M. Sitki Copur

An Algorithm for the Management of Hypertension in the Setting of Vascular Endothelial Growth Factor Signaling Inhibition

Vascular endothelial growth factor (VEGF) signaling is considered to be one of the key factors involved in tumor-associated angiogenesis. Inhibition of angiogenesis has significantly improved anticancer therapy making it one of the cornerstones of treatment for various solid tumors. Several antiangiogenesis inhibitory compounds (eg, bevacizumab, sunitinib, sorafenib) are now widely used in the treatment of patients with colorectal, non-small-cell lung, advanced renal cell, hepatocellular, and breast cancer. One of the most commonly observed side effects of inhibition of VEGF signaling is hypertension, which is dose-dependent and varies in incidence among the different angiogenesis inhibitor drugs. Poorly controlled hypertension not only can lead to cardiovascular events, renal disease, and stroke, but may also necessitate discontinuation of anticancer therapy, thereby potentially limiting overall clinical benefit. In contrast, hypertension induced by VEGF inhibitors has been shown to represent an important pharmacodynamic biomarker of oncologic response. For the practicing oncologist, knowledge and optimal management of this toxicity is essential. Because of the lack of controlled studies on this topic, no clear recommendations are available. In this article, we review the available preclinical and clinical data on the pathogenesis and management of hypertension resulting from anti-VEGF inhibitor therapy and propose a treatment algorithm that our group has now implemented for daily clinical practice.

Safety and efficacy of panitumumab therapy after progression with cetuximab: experience at two institutions.

INTRODUCTION Cetuximab therapy has been effectively combined with cytotoxic chemotherapy in the first-, second-, and third-line treatment settings. In general, treatment with cetuximab is well tolerated, though it has been associated with the development of hypersensitivity reactions (HSRs). In the case of severe HSRs, further therapy with cetuximab is not possible. In contrast with cetuximab, HSRs have been rarely observed with panitumumab therapy. Currently, panitumumab is indicated for patients with metastatic colorectal cancer (mCRC) with progressive refractory disease, and there is recent evidence documenting its clinical efficacy with cytotoxic chemotherapy in the first-line and second-line settings. However, the safety and efficacy of panitumumab after progression with cetuximab has not been well documented. PATIENTS AND METHODS We present a retrospective review of our experience in treating 15 patients with mCRC who tolerated panitumumab with clinical benefit after failure on cetuximab therapy from November 2006 through September 2008 at the Yale Cancer Center in New Haven, CT and at the Saint Francis Cancer Treatment Center in Grand Island, NE. KRAS status was retrospectively assessed in patients with readily available tumor tissue. RESULTS All 15 patients were treated with a standard dose of panitumumab 6 mg/kg intravenously every 2 weeks. No patient received premedication therapy. Of the 15 patients treated, 4 received only 2 doses of panitumumab but stopped further therapy because of deterioration in performance status. Of the 11 evaluable patients, we noted minor radiographic responses (Response Evaluation Criteria in Solid Tumors) in 3 patients and stable disease (SD) in 3 other patients after 8 weeks of therapy. Five patients had evidence for progressive disease, and further therapy was stopped. The median duration of SD was 4 months (range, 2-8 months). Among the 11 evaluable patients, 1 patient achieved > 50% reduction in carcinoembryonic antigen (CEA; 112 to 49 U/L), 3 patients had a 25% reduction (59 to 43 U/L, 84 to 61 U/L, and 67 to 42 U/L), and 1 patient had minor reduction in CEA (98 to 83 U/L). All patients tolerated panitumumab well with no occurrence of hypersensitivity reactions. Grade 3/4 toxicities were skin rash in 5 patients and asthenia in 1 patient. The other adverse events observed included grade 1-2 skin rash in 2 patients, grade 2 paronychia in 4 patients, grade 2 hypomagnesemia in 2 patients, and fatigue in 3 patients. One patient had wild-type KRAS, and this individual experienced a minor response to antibody therapy with > 50% reduction in CEA. A second patient was found to have mutant KRAS and, in terms of clinical response, this patient experienced SD for 6 months. The third patient evaluated had mutant KRAS, and this individual was unable to tolerate more than 2 doses and was therefore not evaluable for response. CONCLUSION Panitumumab may represent an alternative treatment strategy for patients with refractory mCRC who have experienced failure with standard therapy including cetuximab-based regimens. Our relatively small clinical experience suggests that cetuximab and panitumumab may exert their antitumor activity through different mechanisms; however, further work is required to investigate this potentially interesting issue.

Alternating hepatic arterial infusion and systemic chemotherapy for liver metastases from colorectal cancer: a phase II trial using intermittent percutaneous hepatic arterial access.

PURPOSE To evaluate the objective response to a short course of hepatic arterial infusion (HAI) using temporary, percutaneously placed catheters alternating with systemic prolonged continuous infusion fluorouracil (ci 5-FU) and daily oral leucovorin (L). PATIENTS AND METHODS Eligible patients were previously untreated (except for adjuvant therapy) adults with liver-predominant metastases, with Eastern Cooperative Oncology Group performance status of 0 to 2. Treatment regimen included HAI with fluorodeoxyuridine (FUDR) 60 mg/m2/d and L 15 mg/m2/d continuously infused daily for 4 days. After a 1-week rest, ci 5-FU was administered through a central venous access device using a dose of 180 mg/m2/d with a fixed dose of oral L at 5 mg/m2/d for 21 out of 28 days. Cycles were repeated every 6 weeks. After four cycles of therapy, patients were maintained on ci 5-FU and daily oral L until evidence of progression. RESULTS Forty-three patients were enrolled onto this trial. One patient was ineligible. The objective response rate for all patients (17 partial, zero complete) was 41% (95% confidence interval [CI], 26% to 56%). Five patients were not able to receive at least one complete cycle of HAI. Among patients who received at least one complete cycle of HAI, the response rate was 46% (95% CI, 30% to 62%). Five patients underwent a liver resection after enrolling onto the protocol. At the time of analysis, estimated median time to progression was 6 months, and estimated median overall survival was 13 months. CONCLUSION The objective response rate was comparable to that achieved with more prolonged and more frequent HAI using FUDR. This approach should be studied as an acceptable alternative to surgically placed hepatic arterial catheters/pumps and may have a role as neoadjuvant therapy for liver metastases that are unresectable, as well as an adjuvant role for patients with resected hepatic metastatic colorectal cancer.

An Unusual Case of Composite Lymphoma Involving Chronic Lymphocytic Leukemia Follicular Lymphoma and Hodgkin Disease

Composite lymphomas constitute the presence of two different types of non-Hodgkin lymphoma or Hodgkin and non-Hodgkin lymphoma at the same anatomic site. We report an unusual case of a 73-year-old woman who initially presented with a composite lymphoma of chronic lymphocytic leukemia (CLL) and follicular lymphoma. After 5 years of follow-up and intermittent treatment, she developed Hodgkin disease with diffuse liver involvement. Biopsy of the liver showed Reed-Sternberg cells with typical morphology and immunophenotype. While fluorescent in situ hybridization (FISH) analyses for t(14;18) were positive in the lymph node tissue with follicular lymphoma, we were unable to show the same in the liver biopsy specimen. Here, we describe the clinical, morphologic, immunophenotypic, and cytogenetic features of this unusual composite lymphoma case involving CLL and follicular lymphoma, with the subsequent development of a Hodgkin lymphoma.

Impact of Older Age on the Efficacy of Newer Adjuvant Chemotherapy Regimens in Colon Cancer, a Subgroup Analysis of a Meta-analysis: Practice Changing? Certainly Not; Hypothesis Generating? Perhaps

With the overall aging US population and a median age at diagnosis of 72 years, colon cancer is a common disease in the elderly.1 Adjuvant therapy has been the standard of care for stage III disease since 1990.2 Population-based data derived from the Surveillance, Epidemiology, and End Results registry reveals a marked disparity in the administration of adjuvant chemotherapy between younger and older patients with colon cancer. In addition, when adjuvant chemotherapy is initiated, older individuals are more likely to have their treatment discontinued before completion, possibly decreasing its effectiveness.3 Randomized trials have demonstrated that adjuvant and palliative chemotherapies for all patients with colon cancer improve survival and quality of life.4 Unfortunately, due to the underrepresentation of elderly patients in clinical trials, robust evidence-based data for elderly patients with colon cancer is lacking. The existing literature mainly consists of pooled data sets from large studies. In most of these individual large trials, only 10%-20% of patients are elderly. However, at least half of the patients who are treated in the community setting are older than 70 years of age. Any increase in the effective use of adjuvant chemotherapy in this disease might further enhance the survival of stage III colon cancer.5 At this year’s meeting of the American Society of Clinical Oncology, McCleary et al6 presented data from the ACCENT (Adjuvant Colon Cancer End Points) database on 2170 patients with colon cancer aged 70 years or older (out of a total of 12,669 patients) who were treated in 6 phase III adjuvant colon cancer trials. They compared intravenous 5-fluorouracil (5-FU) monotherapy to combination regimens with irinotecan, oxaliplatin, or oral 5-FU. Based on their analysis, they concluded that patients aged 70 years or older did not receive the same clinical benefit compared with patients younger than age 70. The main endpoints of this study were overall survival (OS), disease-free survival, and time to recurrence. Cox models were stratified by age and adjusted for sex and stage. Interaction testing was used to explore the differential benefit by age. In other words, this was a subgroup analysis of a large meta-analysis data set from 6 previously conducted randomized phase III clinical trials. With all possible biases and shortcomings inherent to meta-analyses7 and subgroup analyses,8 how robust and conclusive is this data? Some immediate questions that come to mind include the following: • Were all relevant clinical trials identified and included in this meta-analysis? We know that the data from at least 2 large adjuvant trials—Avant and NSABP C-08—were not included. • Were all randomized patients included in the analysis in accordance with the treatment allocated at randomization? Was an “intention-to-treat” analysis performed? • How were the data for analyses gathered? Were they aggregate data or individual patient data in which the details for each participant in every trial were collected and analyzed centrally? • Were there additional follow-up data since the publication of each individual trial data? Or were the results frozen in time at the time of their initial publication? • Was the subgroup analysis in this presentation performed when randomized clinical trials were running or after they were completed? In other words, were these pre- or post-analysis subgroups? Subgroup analyses can be based on formal tests of interaction, but they should be interpreted with caution. Interaction testing might decrease the risk of finding false-positive subgroups, but its power is low.8 In a trial with 80% power for the overall treatment effect, the interaction test has, at most, a 29% power to detect an interaction effect of the same magnitude of the overall effect, thereby requiring a 4-fold increase in the sample size.9 Thus, is a meta-analysis data set using the ACCENT database sufficiently large to accomplish this goal despite including over 12,000 patients? Increasing age will almost always be associated with a poorer OS because of the probability of dying from noncancer causes. Although it may be viewed as a prognostic factor for OS, chronologic age alone should not be a predictive factor for the benefits of adjuvant chemotherapy in elderly patients with colon cancer. In an era of individualized medicine, with a burgeoning interest and recognition of various biologic and molecular markers in this disease, making a decision about adjuvant chemotherapy based on the chronologic age alone can be very misleading. Results of subgroup analysis of ACCENT database meta-analysis should not be over-interpreted. At this time, the findings from this study can and should not be viewed as practice changing; however, they may be viewed as hypothesis generating. The best way to directly