Sirkku Jyrkkiö

Fluorouracil, Epirubicin, and Cyclophosphamide With Either Docetaxel or Vinorelbine, With or Without Trastuzumab, As Adjuvant Treatments of Breast Cancer: Final Results of the FinHer Trial

PURPOSEnDocetaxel has not been compared with vinorelbine as adjuvant treatment of early breast cancer. Efficacy and long-term safety of a short course of adjuvant trastuzumab administered concomitantly with chemotherapy for human epidermal growth factor receptor 2 (HER2) -positive cancer are unknown.nnnPATIENTS AND METHODSnOne thousand ten women with axillary node-positive or high-risk node-negative breast cancer were randomly assigned to receive three cycles of docetaxel or vinorelbine, followed in both groups by three cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC). Women with HER2-positive cancer (n = 232) were further assigned to either receive or not receive trastuzumab for 9 weeks with docetaxel or vinorelbine. The median follow-up time was 62 months after random assignment.nnnRESULTSnWomen assigned to docetaxel had better distant disease-free survival (DDFS) than those assigned to vinorelbine (hazard ratio [HR] = 0.66; 95% CI, 0.49 to 0.91; P = .010). In the subgroup of HER2-positive disease, patients treated with trastuzumab tended to have better DDFS than those treated with chemotherapy only (HR = 0.65; 95% CI, 0.38 to 1.12; P = .12; with adjustment for presence of axillary nodal metastases, HR = 0.57; P = .047). In exploratory analyses, docetaxel, trastuzumab, and FEC improved DDFS compared with docetaxel plus FEC (HR = 0.32; P = .029) and vinorelbine, trastuzumab, and FEC (HR = 0.31; P = .020). The median left ventricular ejection fraction of trastuzumab-treated patients remained unaltered during the 5-year follow-up; only one woman treated with trastuzumab was diagnosed with a heart failure.nnnCONCLUSIONnAdjuvant treatment with docetaxel improves DDFS compared with vinorelbine. A brief course of trastuzumab administered concomitantly with docetaxel is safe and effective and warrants further evaluation.

Dose-densified chemoimmunotherapy followed by systemic central nervous system prophylaxis for younger high-risk diffuse large B-cell/follicular grade 3 lymphoma patients : results of a phase II Nordic Lymphoma Group study

BACKGROUNDnMany patients with aggressive B-cell lymphomas and high clinical risk score still die of lymphoma after conventional R-CHOP chemoimmunotherapy. We hypothesized that intensified chemoimmunotherapy including systemic central nervous system (CNS) prophylaxis improves outcome and reduces the incidence of CNS-related events.nnnPATIENTS AND METHODSnInclusion criteria were age 18-65 years, primary diffuse large B-cell lymphoma or grade III follicular lymphoma without clinical signs of CNS disease and negative cerebrospinal fluid cytology, age-adjusted International Prognostic Index 2-3 and WHO performance score 0-3. Treatment consisted of six courses of R-CHOEP-14 followed by a course of high-dose cytarabine and a course of high-dose methotrexate. Primary end point was failure-free survival (FFS) at 3 years.nnnRESULTSnA total of 156 eligible patients with a median age of 54 years (range 20-64) were included. Three toxic deaths were observed. Three-year overall survival (OS) and FFS rates (median observation time 52 months for survivors) were 81% and 65%, respectively. Seven patients experienced CNS relapse, all within 6 months.nnnCONCLUSIONSnThe results are promising with favorable 3-year OS and FFS rates, a low toxic death rate and a lower than expected number of CNS events. CNS progression might be further reduced by earlier CNS prophylaxis. CinicalTrials.gov. identifier NCT01502982.

Evaluation of early response to radiotherapy in head and neck cancer measured with [11C]methionine-positron emission tomography

PURPOSEnTo evaluate whether positron emission tomography (PET) with carbon-11-methionine (MET) can be used for detection of early response to external beam radiotherapy (RT) in untreated head and neck cancer using locoregional control and survival as study endpoints.nnnMATERIALSnFifteen patients with head and neck cancer underwent a MET PET study before RT and after a median dose of 24 Gy. Fractionation was standard (n = 6) or hyperfractionated (n = 9), and 13 out of 15 patients had planned surgery after RT. SUV was calculated for primary tumor (n = 13) or largest lymph node metastasis in two patients of whom one had his primary excised before study enrollment and one presented with unknown primary tumor syndrome.nnnMETHODSnAttenuation corrected PET scans acquired 20-40 min from tracer injection were used for evaluation of MET uptake in tumors. A quantitative MET uptake index was expressed as standardized uptake value (SUV) or SUV(lean) (corrected for lean body mass). The PET results were correlated with clinical follow-up data. The median follow-up time is currently 28 months (range 22-34).nnnRESULTSnA total of 13 primary tumors and 12 metastatic lymph nodes were visually identified in MET PET. In the first PET study the median SUV in tumor was 8.6 (range, 5.5-14.0). In the second PET study performed during RT the median SUV decreased to 5.7 (range, 3.1-8.2, P = 0.001). Two out of 15 patients showed no radiation-induced decrease in SUV. The median tumor SUV ratio of patients remaining in local control (CR) after RT was 0.7 (range 0.6-0.8, n = 6), and that of relapsing patients similarly 0.7 (range 0.5-1.0, n = 9, NS). The SUV ratio was not associated with survival time. The MET uptake of submandibular salivary glands decreased in all patients during the first two or three weeks of RT (P = 0.03).nnnCONCLUSIONSnMET uptake in tumor shows a significant decrease during the first two to three weeks of RT of head and neck cancer. It appears that the rate of decrease in tracer uptake is comparable in relapsing patients and those who remain locally controlled and thus the use of MET PET for prediction of response to RT is limited.

Biodistribution of [11C] methylaminoisobutyric acid, a tracer for PET studies on system A amino acid transport in vivo.

Abstract. [N-methyl-11C]α-Methylaminoisobutyric acid (11C-MeAIB) is a potentially useful tracer for positron emission tomography (PET) studies on hormonally regulated system A amino acid transport. 11C-MeAIB is a metabolically stable amino acid analogue specific for system A amino acid transport. We evaluated the biodistribution of 11C-MeAIB in rats and humans to estimate the usefulness of the tracer for in vivo human PET studies, for example, on regulation of system A amino acid transport and on tumour imaging. Healthy Sprague-Dawley rats (n=14) were killed 5, 20, 40 or 60xa0min after the injection of 11C-MeAIB, and the tissue samples were weighed and counted for 11C radioactivity. Ten lymphoma patients with relatively limited tumour burden underwent whole-body (WB) PET imaging with 11C-MeAIB. In addition, three other patients had dynamic PET scanning of the head and neck area, and the tracer uptake was quantitated by calculating the kinetic influx constants (Ki values) for the tracer. In animal studies, the highest activity was detected in the kidney, pancreas, adrenal gland and intestines. In humans, the highest activity was found in the salivary glands, and after that in the kidney and pancreas, similar to the results in animal studies. Rapid uptake was also detected in the skeletal muscle. In the graphical analysis, linear plots were obtained, and the mean fractional tracer uptake values (Ki) of the parotid glands (n=3) and cervical muscles (n=3) were 0.039±0.008xa0min–1 and 0.013±0.006xa0min–1, respectively. The Ki value of the tumour (n=1) was 0.064xa0min–1. Higher uptake of 11C-MeAIB into the tumour tissue was encountered. These results encourage further 11C-MeAIB PET studies in humans on the physiology and pathology of system A amino acid transport and on tumour detection.

Uptake of [N-methyl-11C]α-methylaminoisobutyric acid in untreated head and neck cancer studied by PET

Abstract. Amino acid transport system A is expressed strongly in neoplastic cells. [N-methyl-11C]α-Methylaminoisobutyric acid (11C-MeAIB) is a recently developed tracer for PET studies on system A amino acid transport. 11C-MeAIB is a metabolically stable amino acid analogue which is transported from plasma into the tissue by system A. This study evaluated the kinetics of 11C-MeAIB uptake from plasma into tumour tissue and normal tissues in 13 patients with untreated head and neck cancer. 11C-MeAIB uptake in tumour was compared with histological grade and proliferative activity. Tracer uptake was quantitated by calculating the standardised uptake values (SUVs) and the kinetic influx constants (Ki) using graphical analysis. All tumours accumulated 11C-MeAIB and were visualised clearly. In the graphical analysis, linear plots were achieved; the mean Ki value of tumour was 0.056±0.026xa0min–1, and the mean SUV was 6.1±2.7. A close correlation between graphically obtained Ki and semi-quantitative SUV in tumours was found (r=0.887, P=0.00005). We could not demonstrate a correlation between the uptake of 11C-MeAIB and the grade of malignancy or the proliferative index, as assessed using Ki-67 immunohistochemical assay. Head and neck cancer can be effectively imaged with 11C-MeAIB PET. 11C-MeAIB showed active and rapid transport into tumour tissue and salivary glands. Further studies on the applicability of 11C-MeAIB PET for radiation treatment planning in the head and neck region and the regulation of system A amino acid transport under different metabolic states are warranted.

Very high quantitative tumor HER2 content and outcome in early breast cancer

BACKGROUNDnIt is unknown how a very high tumor total HER2 (human epidermal growth factor receptor-2) content (H2T) influences outcome in early breast cancer treated with adjuvant trastuzumab plus chemotherapy.nnnPATIENTS AND METHODSnH2T was measured using a novel quantitative assay (HERmark(®)) from formalin-fixed tumor tissue of 899 women who participated in the FinHer trial (ISRCTN76560285). In a chromogenic in situ hybridization (CISH) test, 197 (21.9%) patients had HER2-positive cancer and were randomly assigned to receive trastuzumab or control.nnnRESULTSnCancer H2T levels varied 1808-fold. High H2T levels were correlated with a positive HER2 status by CISH (Pu2009<u20090.0001). A nonlinear association was present between H2T and the hazard of distant recurrence in a subpopulation treatment effect pattern plot analysis in CISH-positive disease. Patients with very high H2T (defined by ≥22-fold the median of HER2-negative cancers; 13% of CISH-positive cancers) did not benefit from adjuvant trastuzumab [hazard ratio (HR) 1.23; 95% confidence interval (CI) 0.33-4.62; Pu2009=u20090.75], whereas the rest of the patients with HER2-positive disease by CISH (87%) did benefit (HR 0.52; 95% CI 0.28-1.00; Pu2009=u20090.050).nnnCONCLUSIONnPatients with HER2-positive breast cancer with very high tumor HER2 content may benefit less from adjuvant trastuzumab compared with those whose cancer has more moderate HER2 content.

[N‐methyl‐11C]MeAIB, a tracer for system A amino acid transport: preparation from [11C]methyl triflate and HPLC metabolite analysis of plasma samples after intravenous administration in man

MeAIB, α-methylamino-isobutyric acid, is an achiral synthetic amino acid which is a highly selective substrate for the A-type, or alanine-preferring, amino acid transport system. [N-methyl-11C]MeAIB ([11C]MeAIB) was prepared by reaction of [11C]methyl triflate with AIB methyl ester, generated in situ from its corresponding hydrochloride, followed by hydrolysis of the ester function with aqueous NaOH. After HPLC-purification, the product was obtained in a 60–70% decay corrected yield counted from [11C]methyl triflate. The total synthesis time was 32–37u2009min and the radiochemical purity of the product higher than 98%. HPLC analysis of plasma samples taken 5–30u2009min after the administration of [11C]MeAIB to man showed that more than 95% of the total radioactivity in the plasma consisted of unchanged [11C]MeAIB. The simple preparation and the high metabolic stability of [11C]MeAIB makes this novel tracer a potential candidate for positron emission tomography investigations for the system A amino acid transport system in vivo. Copyright

Human radiation dosimetry of [11C]MeAIB, a new tracer for imaging of system A amino acid transport

Purpose[N-methyl-11C]α-methylaminoisobutyric acid ([11C]MeAIB) is a promising positron emission tomography (PET) tracer for imaging hormonally regulated system A amino acid transport. Uptake of [11C]MeAIB is totally specific for amino acid transport since [11C]MeAIB is metabolically stable both extra- and intracellularly. The aim of this study was to measure cumulated radioactivity in different organs and estimate the absorbed radiation doses to humans with the Medical Internal Radiation Dosimetry (MIRD) method.MethodsRadiation absorbed doses were calculated from PET images for 25 volunteers. Dynamic acquisition data were obtained for the thoracic, abdominal, femoral and head and neck regions. The median dose of intravenously injected [11C]MeAIB was 422±35xa0MBq, with a range of 295–493xa0MBq. After PET imaging the radioactivity in voided urine was measured. Experimental human data were used for residence time estimates. Radiation doses were calculated with commonly used software.ResultsThe effective dose for a 70-kg adult was 0.004xa0mSv/MBq, corresponding to a 1.72xa0mSv effective dose from the PET study with injection of 430xa0MBq [11C]MeAIB. The highest absorbed doses were in the pancreas (0.018xa0mGy/MBq), kidneys (0.017xa0mGy/MBq), intestine (0.014xa0mGy/MBq), liver (0.008xa0mGy/MBq) and stomach (0.005xa0mGy/MBq). Only 0.57% of injected activity was excreted to urine within 1xa0h after injection.ConclusionBiodistribution of [11C]MeAIB in the abdominal region reflected the high activity of the transportation of amino acids via system A and these organs also had the highest radiation doses. An effective dose of 0.004xa0mSv/MBq is fully justified when [11C]MeAIB PET is performed to study system A activity in vivo.

Amino acid uptake in the skeletal muscle measured using [11C]methylaminoisobutyrate (MEAIB) and PET

Abstract. An amino acid analogue, [11C]MeAIB, recently introduced for oncological positron emission tomography (PET) studies, is a highly selective substrate for insulin-sensitive amino acid transport system A. The aim of this study was to study the uptake kinetics of [11C]MeAIB in skeletal muscle in the fasting state and during insulin stimulation. Two dynamic PET studies were carried out in 11 healthy subjects, once in the fasting state and once during euglycaemic hyperinsulinaemia (serum insulin 67±12xa0mUxa0l–1). Graphical analysis was used to calculate the fractional [11C]MeAIB uptake rate (Ki). Amino acid uptake was estimated by multiplying Ki by the serum amino acid concentration. After tracer injection, rapid uptake in muscle tissue was detected both in the fasting state and during insulin stimulation and femoral muscles were clearly visualised in both studies. In the graphical analysis, the volume of distribution of [11C]MeAIB plotted against normalised plasma time yielded a linear curve (the slope of which = Ki). The fractional [11C]MeAIB uptake rate (Ki) in the femoral muscle regions increased from 0.0070±0.0018xa0min–1 (mean±SD) in the fasting state to 0.0079±0.0020xa0min–1 (P<0.05) during insulin stimulation. When compared with the fasting state, serum total amino acid concentration decreased from 2.49±0.22 to 2.16±0.18xa0mmolxa0l–1 (P<0.0001) and the serum concentration of six amino acids typically using system A for their transport decreased from 0.72±0.1 to 0.63±0.07xa0mmolxa0l–1 (P=0.0001) during hyperinsulinaemia. The calculated skeletal muscle total amino acid uptake and the uptake of the six amino acids typically using system A were similar in the fasting state and during insulin clamp (17.1±3.2 vs 17.7±3.7xa0µmolxa0kg–1xa0min–1, NS, and 5.0±1.3 vs 5.0±1.4xa0µmolxa0kg–1xa0min–1, NS, respectively). The uptake rates correlated with perfusion both in the fasting state and during hyperinsulinaemia (P<0.05). [11C]MeAIB PET appears to be a feasible method for measurement of amino acid uptake in human skeletal muscle. As a tracer that is not metabolised in the tissues, [11C]MeAIB provides simple modelling and robust data analysis and thus provides a means to investigate amino acid uptake into muscle tissue in various disease conditions known to affect protein metabolism.

Prolonged immunochemotherapy with rituximab, cytarabine and fludarabine added to cyclophosphamide, doxorubicin, vincristine and prednisolone and followed by rituximab maintenance in untreated elderly patients with mantle cell lymphoma: a prospective study by the Finnish Lymphoma Group

Abstract There is no consensus on treatment strategies for elderly patients with mantle cell lymphoma (MCL). In this prospective phase II study we investigated whether the poor outcome could be improved, with reasonable toxicity, by prolonging the immunochemotherapy. Ten cycles of alternating cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP)/cytarabine (AraC) with eight doses of rituximab (R) were given as induction. The potential synergism of intermediate-dose AraC and fludarabine was tested in cycles 6–8. Induction was followed by bimonthly rituximab maintenance for 2 years. The median age of the 60 included patients was 74 years, and the Mantle Cell Lymphoma International Prognostic Index (MIPI) was intermediate or high risk in 98% of the patients. The overall response rate was 95% (complete response/complete response unconfirmed 87%). The response of 11 patients improved with cycles 6–8 (R-fludarabine-AraC). Progression-free survival was 70% and overall survival 72% at 4 years, respectively. Treatment related mortality was 2%. Severe infections were rare, with only one grade 4 infection. More dose reductions were needed during fludarabine-containing courses as compared to R-AraC. In 20 patients a transient grade 4 neutropenia without severe infections was recorded during maintenance. In conclusion, elderly patients with MCL can be treated relatively intensively with acceptable toxicity.