (ESBC). Reductions and delays in dose administered--e.g., due to advanced age or febrile neutropenia (FN)--are generally believed to increase risk of disease progression and reduce survival. Little is known about incidence of reduced chemotherapy dose intensity among women with ESBC in the current era of US clinical practice. This study employed a retrospective cohort design and electronic medical records from > 65 community oncology/hematology clinics in > 35 states (2004-2010). The study population comprised adult women who received myelosuppressive chemotherapy for ESBC (stages I-IIIA). For each such woman, each unique cycle of chemotherapy within their first observed course was identified. Incidence of chemotherapy dose delays (≥ 7 days for any drug in ≥ 1 cycles), chemotherapy dose reductions (≥ 15% for any drug in ≥ 1 cycles), and low chemotherapy relative dose intensity (RDI <85% over the course) relative to published reference standards were descriptively analyzed for the seven most-frequently planned regimens in the study database. A total of 2,228 women (70% of the subjects who received chemotherapy for ESBC and met other selection criteria) initiated 1 of the 7 most-frequently planned regimens. Mean age of subjects was 54 years and 69% received primary prophylaxis against FN with a colony-stimulating factor. Incidence of dose delays, dose reductions, and low RDI was 31, 24, and 26%, respectively; low RDI typically was due to premature treatment discontinuation. For patients (n = 626) receiving the most common regimen (dose-dense AC-T: doxorubicin/cyclophosphamide, Q2 × 4 cycles, paclitaxel or docetaxel, Q2 × 4 cycles), incidence of dose delays, dose reductions, and low RDI was 42, 29, and 32%, respectively. In the current era of US clinical practice, chemotherapy dose delays and dose reductions are common among women with ESBC receiving frequently used myelosuppressive dose-dense, as well as conventional, chemotherapy regimens.

P5-18-11: Incidence of Chemotherapy Dose Reductions and Dose Delays, and Reduced Chemotherapy Dose Intensity in Early Stage Breast Cancer.

Abstract Background: Chemotherapy is widely used to treat early stage breast cancer (ESBC). Dose reductions and dose delays–e.g., due to advanced age or severe/febrile neutropenia–are generally believed to increase risk of disease progression and reduce survival. Little is known about incidence of chemotherapy dose reductions and dose delays among women with ESBC in clinical practice. Methods: This study employed a retrospective cohort design and electronic medical records from over 60 community oncology clinics in more than 20 states (2004-2010). Study population included adult women who received myelosuppressive chemotherapy for ESBC (stages I-IIIA). For each such woman, each unique cycle of chemotherapy within their first observed course was identified. Incidences of chemotherapy dose delays (≥7 days for any drug in ≥1 cycles), chemotherapy dose reductions (≥15% for any drug in ≥1 cycles), and low relative chemotherapy dose intensity (&amp;lt;85% over the course) – relative to physician-reported planned chemotherapy administration – were descriptively analyzed for the seven most frequently observed regimens among subjects. Results: 2,350 women received seven most frequently observed regimens (80% of study population); mean age – across regimens – ranged from 51–56 years, and 31–94% received primary prophylaxis against severe/febrile neutropenia with a colony-stimulating factor. Incidence of dose reductions ranged from 17–48%, and dose delays, from 24–45%. Overall mean relative dose intensity (RDI) ranged from 80%-99%, and 17–50% of subjects received RDI &amp;lt;85%; mean RDI among those with low RDI ranged from 40%-67%. Discussion: Chemotherapy dose delays and dose reductions are common in ESBC, among those receiving dose-dense as well as conventional regimens. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-18-11.

Relation between bevacizumab dose intensity and high-grade glioma survival: a retrospective study in two large cohorts

Bevacizumab is one of the rare drugs that could improve high-grade glioma outcome after failure of chemoradiotherapy. However, to date, there is no biomarker predictive for efficacy of bevacizumab therapy in terms of survival improvement for patients with high-grade glioma. We performed a retrospective analysis of clinical factors associated with patient survival using a training cohort of 110 consecutive patients treated with bevacizumab for recurrent high-grade glioma and an independent validation cohort of 109 patients. In the training cohort, 110 consecutive patients received bevacizumab-based therapy. The number of chemotherapy cycles delivered was 1,411. Median follow-up was 12 months. Thirty-four patients (31%) had objective partial response and 24% had stable disease on magnetic resonance imaging evaluation. Median progression-free survival (PFS) and overall survival (OS) were 4.3 and 9.2 months, respectively. On univariate analysis, among classical prognosis factors, only Karnofsky status ≥70% was associated with improved outcome. Surprisingly, patients with low bevacizumab dose intensity (<5 mg/kg/week) had better PFS (12 vs. 2 months, P < 0.0001) and OS (16 vs. 6 months, P = 0.0002). On multivariate analysis, low bevacizumab dose intensity was the most significant independent prognostic factor of survival. Analysis of the validation cohort yielded similar results, externally validating this observation. This large retrospective study using two independent cohorts of high-grade glioma suggests that the currently recommended dosage of bevacizumab (5 mg/kg/week) is not optimal. Further prospective randomized trials using lower dosages are warranted.

9098 POSTER First-Line Modified Schedule of Gemcitabine With a Lower Dose Than Standard in Elderly or PS 2 Patients With Advanced Non-Small Cell Lung Cancer

Background: Monochemotherapy with gemcitabine (Gem) is often the treatment of choice in elderly or poor performance status (PS) patients with advanced non-small cell lung cancer (NSCLC). Our study was aimed to assess the efficacy and tolerability of a modified schedule of Gem using a lower dose than standard. Patients and Methods: From May 2009 through December 2010, fifty patients (43 males and 7 females with a median age of 76 years ranging from 64 to 85) with advanced NSCLC (stage IIIB 34.0% and IV 66.0%) were enrolled. Histology was: squamous 39.6%, adenocarcinoma 31.2%, large cell 6.2%, undifferentiated 4.2%, undetermined 18.8%. Only eight patients (16.0%) had a WHO PS 0 whereas nineteen (38.0%) were PS 1 and eleven (46.0%) PS 2. All patients received first-line chemotherapy with 6 cycles of Gem 1000mg/sq on days 1 and 8 every 4 weeks. Results: At the time of analysis 35 patients were evaluable for response. Partial response (PR) was achieved in 7 patients (20.0%), stable disease >12 weeks (SD) in 16 (45.7%) whereas 12 had progressive disease (34.3%). Importantly, the clinical benefit rate (PR + SD) was 65.7%. Tumour markers (CEA and NSE) were high in 28 patients with a reduction in their values observed in 11 of them (39.3%). Both pain and PS improved in 6 patients (17.1%) whereas 19 (54.2%) had an improvement in pain with no worsening of PS. We observed only grade 2 WHO haematological toxicities including anemia, leucopenia, neutropenia and trombocytopenia. Not-neutropenic fever occurred in 4 patients (11.4%). Overall, we did not observe any not-haematological treatment-related event. Conclusions: Our data show that a modified schedule of Gem with a lower dose intensity than standard may be beneficial in terms of both disease control and tolerability when employed in elderly or PS 2 patients with advanced NSCLC.

Primary frontal sinus squamous cell carcinoma in three dogs treated with piroxicam combined with carboplatin or toceranib

In human medicine, primary frontal sinus squamous cell carcinoma (pFS-SCC) is not frequently reported. In veterinary medicine, frontal sinus SCC is exclusively described as an extension of nasal cavity SCC. To our knowledge, this is the first publication concerning canine pFS-SCC, diagnosed using histology or cytology and medical imaging, in three dogs. The tumours extended into the orbit or brain cavity, without nasal involvement. Treatment was initiated with piroxicam-carboplatin. Prolongation of carboplatin delivery with a low dose intensity was performed on dogs with a favourable initial response. Dog 1 achieved a complete remission (CR), but was euthanized 344 days after start of therapy. Dog 2, still alive 3 years after start of therapy and in CR, received 14 carboplatin deliveries. In dog 3, after changing the treatment protocol into piroxicam-toceranib, a significant tumour reduction occurred, but the dog was euthanized after 195 days because of a relapse.

The effect of age on first-line sunitinib treatment in patients with renal cell carcinoma (RCC).

e15096 Background: Sunitinib is a first line treatment for majority of patients with metastatic RCC. The recommended dose of 50mg often results in a spectrum of serious side effects which subsequently lead to dose reduction and may have an impact on response rates. Methods: We conducted a retrospective analysis of 62 RCC patients from single institution treated with sunitinib between September 2007-May 2010. Patients were stratified according to age groups, into ≤ 70 year old (y.o.) and > 70 y.o. to compare tolerability, response rates and median survival. Results: All patients were evaluable for toxicity, 55 patients were evaluable for response. 38 (61.2%) were ≤ 70 y.o. and 24 (38.8%) were >70y.o. 2 patients (5%) of ≤70 and 5 (20%) of > 70y.o. were non-evaluable for response due to early treatment discontinuation. The response rate was 36% in ≤70y.o. and 21% in >70 y.o., stable disease (SD) was observed in 41% ≤70 y.o. vs 47% in the older age group and progressive disease PD:22% vs 31.5% respectively. 24 (38.7%) of patients required dose reductions after the first or second cycle- 12 (33%) in ≤70 vs 11 (59%) in >70 yrs old. A small number of patients presented with PS 2 and these were started on a reduced dose of 37.5mg: 3 (8%) in ≤70y.o. and 11 (58%) > 70y.o. Toxcities were comparable in both groups however grade 3 palmar-plantar erythema (PPE) and mucositis (18% vs 1.6% and 18 vs 8% respectively) were more prevalent in the younger cohort. Grade 3 diarrhoea and fatigue were more common in older patients (10% in >70y.o vs 1.6% in ≤70y.o. and 16% vs 9.6% respectively). Median survival was 23 months for both age groups. Conclusions: Elderly patients more commonly require dose reduction due to poor performance status and toxicity profile. The objective response rate is lower with the lower dose intensity however the rate of disease stabilisation is comparable in both groups. The lower dose of Sunitinib is well tolerated in the elderly and this regimen should be considered for older patients with poor performance status.

Updating data about a first-line modified schedule of gemcitabine with a lower dose than standard in very elderly or PS 2 patients with advanced non-small cell lung cancer.

e18031 Background: Monochemotherapy with gemcitabine (Gem) is often the treatment of choice in elderly or poor performance status (PS) patients with advanced non-small cell lung cancer (NSCLC). Our study was aimed to assess the efficacy and tolerability of a modified schedule of Gem using a lower dose than standard. Methods: From May 2009 through December 2010, fifty patients (43 males and 7 females with a median age of 76 years (64 to 85) with advanced NSCLC (stage IIIB 34,0% and IV 66,0%) were enrolled. Histology were: squamous 39,6%, adenocarcinoma 31,2%, large cell 6,2 %, undifferentiated 4,2 %, undetermined 18,8%. Only eight patients (16,0%) had a WHO PS 0 whereas nineteen (38,0%) were PS 1 and eleven (46,0%) PS 2. All patients received first-line chemotherapy with 6 cycles of Gem 1000 mg/sq on days 1 and 8 every 4 weeks. Results: At the time of analysis 35 patients were evaluable for response. Partial response (PR) was achieved in 7 patients (20,0%), stable disease > 12 weeks (SD) in 16 (45,7%) whereas 12 had progressive disease (34,3%). Importantly, the clinical benefit rate (PR + SD) was 65,7%. Quality of life was mesured with EORTC QoL 3.0 Questionary. Both pain and PS improved in 6 patients (17,1%) whereas 19 (54,2%) had an improvement in pain with no worsening of PS. We observed only grade 2 NCCTs version 3 haematological toxicities including anemia, leucopenia, neutropenia and trombocytopenia. Not febrile neutropenia occurred in 4 patients (11,4%). Overall, we did not observe any not-haematological treatment-related event. Conclusions: Our data show that a modified schedule of Gem with a lower dose intensity than standard may be beneficial in terms of both disease control and tolerability when employed in elderly or PS 2 patients with advanced NSCLC. These data are similar to published data in elderly. At ASCO meeting we present all data about 50 pts enrolled.

Feasibility of vincristine, dactinomycin, and cyclophosphamide (VAC) chemotherapy for adult rhabdomyosarcoma (RMS) with regard to dose intensity (DI).

10083 Background: The prognosis of adult RMS has been considered dismal. The question is raised that VAC chemotherapy may not be administered as per schedule for adult RMS, consequently low DI leads to poor prognosis. Herein, we examined whether the administration of VAC chemotherapy for adult RMS is feasible with regard to the DIs of V and C. Methods: We extracted the data on adult RMS from pts aged greater than or equal to 21 years. Chart review was performed for all identified pts. DI for V or C was calculated according to the following formula: DI (V) = Total dose of V (mg/m2)/[(last date of injection – first date of injection) + 7]/7 or DI (C) = Total dose of C (mg/m2)/[(last date of injection – first date of injection) + 21]/7, respectively. The percentage of relative DI (RDI) was calculated according to the Children's Oncology Group D9803 protocol. Further, we examined the DI in the first 6 cycles of VAC (induction phase) and the DI after the first 6 cycles of VAC (maintenance phase). Results: We identified a total of 27 pts, and a total of 316 cycles of VAC were administered. In the induction phase, the median DIs (mg·m-2·week-1) of V and C were 1.09 and 684.4, respectively. The RDIs for V and C were 81.3% and 93.3%, respectively. In the maintenance phase, the DIs of V and C were 0.77 and 508.0, respectively, while in the maintenance phase, the RDIs for V and C were 51.1% and 69.2%, respectively. The number of pts with RDI more than 80% in the induction phase significantly decreased in the maintenance phase for V (p = 0.0008). Lower RDI of C in the maintenance phase was also showed borderline significance (p = 0.09). In the induction phase (total 168 cycles), the following adverse events were observed: grade 4 neutropenia (77.4%), grade 3/4 anemia (45.8%), grade 4 thrombocytopenia (14.9%), grade 3/4 febrile neutropenia (38.1%), and grade 2 peripheral neuropathy (40.7%). Conclusions: The RDIs of V and C in the maintenance phase were significantly lesser than the corresponding values in the induction phase. Low RDI was mainly attributable to hematologic toxicity and peripheral neuropathy. The maintenance phase chemotherapy for adult RMS should be developed urgently.

Vatalanib in Advanced Colorectal Cancer: Two Studies With Identical Results

Vatalanib in Advanced Colorectal Cancer: Two Studies With Identical Results

Five-Year Results From a Scandinavian Sarcoma Group Study (SSG XIII) of Adjuvant Chemotherapy Combined With Accelerated Radiotherapy in High-Risk Soft Tissue Sarcoma of Extremities and Trunk Wall

To evaluate adjuvant chemotherapy and interpolated accelerated radiotherapy (RT) for adult patients with high-risk soft tissue sarcoma in the extremities or trunk wall. High-risk soft tissue sarcoma was defined as high-grade malignancy and at least two of the following criteria: size≥8 cm, vascular invasion, or necrosis. Six cycles of doxorubicin and ifosfamide were prescribed for all patients. RT to a total dose of 36 Gy (1.8 Gy twice daily) was inserted between two chemotherapy cycles after marginal margin resection regardless of tumor depth or after wide-margin resection for deep-seated tumors. RT was boosted to 45 Gy in a split-course design in the case of intralesional margin resection. A total of 119 patients were eligible, with a median follow-up of 5 years. The 5-year estimate of the local recurrence, metastasis-free survival, and overall survival rate was 12%, 59%, and 68%, respectively. The group receiving RT to 36 Gy had a local recurrence rate of 10%. In contrast, the local recurrence rate was 29% in the group treated with RT to 45 Gy. The presence of vascular invasion and low chemotherapy dose intensity had a negative effect on metastasis-free and overall survival. Toxicity was moderate after both the chemotherapy and the RT. Accelerated RT interposed between chemotherapy cycles in a selected population of patients with high-risk soft tissue sarcoma resulted in good local and distant disease control, with acceptable treatment-related morbidity. The greater radiation dose administered after intralesional surgery was not sufficient to compensate for the poorer surgical margin. Vascular invasion was the most important prognostic factor for metastasis-free and overall survival.

Effect of first-line modified schedule of gemcitabine on clinical benefit rate and toxicity in elderly or PS 2 patients with advanced non-small cell lung cancer.

e18131 Background: Monochemotherapy with gemcitabine (Gem) is often the treatment of choice in elderly or poor performance status (PS) patients with advanced non-small cell lung cancer (NSCLC). Our study was aimed to assess the efficacy and tolerability of a modified schedule of Gem using a lower dose than standard. Methods: From May through December 2009, twenty-four patients (18 male and 6 female with a median age of 75 years ranging from 64 to 84) with advanced NSCLC (stage IIIB 37,5% and IV 62,5%) were enrolled. Histology was: squamous 38%, adenocarcinoma 25%, large cell 4%, undifferentiated 4%, undetermined 29%. Only four patients (17%) had a WHO PS 0 whereas thirteen (54%) were PS 1 and seven (29%) PS 2. All patients received first-line chemotherapy with 6 cycles of Gem 1,000 mg/sq on days 1 and 8 every 4 weeks. Results: At the time of analysis 17 patients were evaluable for response. Partial response (PR) was achieved in 2 patients (12%), stable disease > 12 weeks (SD) in 8 (47%) whereas 7 had progressive disease (41%). Importantly, the clinical benefit rate (PR + SD) was 59%. Tumour markers (CEA and NSE) were high in 11 patients with a reduction in their values observed in 4 of them (36%). Both pain and PS improved in 2 patients (8%) whereas 12 (50%) had an improvement in pain with no worsening of PS. We observed only grade 2 WHO haematological toxicities including anemia, leucopenia, neutropenia and trombocytopenia. Not-neutropenic fever occurred in 4 patients (17%). Overall, we did not observe any not-haematological treatment-related event. Conclusions: Our data show that a modified schedule of Gem with a lower dose intensity than standard may be beneficial in terms of both disease control and tolerability when employed in elderly or PS 2 patients with advanced NSCLC. No significant financial relationships to disclose.

Changing the Paradigm in Conducting Randomized Clinical Studies in Advanced Pancreatic Cancer: An Opportunity for Better Clinical Development

Changing the Paradigm in Conducting Randomized Clinical Studies in Advanced Pancreatic Cancer: An Opportunity for Better Clinical Development