Debra Sarasohn

Phase II-I-II Study of Two Different Doses and Schedules of Pralatrexate, a High-Affinity Substrate for the Reduced Folate Carrier, in Patients With Relapsed or Refractory Lymphoma Reveals Marked Activity in T-Cell Malignancies

PURPOSE To determine the maximum-tolerated dose (MTD) and efficacy of pralatrexate in patients with lymphoma. PATIENTS AND METHODS Pralatrexate, initially given at a dose of 135 mg/m(2) on an every-other-week basis, was associated with stomatitis. A redesigned, weekly phase I/II study established an MTD of 30 mg/m(2) weekly for six weeks every 7 weeks. Patients were required to have relapsed/refractory disease, an absolute neutrophil greater than 1,000/microL, and a platelet count greater than 50,000/microL for the first dose of any cycle. RESULTS The every-other-week, phase II experience was associated with an increased risk of stomatitis and hematologic toxicity. On a weekly schedule, the MTD was 30 mg/m(2) weekly for 6 weeks every 7 weeks. This schedule modification resulted in a 50% reduction in the major hematologic toxicities and abrogation of the grades 3 to 4 stomatitis. Stomatitis was associated with elevated homocysteine and methylmalonic acid, which were reduced by folate and vitamin B12 supplementation. Of 48 assessable patients, the overall response rate was 31% (26% by intention to treat), including 17% who experienced complete remission (CR). When analyzed by lineage, the overall response rates were 10% and 54% in patients with B- and T-cell lymphomas, respectively. All eight patients who experienced CR had T-cell lymphoma, and four of the six patients with a partial remission were positron emission tomography negative. The duration of responses ranged from 3 to 26 months. CONCLUSION Pralatrexate has significant single-agent activity in patients with relapsed/refractory T-cell lymphoma.

Pralatrexate, a novel class of antifol with high affinity for the reduced folate carrier-type 1, produces marked complete and durable remissions in a diversity of chemotherapy refractory cases of T-cell lymphoma

T‐cell lymphomas (TCLs) are characterised by poor responses to therapy with brief durations of remissions. An early phase study of pralatrexate has demonstrated dramatic activity in patients with relapsed/refractory disease. Of the first 20 lymphoma patients treated, 16 had B‐cell lymphoma and four had refractory aggressive TCL. All four patients with TCL achieved a complete remission. Patients with B‐cell lymphoma achieved stable disease at best. For each TCL patient, the response was more durable than their best response with chemotherapy. This early experience is the first to document this unique activity of pralatrexate in TCL.

Patients with chemotherapy-refractory mantle cell lymphoma experience high response rates and identical progression-free survivals compared with patients with relapsed disease following treatment with single agent bortezomib: Results of a multicentre phase 2 clinical trial

The recent approval of bortezomib for the treatment of mantle cell lymphoma (MCL) by the US Food and Drug Administration is based on the results of the multicentre PINNACLE study with supportive data from a number of single and multicentre Phase 2 studies. This multicentre Phase 2 study enroled 40 patients with heavily pretreated MCL. The overall response rate (ORR) was 47%, including 5 complete remissions and 14 partial remissions. Overall, these remissions are relatively durable. The ORR in relapsed and refractory patients was 50% and 43% respectively (P = 0·74), while both populations of patients exhibited essentially similar progression‐free survival (PFS; 5·6 months vs. 3·9 months, P = 0·81). Responding patients experienced a PFS from bortezomib that was similar to their line of prior therapy (7·8 months vs. 8·4 months, respectively). The data showed similar responses in relapsed and refractory patients as well as remission durations similar to prior therapy, suggesting that there may be little cross‐resistance with other conventional cytotoxic agents. Importantly, these data suggest that MCL patients with refractory or poorly responsive disease may still derive meaningful clinical benefit from treatment with bortezomib.

Phase 2 study of weekly bortezomib in mantle cell and follicular lymphoma.

Twice‐weekly bortezomib has proven activity in mantle cell (MCL) and indolent lymphomas. This study explored a weekly schedule of bortezomib in follicular lymphoma (FL) and MCL. Although weekly bortezomib was better tolerated, the overall response rate (ORR) was inferior (18% vs. 50%, P = 0·02) with no complete remissions (CR) (compared with 18% CR for the twice‐weekly schedule). Progression‐free survival (PFS) was not different. The weekly schedule of bortezomib was less toxic, but yielded fewer and lower quality responses than twice‐weekly bortezomib. Given the similar PFS, the weekly schedule may still be appropriate for some patients.

Implementation of Evidence-Based Guidelines for Thyroid Nodule Biopsy: A Model for Establishment of Practice Standards

OBJECTIVE Multiple studies have defined criteria for the selection of thyroid nodules for biopsy. No set of criteria is sufficiently sensitive and specific. The aim of this study is to develop a method for assessing consistency of practice in an ultrasound group and to determine whether a 5-point malignancy rating scale can be used to select patients for biopsy. MATERIALS AND METHODS One hundred one nodules (50 benign and 51 malignant) were selected from a thyroid biopsy database. Seven radiologists were educated on evidence-based criteria used to select nodules for biopsy. Using this information, readers graded the likelihood of malignancy using a 5-point malignancy rating scale, where 1 equals the lowest probability of malignancy and 5 equals the highest probability of malignancy, on the basis of overall impression of sonographic findings. Interobserver agreement on biopsy recommendation, reader sensitivity, specificity, and accuracy were determined. RESULTS The sensitivity and specificity of biopsy recommendation were 96.1% and 52%, respectively. The misclassification rate was 25.7%, and accuracy was 74.3%. Interobserver agreement on biopsy recommendation was fair to substantial (κ, 0.38-0.69). The proportion of agreement was excellent for malignant nodules (0.88-1.0). The risk of malignancy increased with increasing malignancy rating: 4.3% of nodules with a malignancy rating of 1 were malignant versus 93.4% of those assigned a rating of 5. CONCLUSION Our study illustrates a method to evaluate the standard of practice for thyroid nodule assessment among radiologists within an ultrasound group. Application of a 5-point malignancy rating scale to select nodules for biopsy is feasible and shows good diagnostic accuracy.

Time to Treatment Response in Patients with Follicular Lymphoma Treated with Bortezomib Is Longer Compared with Other Histologic Subtypes

Purpose: To determine the antitumor activity of the novel proteasome inhibitor bortezomib in patients with indolent non–Hodgkins lymphoma. Experimental Design: Patients with follicular lymphoma (FL), marginal zone lymphoma, mantle cell lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia, and Waldenstroms macroglobulinemia were eligible for study. Bortezomib was given at a dose of 1.5 mg/m2 as an i.v. push on days 1, 4, 8, and 11 of a 21-day cycle. Eligibility included the following: (a) no more than three prior therapies, (b) at least 1 month since prior chemotherapy, (c) measurable disease, and (d) an absolute neutrophil count of >1,000/μL and a platelet count >50,000/μL for the first dose of any cycle. Results: Seventy-seven patients were registered, of which 69 were assessable for response based on the completion of two cycles of therapy. Subtypes included FL (59.5%), mantle cell lymphoma (52%), small lymphocytic lymphoma/chronic lymphocytic leukemia (16.2%), marginal zone lymphoma (21.6%), and one Waldenstroms macroglobulinemia. The median number of prior therapies was three. The most common grade 3 toxicity was lymphopenia (35%) and thrombocytopenia (31%). Twenty-five patients experienced grade ≤2 sensory neuropathy (32), and 8% experienced grade 3 neurosensory toxicity. The overall response rate was 45% (40% on an intention to treat) including 10 complete remissions. Of 18 patients with FL, 9 responded with 4 complete response. The median time to treatment response for FL was 12 weeks, whereas the median time to treatment response for other subtypes of non–Hodgkins lymphoma was only 4 weeks. Conclusions: These data suggest that bortezomib has significant single agent activity in patients with FL, and that longer durations of treatment may improve overall response. Clin Cancer Res; 16(2); 719–26

Safe and effective use of rivaroxaban for treatment of cancer-associated venous thromboembolic disease: a prospective cohort study

Low-molecular weight heparin (LMWH) has been the standard of care for treatment of venous thromboembolism (VTE) in patients with cancer. Rivaroxaban was approved in 2012 for the treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT), but no prior studies have been reported specifically evaluating the efficacy and safety of rivaroxaban for cancer-associated thrombosis (CAT). Under a Quality Assessment Initiative (QAI), we established a Clinical Pathway to guide rivaroxaban use for CAT and now report a validation analysis of our first 200 patients. A 200 patient cohort with CAT (PE or symptomatic, proximal DVT), whose full course of anticoagulation was with rivaroxaban, were accrued. In competing risk analysis, primary endpoints at 6 months included new or recurrent PE or symptomatic proximal lower extremity DVT, major bleeding, clinically-relevant non-major bleeding leading to discontinuation of rivaroxaban, or death. In competing risk analysis, the 6 months cumulative incidence of new or recurrent VTE was 4.4 % (95 % CI = 1.4–7.4 %), major bleeding was 2.2 % (95 % CI = 0−4.2 %) and all-cause mortality 17.6 % (95 % CI = 11.7–23.0 %). In this cohort of 200 patients with active cancer and CAT the rates of new or recurrent VTE and major bleeding were comparable to the cancer subgroup analysis from the EINSTEIN studies. The results of our Clinical Pathway provide guidance on Rivaroxaban use for treatment of CAT, and suggest that safety and efficacy is preserved, compared with past-published experience with LMWH.

Stage IB1 Cervical Cancer: Role of Preoperative MR Imaging in Selection of Patients for Fertility-Sparing Radical Trachelectomy

PURPOSE To determine whether magnetic resonance (MR) imaging evaluation of key morphologic tumor characteristics can improve patient selection for radical trachelectomy. MATERIALS AND METHODS The institutional review board approved and waived informed consent for this study of 62 patients (mean age, 32 years; age range, 23-42 years) with International Federation of Gynecology and Obstetrics stage IB1 cervical carcinoma who underwent attempted radical trachelectomy between November 2001 and January 2011 and had preoperative MR imaging. Retrospectively, two radiologists reviewed MR images for tumor presence and size, distance between tumor and internal os, and presence of deep cervical stromal invasion. Associations between MR imaging findings and surgery type were tested. RESULTS Sensitivity and specificity of tumor detection were, respectively, 87% and 100% (reader 1) and 76% and 95% (reader 2). Six of six patients with negative cone biopsy margins and no tumor at postconization MR imaging were without tumor at trachelectomy pathologic analysis. Mean differences between MR imaging and histologic tumor sizes were 0.7 mm (range, -15 to 11 mm) for reader 1 and 2.2 mm (range, -9 to 15 mm) for reader 2. Sensitivities for deep cervical stromal invasion were 75% (reader 1) and 50% (reader 2). For each reader, nine of nine (100%) patients with tumor 5 mm or less from the internal os and three of five (60%) patients with tumor 6-9 mm from the internal os at MR imaging needed radical hysterectomy. For both readers, tumor size of 2 cm or larger (P < .001) and deep cervical stromal invasion (P ≤ .003) at MR imaging were associated with increased chance of radical hysterectomy. CONCLUSION Pretrachelectomy MR imaging can help identify high-risk patients likely to need radical hysterectomy or confirm the absence of residual tumor in the cervix after a cone biopsy with negative margins.

Phase I Trial of Weekly and Twice-Weekly Bortezomib with Rituximab, Cyclophosphamide, and Prednisone in Relapsed or Refractory Non-Hodgkin Lymphoma

Purpose: To determine the safety and efficacy of substituting weekly or twice-weekly bortezomib for vincristine in the R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone) regimen in patients with relapsed/refractory indolent and mantle cell lymphoma (MCL). Experimental Design: Of the 57 patients in this phase I trial, 55 participated in 1 of 2 dosing schedules that included rituximab (375 mg/m2) and cyclophosphamide (750 or 1,000 mg/m2) administered on day 1 of each 21-day cycle and prednisone (100 mg orally) days 2 to 6. In the once-weekly schedule, bortezomib was administered on days 2 and 8; on the twice-weekly schedule, bortezomib was given on days 2, 5, 9, and 12. Bortezomib and cyclophosphamide were alternately escalated. A separate cohort of 10 patients in the twice-weekly schedule received concurrent pegfilgrastim (PegG) on day 2. Results: Both schedules of R-CBorP (rituximab, cyclophosphamide, bortezomib, and prednisone) were well tolerated. Most toxicities across all dose levels and cycles were grade 1 or 2. The overall response rates for patients on the weekly (n = 13) and twice-weekly (n = 33) schedules were 46% [23% complete response/complete response unconfirmed (CR/CRu)] and 64% (36% CR/CRu), respectively. Concurrent PegG did not increase hematologic toxicities in this regimen. A randomized phase II study is under way to further compare toxicity and efficacy of the 2 dosing schedules. Conclusions: R-CBorP is a safe and effective regimen in patients with relapsed/refractory indolent and MCLs. Most toxicities were grade 1 or 2, and a promising response rate was seen in this phase I study. Clin Cancer Res; 17(8); 2493–501. ©2011 AACR.

Follow-up study of the correlation between postoperative computed tomographic scan and primary surgeon assessment in patients with advanced ovarian, tubal, or peritoneal carcinoma reported to have undergone primary surgical cytoreduction to residual disease of 1 cm or smaller

Introduction: We previously reported a 52% correlation between the primary surgeons assessment and the postoperative computed tomographic (CT) scan findings of residual disease in patients reported to have undergone cytoreduction to residual disease of 1 cm or smaller. This is a follow-up analysis of survival and prognostic factors for patients who had concordant and discordant postoperative CT scan findings. Methods: Patients scheduled for primary cytoreductive surgery for presumed advanced ovarian carcinoma were offered enrollment in a prospective study evaluating the ability of preoperative CT scan to predict cytoreductive outcome. If cytoreduction to residual disease of 1 cm or smaller was reported, a CT scan was done 7 to 35 days postoperatively. The CT scan findings were graded by protocol radiologists using a qualitative analysis scale from 1 (normal) to 5 (definitely malignant). Results: From January 2001 to September 2006, 285 patients were enrolled; 67 patients were eligible. Postoperative CT scans confirmed the primary surgeons assessment of no residual disease larger than 1 cm in 38 cases (57%). In 29 cases (43%), the radiologist found residual disease larger than 1 cm and reported it as probably or definitely malignant. Comparing concordant versus discordant findings, there was no significant difference in median progression-free survival (21 vs 17 months; P = 0.365) or overall survival (60 vs 43 months; P = 0.146). Age (P = 0.040), stage (P = 0.038), and residual disease of 0.5 mm or smaller versus 0.6 to 1.0 cm (P = 0.018) were significant for overall survival on multivariate analysis. Conclusions: On this follow-up analysis, only age, stage, and residual disease were significant prognostic factors for overall survival. Discordant findings between the primary surgeons assessment and the postoperative CT scan findings of residual disease was not an independent prognostic factor.