Anthony F. Shields

Capecitabine and Oxaliplatin in the Preoperative Multimodality Treatment of Rectal Cancer: Surgical End Points From National Surgical Adjuvant Breast and Bowel Project Trial R-04

PURPOSEnThe optimal chemotherapy regimen administered concurrently with preoperative radiation therapy (RT) for patients with rectal cancer is unknown. National Surgical Adjuvant Breast and Bowel Project trial R-04 compared four chemotherapy regimens administered concomitantly with RT.nnnPATIENTS AND METHODSnPatients with clinical stage II or III rectal cancer who were undergoing preoperative RT (45 Gy in 25 fractions over 5 weeks plus a boost of 5.4 Gy to 10.8 Gy in three to six daily fractions) were randomly assigned to one of the following chemotherapy regimens: continuous intravenous infusional fluorouracil (CVI FU; 225 mg/m(2), 5 days per week), with or without intravenous oxaliplatin (50 mg/m(2) once per week for 5 weeks) or oral capecitabine (825 mg/m(2) twice per day, 5 days per week), with or without oxaliplatin (50 mg/m(2) once per week for 5 weeks). Before random assignment, the surgeon indicated whether the patient was eligible for sphincter-sparing surgery based on clinical staging. The surgical end points were complete pathologic response (pCR), sphincter-sparing surgery, and surgical downstaging (conversion to sphincter-sparing surgery).nnnRESULTSnFrom September 2004 to August 2010, 1,608 patients were randomly assigned. No significant differences in the rates of pCR, sphincter-sparing surgery, or surgical downstaging were identified between the CVI FU and capecitabine regimens or between the two regimens with or without oxaliplatin. Patients treated with oxaliplatin experienced significantly more grade 3 or 4 diarrhea (P < .001).nnnCONCLUSIONnAdministering capecitabine with preoperative RT achieved similar rates of pCR, sphincter-sparing surgery, and surgical downstaging compared with CVI FU. Adding oxaliplatin did not improve surgical outcomes but added significant toxicity. The definitive analysis of local tumor control, disease-free survival, and overall survival will be performed when the protocol-specified number of events has occurred.

PET Imaging of Proliferation with Pyrimidines

Several new tracers are being developed for use with PET to assess pathways that are altered in cancers, including energy use, cellular signaling, transport, and proliferation. Because increased proliferation is a hallmark of many cancers, several tracers have been tested to track the DNA synthesis pathway. Thymidine, which is incorporated into DNA but not RNA, has been used in laboratory studies to measure tumor growth. Because thymidine labeled with 11C undergoes rapid biologic degradation and has a short physical half-life, tracers labeled with 18F have been preferred in PET imaging. One such tracer is 18F-labeled 3′-deoxy-3′-fluorothymidine (18F-FLT). 18F-FLT is trapped after phosphorylation by thymidine kinase 1, whose expression is increased in replicating cells. Several studies on breast, lung, and brain tumors have demonstrated that retention of 18F-FLT correlated with tumor proliferation. Although 18F-FLT has been used to image and stage several tumor types, the standardized uptake value is generally lower than that obtained with 18F-FDG. 18F-FLT can be used to image many areas of the body, but background uptake is high in the liver, marrow, and renal system, limiting use in these organs. 18F-FLT PET imaging has primarily been studied in the assessment of treatment response. Rapid declines in 18F-FLT retention within days to weeks have been demonstrated in several tumor types treated with cytotoxic drugs, targeted agents, and radiotherapy. Further work is ongoing to validate this approach and determine its utility in the development of new drugs and in the clinical evaluation of standard treatment approaches.

Oxaliplatin-induced neurotoxicity is dependent on the organic cation transporter OCT2

Oxaliplatin is an integral component of colorectal cancer therapy, but its clinical use is associated with a dose-limiting peripheral neurotoxicity. We found that the organic cation transporter 2 (OCT2) is expressed on dorsal root ganglia cells within the nervous system where oxaliplatin is known to accumulate. Cellular uptake of oxaliplatin was increased by 16- to 35-fold in cells overexpressing mouse Oct2 or human OCT2, and this process was associated with increased DNA platination and oxaliplatin-induced cytotoxicity. Furthermore, genetic or pharmacologic knockout of Oct2 protected mice from hypersensitivity to cold or mechanical-induced allodynia, which are established tests to assess acute oxaliplatin-induced neurotoxicity. These findings provide a rationale for the development of targeted approaches to mitigate this debilitating toxicity.

Impact of 18F-Fluoride PET in Patients with Known Prostate Cancer: Initial Results from the National Oncologic PET Registry

Under Medicare’s Coverage with Evidence Development policy, PET using 18F-sodium fluoride (NaF PET) to identify osseous metastasis became a covered service if prospective registry data were collected. The National Oncologic PET Registry (NOPR) developed a NaF PET registry built on the foundation of its prior registry for PET with 18F-FDG. Men with prostate cancer represented 72% of the cases. Methods: Prospective data before and after NaF PET were collected from referring and interpreting physicians. The analysis set consisted of consenting men age 65 y or older with prostate cancer undergoing NaF PET for initial staging (IS, n = 1,024), suspected first osseous metastasis (FOM, n = 1,997), or suspected progression of osseous metastasis (POM, n = 510). Results: Referring physicians indicated that if NaF PET were not available, other advanced imaging (body CT, MR imaging, or 18F-FDG PET) would be their plan in about half of the cases. After NaF PET, the postimaging plan was revised to treatment in 77%, 52%, and 71% for IS, FOM, and POM, respectively. When intended management was classified as either treatment or nontreatment, the overall change in intended management ranged from 44% to 52% and from 12% to 16% if no effect was assumed for those cases with pre-PET plans for other imaging (imaging-adjusted impact). Interpreting physicians recorded definite findings of bone metastasis in 14%, 29%, and 76% for IS, FOM, and POM, respectively. The intended care patterns varied widely across indication and scan abnormality category combinations. Conclusion: NaF PET has high overall impact, principally related to its effect on replacing intended use of other advanced imaging. Its imaging-adjusted impact was similar to that observed with 18F-FDG PET for restaging or suspected recurrence in other cancer types.

Carbohydrate antigen 19-9 is a prognostic and predictive biomarker in patients with advanced pancreatic cancer who receive gemcitabine-containing chemotherapy: a pooled analysis of 6 prospective trials.

Carbohydrate antigen 19‐9 (CA19‐9) is a widely used biomarker in pancreatic cancer. There is no consensus on the interpretation of the change in CA19‐9 serum levels and its role in the clinical management of patients with pancreatic cancer.

Comparison of FOLFIRI With or Without Cetuximab in Patients With Resected Stage III Colon Cancer; NCCTG (Alliance) Intergroup Trial N0147

BACKGROUNDnTwo arms with FOLFIRI, with or without cetuximab, were initially included in the randomized phase III intergroup clinical trial NCCTG (North Central Cancer Treatment Group) N0147. When other contemporary trials demonstrated no benefit to using irinotecan as adjuvant therapy, the FOLFIRI-containing arms were discontinued. We report the clinical outcomes for patients randomized to FOLFIRI with or without cetuximab.nnnPATIENTS AND METHODSnAfter resection, patients were randomized to 12 biweekly cycles of FOLFIRI, with or without cetuximab. KRAS (Kirsten rat sarcoma viral oncogene homolog) mutation status was retrospectively determined in a central lab. The primary end point was disease-free survival (DFS). Secondary end points included overall survival (OS) and toxicity.nnnRESULTSnOne hundred and six patients received FOLFIRI and 40 received FOLFIRI plus cetuximab. Median follow-up was 5.95 years (range, 0.1-7.0 years). The addition of cetuximab showed a trend toward improved DFS (hazard ratio [HR], 0.53; 95% CI, 0.26-1.1; P = .09) and OS (HR, 0.45; 95% CI, 0.17-1.16; P = .10) in the overall group, regardless of KRAS status, and in patients with wild type KRAS. Grade ≥ 3 nonhematologic adverse effects were significantly increased in the cetuximab versus FOLFIRI-alone arm (68% vs. 46%; P = .02). Adjuvant FOLFIRI resulted in a 3-year DFS less than that expected for FOLFOX.nnnCONCLUSIONnIn this small randomized subset of patients with resected stage III colon cancer, the addition of cetuximab to FOLFIRI was associated with a nonsignificant trend toward improved DFS and OS. Nevertheless, considering the limitations of this analysis, FOLFOX without the addition of a biologic agent remains the standard of care for adjuvant therapy in resected stage III colon cancer.

Impact of 18F-Fluoride PET on Intended Management of Patients with Cancers Other Than Prostate Cancer: Results from the National Oncologic PET Registry

The National Oncologic PET Registry prospectively assessed the impact of PET with 18F-sodium fluoride (NaF PET) on intended management of Medicare patients with suspected or known osseous metastasis. We report our findings for cancers other than prostate and make selected comparisons to our previously reported prostate cancer cohort. Methods: Data were collected from both referring and interpreting physicians before and after NaF PET in patients (age ≥ 65 y) stratified for initial staging (IS; n = 570), for suspected first osseous metastasis (FOM; n = 1,814; breast, 781 [43%]; lung, 380 [21%]; and all other cancers, 653 [36%]), and for suspected progression of osseous metastasis (POM; n = 435). Results: The dominant indication was bone pain. If NaF PET were unavailable, conventional bone scintigraphy would have been ordered in 85% of patients. In IS, 28% of patients had suspected or confirmed nonosseous metastasis. If neither conventional bone scintigraphy nor NaF PET were available, referring physicians would have ordered other advanced imaging more than 70% of the time rather than initiate treatment for suspected FOM (11%–16%) or POM (18%–22%). When intended management was classified as either treatment or nontreatment, the intended management change for each cancer type was highest in POM, lower in IS, and lowest in FOM. For suspected FOM, intended management change was lower in breast (24%), lung (36%), or other cancers (31%), compared with prostate cancer (44%) (P < 0.0001), but the NaF PET finding (normal/benign/equivocal, probable, or definite metastases) frequencies were similar across cancer types. After normal/benign/equivocal PET results, 15% of breast, 30% lung, and 38% prostate cancer patients had treatment, likely reflecting differences in management of nonosseous disease. For patients with definite metastasis on NaF PET, nonprostate, compared with prostate, cancer patients had post-PET plans for more frequent biopsy, alternative imaging, chemotherapy, and radiotherapy. In the smaller IS and POM cohorts, differences among cancer types were not significant. Conclusion: Overall, NaF PET led to change in intended management in a substantial fraction of nonprostate cancer patients. In the setting of suspected FOM, NaF PET had a lower immediate impact on the treat/nontreat decision in nonprostate versus prostate cancer patients, which is consistent with current practice guidelines.

Glucocorticoid Receptor Status Is a Principal Determinant of Variability in the Sensitivity of Non–Small-Cell Lung Cancer Cells to Pemetrexed

Introduction: Pemetrexed is an S-phase targeted drug in front-line or maintenance therapy of advanced nonsquamous non–small-cell lung cancer (NSCLC) but methods are needed for predicting the drug response. Dexamethasone is typically administered the day before, the day of, and the day after pemetrexed. As dexamethasone strongly regulates many genes including p53 through the glucocorticoid receptor (GR), we hypothesized that dexamethasone influences tumor response to pemetrexed. Methods: Eight nonsquamous NSCLC cell line models with varied p53 and GR&agr;/GR&bgr; status were used for gene expression and cell-cycle analyses and for loss- or gain-of-function experiments. Results: In three cell lines dexamethasone profoundly, but reversibly, suppressed the fraction of S-phase cells. Dexamethasone also reversibly repressed expression of thymidylate synthase and dihydrofolate reductase, which are primary targets of pemetrexed but are also quintessential S-phase enzymes as well as the S-phase–dependent expression of thymidine kinase 1. Dexamethasone also decreased expression of the major pemetrexed transporters, the reduced folate carrier and the proton coupled folate transporter. Only cells expressing relatively high GR&agr; showed these dexamethasone effects, regardless of p53 status. In cells expressing low GR&agr;, the dexamethasone response was rescued by ectopic GR&agr;. Further, depletion of p53 did not attenuate the dexamethasone effects. The presence of dexamethasone during pemetrexed treatment protected against pemetrexed cytotoxicity in only the dexamethasone responsive cells. Conclusions: The results predict that in nonsquamous NSCLC tumors, reversible S-phase suppression by dexamethasone, possibly combined with a reduction in the drug transporters, attenuates responsiveness to pemetrexed and that GR status is a principal determinant of tumor variability of this response.

Radiographic Parameters in Predicting Outcome of Patients with Hepatocellular Carcinoma Treated with Yttrium-90 Microsphere Radioembolization

Background. In patients with hepatocellular carcinoma, selection criteria for transarterial hepatic selective internal radiotherapy are imprecise. Additionally, radiographic parameters to predict outcome of transarterial hepatic selective internal radiotherapy have not been fully characterized. Patients and methods. Computed tomography (CT) scans of 23 patients with unresectable primary hepatocellular carcinoma before and after transarterial hepatic selective internal radiotherapy with yttrium-90 microspheres were retrospectively reviewed. Selected radiographic parameters were evaluated and correlated with progression-free survival and overall survival. Response to treatment was assessed with Response RECIST 1.1 and Morphology, Attenuation, Size, and Structure (MASS) criteria. Results. On the post-SIRT CT, 68% of tumors demonstrated decreased size (median decrease of 0.8u2009cm, P = 0.3); 64% had decreased attenuation (median decrease 5.7u2009HU, P = 0.06), and 48% demonstrated increased tumor necrosis (P < 0.001). RECIST-defined partial response was seen in 10% patients, stable disease in 80%, and 10% had disease progression. Median progression-free survival was 3.9 months (range, 3.3 to 7.3), and median overall survival was 11.2 months (7.1 to 31.1). Pretreatment lower hepatopulmonary shunt fraction, central hypervascularity, and well-defined tumor margins were associated with improved progression-free survival. Conclusion. In patients with unresectable hepatocellular carcinoma, pretreatment CT parameters may predict favorable response to SIRT and improve patient selection.