Multiple Lines Of Therapy Research Articles

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.

Experience of first- and subsequent-line systemic therapy in the treatment of non-small cell lung cancer

The treatment of advanced non-small cell cancer (NSCLC) has changed with multiple new treatment algorithms proposed based on histological and molecular subtyping but low mutation rates will ensure the dominance of cytotoxic chemotherapy. Accordingly, we undertook a detailed review of our practice delivering multiple lines of systemic therapy. We undertook a retrospective review of consecutive patients presenting with advanced (stage IIIb/IV) NSCLC treated with systemic therapy at two UK hospitals during a 2-year period, January 2007 to December 2008. A total of 130 patients were identified, treated with predominantly carboplatin/gemcitabine (20 initially radically). Fifty of 110 patients (45%) treated with first-line systemic therapy subsequently received second-line therapy, of which 10 patients received third-line and two patients fourth-line therapy. Sixty three of 110 first-line patients (58%) achieved clinical benefit, 19 out of 50 (38%) in the second-line, 6 out of 10 (60%) in third-line but both patients progressed at fourth-line. Median overall survival for 110 patients was 10 months (95% confidence interval [CI] 8.6-11.4); but 16 months (95% CI 14-17.9) in those receiving multiple lines. Median survival from the first cycle of last-line treatment to death in the multiple therapy lines was 5 months (95% CI 2.6-7.3) and the majority of patients spent more time off treatment. Overall our outcomes are consistent with published data and show good survival times can be achieved. The future of advanced NSCLC is in selecting the best treatment approach on a histological and genotypic basis.

Patient (Pt)-reported symptoms of chemotherapy (chemo) and VEGFR/EGFR antibody therapies for the treatment of metastatic colorectal cancer (MCRC) in a U.S. community-based oncology practice network.

575 Background: Targeted therapies for MCRC have increased treatment (Tx) options in multiple therapy lines. Symptoms associated with MCRC Tx have not been well studied from the Pt perspective. Objective: To characterize symptoms reported by MCRC Pts treated with chemotherapy and/or targeted drugs at a large US oncology network. Methods: Pt reported symptom data were linked to electronic medical records and Pt charts from Georgia Cancer Specialists in Southeast US. MCRC Pts aged ≥18 years with ≥1 administration of chemo or targeted therapy between 1/2007-3/2009 were included. Pt reports captured 13 symptoms, onset, and severity. Due to small sample sizes, no statistical comparisons were conducted. Results: 332 MCRC Pts were included (median age 62 years, 47% male, median weight 74 kg, 48% ECOG PS 0 or 1). Amongst Pts receiving 1L Tx (n=299), 78% received bevacizumab (BV) +/- chemo, 4% cetuximab (CX) +/- chemo, 15% chemo only, and 2% other. 162 Pts received 2L Tx: 49% BV +/- chemo, 17% chemo only, 28% CX +/- chemo, and 6% other. The 5 most common symptoms in 1L Tx for all severity ratings were 36% fatigue, 20% nausea, 17% weight (wt) loss, 15% diarrhea, and 9% constipation. The 5 most common symptoms in all 2L Tx groups were 44% fatigue, 27% nausea, 19% diarrhea, 16% wt loss, and 11% abdomen pain. 2L moderate, severe, or disabling symptoms reported in >10% Pts receiving BV +/- chemo, CX +/- chemo, and chemo only Tx are shown in the table. Conclusions: The most commonly reported symptoms by 1L and 2L MCRC Pts were fatigue, nausea, diarrhea, and weight loss. Overall, a numerically higher % of 2L Pts treated with CX +/- chemo reported moderate, severe, and disabling symptoms than Pts receiving BV +/- chemo and chemo alone. Rash was not observed in the BV +/- chemo group. Further research of MCRC Pt reported symptoms in a larger sample size are warranted. [Table: see text] [Table: see text]

Fludarabine and Rituximab (FR) Is a Safe and Effective Treatment Alternative for Relapsed or Refractory Hairy Cell Leukemia (HCL)

Abstract 2454 Background: Purine nucleoside analogs have been shown to produce high remission rates of 75–90% when used as first-line monotherapy for HCL. Long-term studies have shown that remissions may be lasting but are not durable. Median progression-free survival is approximately 8 years. Fludarabine (F) is an attractive option for treatment of relapsed HCL due to its similar mechanism of action, the ability to administer multiple courses for repeated exposure and its oral bioavailability. Rituximab (R) has shown single-agent activity in HCL as well as synergy with fludarabine in vivo. In addition, clinical trials have demonstrated that FR is effective in other indolent B-cell lymphoproliferative disorders. We assessed the tolerability and efficacy of FR for relapsed or refractory HCL. Patients and Methods: The British Columbia Cancer Agency (BCCA) Lymphoid Cancer Database was searched to identify patients treated with FR for relapsed or refractory HCL (F 40 mg/m2/d orally d 1–5 [adjusted for renal function] and R 375 mg/m2 IV d 1, every 28 days for 4 cycles). All cases were centrally reviewed to exclude variant HCL and splenic marginal zone lymphoma. Results: 252 patients with HCL were identified, of whom 90 developed progressive disease after initial therapy (36%). 13 patients were treated with FR between 2004–2009 for relapsed or refractory disease after first-line cladribine (n=2) or after multiple lines of therapy (n=11). Median age at FR was 59 years (range, 46–82 years); 85% of patients were male. Patients were heavily pre-treated with a median of 2 prior systemic treatments (range, 1–5). All patients had received at least 1 course of cladribine; 5 had received 2 courses (38%). Additional systemic treatments included interferon (n= 5, 38%) and deoxycoformycin (n= 4, 31%). A purine analogue was the therapy immediately prior to FR in all patients with cladribine in 11 (85%) and fludarabine alone in 2 (15%). 11 patients had a response to their last course of purine analog therapy, while 2 patients had refractory disease. FR therapy was administered at a median of 12.9 years from diagnosis (range, 3.4 –27.5) and at a median of 58 months from the last therapy (range, 2–155). Prior to FR therapy, the average interval between therapies was 46 months (range, 15–165). Median counts at time of FR were (data missing on 2 patients): hemoglobin 115 g/L (range, 79–145), white blood cell count 2.2 × 109/L (range, 0.9–8.6), lymphocyte count 1.0 × 109/L (range, 0.4–7.14), neutrophil count 1.09 × 109/L (range, 0.3–1.6), and platelets 98 × 109/L (range, 29–203). Patients underwent a median of 4 cycles of FR (range, 2–4) with oral fludarabine well tolerated in all cycles. Treatment was discontinued in 1 patient after 2 cycles due to a hypersensitivity reaction to rituximab and fludarabine was discontinued in 1 patient after 3 cycles due to the development of interstitial lung disease. The latter patient went on to receive a total of 6 rituximab infusions. Herpes zoster occurred in 2 patients, during and 6 months after completion of FR therapy, respectively. No patients required hospitalization during therapy. Information regarding response was available in 10 patients. All 10 patients had complete normalization of peripheral blood counts, absence of abnormal circulating lymphocytes and resolution of splenomegaly if present at initiation of FR. 3 patients had bone marrow biopsies at completion of therapy and all showed an absence of minimal residual disease by immunophenotyping. Currently, 12 patients (92%) remain in remission without further therapy while 1 patient has developed recurrent disease, 31 months after FR. With a median follow-up of 26 months from FR (range, 5–72), progression-free survival is 80% and overall survival 100%. Conclusion: In this multiply relapsed and heavily pre-treated group of patients with HCL, including patients previously exposed to purine analog therapy, the combination of oral fludarabine and rituximab was well tolerated, safe and effective. FR is a reasonable treatment option for patients with relapsed or refractory HCL. Disclosures: Off Label Use: Rituximab is being included because of previously documented phase II clinical trial activity against hairy cell leukemia.

Single Center Experience with Rituximab as First Line Immunosuppression Regimen for Acquired Hemophilia

AbstractAbstract 1419The use of Rituximab (R), a chimeric monoclonal antibody against CD20, has been reported in the treatment of various non-neoplastic immune disorders including Acquired Hemophilia (AH). Approximately 1/3 of patients with AH are refractory to traditional immunosuppressive regimens (e.g. prednisone/cyclophosphamide) and therefore R has been advocated as an initial therapeutic option. When R is utilized in the treatment of AH it has typically been paired with corticosteroids. However, there is considerable morbidity associated with prolonged courses of corticosteroids in what is typically an elderly patient population. Published case series investigating single agent R have been limited to very small numbers of cases. Therefore, we investigated the use of single agent R as the first line immunosuppressive regimen in patients with AH. Methods:We identified all patients evaluated at the University of North Carolina for AH from 8/2005 until 8/2010. Demographic data and clinical characteristics were available for all patients. Complete remission (CR) was defined as FVIII:c >70 IU/dL or Bethesda Inhibitor Unit (BIU) titer of 0. Results:Our single center experience includes data on 22 patients with an average age of 76 years (range 52–92). 55% were male and 59% self identified as Caucasian and 18% African American. 86% were diagnosed during the course of an inpatient admission to our medical center. The remaining patients were clinic referrals that completed their evaluation and treatment as outpatients.At diagnosis the average BIU titer was 193 BU/mL (range 1–1148, median 49.5, IQR 17.8–177.8) and the average FVIII:c was 3.5 IU/dL (range 0–25, median 1.0, IQR 0–5.3). The average time from onset of symptoms (hemorrhage, elevated aPTT, etc) to diagnosis was 27 days (range 1–240, median 14, IQR 7–26.3). The following associated conditions were noted: a) infection (4.2%), b) past malignancy (12.5%), c) active or suspected malignancy (25%), d) autoimmune disorder (25%), and e) idiopathic (33.3%). Notably our series includes no cases of postpartum AH.Of these 22 patients, 2 were lost to follow-up after their initial hospitalization. Six additional patients died during their initial hospitalization or were discharged to hospice (unrelated to their response to immunosuppressive treatment). Notably, there were no statistically significant differences between these groups in regards to baseline FVIII levels or BIU titers. Fourteen patients were therefore evaluable for response to an initial immunosuppressive regimen. Of these, 12 received R as a single agent, 1 received a combination of R and prednisone (initiated prior to referral), and 1 received prednisone and cyclophosphamide. Of the 12 individuals who received R alone, 7/12 achieved a CR with 1 additional patient (who is under active follow-up) achieving a PR. The remaining 4 patients required additional immunosuppressive agents to achieve a CR (most commonly cyclophosphamide, although one patient required both cyclophosphamide and another course of R). Additional immunosuppressive agents were employed when BIU titer was not felt to be responding adequately. One of these 4 relapsed after an initial CR had been achieved.Those patients who achieved a CR or PR on R alone had an average baseline BIU titer of 51 (range 1–163, median 22, IQR 5.3–112.8) vs. those who achieved CR with multiple lines of therapy who had an average initial BIU titer of 712 (range 34–1148, median 833.5, IQR 192.8–1111). This difference was statistically significant (p=0.0283). There was no significant difference in baseline FVIII levels between these two groups. Approximated time to CR was also not statistically significant between the two groups (median 127 vs. 258 days, p=0.1274). No significant adverse reactions were encountered in patients treated with R. Conclusion:R appears to be an effective single agent immunosuppressive agent in AH with little morbidity, especially in patients with baseline BIU titers <150. Additional agents may be indicated for patients with higher baseline titers. This appears to be the largest single center experience with first line immunosuppression in AH with single agent R described to date. Disclosures:No relevant conflicts of interest to declare.

Guesstimates are not good enough for determining what is happening in routine care

Guesstimates are not good enough for determining what is happening in routine care

KRAS Mutation in Colon Cancer: A Marker of Resistance to EGFR-I Therapy

Introduction and DesignThe introduction of the epidermal growth factor receptor inhibitors (EGFR-I) has increased the treatment options available for patients with metastatic colorectal cancer (mCRC). Two EGFR-I agents currently approved for the treatment of mCRC are the fully human monoclonal antibody panitumumab and the mouse-human chimeric monoclonal antibody cetuximab. While these agents have demonstrated activity across multiple lines of therapy, early studies suggested that clinical benefit was confined to a subset of patients treated. Mutation of the KRAS oncogene has emerged as a powerful negative predictive biomarker to identify patients with mCRC who do not benefit from EGFR-I therapy. Multiple retrospective analyses have demonstrated that clinical benefit from treatment with EGFR-I is limited to patients with tumors harboring the wild-type KRAS gene. In this review, the KRAS pathway and studies evaluating KRAS as a prognostic marker in CRC are discussed along with advances in KRAS gene mutation testing. Clinical trials evaluating the role of KRAS status in response to EGFR-I monotherapy or in combination with chemotherapy are also highlighted along with ongoing studies evaluating the role of EGFR-I treatment on curative resections rates.Results and ConclusionFuture studies investigating EGFR-I therapy in mCRC should incorporate KRAS mutation testing into the study protocol in order to more accurately determine the patient population that will obtain clinical benefit from these novel agents.

Two Distinct Syndromes of Lymphoma-Associated Amyloidosis: Findings From a Case Series.

Abstract 2938 Poster Board II-914 Introduction: Light chain (AL) amyloidosis has a rare but recognized association with non-Hodgkin lymphoma; however, limited information regarding this association exists. We present the clinical features and outcomes of patients with lymphoma -associated AL amyloidosis identified at Princess Margaret Hospital (PMH). We describe two distinct syndromes of lymphoma-associated amyloidosis: 1) peritumoral amyloidosis in which amyloid deposition occurs in the immediate vicinity of the lymphoma and 2) systemic amyloidosis where deposition is in sites remote from the underlying lymphoma. Methods: Cases were identified retrospectively at PMH by survey of hematologists and a pathologist. The International Consensus Criteria (ICC) (Gertz et al., 2005) were used to determine organ involvement by amyloid. Results: We identified 10 patients with lymphoma -associated AL amyloidosis seen between 1997 and 2008. The median age was 69 (52-81) and 50% were female. Five patients had peritumoral amyloidosis. All had extranodal marginal zone lymphoma, MALT subtype (MALT lymphoma).A monoclonal immunoglobulin (M-protein), as determined by serum protein electrophoresis (SPEP) and free light chain (FLC) analysis, was undetectable in two patients, was present in trace amount in two patients and detected but not quantified in a fifth. Of the patients with detectable M-protein, the isotype was IgM in two and IgG in one. Four had lambda light chain restriction while biclonality was questioned in the fifth. All but one patient had single organ involvement by amyloid with lung and soft tissues being the only sites affected. Rectal biopsies and fat pad aspirates, when performed, were negative. Four patients received systemic therapy: two patients were treated with chlorambucil, one received melphalan and prednisone, and one received rituximab, cyclophosphamide, and prednisone followed by rituximab maintenance. Radiographic follow-up of pulmonary lesions in two patients did not identify significant change in lymphoma/amyloid related abnormality. No complete responses were seen. Despite therapy, three patients experienced continuing local symptoms at the site of lymphoma/amyloid involvement while one remained asymptomatic. A fifth patient, untreated at last follow up, was asymptomatic. No patients with peritumoral amyloidosis were found to develop systemic amyloidosis even after a median follow up of 11 months (3-60 mo). The other five patients had lymphoma with systemic amyloidosis. These patients had lymphoma restricted to the bone marrow with histology showing lymphoplasmacytic lymphoma (LPL) in three and small B cell lymphoma with plasmacytic differentiation in two (differential diagnosis LPL vs marginal zone lymphoma). An IgM M-protein was detectable in all five patients. Waldenstrom's macroglobulinemia was therefore present in at least three patients. High levels of M-protein were detected by SPEP in four patients (mean 31 g/L) and FLC analysis in one. Kappa was more common than lambda light chain restriction (3:2). Amyloid was detected in a median of three organs (1-5) including cardiac involvement in four patients. Four patients received multiple lines of therapy with first line being R-CVP in three and ASCT in a fourth. Organ responses, as defined by the ICC, in sites affected by amyloid were not observed. Three of the four treated patients had &gt;50% reductions in M-protein levels, but none had complete haematological response. Response of the underlying lymphoma, which would have required repeat biopsy, was not assessed. Median follow up was 30 months (4-100) with one patient dying of sepsis, one developing therapy-related AML and three surviving with ongoing symptoms of congestive heart failure, dyspnea and/or neuropathy. Conclusions: Lymphoma-associated amyloidosis presents as two distinct syndromes which are associated with characteristic clinical, laboratory and pathologic features. Patients with peritumoural amyloidosis have low level M-protein expression with predominant lambda light chain restriction, symptoms confined to the site of their MALT lymphoma and poor radiological responses to systemic therapy. Patients with systemic amyloidosis have high M-protein levels with a uniform IgM isotype, lymphoma localized to the bone marrow, multiorgan involvement by amyloid and worse outcomes. Future studies aimed at better defining prognosis and optimal treatment in these patients are warranted. Disclosures: Kukreti: Celgene: Honoraria.

Re-Evaluating Duration of Therapy in Advanced Non–Small-Cell Lung Cancer: Is It Really Duration or Is It More About Timing and Exposure?

The optimal therapeutic approach for the individual patient diagnosed with advanced stage IV non–small-cell lung cancer (NSCLC) in 2009 is becoming increasingly difficult to define. Platinum-based doublets have been a mainstay of therapy in the first-line setting since a landmark meta-analysis clearly demonstrated a significant, yet modest, survival benefit compared to best supportive care. The development of several active drugs in patients previously treated with platinum-based doublets has lead to the approval of four agents in the secondand third-line setting: docetaxel, pemetrexed, gefitinib, and erlotinib. The validation of both the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways as therapeutic targets in advanced NSCLC has been an important step in modestly improving outcomes. Scagliotti et al recently showed a therapeutic advantage for pemetrexed and cisplatin compared to gemcitabine and cisplatin in nonsquamous NSCLC. This finding shattered the concept that all platinum-based doublets are created equal. Histology now matters both for the safety of bevacizumab and the efficacy of pemetrexed. Two major questions have been addressed over the past decade or so. One has been the optimal duration of first-line platinum-based therapy in advanced NSCLC. The initial trials addressing this issue were performed because of observations suggesting that responses occurred early (after the first two to three cycles) and because of cumulative toxicity to prolonged therapy. The message from these trials was that survival was not improved by prolonged therapy with platinum-based doublets led to most major guidelines recommending a brief duration (four cycles) in the first-line setting. These trials were done before the validation of both the EGFR and VEGF pathways with cetuximab and bevacizumab where the targeted agent was continued until disease progression. Whether this should be called prolonged therapy or maintenance therapy is a matter of debate. A second question addressed the continuation of therapy with a single agent (which had known activity in advanced, refractory NSCLC) following a defined duration of first-line platinum-based therapy. Many of these trials evaluated agents approved in the secondor third-line setting. Again, whether this is prolonged duration, sequential therapy, maintenance therapy, or early administration of second-line therapy remains a matter of debate. Interestingly, these trials seem to have had a much greater impact on both progression-free survival (PFS) as well as overall survival (OS) compared to the extended use of platinumbased doublets. In practice, first-line therapy with platinum-based doublets is typically delivered for four (maybe six in some cases) cycles. If bevacizumab or cetuximab was part of the original regimen, it would typically be continued until disease progression based on the design of the pivotal trials. There are virtually no data regarding the appropriate surveillance strategy for patients once they have completed first-line therapy (ie, what tests should be done and when, how often should patients be evaluated). There is also no information on the value of a treatment break. Many patients who have significant cumulative toxicities during the first four cycles of therapy often resolve these toxicities with a short break or time off therapy. Second-line therapy administered at the time of disease progression (presumably radiographic or symptomatic) has been demonstrated to improve survival and palliate symptoms. However, many patients never receive such therapy due to rapid disease progression or disease-related events which significantly compromises their performance status. Strategies which would identify disease progression earlier or routine administration of effective second-line therapy at a defined time point may increase the number of patients receiving subsequent lines of therapy. In this issue of Journal of Clinical Oncology, Soon et al provided a very timely and insightful meta-analysis addressing the duration of therapy in advanced NSCLC. They identified 13 randomized clinical trials (comprising 3,027 patients) of varying designs, none of which included bevacizumab or other targeted agents. The authors concluded that extending therapy, particularly with a third generation agent or regimen, substantially improved PFS (hazard ratio [HR], 0.75; 95% CI, 0.69 to 0.81; P .00001) but had a far less dramatic, but still statistically significant, effect on OS (HR, 0.92; 95% CI, 0.86 to 0.99; P .03). Soon et al should be commended for completing this analysis, as it helps us to refocus the issue of treatment strategies in the era of multiple lines of therapy. Several issues with this meta-analysis deserve further consideration. Five of the 13 trials (1,369 patients or 45% of all the patients included in the meta-analysis) simply evaluated the duration of first-line therapy with platinum-based doublets comparing three to four cycles with six or more cycles. None of these trials were individually positive for OS. In almost all trials comparing JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 20 JULY 1

Therapy-related patterns of cytogenetic abnormalities in acute myeloid leukemia and myelodysplastic syndrome post polycythemia vera

A minor fraction of patients with polycythemia vera (PV) develop a terminal acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Analysis of the cytogenetic abnormalities during AML or MDS may help in understanding if this development is part of the natural course of the disease or induced by myelosuppressive therapy. Thirty-six cases with AML or MDS post PV, collected in a single Swedish institution during a 33-year period, are described with special regard to time to development of AML or MDS, therapy given during active PV, and cytogenetic findings during AML or MDS. A further 118 cases of AML or MDS post PV, in whom type of therapy during active PV and cytogenetic findings during AML or MDS were reported, were collected from the literature. AML or MDS developed in our own series after 1-30 years with a fairly constant rate (two cases per year). The most frequent cytogenetic abnormalities were +1q, -5, 5q-, -7, 7q-, +8, +9, 11q-, 13q-, and 20q-. When patients in the total material (n = 154) were divided with regard to treatment during active PV, marked differences were observed. The highest frequency of abnormalities was found in patients given multiple lines of therapy (n = 61), dominating features being -5/5q- in 28 patients (46%), -7/7q- in 19 patients (31%), numerous translocations in 24 patients (39%), and unidentified markers in 22 patients (36%). Half of the patients treated with hydroxyurea alone showed a -5 or 5q- abnormality. In patients treated with phlebotomy alone, +8 and +9 were the most frequent findings. The type of therapy given during active PV influences the type of chromosome abnormalities present during terminal AML or MDS and can also be instrumental in the development of leukemia.

Targeted, Evidence-Based Colorectal Cancer Therapies: Shifting the Patient Outcome

Targeted, Evidence-Based Colorectal Cancer Therapies: Shifting the Patient Outcome

Planned Treatment Interruptions and Chemotherapy-Free Intervals in the Treatment of Metastatic Colorectal Cancer: Time to Start Stopping?

Studies have begun to examine stop-and-go or intermittent chemotherapy strategies in patients with advanced colorectal cancer. Such strategies potentially may reduce cumulative toxicities associated with long-term therapies. In addition, planned interruptions in treatment would be expected to lower overall costs of treatment, and would clearly offer patients the opportunity to have breaks from oncology visits and associated toxicities of therapy. Greater efforts to define such strategies are necessary, particularly because patients with advanced colorectal cancer now have multiple lines of therapy planned and spend greater amounts of time on treatment. Several studies have suggested that interrupting oxaliplatin or irinotecan treatment may be acceptable in terms of efficacy and beneficial in terms of toxicity. This article will address these and other trials, as well as data relating to incorporation of biologic therapies into combination chemotherapy for patients with advanced colorectal cancer.

Distal Limb Infiltration by Transformed Lymphoplasmacytoid Lymphoma.

We report 2 cases of lymphoplasmacytoid lymphoma (LPCL) with aggressive, high-grade transformation accompanied by extensive distal lower limb skeletal disease.Case 1: a 26-year-old man with stage IVA anaplastic Ki-1+ NHL achieved durable CR1 with VAPEC-B induction, AC consolidation & mediastinal radiotherapy. In 1997 he re-presented with lymphadenopathy: biopsy & marrow showed small CD20+CD79a+ B lymphocytes with IgM(κ) light chain restriction & increased mature plasma cells, but no evidence of anaplastic NHL. He received VAD (×6) & autologous PBSCT (melphalan 200mg/m2) to CR1. Relapse in 2004 was treated with cyclophosphamide & dexamethasone, then fludarabine (×4). Ten months later he presented with B symptoms & painful right tibial swelling. MR showed multiple medullary lesions in proximal femoral shafts, tibiae & upper fibulae. CT confirmed widespread lymphadenopathy & bilateral renal deposits. Marrow had dense infiltrate of CD20+CD79a+ small lymphoid cells with additional immature CD20+CD79a+ blasts, consistent with transformation to high-grade DLBCL. New complex cytogenetics included XXY with t(14;22) (IGH rearrangement), add(1q), del(6q), del(9p) & trisomy 3. He received R-mini-BEAM (×2) & 2nd PBSCT (R-BEAM conditioning) in 2006 using residual 1997 PBSCH, acheiving CR4 with bony regression on MRI. Four months later B symptoms & right tibial pain recurred & the disease is currently being held by rituximab & steroid.Case 2 was diagnosed with WM/LPCL in 1996, aged 54, following 8 years history of IgM MGUS. He received chlorambucil (1996), CVP (×6) (1997), fludarabine (×5) (1999/2000), chlorambucil (2001) rituximab (×8), further fludarabine (×3) (June 2003) & repeated R-CVP (2004/5). In Sept 2005 he presented with lower limb & right heel pain. MR revealed diffuse abnormality within tibiae, fibulae & distal femorae: a soft tissue mass infiltrated the right talus bone, & left calcaneus, talus & anterior malleolus showed patchy involvement. Biopsy of right talus yielded small lymphocytes, lymphoplasmacytoid cells & plasma cells, strongly CD20+ & κ light chain restricted (with smaller % CD138+ cells), in keeping with lymphoplasmocytic lymphoma. Bisphosphonate exacerbated the pain & single fraction of radiotherapy had no effect. He received salvage R-CVP (×6), reducing paraprotein from 6.9 to 2.7g/L. Nevertheless, the bone deposits continue to cause significant discomfort.Transformation of WM/LPCL to high-grade lymphoma is rare but well-described. Lin et al. describe DLBCL transformation in 13% cases, at median 44 months after diagnosis & associated with poor outcome. Seven of the 12 cases had received cladrabine. Purine analogues have been implicated in pathogenesis of Richter's syndrome, in which CLL transforms to aggressive NHL (estimated <3% CLL patients). MRI reliably demonstrates marrow involvement in WM/LPCL but changes are diffuse. In contrast to MM, focal skeletal MR abnormalities are not observed in WM/LPCL.We present 2 cases of LPCL with focal distal lower limb bone involvement. The focal nature of skeletal involvement in sites not active in adult haemopoeisis (& atypical for LPCL or MM involvement), with B symptoms & rapidly progressive NHL are unusual features. Other features include >10year disease course, multiple lines of therapy (incl. purine analogues) & high-grade transformation/behaviour. Involvement of distal bones (e.g. talus) is rare in NHL, & we could find no previous reports of focal distal lower limb LPCL. We observe that LPCL can undergo high-grade transformation (analogous to Richter's syndrome) with distinct trophic phenotype, & postulate that purine analogues may be implicated in selecting for this behaviour.

Do more lines of chemotherapy make you live longer? Treatment for ovarian cancer comparing cohorts of patients 1989–90 with 1995–6 in multivariate analysis of survival

5062 Background: Recurrent epithelial ovarian cancer (EOC) has come to be considered a chronic cancer frequently treated with multiple lines of chemotherapy. It remains unclear whether response to sequential treatment improves survival or simply reflects the biology of the disease. Methods: We reviewed 154 patients with EOC presenting in 1989–90 (n=72) and 1995–6 (n=82). The prognostic relevance of disease and treatment characteristics were examined in multivariate survival analysis. Results: Median overall survival (OS) was similar in the early (22.9) and late (22.3 months) cohorts (p=0.29). Median progression free survival (PFS) was apparently longer in the later cohort (9.4 (95%CI 7.1–13.1) vs. 14.9 (95%CI 11.8–20.7)) but did not reach statistical significance (p=0.88) Nearly twice as many patients received >3 lines of chemotherapy (22 vs. 12) for recurrent disease in the later cohort. Univariate and multivariate analysis showed that two parameters were associated with a longer survival time: early stage (p=0.013) and the use of paclitaxel (p=0.032). Patients treated with ≥ 3 lines of chemotherapy for recurrent disease lived for >3x as long as those with 2 or less (15.3 (95% CI 11.6–20.5) vs. 50.1 (95% CI 46.1–59.2) months, p=0.0009). Conclusions: Over the study period there has been little improvement in OS and although more treatment was given to patients in the later cohort, the combination of new agents in first line therapy, rather than the serial use of chemotherapy for recurrent disease, appears to have a greater impact on PFS. The dramatic difference in apparently better survival with multiple lines of therapy may reflect favorable tumor biology, more than the effect of treatment. No significant financial relationships to disclose.