Time Of Restaging Research Articles

Serum CEA as a Prognostic Marker for Overall Survival in Patients with Localized Pancreatic Adenocarcinoma and Non-Elevated CA19-9 Levels Treated with FOLFIRINOX as Initial Treatment: A TAPS Consortium Study.

About 25% of patients with localized pancreatic adenocarcinoma have non-elevated serum carbohydrate antigen (CA) 19-9 levels at baseline, hampering evaluation of response to preoperative treatment. Serum carcinoembryonic antigen (CEA) is a potential alternative. This retrospective cohort study from five referral centers included consecutive patients with localized pancreatic adenocarcinoma (2012-2019), treated with one or more cycles of (m)FOLFIRINOX, and non-elevated CA19-9 levels (i.e., < 37U/mL) at baseline. Cox regression analyses were performed to assess prognostic factors for overall survival (OS), including CEA level at baseline, restaging, and dynamics. Overall, 277 patients were included in this study. CEA at baseline was elevated (≥5ng/mL) in 53 patients (33%) and normalized following preoperative therapy in 14 patients (26%). In patients with elevated CEA at baseline, median OS in patients with CEA normalization following preoperative therapy was 33 months versus 19 months in patients without CEA normalization (p = 0.088). At time of baseline, only elevated CEA was independently associated with (worse) OS (hazard ratio [HR] 1.44, 95% confidence interval [CI] 1.04-1.98). At time of restaging, elevated CEA at baseline was still the only independent predictor for (worse) OS (HR 1.44, 95% CI 1.04-1.98), whereas elevated CEA at restaging (HR 1.16, 95% CI 0.77-1.77) was not. Serum CEA was elevated in one-third of patients with localized pancreatic adenocarcinoma having non-elevated CA19-9 at baseline. At both time of baseline and time of restaging, elevated serum CEA measured at baseline was the only predictor for (worse) OS. Therefore, serum CEA may be a useful tool for decision making at both initial staging and time of restaging in patients with non-elevated CA19-9.

Upfront Radiation Therapy (RT) for Post-Stem Cell Transplant Multiple Myeloma (MM) Patients with Oligo-Relapse/Progressive Disease: Factors Associated with Favorable Outcomes

Introduction: Relapsed or refractory disease post-stem cell transplant (SCT) for Multiple Myeloma (MM) can be clinically challenging. For localized relapses, radiation therapy (RT) can represent an attractive treatment modality. However, data on outcomes with RT remains scarce. We investigated the impact of RT as a treatment modality in the setting of oligo-relapse and oligo-progressive plasmacytomas after SCT and explored prognostic factors associated with favorable long-term outcome Methods: In this single-institution retrospective analysis, we identified 31 MM patients who underwent upfront RT for oligo-relapse or oligo-progressive MM after SCT between 2000 and 2021. Patients were excluded if they had received systemic therapy for evidence of concurrent biochemical relapse prior to RT start. The treatment responses to stem cell transplantation (SCT) and RT were assessed following the response criteria established by the International Myeloma Working Group (IMWG), which includes the categories: complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), stable disease (SD) and progressive disease (PD). Additionally, we utilized the R-ISS staging system to classify patients into Standard-Risk (R-ISS I), Intermediate-Risk (R-ISS II), and High-Risk (R-ISS III) groups, to allow for a comprehensive evaluation of treatment efficacy and outcomes. Results: Disease and treatment characteristics for the cohort are summarized inFigure 1. Of the 27 patients with imaging available prior to SCT, 67% (18) were assessed with PET, 22% (6) with skeletal survey, 3.7% (1) with MRI/CT, 3.7% with CT, and 3.7% (1) with x-ray. Following SCT, 48% (13) of patients were noted to have radiographic progression, 23% (7) had sCR, 23% (7) had a CR, 10% had a serologic CR, and 45% (14) had a VGPR. Among the 18 patients with radiographic evaluation (in addition to bone marrow biopsy and/or labs) post-SCT, 67% (12) were in radiographic CR at time of re-staging. Median times from SCT to new site of oligo-relapsed disease (20, 64.5%) and pre-existing but inactive sites of oligo-relapsed MM (4, 12.9%) were 31 months (3.2-117.5) and 9 months (3.4-15.9), respectively. Oligo-progressive MM, defined as active sites of disease both pre- and post-SCT were present in 22.6% (7) of patients. Prior to RT, 94% (29) had PET/CT imaging, with a median SUV of 4.4 (2.6-7.2) for target lesions. Solitary bone (77%) and extramedullary (23%) disease were treated to median dose of 30 Gy (8-49 Gy). At first disease response assessment post-RT, 77% (24) of which was done with PET/CT imaging , 42% (13) achieved CR. Among the 18 patients that did not achieve CR, 15 subsequently achieved CR at a median time of 7 months (1.7-44.5). A majority of patients (87%) received systemic therapy post-RT, with a median number of lines of therapy post-RT of 3 (1-17). The remaining 13% (4) of patients did not receive additional systemic therapy post-RT and did not experience progression. Median overall survival for the full cohort was 38 months (3.5-37.9). Conclusions: Utilizing modern systemic therapies in combination with post-transplant RT for patients with limited refractory or relapsed MM is a promising therapeutic approach. For those that remain refractory or relapse in a single site RT local control merits consideration supported by our report. Further investigation to identify patients at highest risk of progression and who may therefore benefit most from RT would be valuable. We plan to conduct additional analyses on the radiographic characteristics that may portend high risk disease, with the ultimate goal of developing well-defined criteria for giving RT earlier.

Cell-Free Methylated PTGER4 and SHOX2 Plasma DNA as a Biomarker for Therapy Monitoring and Prognosis in Advanced Stage NSCLC Patients

Notwithstanding some improvement in the earlier detection of patients with lung cancer, most of them still present with a late-stage disease at the time of diagnosis. Next to the most frequently utilized factors affecting the prognosis of lung cancer patients (stage, performance, and age), the recent application of biomarkers obtained by liquid profiling has gained more acceptance. In our study, we aimed to answer these questions: (i) Is the quantification of free-circulating methylated PTGER4 and SHOX2 plasma DNA a useful method for therapy monitoring, and is this also possible for patients treated with different therapy regimens? (ii) Is this approach possible when blood-drawing tubes, which allow for a delayed processing of blood samples, are utilized? Baseline values for mPTGER4 and mSHOX2 do not allow for clear discrimination between different response groups. In contrast, the combination of the methylation values for both genes shows a clear difference between responders vs. non-responders at the time of re-staging. Furthermore, blood drawing into tubes stabilizing the sample allows researchers more flexibility.

Abstract A07: Changes in immune profiles of osteosarcoma dogs receiving a GD3-based vaccine concurrently with carboplatin chemotherapy and surgery

Abstract Introduction: The disialyl gangliosides GD2/GD3 have been implicated in the enhancement of malignancy in a number of human and animal cancers and as a tumor antigen target for immunotherapy. In a recent abstract presented at an AACR Conference we reported on the coexpression of GD2/GD3 in four canine osteosarcoma (OSA) cell lines (1). In a prospective IACUC approved clinical trial we vaccinated dogs with a GD3-based vaccine with naturally occurring OSA receiving surgery and carboplatin chemotherapy to investigate the expression profiles of immune modulating cells overtime. Methods: Dogs will be entered into the study only if they meet the following inclusion criteria: have a confirmed diagnosis of OSA and no other life-threatening diseases. The study will accrue 40 cases; 20 will receive the vaccine plus standard of care and 20 dogs will receive only the standard of care (amputation and intent to treat with 6 doses of carboplatin). On admission blood will be collected according to the protocol for monitoring of the immune response. The dogs will then be vaccinated according to a predetermined protocol during chemotherapy and staged. The immune response profile of the vaccine group will be compared to dogs receiving standard of care alone and normal dogs. Flow cytometric platforms were developed to monitor changes in immune cells (CD5, CD21, CD4, CD8, CD14, CD11b, MHCII, and Foxp3). In addition, IHC arrays and RNA Scope will be developed for checkpoints of immunity PD1, PDL-1 and expression of intratumoral immune cells. Results: Currently twenty dogs with osteosarcoma have enrolled into the study and have received standard of care and vaccination. Complete flow cytometric immune profiles are available for nine dogs with osteosarcoma. On admission, all dogs with OSA showed elevated cell counts of Treg (FoxP3+/CD4+) cells, Monocytic (m-) and Granulocytic (g-) myeloid derived suppressor cells (MDSCs) when compared to normal dogs (all dogs had normal CBCs). All m-MDCSs and g-MDSCs and Treg cells decreased significantly after the first dose of chemotherapy. Serial sampling over weeks showed sustained inhibition even after chemotherapy was completed (18 weeks). Two OSA cases which relapsed with metastasis to the lungs showed significant increases in Treg cells at the time of restaging. Complete necropsy post-therapy in three dogs showed changes in metastatic profiles; 2/3 showed no metastatic disease to the lungs, but metastases occurred to bone and kidneys. Discussion: MDSCs series of cells and Treg cells are increased in OSA compared to normal dogs and may be a factor in maintaining a welcoming tumor microenvironment and resistance to immunotherapy. MDSCs are reported to be elevated in other cancers, but not in naturally occurring OSA. Furthermore, canine OSA cell lines show increased expression of CCL2 and COX2 (data not shown). Recruitment of MDSCs to the cancer micro-tumor environment are thought to be mediated by the chemokine CCL2 and COX2. Abrogation of these pathways with chemotherapy and possibly immunotherapy may enhance overall survival. Early necropsy data seem to support the attenuation of the metastatic profile in dogs receiving standard of care and GD3-based vaccine. Conclusions: Anticipated results from the study will be used to adjust the vaccine protocol according to the changes in immune profiles. Data is not mature enough to evaluate survival at this time. Acknowledgment: The study is funded by a grant from the American Kennel Club Health Foundation and The UF CVM. Reference: 1. Milner RJ, Chimura N, Bowles KD, Salute M. Abstract A29: Differential expression of the gangliosides GD3 and GD2 in canine and human osteosarcoma cell lines: An immunotherapy target. Cancer Immunol Res 2015 Oct 1;3(10 Supplement):A29. Citation Format: Bikash Sahay, Shana Hutchison, Matt Cascio, Amandine Lejeune, Carlos Souza, Anna Szivek, Keijiro Shiomitsu, Kayla Harding, Stacey Fox-Alvarez, Mia Livaccarri, Lindsay Powers, Rowan James Milner. Changes in immune profiles of osteosarcoma dogs receiving a GD3-based vaccine concurrently with carboplatin chemotherapy and surgery [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A07.

Phase I trial of safety of combining BCG with pembrolizumab in patients with high grade superficial bladder cancer unresponsive to previous intravesical therapy.

TPS111 Background: Bacille Calmette-Guerin (BCG) is the most effective agent in the treatment of high grade superficial bladder cancer (HGSBC); however, not all patients respond to BCG, and recurrent disease is associated with a poor prognosis. The blockade of immune checkpoints of the pathway involving programmed death 1 (PD1) has been shown recently to be effective in cancer therapy. We started the first trial in the United States to combine an anti-PD1 drug (pembrolizumab) with BCG therapy in patients with HGSBC. Methods: The primary objective of the study was to determine the safety of administering a 200 mg fixed dose of pembrolizumab in conjunction with intravesical BCG treatment in HGSBC patients who have failed two courses of induction therapy or one course of BCG induction therapy followed by maintenance therapy. Patients included had to have pathologically documented HGSBC (Ta, T1) at time of restaging, or have pathologically documented high grade CIS of the bladder at time of initial resection for recurrent/persistent bladder cancer. Subjects were treated with six cycles (21 day cycle) of pembrolizumab treatment combined with six consecutive weeks of concurrent BCG installation beginning with cycle 3 of pembrolizumab. The first three subjects were to be treated at a dose of 100 mg pembrolizumab to ensure safety for the combination. If no safety issues were to happen, dosing was to be escalated to 200 mg every three weeks. Our secondary objective was to determine the 19 week and the three, twelve, and twenty-four month post-treatment completion complete response rate. The first patient received cycle 1 of pembrolizumab treatment in July of 2015. As of the date of writing this letter, five patients have completed treatment on this trial. The trial is soon to open a second site at Henry Ford Health System in addition to Southern Illinois University with the goal of full enrollment to be achieved in the next 6 months. Clinical trial information: NCT02324582.

Radiation-induced liver injury mimicking liver metastases on FDG-PET-CT after chemoradiotherapy for esophageal cancer : Aretrospective study and literature review.

For esophageal cancer patients treated with neoadjuvant chemoradiotherapy (nCRT), restaging using F‑18-fluorodeoxyglucose (FDG) positron emission tomography computed tomography (PET-CT) following nCRT can detect interval metastases, including liver metastases, in almost 10% of patients. However, in clinical practice, focal FDG liver uptake, unrelated to liver metastases, is observed after chemoradiotherapy. This radiation-induced liver injury (RILI) can potentially lead to overstaging. Asystematic search for potential cases of RILI after (chemo)radiotherapy for esophageal cancer was performed in the electronic reports from all PET-CT scans made between 2006 and 2015 in our hospital. Additional data about potential cases were obtained from the electronic medical records. Aliterature review of RILI was also performed. Of 205 patients undergoing nCRT, 6cases with localized increased FDG uptake in the caudate or left liver lobe following nCRT for esophageal cancer were identified. None of these patients had signs of liver metastases with additional imaging, during surgery, on biopsy, or during follow-up (range 11-46months). At our institute, the incidence of RILI after neoadjuvant chemoradiotherapy for esophageal cancer was 3%. In the literature, RILI is described in about 8% of patients at the time of restaging. FDG-avid lesions occur in the high radiation dose area, usually corresponding to the caudate or left liver lobe. FDG accumulation in the caudate or left liver lobe after CRT in the area that received ahigh radiation dose may be caused by metastases or RILI. Awareness of the pitfall of high FDG uptake in RILI is crucial to avoid misinterpretation and overstaging.

Venous thromboembolism risk prediction in ambulatory cancer patients: clinical significance of neutrophil/lymphocyte ratio and platelet/lymphocyte ratio.

Neutrophil/lymphocyte (NLR) and platelet/lymphocyte (PLR) ratios might represent a yet unrecognized risk factor for venous thromboembolism (VTE) in cancer out-patients receiving chemotherapy. Accordingly, this study was aimed at analyzing the significance of these novel markers in the risk prediction of a first VTE episode in a population representative of a general practice cohort. To this purpose, a mono-institutional cohort study was conducted to retrospectively analyze NLR and PLR in 810 consecutive cancer out-patients with primary or relapsing solid cancer at the start of a new chemotherapy regimen. Over a median follow-up of 9.2 months, VTE occurred in 6.7% of patients. Incidental VTE was diagnosed at time of restaging in 47% of cases. Median pre-chemotherapy NLR (p = 0.015) and PLR (p = 0.040) were significantly higher in patients with intermediate risk class who developed symptomatic VTE with a twofold increased VTE risk for both inflammation-based markers (NLR: p = 0.022; PLR: p = 0.037) and a worst 1-year VTE-free survival for patients with high NLR or PLR. However, only PLR (HR = 2.4, p = 0.027) confirmed to be an independent predictor of future VTE in patients in the intermediate risk class in multivariate analysis, together with ECOG performance status (HR = 3.4, p = 0.0002) and bevacizumab use (HR = 4.7, p = 0.012). We may, thus, conclude that PLR, but to a lesser extent NLR, could represent useful clinical predictors of VTE, especially in selected categories of patients such as those in the intermediate risk class in whom the assessment of PLR could allow a better risk stratification of VTE without additional costs to the national health systems.

Predictive factors of [18F]-Choline PET/CT in 170 patients with increasing PSA after primary radical treatment

The purpose of this study was to evaluate the potential usefulness of [18F]-Choline PET/CT in the restaging of prostate cancer patients, who presented a rising PSA. We evaluated 170 prostate cancer patients, previously radically treated, that were referred for restaging with [18F]-Choline PET/CT. A total of 129 patients (median PSA 4.29 ng/ml at relapse) showed one or more areas of high uptake on PET/CT scan, while 41 patients with a median PSA of 1.07 ng/ml at relapse showed negative PET/CT scans. No false negative was found, while 31 patients were identified as false positive. Specificity of Choline PET/CT in our series was 56.9 %, while sensibility was 100 %. At the time of restaging, a PSA value superior or equal to 1 ng/ml was found to be a statistically significant predictive factor of PET positivity, either at the univariate (p < 0.0001) and at the multivariate analysis (p < 0.0001). Based on our findings, [18F]-Choline PET/CT is confirmed as a useful diagnostic tool to detect early recurrence, in patients with increasing PSA after primary treatment. However, in case of a mild increase in PSA, positive results must be validated with other techniques, as specificity and positive predictive value of [18F]-Choline PET/CT decrease with the lower values of PSA.

Usefulness of Flow Cytometric Immunophenotyping for Bone Marrow Staging in Patients With Mantle Cell Lymphoma After Therapy

We evaluated the role of flow cytometric immunophenotyping (FCI) in the assessment of bone marrow (BM) specimens in 104 patients with mantle cell lymphoma (MCL) following treatment with aggressive combination chemotherapy. Of the patients, 77 had no morphologic or FCI evidence of MCL, 13 had morphologic and FCI evidence of MCL, and 14 patients were morphologically negative but FCI showed CD5+ clonal B-cells (M-/FCI+). Retrospective cyclin D1 immunostaining was positive in 3 of 12 M-/FCI+ cases. Clinical staging and follow-up showed that 4 of 12 patients had concurrent extramedullary involvement by MCL, 5 patients subsequently became M+ for MCL in BM (within 2-24 months), and 3 patients had no recurrent MCL on follow-up. We conclude that FCI is more sensitive than morphologic examination of BM at the time of restaging in patients with MCL and that positivity by only FCI in BM often correlates with concurrent disease or subsequent relapse.

Lenalidomide Consolidation Appears to Prolong Time to Retreatment After First-Line Chemoimmunotherapy for Patients with Previously Untreated CLL,

Abstract 3899 BACKGROUND:Although chemoimmunotherapy (CIT) has substantially improved response rates, treatment free survival, and overall survival in patients with chronic lymphocytic leukemia (CLL), only 40–50% of patients achieve a complete remission and the majority have residual disease when evaluated using sensitive assays for minimal residual disease (MRD). While these facts generated interest in consolidation strategies for patients with residual disease, previous trials of alemtuzumab-based consolidation found excess morbidity/mortality. In 2008 we began a trial of lenalidomide-based consolidation for patients with previously untreated CLL who had received 6 cycles of CIT induction. Preliminary analysis suggested that lenalidomide consolidation may improve the quality of response and prolong time to retreatment (Shanafelt; ASH 2010), although follow-up was short (median 16 months). METHODS:Eligible patients were previously untreated and had CLL in need of treatment according to the NCI-WG criteria (Blood 111:5446). Treatment schema consisted of 6 cycles of pentostatin (2 mg/m2), cyclophosphamide (600 mg/m2) and rituximab (375 mg/m2) given every 21 days (Blood 109:405). All patients completing 6 cycles of PCR induction, underwent complete restaging including evaluation for MRD using sensitive flow cytometry. Patients subsequently received 6 months of lenalidomide consolidation by daily administration with a starting lenalidomide dose of 5 mg/day and escalation to 10 mg/day after the first cycle as tolerated. Patients again underwent complete restaging including MRD evaluation after 6 months of lenalidomide. At the time of restaging, MRD negative patients entered observation. Those with residual disease continued on lenalidomide and underwent repeat MRD assessment every 3 months until an MRD negative state was achieved. RESULTS:45 patients were enrolled at Mayo Clinic between 3/2008 and 12/2009 of whom 44 were eligible. Median age was 65 (range: 44–78) and 71% of patients were male. 61% of patients had intermediate Rai risk and 39% high Rai risk. On prognostic testing 32% were CD38+, 52% Zap-70+, 52% IGHV unmutated, and 16% had high risk FISH (del 17p13; del 11q22). Of the 38 eligible patients who completed 6 cycles of PCR induction, 34 (89%) initiated lenalidomide consolidation. Thus by intent to treat analysis, 34/44 (77%) patients starting CIT with PCR were able to receive consolidation therapy.Among the 34 patients who initiated consolidation, the median number of cycles of lenalidomide received was 6 (range: 1–29). Nine of 34 (26%) patients had the lenalidomide dose increased to 10 mg daily while 18 (53%) required a reduction to 5 mg every other day. Five patients are still on lenalidomide at the time of this report. No cases of tumor lysis syndrome or tumor flare reaction were observed. Adverse events deemed at least possibly related to lenalidomide consolidation included 23 (68%) patients with grade 3+ hematologic toxicity and 5 (15%) with grade 3+ non-hematologic toxicity.Among the 34 patients who received at least 1 cycle of lendalidomide, 6 patients have improved the quality of their response including 3 patients who converted from having residual disease to a MRD- state. After a median follow-up of 29 months, 39/44 patients are alive and the median duration of response has not been reached. To date 8/44 (18%) patients have progressed to require additional treatment.Finally, since the eligibility criteria were nearly identical to our historic trial of PCR without lenalidomide consolidation, we conducted an intent to treat analysis that compared all 44 patients in the present trial (i.e. regardless of whether they received lenalidomide consolidation) to the 64 patients previously treated on our PCR trial (Blood 109:405). The demographic and prognostic characteristics of patients in the two studies were similar. With the caveat it represents a comparison across phase II trials, the proportion of patients free of retreatment at 30 months was 79% (95% CI:67–93) for PCR followed by lenalidomide consolidation vs 66% (95% CI: 54–80) for PCR alone (Figure 1). [Display omitted] CONCLUSION:Lenalidomide-based consolidation for CLL patients receiving first-line CIT induction appears to improve the quality of response and prolong time to retreatment. Randomized clinical testing of lenalidomide-based consolidation appears warranted. Disclosures:Shanafelt:Celgene: Research Funding; Hospira: Research Funding; Genentech: Research Funding. Off Label Use: PCR-Lenalidomide (off label use of pentostatin and lenalidomide). Tun:Celgene: Research Funding. Kay:Biothera: Research Funding; Clegene: Research Funding; Cephalon: Research Funding; Genentech: Research Funding; Glaxo Smith Kline: Research Funding; Hospira: Research Funding; Novartis: Research Funding; Supergen: Research Funding; Calistoga: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Emergent Biosolutions (Formerly Trubion): Membership on an entity's Board of Directors or advisory committees.

LONG-TERM OUTCOME OF PATIENTS WITH PERIPHERAL T-CELL LYMPHOMA TREATED WITH FIRST-LINE INTENSIVE CHEMOTHERAPY FOLLOWED BY AUTOLOGOUS STEM CELL TRANSPLANTATION

Peripheral T-cell lymphomas (PTCL) are infrequent subtypes of non-Hodgkin's lymphomas. The clinical course is aggressive and the median survival is about 2-3 years. An optimal first-line chemotherapy protocol has not been established and the role of high-dose therapy with autologous stem cell transplantation (ASCT) is still unclear. To analyze the long-term outcome of unselected PTCL patients treated with intensive first-line chemotherapy with high-dose therapy and ASCT. Here we report our experience with 29 patients with PTCL. The histological subtypes were as follows: peripheral T-cell lymphoma, not otherwise specified n=13; anaplastic large cell lymphoma (ALCL) ALK-negative n=5; ALCL ALK-positive n=3; ALCL with an unknown ALK status n=3; angioimmunoblastic lymphoma n=1; hepatosplenic lymphoma n=1; Sézary syndrome n=1; and enteropathy-associated T-cell lymphoma n=2. The median age at diagnosis was 48 years (29-64), most patients had advanced Ann Arbor stages (22 patients, 77%), IPI score ≥3 was found in 13 (45%) and PIT score ≥2 in 17 (59%) of the 29 patients. Eighteen patients received first-line high-dose therapy and autologous SCT consolidation; two patients were consolidaed with allogeneic SCT in the 1st complete remission and one patient in the 1st relapse. Ten patients with FDG-avid lymphoma were examined with integrated Positron emission tomography/ Computed tomography (PET/CT) at the time of diagnosis and after first-line therapy, two other patients were assessed with Positron emission tomography/ Computed tomography (PET/CT) only at time of restaging. Nineteen (66%) patients achieved complete remission, 3 (10%) partial remission and 7 (24%) patients failed the treatment. The overall response rate was 76%. PET negativity (complete metabolic response) after therapy was achieved in 8/12 (75%) individuals. After a median follow-up of 55.1 months, 14 (48.3%) patients relapsed or progressed and nine patients died (lymphoma progression). Eleven patients (50% of chemosensitive patients) survived more than 50 months. Three of the long-term survivors were treated with allogeneic SCT. The 2-year event-free survival (EFS) was 52% (95% confidence interval [CI], 0.33-0.71); the 2-year overall survival (OS) rate reached 65% (95%CI, 0.47-0.84). PET negativity was associated with a lower probability of relapse (chi-square p=0.09). Our data show that intensive first-line therapy with etoposide-doxorubicine-based regimens and ASCT consolidation may lead to long-term disease control in about a half of patients with chemosensitive PTCL. Achievement PET negativity is probably an essential prerequisite for long-term complete remission.

Results of a Phase I Trial of SGN-40 (Anti-huCD40 mAb) in Patients with Relapsed Multiple Myeloma.

SGN-40 is a humanized anti-CD40 monoclonal antibody that has demonstrated potent in vitro and in vivo efficacy against cell lines expressing CD40, a member of the tumor necrosis factor receptor family. CD40 is widely expressed on tumors of B-cell origin, including myeloma, non-Hodgkin's lymphoma, Hodgkin's disease, and chronic lymphocytic leukemia. SGN-40 has been evaluated in a phase I, multi-dose, single-agent, dose escalation study for patients with relapsed or refractory multiple myeloma. This single-arm trial was designed to evaluate safety, pharmacokinetics, immunogenicity, and antitumor activity. Thirty-two patients were treated at five clinical sites. Patients had been heavily pretreated with a median of four prior regimens and 4.8 years since diagnosis. Initially, patients were treated with four weekly infusions at a cohort-specific dose. This schedule was well-tolerated at 0.5, 1.0 and 2.0 mg/kg/wk; however, two of three patients experienced dose-limiting toxicities following the first dose at 4 mg/kg. One patient had aseptic meningitis (grade 3) and another had headache (grade 3) and aseptic meningitis (grade 4); both patients fully recovered after several days of symptom management. Subsequently, the protocol was amended to allow intra-patient dose-loading, which resulted in successful dose escalation to 8 mg/kg, the highest dose tested. There was neither recurrence of grade 3 neurotoxicity nor evidence of cumulative toxicity. Drug-related adverse events were mostly grade 1 or 2 and included: fatigue (38%), headache (34%), nausea (16%), conjunctivitis (13%), diarrhea (13%), vomiting (13%), anemia (9%), anorexia (9%), chills (9%), and pyrexia (9%). Transient grade 3 elevation of hepatic transaminases (1) and grade 3 neutropenia (1) were observed. Overall, toxicity did not appear to increase in incidence or severity at higher doses. Patients were evaluated at baseline and end of treatment for development of anti-SGN-40 antibodies. Of 30 patients for whom appropriate samples were available for testing, only one low-titer immune response (16 ng/mL) was detected, suggesting that immunogenicity does not appear to be a significant problem in this patient population. Pharmacokinetic analysis demonstrates dose-proportional changes in Cmax and AUC with a relatively short terminal half-life, similar to that seen in non-human primates. Final analysis of SGN-40 serum levels is ongoing. Although several patients demonstrated decreased M-protein and improvement in subjective symptoms, no patients met criteria for objective response. Five patients (16%) had stable disease at the time of restaging. In summary, dose-dependent toxicity was established only in relation to the first dose of SGN-40, which may be due to partial agonistic signal transduction. Using a dose-loading schedule, SGN-40 was administered up to 8 mg/kg without reaching a maximum tolerated dose. Some patients with advanced myeloma appeared to derive clinical benefit from therapy, and further development of this antibody, either as monotherapy or in combination with other anti-myeloma therapies, is indicated.

Survival Impact of Planned Restaging and Early Surgical Salvage Following Definitive Chemoradiation for Locally Advanced Squamous Cell Carcinomas of the Oropharynx and Hypopharynx

Patients who have received definitive radiation therapy (RT) for a nonlaryngeal T3/4 head and neck squamous cell carcinoma have a limited opportunity for post-RT surgical salvage. The authors reviewed the practice of planned post-RT restaging to determine its impact on the success of early surgical salvage. A retrospective review was performed for patients with resectable T3/4 cancers of the oropharynx and hypopharynx treated with RT +/- chemotherapy who underwent planned restaging clinically, radiographically (CT or MRI), and by direct laryngoscopy with biopsy at 4 to 8 weeks post-RT. Chemotherapy was given as induction, concurrently, or both. Neck dissection was performed at time of restaging in patients with primary tumor control and initial N2/N3 neck disease or persistent lymphadenopathy. A total of 54 patients had a median follow-up of 34.7 months (range, 7.6-97.8 months). Forty-two patients (78.8%) achieved a complete response (CR) at the primary site immediately after RT. Six developed late local failure at 9 to 61 months, of whom 2 were successfully salvaged. The ultimate 2-year local control among patients with initial CR was 94.8%. The 2-year organ preservation, disease-free survival, and overall survival (OS) rates were was 92.5%, 87%, and 90%, respectively. Twelve patients did not achieve initial CR. Two patients with bulky stage IV disease had unresectable cancers. Ten underwent immediate surgical salvage and 7 achieved local control (1 of whom developed distant metastases) whereas 3 had continued local failure. For patients without initial CR, the 2-year ultimate local control rate was 46.7% and OS was 46.8%. For all patients, overall 2-year local control, organ preservation, and OS rates were 85.6%, 75.6%, and 81.8% respectively. The rate of local failure-free organ preservation was 71.5%. For patients with T3/4 resectable nonlaryngeal head and neck cancers, planned clinical, radiographic, and pathologic restaging at 1 to 2 months after definitive RT provides the opportunity for early surgical salvage in those who fail at the primary site. This practice produces improved overall local control and survival rates compared with the literature reports for delayed attempted salvage with timing based on the findings of routine postradiation clinical surveillance. Future efforts may focus on the improved selection of patients who would be most likely to require early surgical intervention.

High pathological response rates with a novel preoperative chemoradiaton regimen in locally advanced rectal cancer: Preliminary results and dynamic evaluation by PET

High pathological response rates with a novel preoperative chemoradiaton regimen in locally advanced rectal cancer: Preliminary results and dynamic evaluation by PET

Rapid-fractionation preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for resectable pancreatic adenocarcinoma.

To evaluate the toxicities, radiographic and pathologic responses, and event-free outcomes with combined modality treatment that involves preoperative rapid-fractionation chemoradiation, pancreaticoduodenectomy, and electron-beam intraoperative radiation therapy (EB-IORT) for patients with resectable pancreatic adenocarcinoma. Patients with radiographically resectable localized adenocarcinoma of the pancreatic head were entered onto a preoperative protocol that consisted of a 2-week course of fluorouracil (5-FU) 300 mg/m2 daily 5 days per week and concomitant rapid-fractionation radiation 30 Gy, 3 Gy daily 5 days per week. Radiographic restaging was performed 4 weeks after chemoradiation, and patients with localized disease underwent pancreaticoduodenectomy with EB-IORT 10 to 15 Gy. Thirty-five patients were entered onto the study and completed chemoradiation, 34 (97%) as outpatients. Three patients (9%) experienced grade 3 nausea and vomiting; no other grade 3 or 4 toxicities were observed. Of the 27 patients taken to surgery, 20 patients (74%) underwent pancreaticoduodenectomy with EB-IORT. All patients had a less than grade III pathologic response to preoperative chemoradiation. At a median follow-up of 37 months, the 3-year survival rate in patients who underwent combined modality therapy was 23%. Combined modality treatment with preoperative rapid-fractionation chemoradiation, pancreaticoduodenectomy, and EB-IORT is associated with minimal toxicity and excellent locoregional control. This represents one approach to maximize the proportion of patients who receive all components of combined modality therapy and avoids the toxicity of pancreaticoduodenectomy in patients found to have metastatic disease at the time of restaging.