Median OS Of Patients Research Articles

Gemcitabine-Based Regional Intra-Arterial Infusion Chemotherapy in Patients With Advanced Pancreatic Adenocarcinoma.

The present study was carried out to investigate the prognostic factors in patients who received intra-arterial infusion for advanced pancreatic cancer. In addition, the detailed procedure of intra-arterial infusion chemotherapy was described.A total of 354 patients with advanced unresectable pancreatic adenocarcinoma were recruited from January 2012, to April 2015, at Zhongshan Hospital Fudan University, Shanghai, China. Demographic and clinic characteristics of the patients were extracted from electronic medical records. Restricted cubic spline was used to assess the nonliner regression between baseline CA19-9 value and overall survival. Kaplan–Meier analysis and Cox proportional hazard models were used to estimate the association between overall survival and clinical characteristics.Of all 354 included patients, 230 (65%) were male (male/female ratio = 1.8), and 72 (20%) patients were diagnosed with detectable distant metastases. Pretreatment CA19-9 value of patients with metastases was significantly higher as compared to those with locally advanced cancer (median: 922.30 vs 357.00 U/mL, P = 0.0090). Totally 274 patients completed 1 cycle of intra-arterial infusion, whereas 80 patients received 2 or more cycles of the chemotherapy. For all the 354 patients, median OS was 7.0 months (95% CI: 6.0, 8.0 months) with a 6-, 12-, and 18-month survival rate of 0.48, 0.28, and 0.18, respectively. The median OS of patients, who received 1 cycle of intra-arterial infusion therapy, was 6.0 months (95% CI: 5.0, 8.0 months), which was similar to 7.0 months (95% CI: 6.0, 9.0 months) in patients who received 2 or more cycles. Restricted cubic spline revealed the nonline association between baseline CA19-9 and prognosis. The Cox proportional hazard model showed that age, CA19-9 baseline, CA19-9 value, and tumor location were significantly associated with the OS.In conclusion, the gemcitabine-based RIAC presented a potential treatment method for advanced pancreatic adenocarcinoma. Young age, pretreatment CA19-9 value <1000 U/mL, and tumor located at the head of pancreas indicated better response to the regional intra-arterial chemotherapy and better overall survival.

Rituximab is an effective and safe treatment of relapse in elderly patients with resistant warm AIHA.

We evaluated the efficacy and safety of rituximab for the treatment of 23 elderly patients (median age 78 years) with warm autoimmune haemolytic anaemia (AIHA). The median follow-up was 31 months. Patients had received one to five previous treatments. Rituximab was administered by intravenous infusion at a dose of 375 mg/m(2) once weekly for 4 weeks. The OR rate was 86.9 % (CR = 39.1 %, PR = 47.8 %). Median OS was 87 months. The median OS of patients who reached CR could not be calculated, and that of patients with PR was 67 months. At last follow-up, eight of the 20 responding patients, including one patient in CR and seven in PR, had relapsed after a median of 6 months. Failure to achieve CR was a risk factor for relapse (p = 0.028). We did not identify any pretreatment characteristics predictive of response to rituximab. In conclusion, rituximab is an effective treatment for elderly patients with refractory warm AIHA.

Which Should be Pursued, Cumulative Dose or Dose Intensity: A Real-World Effectiveness Analysis of Bortezomib-Based First Line Treatment for Untreated Multiple Myeloma Patients

Background: The higher cumulative dose of bortezomib associated with better OS was demonstrated by some prospective studies of bortezomib continuing therapy. A cutoff of cumulative bortezomib dose of 39mg/m2 was found in the treatment of multiple myeloma (MM) with VISTA trial recently. However, dose reduction due to adverse events was common. Moreover, many Chinese patients accepted bortezomib injections at a fixed dose of 1.75mg, the half volume of a vial because of economic problems. To clarify if a reasonable cumulative bortezomib dose achieved by prolonged treatment duration with reduced dose intensity can do the same work, we conducted a multicenter retrospective analysis in previously untreated MM patients with the initial treatment of bortezomib-based regimens.Method: From March 2005 to December 2014, 579 previously untreated MM patients received the bortezomib-based chemotherapy with informed consents in three hematologic centers of Beijing. Median age at the diagnosis was 59 years (range: 27~89). Initial chemotherapeutic regimens included BD, PAD, BCD and VMP. After median of 4 cycles (range: 0.25~13.00) of treatment, the median cumulative dose of bortezomib was 28mg (range: 1.75~124.80). The median follow-up of surviving patients was 26.0 months (2.0-123.0). Seventy nine patients recieved autologous hematopoietic cell transplantation (ASCT) according to the eligibility and patients' desire.Results: To overcome confounding effects of early discontinuations/deaths on the cumulative dose, a landmark analysis was conducted at 6 months, eliminating patients who died before this time from the analysis. Among the patients survived the initial 6-month treatment, 450 treated with chemotherapy alone and 78 received ASCT.ROC analysis showed the cumulative bortezomib dose predicted survival in chemotherapy group with the AUC of 0.617 (95%CI: 0.565~0.670, P<0.001). A cutoff value of cumulative bortezomib dose was 20.75mg with optimal sensitivity and specificity of 0.831 and 0.373, respectively. The patients' characteristics of both low (<20.75mg) and high (≥20.75mg) cumulative bortezomib dose groups were comparative. The high cumulative dose group had superior OS than the low cumulative dose group (median OS: 51.0 months (95%CI: 44.66-57.34) vs. 42.0 months (95%CI: 33.24-50.76), P=0.015). However, PFS was not significantly different between the two groups (P=0.994). Two hundred and forty eight (65.3%) patients initiated treatment of bortezomib with the fixed dose of 1.75mg, and 202 (34.7%) patients had the standard dose of 1.3 mg/m2. Bortezomib dose reduction occured in 50 patients. Twenty nine (11.7%) patients of the standard dose intensity group and 2(1.0%) of the fixed dose intensity group had the dose reduction due to adverse events. And the other 19 patients reduced bortezomib dose for other reasons. PFS and OS of the patients with reduced dose intensity were not significantly different from the patients with the standard dose intensity of 1.3 mg/m2 (P=0.183 and 0.482, respectively). However, in the patients with the cumulative bortezomib dose of ≥20.75mg and the standard dose intensity of 1.3mg/m2 was associated with superior survival (P=0.05). Median OS of these patients was 57.0 months (95%CI: 50.62-63.38), while median OS of other patients treated with the cumulative bortezomib dose of <20.75mg or reduced dose intensity was 45.0 months (95%CI: 41.45-48.55). In the ASCT group, we could not find any association between bortezomib dose and the survival.Conclusion: For previously untreated MM patients intend to be treated with chemotherapy alone, we suppose cumulative bortezomib dose ≥20.75mg in the first line treatment should be administered for better OS. Despite reasonable cumulative bortezomib dose, any reduction of the dose intensity from 1.3mg/m2 is associated with inferior OS. For patients treated with ASCT, the association between the bortezomib dose and the survival needs to be elucidated with a long term follow-up. DisclosuresNo relevant conflicts of interest to declare.

The Impact of Genetic Abnormalities (GA) and Other Factors on Survival in Patients after 65 Years with Multiple Myeloma (MM)

Background. The increase of life expectancy in patients after 65 years with MM is the main aim of treatment. Lack of carrying out aggressive anti-multiple myeloma therapy increase influence of different factors on OS.Aims. To compare influence GA and other different factors on overall survival in 65 and more years old patients with MM.Methods. We retrospectively analyzed 40 patients 65 and more years (median age 71 years, range 65-86; male/female - 1:1.35). The incidences of genetic abnormalities were determined in all cases. Cytogenetic analysis was performed on bone marrow samples using standard GTG-method. Metaphase FISH analysis was performed according to the manufacturer's protocol using DNA probes: LSI 13(RB1)13q14, IGH/CCND1, IGH/FGFR3, LSI TP53 (17q13.1). Stratification of patients was carried in groups of risk according to the modified molecular classification mSMARTmod 1.0 and mSMARTmod 2.0. Patients with 2 and more chromosomal aberrations were additionally entered in high-risk group of both systems.Results. GA in multiple myeloma after 65 years old patients were detected in 22.8% (9/40). The occurrence frequency of t(11;14) was 26.0% (6/23), del(13q) - 20.8% (5/24), t(4;14) - 4.3% (n=1/23), del(17p) - 0% (n=0/11). 33/40 (82.5%) patients entered into standard risk group, 4/40 (10%) - into intermediate risk, 3/40 (7,5%) - into high-risk. Median OS (MOS) according to mSMARTmod 1.0 in standard risk group (33/40) was 78 months, in high-risk (7/40) - 54 months. Median OS according to mSMARTmod 2.0 in standard risk group (33/40) was 78 months, in intermediate-risk (4/40) - 56 months, in high-risk (3/40) - 49 months. In patients groups without renal failure (35/40) MOS was 78 vs. 46 months with renal failure (5/40). MOS isn't reached in patients with ISS I (4/27), but MOS in patients with ISS II (13/27) and ISS III (10/27) were 50 and 54 months, respectively. MOS in patients group (10/40), who have both (bortezomib and lenolidomide) anti-myeloma agents was 110 months vs. 57 months in group (30/40) only with bortezomib-based regimen of treatment.Conclusions. Many factors influence on OS in 65 and more years old patients with MM. However, patients, who had treatment with bortezomib and lenelidomide had the best results of OS. DisclosuresNo relevant conflicts of interest to declare.

Tolerability and efficacy of gamma knife radiosurgery on hepatocellular carcinoma with portal vein tumor thrombosis.

This is a retrospective study on the safety and efficacy of gamma knife radiosurgery (GKR) in treating hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). Patients with confirmed HCC and PVTT were allocated into two groups based on the treatments they received (palliative or GKR). A total of 138 patients were included (74 in the palliative group, 64 in GKR group). No significant differences in baseline characteristics existed between the two groups. Treatment-related adverse events (AEs) were recorded and compared between groups. The majority of AEs were mild to moderate and subsided naturally or after medication. There was no AE-induced death. The influences of baseline characteristics and treatment options on patients' OS were analyzed. The median OS of patients in the palliative and GKR group were 3.0 months (95% CI: 2.719-3.281) and 6.1 months (95% CI: 4.706-7.494) respectively (p = 0.003). Multivariate analysis revealed that GKR treatment, performance status 0-1, Child A, smaller tumor diameter and monolobar distribution were significant favorable prognosticators. Subgroup analyses showed OS benefit of GKR regardless of PVTT location (main or branch of PVTT). In conclusion, GKR is well tolerated in selected HCC-PVTT patients and can confer OS benefit, which needs validation in future prospective studies.

Analysis of BRAF and NRAS Mutation Status in Advanced Melanoma Patients Treated with Anti-CTLA-4 Antibodies: Association with Overall Survival?

Ipilimumab and tremelimumab are human monoclonal antibodies (Abs) against cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab was the first agent to show a statistically significant benefit in overall survival in advanced melanoma patients. Currently, there is no proven association between the BRAFV600 mutation and the disease control rate in response to ipilimumab. This analysis was carried out to assess if BRAFV600 and NRAS mutation status affects the clinical outcome of anti-CTLA-4-treated melanoma patients. This is a retrospective multi-center analysis of 101 patients, with confirmed BRAF and NRAS mutation status, treated with anti-CTLA-4 antibodies from December 2006 until August 2012. The median overall survival, defined from the treatment start date with the anti-CTLA-4. Abs-treatment to death or till last follow up, of BRAFV600 or NRAS mutant patients (n = 62) was 10.12 months (95% CI 6.78–13.2) compared to 8.26 months (95% CI 6.02–19.9) in BRAFV600/NRASwt subpopulation (n = 39) (p = 0.67). The median OS of NRAS mutated patients (n = 24) was 12.1 months and although was prolonged compared to the median OS of BRAF mutated patients (n = 38, mOS = 8.03 months) or BRAFV600/NRASwt patients (n = 39, mOS = 8.26 months) the difference didn’t reach statistical significance (p = 0.56). 69 patients were able to complete 4 cycles of anti-CTLA-4 treatment. Of the 24 patients treated with selected BRAF- or MEK-inhibitors, 16 patients received anti-CTLA 4 Abs following either a BRAF or MEK inhibitor with only 8 of them being able to finish 4 cycles of treatment. Based on our results, there is no difference in the median OS in patients treated with anti-CTLA-4 Abs implying that the BRAF/NRAS mutation status alone is not sufficient to predict the outcome of patients treated with anti-CTLA-4 Abs.

Abstract 4338: Clinical significance of soluble CD26 in malignant pleural mesothelioma

Abstract There is no established diagnostic marker for malignant pleural mesothelioma (MPM). CD26 is a 110 kDa, multifunctional, membrane-bound glycoprotein on the surface of many cell types that has dipeptidyl peptidase IV (DPPIV) enzyme activity. The aim of this study was to evaluate the clinical significance of soluble CD26 in patients with MPM. The study included 80 MPM patients, 79 subjects with past asbestos exposure (SPE), and 134 patients with other benign pleural diseases (OPD) that were included as a control group. Soluble CD26 levels and DPPIV activity in serum and/or pleural fluid were determined using an ELISA kit. Serum sCD26 levels and DPPIV enzyme activity in patients with MPM were significantly decreased compared with those in the SPE group (P = 0.000). The level of serum sCD26 was significantly decreased in patients with advanced stages of MPM compared with those with earlier stages (P = 0.047). The median OS of patients with MPM who had higher DPPIV enzyme activity was significantly longer than that of those with lower DPPIV enzyme activity (P = 0.032). The sCD26 levels in the pleural fluid of MPM patients with an epithelioid subtype were significantly increased compared with the OPD cohort (P = 0.012). Moreover, DPPIV enzyme activity in the pleural fluid of patients with MPM with an epithelioid subtype were significantly increased compared with those in the OPD cohort (P = 0.009). Patients with MPM who had lower specific DPPIV activity, determined as DPPIV/sCD26, showed significantly prolonged survival compared with those with higher specific DPPIV activity (P = 0.028). Serum sCD26 and DPPIV enzyme activity appear to be useful biomarkers for differentiating patients with MPM from SPE. The sCD26 levels or DPPIV enzyme activity in pleural fluid appear to be biomarkers in patients with an epithelioid subtype of MPM. DPPIV activity in serum or pleural fluid appears to be predictive for the prognosis of patients with MPM. Citation Format: Nobukazu Fujimoto, Kei Ohnuma, Keisuke Aoe, Osamu Hosono, Taketo Yamada, Takumi Kishimoto, Chikao Morimoto. Clinical significance of soluble CD26 in malignant pleural mesothelioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4338. doi:10.1158/1538-7445.AM2015-4338

Clinical significance of soluble CD26 in malignant pleural mesothelioma.

There is no established single diagnostic marker for malignant pleural mesothelioma (MPM). CD26 is a 110 kDa, multifunctional, membrane-bound glycoprotein that has dipeptidyl peptidase IV (DPPIV) enzyme activity. The aim of this study was to evaluate the clinical significance of soluble CD26 (sCD26) in patients with MPM. The study included 80 MPM patients, 79 subjects with past asbestos exposure (SPE), and 134 patients with other benign pleural diseases (OPD) that were included as a control group. sCD26 levels and DPPIV activity in serum and/or pleural fluid were determined using an ELISA kit. Serum sCD26 levels and DPPIV enzyme activity in patients with MPM were significantly decreased compared with those in the SPE group (P = 0.000). The level of serum sCD26 was significantly decreased in patients with advanced stages of MPM compared with those with earlier stages (P = 0.047). The median OS of patients with MPM who had higher DPPIV enzyme activity was significantly longer than that of those with lower DPPIV enzyme activity (P = 0.032). The sCD26 levels in the pleural fluid of MPM patients with an epithelioid subtype were significantly increased compared with the OPD cohort (P = 0.012). Moreover, DPPIV enzyme activity in the pleural fluid of patients with MPM with an epithelioid subtype were significantly increased compared with those in the OPD cohort (P = 0.009). Patients with MPM who had lower specific DPPIV activity, determined as DPPIV/sCD26, showed significantly prolonged survival compared with those with higher specific DPPIV activity (P = 0.028). Serum sCD26 and DPPIV enzyme activity appear to be useful biomarkers for differentiating patients with MPM from SPE. The sCD26 levels or DPPIV enzyme activity in pleural fluid appear to be biomarkers in patients with an epithelioid subtype of MPM. DPPIV activity in serum or pleural fluid appears to be predictive for the prognosis of patients with MPM.

Serum Free Light Chain Escape In Progression and Treatment Resistance In Multiple Myeloma: A Marker For The Impact Of Intra-Clonal Heterogeneity

IntroductionIntra-clonal heterogeneity has recently been described in Multiple Myeloma (MM), but as yet its clinical impact on disease progression and relapse has not been fully explored. The immunoglobulin type produced by the plasma cells provides an excellent marker, which can be used to address this issue by allowing us to follow clonal sub-structure over time and we have previously noted sub-clonal differences in heavy and light chain production within the predominant myeloma clones. Relapses characterized by an increase in FLC without a correspondent increase in paraprotein level have also been described, a phenomenon that has been termed “serum free light chain escape” (FLC escape). AimsAs FLC escape can serve as a marker of sub-clonal evolution and intra-clonal heterogeneity and, to better understand the extent of sub-clonal evolution over time as well as its impact on outcomes following relapse, we have prospectively evaluated serial FLC and paraprotein measurements on a large population of newly diagnosed MM patients treated within the Myeloma IX clinical trial. MethodsThe trial comprised an intensive and a non-intensive pathway based on patient eligibility for autologous transplantation. Patients were randomized to receive conventional treatment or thalidomide containing induction. A randomization between maintenance thalidomide versus no maintenance was also performed. The International Myeloma Working Group uniform response criteria were used to assess response based on central laboratory analysis of serial blood and urine samples. FLC escape at relapse was defined as an increase of FLC with a paraprotein value either undetectable or stable compared to the best response. Median follow up was 5.9 years. ResultsA complete FLC dataset for diagnosis, response and relapse was available in 647 patients with IgG or IgA myeloma; 29% achieved a complete response (CR), of which 66% were in stringent CR (sCR). To date 520 of these 647 patients have relapsed (80%) and of these 96% (503/520) had abnormal FLC levels at relapse. In 6% of patients (N=31, 4.4% of IgG and 9.8% of IgA paraprotein MM patients) relapse was characterised by FLC escape.The median OS of patients with FLC escape was approximately 12 months shorter compared to patients relapsing with a whole paraprotein. This was mostly attributable to a significantly shorter survival from relapse (19.2 vs 32 months, p=0.013). When looking at FLC escape according to the isotype of paraprotein at diagnosis, we found that IgG patients had the worse survival from relapse (median survival 9.9 vs 33.6 months for FLC escape and normal relapse respectively, p=0.019). In contrast the outcome of IgA patients was not significantly influenced by the presence of FLC escape (median survival post relapse 20.3 vs 28.7 respectively, p=0.425). A Cox regression analysis including maximum response, age, paraprotein isotype, treatment pathway, thalidomide therapy and the type of relapse identified a maximum response <VGPR, an IgA paraprotein, non intensive treatment and a relapse with FLC escape as variables independently associated with a reduced OS (Table 1). ConclusionsMonitoring for light chain escape at relapse provides an excellent tool to study the global impact of intra-clonal heterogeneity. Our observations fit with a model in which different clones have a different secretory behaviour. One clone is able to produce a complete antibody, while the other secretes only FLC. In such a model FLC escape is a marker of a heterogeneous disease and represents the outgrowth of the clone producing only light chains, which is more resistant to therapy. The results presented here provide evidence to support the idea that intra-clonal heterogeneity and clonal evolution is a general feature associated with disease progression and treatment resistance in myeloma. These results also illustrate the importance of disease monitoring using FLC analysis when there is a suspicion of clinical relapse. Disclosures:Cavo:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Morgan:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Chromosome 1q21 Gains Confer Inferior Outcomes In Multiple Myeloma Treated With Bortezomib But Copy Number Variation and Percentage Of Plasma Cells Involved Have No Additional Prognostic Value

BackgroundChromosome 1q21 aberrations have not been implemented into the routine clinical test yet, and their effect in multiple myeloma is still under investigation. Heterogeneity exists among patients presenting 1q21 gains, e.g., variation in the copy numbers and the size of clone carrying 1q21 gains. The prognostic value of copy number variation and percentage of plasma cells involved remained unclear. Materials and MethodsIn the present study, we analyzed the prognostic value of 1q21 in a in a series of 290 cases of newly diagnosed multiple myeloma treated in a prospective, nonrandomized clinical trial (BDH 2008/02). ResultsThe incidence of patients carrying at least three copies of 1q21 was significantly higher in relapsed MM than in newly diagnosed MM (73 out of 107 [68.2%] vs. 142 out of 290 [48.9%], p=0.001). Among the whole cohort, 278 newly diagnosed MM and 102 relapsed MM had copy number variation information. No statistical difference in the frequency of three, four, or at least five copies copies of 1q21 was found between relapsed and initially diagnosed cases.1q21 gains showed a profoundly negative impact on survival in patients receiving bortezomib treatment. Patients with 1q21 gains had a significantly shortened PFS (13.5 months vs. 43.0 months, p<0.001) and OS (24.0 months vs. 54.0 months, p<0.001) than patients with two copies of 1q21. Further investigation of the impact of copy number variation on survival indicated that the median PFS of patients who had three, four, or at least five copies of 1q21 were 14.0 months (95% CI: 8.07-19.93), 14.0 months (95% CI: 5.47-22.53), and 10.0 months (95% CI: 4.12-15.88), respectively. The median OS of patients who had three and four copies were 24.0 months (95% CI: 11.85-36.14) and 30.0 months (95% CI: 18.14-41.85) respectively, while the OS of patients with at least five copies was not obtained due to the small sample size; no statistically significant differences were found. When the patients with four and five copies were analyzed as a whole, i.e., as one group of patients with at least four copies, patients with at least four copies of 1q21 also exhibited a comparable PFS (14.0 months vs.10.0 months, p=0.737) and OS (24.0 months vs. 30.0 months, p=0.382), compared with patients harboring three copies of 1q21.Patients with 1q21 gains were divided into two groups according to the percentage of plasma cells involved, i.e., 20%-50% and >50%, which were seen respectively in 28/290 (9.7%) and 114/290 (43.8%) patients with newly diagnosed MM. The median PFS was 6.0 months (95% CI: 1.00-21.5) and 13.5 months (95% CI: 8.87-18.14) respectively, and median OS was 6.0 months (95% CI: 1.00-21.49) and 24.0 months (95% CI: 18.94-29.05) respectively. The difference in PFS and OS were not statistically significant between the two groups (p=0.753 and 0.273 respectively;).No statistically significant differences were found in patients harboring 1q21 gains between bortezomib-based and thalidomide-based chemotherapy groups, and the median PFS and OS in patients receiving bortezomib-based regimens were 13.5 months (vs. 20.0 months; p=0.176) and 24.0 months (vs. 21.0 months; p=0.773) respectively. Therefore, bortezomib was unable to overcome the negative impact of 1q21 gains on survival, and to significantly improve the survival of these patients. ConclusionOur data demonstrated that copy numbers of 1q21 increased with progression of myeloma and predicted a poor prognosis in MM patients treated with bortezomib-based therapy. Our results also indicate that three copies of 1q21 gains and 20% of plasma cells with this abnormality were enough to confer bortezomib resistance. Chromosome 1q21 gains should be considered a high-risk feature in MM, and 1q21 analysis should be added to the diagnostic panel of FISH probes used in routine assessment of prognosis in patients with MM, especially those receiving bortezomib-based regimens. Disclosures:No relevant conflicts of interest to declare.

Individually Tailored Treatment Strategies For Frail Myeloma Patients In Japan

BackgroundHistorically, treatment decision of multiple myeloma (MM) has been largely based on age, and elderly patients with comorbidities are often excluded from clinical trials. Although tailored therapy is implicated to be inevitable for these patients, no data are available that account for assessing vulnerability of MM patients, especially of elderly. In order to explore a useful index to screen patients with Japanese MM patients leading to a proper individualized therapy based on our daily clinical practice, we analyzed our local urban area patients. MethodsWe conducted a retrospective analysis of 77 patients (40 male, 37 female) who were diagnosed between June 2009 and November 2012 in two core hospitals in Kitakyushu city. Patients were stratified by age (<65, 65-75 or >75 years), ISS (1, 2 or 3) and FCI (0, 1 or ≥2) consisting of renal impairment, pulmonary disease and performance status. ResultsThe median PFS and OS are not significantly different among patients aged <65, 65-75 or >75 years. The median OS of patients with ISS = 1 and 2 was significantly better than that with ISS = 3 patients (525, 583 and 319 days, respectively; p = 0.03, 0.04), but there was no significant difference between ISS = 1 and 2. These indicate that age and ISS are not applicable to prognostic prediction by themselves for MM patients in the novel agent era. When patients were stratified by FCI, 36 out of 77 patients were subdivided into FCI = 0, 35 into FCI = 1, and 6 into FCI ≥ 2. Combination of three risk factors identified significantly different median OS between FCI = 0 and FCI=1 (533 and 377 days; p = 0.03). Significance was alsofound in PFS between FCI = 0 and FCI = 1 (p = 0.02) and between FCI = 0 and FCI ≥ 2 (p = 0.01). When we examined factors involved in FCI in detail, KPS, rather than renal or pulmonary dysfunction, was found to be a more reliable prognostic factor of FCI.Then we examined prospectively to verify the applicability of this result. An 88-year-old Japanese woman was referred to our institute with a left-sided bone pain with fever. Disease stage was stage II according to the ISS. FCI score was 0, assessed by KPS, renal function and pulmonary function. She was first treated by MP (melphalan of 8 mg/day and prednisone or 30 mg/day) according to a conventional strategy based on age, but this regimen was unsuccessful because of refractoriness. Then she received 10 mg/day of Lenelidomide and 20 mg/day of dexamethasone. The clinical symptoms were improved during the first cycle of Len+Dex treatment. This result indicates the importance of quantifying frailty for clinical management of MM. ConclusionIn this study we provide an evidence for the utilization of comorbidity assessment in MM patients and facilitate treatment, in the extent of retrospective analysis. We suggest that assessing the frailty, rather than chronological age alone, may allow us to better define each patient's condition and tolerability for the treatment. Deciding treatment strategy of patients with MM inthe era of novel agents, we recommend considering patient's frailty which intensely influences patient treatment outcome, and we are eager to develop a simple and powerful method for estimating frailty which can be utilized in our busy clinical practice, named as Kyushu Comorbidity Index (KCI). Disclosures:No relevant conflicts of interest to declare.

The Blood Neutrophil-to-lymphocyte Ratio Predicts Survival in Patients with Advanced Hepatocellular Carcinoma Receiving Sorafenib

Increasing evidence correlates the presence of systemic inflammation with poor survival in patients with hepatocellular carcinoma (HCC). The aim of this study was to investigate the prognostic significance of the blood neutrophil-to-lymphocyte ratio (NLR) in patients with advanced HCC who received sorafenib monotherapy. A total of sixty-five patients with advanced HCC, not eligible for locoregional therapy, treated with sorafenib were enrolled. Potential prognostic factors such as age, gender, tumoral characteristics, performance status and NLR were analyzed. Median OS and TTP for the entire cohort were 10.0 months (95%CI, 7.6-12.3 months) and 4.5 months (95% CI, 4.0-4.9 months). The mean NLR at baseline was 2.89. The median OS of patients with a high NLR (>4) was 6.5 months (95%CI, 5.2-7.7 months) compared with 12.5 months (95%CI, 9.9-15.0) for patients with a normal NLR (≤ 4) (P = 0.01). Age ≤ 65, NLR >4, extrahepatic metastases and vascular invasion were all predictors of poorer overall survival. Multivariate analysis showed that NLR > 4, vascular invasion and extrahepatic metastases were independent predictors of poorer overall survival. The median TTP of patients with a high NLR was 2.5 months (95%CI, 1.4-3.6 months) compared with 4.5 months (95%CI, 3.9-5.1 months) for patients with a normal NLR (P=0.012). High baseline NLR was associated with worse OS and TTP for patients with advanced HCC treated with sorafenib.

Outcome and prognostic factors in BRAF mutation positive metastatic melanoma treated with a BRAF inhibitor: A population-based study in British Columbia.

e20045 Background: BRAF mutations are present in approximately 40-60% of cutaneous melanomas. The BRAF inhibitor vemurafenib has demonstrated dramatic anti-tumour activity in phase III trials in BRAF mutation positive (BRAFm) metastatic/unresectable melanoma; however, there is limited data outside of clinical trials. Methods: All patients &gt; 18 years of age, PS 0-2, with metastatic/unresectable melanoma considered for treatment with vemurafenib in British Columbia between March 2011 to December 2012 were identified. CNS disease, if present, had to be radiographically stable/asymptomatic and treated with radiation and/or surgery. The BRAF V600E mutation status was evaluated centrally on primary or metastatic biopsies using a real-time PCR assay (Cobas 4800 BRAF Mutation Test, Roche Molecular Systems). Vemurafenib was initially provided through an Expanded Access Program/Roche patient assistance program and subsequently through provincial funding. Results: In total, 84 patients were identified that had undergone BRAF mutation screening, 49(58%) were BRAFm, 35(42%) were BRAFwt. For the BRAFm patients 33 have received 1 cycle of vemurafenib and are included in the present analysis (n=21 (64%) 1st line therapy; 12(36%) &gt; 1st line therapy). BRAFm patients: median age 53 y; 64% male; PS 0/1 76%; LDH elevated 51.5%; M1c 91%; 27% history CNS metastases. With a median follow-up of 4.9 m the median PFS, measured from the 1st dose of vemurafenib, was 9 m and the median OS was 12.4 m. The 1 year PFS and OS were 47% and 50%, respectively. The median OS of patients who progressed following vemurafenib was only 2 months. There was an inferior PFS in patients with an elevated LDH (median PFS 5 m vs not reached, p=0.024) prior to receiving vemurafenib. Conclusions: The efficacy of vemurafenibin BRAF + melanoma in this population-based analysis compares favorably to estimates in the clinical trial setting. The survival of patients who progress on vemurafenib is short, highlighting the need to explore combination therapies. An updated analysis will be presented.

Human Telomerase Reverse Transcriptase (hTERT): A New Potential Prognostic Marker in AML?

AbstractAbstract 4790Our study, was aimed at establishing whether hTERT expression correlates with karyotype complexity, molecular findings, clinico-biological parameters, and has any prognostic impact. The 90 de novo AML patients included within the present study came at our Institution within a three-years period (January 2008 – January 2011). They were 37 females and 53 males with a median age of 59 years (range 18–84). According to WHO classification 4 (4.4%) patients were classified as M0/M1, 43 (47.8%) as M2, 37 (41.1%) as M4, 5 (5.5%) as M5 and one as M6. Fifty-one (56.6%) presented a normal karyotype (NK) and 39 (43.45) a CK (≥3 defects); the two patient groups were comparable by age. An internal tandem duplication (ITD) of the FLT3 gene and a NPM1 mutation were revealed in 12 and 2 chromosomally normal patients. No CK presented a FLT3 ITD. All patients received standard induction chemotherapy followed by two courses of consolidation treatment. At the time of the study 38 patients achieved a complete remission (CR) and 36 died. Median follow-up was 19.1 months (range: 11.5–58.6). hTERT expression was determined on patients bone marrow samples and 26 unselected cord blood (CB) cells (internal controls) by real-time reverse transcriptase PCR with SYBR Green I. Primers, designed using BLAST (http//www.ncbi.nlm.nih.gov/BLAST/), were complementary to hTERT exon 13 and allowed amplification of all transcripts coding for TA active and inactive forms. hTERT expression was normalized against the ABL gene and relative quantification was made using the 2ΔΔCt method. At clinical diagnosis NK and CK presented a significantly different median hTERT expression: 1.91 (range 0.9–5.54) versus 5.19 (range 2.37–21.1) p<0.001. This difference remained significant even when age was considered. Interestingly, the median hTERT expression of NKs was significantly different from that of CB cells (1.91 versus 10.31, p<0.0001) which median hTERT expression was similar to that of CKs. In order to perform statistical analysis, hTERT expression was dichotomized using the median value (3.12; 95% Confidence Intervals: 2.14–4.85) as the cut-off value. A low hTERT expression (<3.12, LE) was associated with a median white blood cell count significantly higher than that associated with a high hTERT expression (≥3.12, HE): 12.0×109/l (range: 7.3–58.0) versus 9.9×109/l (range 2.8–18.3) (p=0.02). No significant difference for other clinical parameters was noted. A high hTERT expression was never associated with a FLT3 ITD mutation. Although the median OS of patients with LE and HE was 17.4 months (range: 7.7- not reached) versus 10.2 months (4.2–22.9), a long-rank test revealed a only trend toward a statistical significant difference (p=0.09). Patients with a high hTERT expression showed a HR=1.6 (95% CI=0.9–2.8). When the analysis was adjusted for karyotype, this variable maintained its statistical power (p<0.001). CR was achieved in 22 patients with LE versus 16 patients with HE: median time to CR achievement was 1.3 months (range 1.1–3.0) versus 3.6 months (range 1.5–37.3). When a long-rank test was applied, a significant difference between LE and HE groups became apparent (p<0.02). Instead, no significant difference between these two patient groups was noted when CR duration and relapse were considered. In conclusion, i) the significant correlation between a high hTERT expression and CKs may account for AML genetic instability which may prevent leukemic cells from replicative senescence and may promote clonal selection; ii) a high hTERT expression may be an additional prognostic marker as it significantly lowers the probability of CR achievement and determines an OS and DFS shorter, although not significantly shorter, than those associated with low hTERT expression. Disclosures:No relevant conflicts of interest to declare.

Treatment outcomes of peritoneal carcinomatosis arising from gastric cancer with no measurable disease using systemic chemotherapy.

e14558 Background: Although many clinical trials of newly developed chemotherapeutic drugs have been conducted, limited studies have focused on gastric cancer patients specifically diagnosed with peritoneal carcinomatosis (PC) without measurable regions. In the current study, we characterized the outcomes of systemic chemotherapy and prognostic factors for patients with gastric cancer PC, particularly in cases without measurable disease. Methods: Clinical data from 211 gastric cancer PC patients (137 without and 74 with measurable disease) subjected to systemic chemotherapy between January 2000 and December 2010 at a single center were reviewed. Results: Median OS rates of gastric cancer PC patients with no measurable disease were significantly longer than those of patients with measurable disease (18.2 vs 12.0 months, p=0.011). In multivariate analysis, poor PS (Hazard ratio (HR) = 2.33, 95% CI, 1.42-3.8, P=0.001), presence of metastatic lymphadenopathy (LAP) (HR=2.23, 95% CI, 1.42-3.5, p=0.002) and high-grade PC (HR=1.82, 95% CI, 1.09-3.04, p=0.025) were associated with significantly decreased OS. Combined with clinical PC grade and measurability of disease, median OS of patients with low-grade PC without measurable disease was 19.6 months (95% CI, 15.5-23.7 months). Median OS rates of 12.6, 13.7 and 6.8 months were estimated in high-grade PC without measurable disease, low-grade PC with measurable disease, and high-grade PC with measurable disease, respectively. Median OS of low-grade PC patients with no measurable disease was significantly higher than that of patients in all other groups (p=0.001, p=0.029 and p&lt;0.001, respectively). Conclusions: Gastric cancer PC is a heterogeneous disease entity. In our study, clinically low-grade PC without measurable disease was associated with better outcomes than other groups following systemic chemotherapy. According to the carcinomatosis grade, specific groups of patients may benefit from systemic chemotherapy. Despite the difficulties of response assessment, further clinical trials for newer treatment strategies and molecular studies focusing on the heterogeneity of gastric cancer PC should be introduced.

Second-line treatment of metastatic renal cell carcinoma: The Institut Gustave Roussy experience with targeted therapies in 251 consecutive patients.

e15049 Background: Sequential treatment is currently the standard of care in metastatic renal cell carcinoma (mRCC). However, very little is known on how many patients (pts) can receive second line or further, and on how to predict those pts. Methods: Data from all mRCC patients treated at the IGR from 2005 to 2009 with first-line targeted therapy (sunitinib (SU), sorafenib (SO), bevacizumab (B), temsirolimus or everolimus (pooled together as mTOR)) were analyzed. Only patients with subsequent follow up have been included in this analysis. Patients were defined as “non eligible” for second treatment if: they were (i) still on first line treatment, (ii) not showing progressive (durable stable disease or partial response or complete response), or (iii) if they refused a second line treatment. Results: 251 patients, median age 60 years, median follow-up 20.2 months were treated with targeted therapy with a median OS of 25.8 months. Median OS with SU (127), SO (60) or B (61) were respectively 26.3, 16.4 and 32.5 months respectively. Only 3 patients received an mTOR inhibitor as first line. According to the eligibility criteria, the percentage of patients who received a second line was 59% (n=61/103), 52% (n=30/58) and 79% (n=38/48) for Su, So and B, respectively. MSKCC classification (p = 0.02) and first line agent (p = 0.001) were significant predictive factor for receiving a second line of treatment. Overall, patients receiving B were in better general condition, with 77% of PS = 0 compared to SO (53%) and SU (48%) (p = 0.005). Among the 131 patients who received a second line, the median OS from the start of second line treatment was 20.8 months for a TKI (n=98; 75%) and 16.6 months for an mTOR (n=32; 42%) (p = 0.12). Furthermore, the percentage of patients who received a third line was 56% (27/48), 28% (7/25) and 65% (13/20) for SU, SO and B, respectively. Conclusions: The median OS in patients treated with targeted therapies for mRCC in The Institut Gustave Roussy exceeds 2 years. The use of second line varies from 52% to 79%. Further studies are needed to validate the MSKCC groups and first line therapy as predictive factor for 2nd line treatment.

Systemic inflammatory response to predict clinical outcome in patients with resected pancreatic cancer treated with adjuvant gemcitabine monotherapy.

223 Background: Systemic inflammatory response (SIR) has been shown to associate with poor outcome in either inoperable or operable pancreatic cancer. However, whether the presence of a SIR predicts poor clinical outcome of pancreatic cancer patients in adjuvant setting is unclear. The aim of present study was to determine the relationship between SIR, as evaluated by Modified Glasgow prognostic score (mGPS), and outcome of pancreatic cancer patients treated with adjuvant chemotherapy. Methods: A total of 42 resected pancreatic cancer patients were analyzed for mGPS before adjuvant gemcitabine chemotherapy. The mGPS was constructed as follows: patients with both an elevated C-reactive protein (&gt; 0.3mg/dl) and hypoalbuminaemia (&lt; 3.5mg/dl) were allocated a score of 2. Patients with one or none of these abnormalities were allocated a score of 1or 0, respectively. Results: There were 25 patients assigned to score 0, 12 patients to score 1, and 5 patients to score 2. The median OS in patients with score 0, score 1, and score 2 were 23.9 months, 10.3 months, and 9.9 months, respectively. The DFS in patients with score 0, score 1, and score 2 were 11.0 months, 5.9 months, and 3.6 months, respectively. The OS and DFS after surgery of the patients with SIR (score 1 and 2) were significantly poorer than that of the patients with score 0 (P=0.0278 for OS, P=0.0011 for DFS by log-rank test). Conclusions: The presence of SIR, as evaluated by Modified Glasgow prognostic score (mGPS), predicts poor clinical outcome in resected pancreatic cancer patients treated with adjuvant gemcitabine monotherapy.

Molecular Detection of Minimal Residual Disease Based on NPM1-Real-Time PCR At the Time of Complete Remission Is a Strong Predictor of Disease Free and Overall Survival in AML

Abstract 1445 Introduction:Several recently identified molecular markers, i.e. FLT3-ITD, NPM1 and CEBPA and a number of others, have completely redefined our understanding of disease development in patients with acute myeloid leukemia and have already profound effects on risk assessment and treatment in AML. In addition, some of these novel markers, especially NPM1 -mutations, can be very efficiently used to detect minimal residual disease (MRD). In this study we investigated the suitability of NPM1 as MRD-marker, evaluated optimal cut-off points to define molecular relapse and analyzed the impact of MRD and additional risk factors on survival in a large cohort of patients with AML. Methods: The study population consisted of 164 NPM1 -mutant AML patients (pts) (median age 51 yrs. (range, 20–79 yrs.)), having one of the three most common NPM1 -mutations, A (N=139), B (N=16) and D (N=9). The patients were treated in protocols of the Study Alliance Leukemia (SAL) and were prospectively monitored. Consolidation treatment included autologous (N=18) and allogeneic transplantation from HLA-matched related (N=20) and unrelated (N=21) donors. An optimized assay for the sensitive cDNA based detection of the three most common NPM1-mutations using a Real-Time-Q-PCR based on locked-nucleic acid (LNA) containing primers was used. MRD-levels were expressed as percent of ABL1 -copies, which was assessed in all samples to control for sample quality. Results: Of the primary group, 154 patients were available for further analysis, 10 patients did not achieve CR and were excluded. A total of 1671 samples (972 BM; 699 PBL) were analyzed, the median number of samples per patient was 8 (range, 3–59), PBL and BM were analyzed in parallel at 138 time points. Although in general the median NPM1 levels in PBL samples were alsmost one log10 lower, a good qualitative concordance was found between both sources, with 48.6% of the samples being positive and 34.1% negative in both materials, whereas BM was pos. and PBL neg. in 14.5% and PBL pos and BM neg. in 2.9% of the samples, respectively. Using receiver operator characteristic (ROC) curves and regression models, the optimal cut-off value for detection of subsequent clinical relapse was found to be 1% NPM1/ABL1. In a competing risk analysis using Gray’s algorithm, the cumulative incidence of relapse in patients >1% and <=1% at twelve months was 34.8% [95% CI: 18.4–51.2%] vs. 7.7% [95% CI: 0–16.1%] (p=.0007). We also analyzed, whether the level of MRD at the time of achievement of CR had an impact on outcome. Both, NPM1 -MRD negativity and MRD-values below 1% were associated with significantly improved disease free (DFS) and overall (OS) survival, e.g. median OS in patients with NPM1 >1%: 20.2 months vs. NPM1 <1% not reached (p=.003), median DFS 13.6 months [95% CI: 9.7-35.3 mo] vs. 61.1 months [95% CI: 27.3 mo -not reached] (p=.0003). Not surprisingly, when we further differentiated the NPM1- positive patients into FLT3-ITD positive and negative, the subgroup of patients with FLT3-ITD andNPM1 >1% was associated with the poorest outcome. Conclusions: Our data clearly support the reported strong predictive value of NPM1 -positivity for the detection of relapse. In addition, our data show that the quality of CR as assessed by molecular methods profoundly affects long term outcome. Taken together, in NPM1 positive patients, MRD should be prospectively monitored to detect impeding relapse and to potentially start preemptive therapy, e.g. treatment with 5-Azacytidine or allo-SCT in eligible patients. Disclosures:Thiede:AgenDix GmbH: Employment, Equity Ownership. Platzbecker:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract A112: Postoperative prognostic predictors of pancreatic ductal adenocarcinoma: Clinical analysis and immunoprofile on tissue microarrays

Abstract Background: The most of pancreatic ductal adenocarcinomas metastasize even after curative resection. Our goals were to investigate the important factors affecting metastasis and overall survival. Patients and methods: We studied 88 PDACs with R0 resection and evaluated immunohistochemical markers on tissue microarrays to assess the expression levels of the following: EGFR, amphiregulin, VEGF, p-c-met, MMP2, MMP7, MMP9, CXCR3 and CXCR4. Results: The median OS in patients who had positive vs. negative expression of AREG and MMP9 were 25 vs. 16mo and 24 vs. 13mo respectively (p=0.03, p=0.006). However, the median OS in patients with positive vs. negative expression of MMP2 was 22 vs. 37mo (p=0.04). Adjuvant treatment, postoperative decrement of CA 19–9, angiolymphatic invasion, AREG and MMP2 were independent prognostic factors affecting OS in multivariate analysis. Immunoprofiles revealed that patients with positive expression of p-c-met or VEGF had significantly shorter distant metastasis free survival. Conclusions: Immunoprofiles revealed the groups with unfavorable tumor biology: negative expression of AREG and positive expression of MMP2. Also, high immunoreactivity of p-c-met or VEGF can be considered as indicators of early distant organ metastasis. These results may give us useful insights in choosing adjuvant treatment modalities and understanding the patterns of PDAC dissemination. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A112.

The significance of progression-free survival as an endpoint in evaluating the therapeutic value of antineoplastic agents

In the last decade, thanks to the development of new and effective cytotoxic and biologic agents, significant progress has been achieved in the treatment of various forms of cancer. These new treatments, consisting of novel combinations of compounds, have contributed to significant increases in progression-free survival (pfs) and overall survival (os) for patients. Nowhere has this progress been more apparent than in the overall improved efficacy in the treatment of what were traditionally very resistant tumours—for example, metastatic colorectal cancer. The earlier fluoropyrimidine-based monotherapies were associated with a median survival of 12 months. However, the availability of new cytotoxic agents (oxaliplatin, irinotecan, and new biologic agents with anti–vascular endothelial growth factor and anti–epidermal growth factor receptor effects), coupled with the implementation of sequential doublet combination chemotherapies, has increased median os in patients to more than 24 months. Similar advances have also been demonstrated in other traditionally resistant tumour sites such as renal cell carcinoma, malignant melanoma, and ovarian cancer. Although a welcome development, the availability of multiple lines of therapy leading to an overall increase in survival has also led to new challenges in the evaluation of specific lines of therapy, particularly when those therapies are associated with crossover or contamination effects from other available therapies. Such occurrences are so frequent that the approval of new agents and combinations has also become more challenging to regulatory agencies, because it becomes more difficult to tease out survival benefits for any specific or individual line of therapy. Continued reliance on os as an endpoint therefore limits the ability to evaluate new therapies when multiple lines of treatment are available to the patient and are regularly offered as therapy. The lack of consensus surrounding new antineoplastic therapies centres on the question of which endpoints are appropriate and valid in evaluating new treatments. The retention of os, considered the “gold standard,” as the primary endpoint for the evaluation of therapies has led, in many cases, to an inability to assess certain drugs for approval, difficulties in establishing new standards of care and evidence-based clinical guidelines, and delays in the approval of effective new therapies. In the meantime, failure to approve valuable new compounds in a timely fashion may result in suboptimal treatment for cancer patients. To address those issues, leading Canadian and international clinicians, statisticians, and researchers participated in several workshops to discuss the most appropriate endpoints for the evaluation of each line of therapy. The participants discussed the value of pfs as a valid and realistic endpoint for tumour sites in which they are experts. Those workshops led to pfs being identified to be as realistic an endpoint as the “gold standard” os. The proceedings of three workshops, organized under the auspices of the Canadian Oncology Societies (COS) and the Canadian Association of Medical Oncologists (CAMO) in cooperation with the Canadian Urological Oncology Group (CUOG) and with members of the Society of Gynecologic Oncologists of Canada, are published herein, thus providing a Canadian perspective to this important ongoing debate. The separate issue of whether pfs can be accepted as a surrogate for os was also discussed. However, that question has its own challenges because of the confounding effects of having to rely on older clinical trials with drugs that do not reflect current standard practice and of having to deal with variations in the statistical interpretation of the data. Despite those limitations, most experts believed that pfs could be a surrogate for os. However, it is important to emphasize that, even if pfs is considered a relevant and valid endpoint, its implementation requires rigorous application criteria as outlined in the discussions. In the articles that follow, pfs is discussed in relation to three tumour sites: colorectal cancer, renal cell carcinoma, and ovarian cancer. Further discussions are ongoing in lung cancer, malignant melanoma, and neuroendocrine tumours, which have traditionally been resistant to therapy. The use of pfs as an evaluation endpoint is contributing to a demonstration of the effectiveness of several compounds. We hope that publication of this Canadian perspective on the relevance of pfs as a valid endpoint in therapy at specific tumour sites will initiate further debate between experts and regulatory agencies, and will result in resolution of the pertinent issues. Ultimately, recognition of pfs as an endpoint by regulatory agencies and experts could have a significant impact on the welfare of cancer patients by providing earlier access to new and effective therapies. We hope that the overview provided here will act as a stimulus to this emerging debate. We welcome your views and comments on this important discussion.