C.M.L. van Herpen

Beyond RECIST: molecular and functional imaging techniques for evaluation of response to targeted therapy.

The development of targeted therapies is a major breakthrough in the treatment of cancer. By evoking necrosis and cavitation, evaluation based on tumour size alone, as is done in the RECIST criteria, is no longer an adequate method. New molecular and functional imaging techniques are developed. This review focuses on the use of new imaging modalities for the evaluation of treatment response of pathway based targeted therapies. First, the basic principles of functional and molecular imaging modalities are briefly discussed. Thereafter, their clinical application in targeted therapies is correlated to the underlying biological mechanism. In this way, the best method for response evaluation for a new agent can be identified.

Pharmacogenetic Screening of CYP3A and ABCB1 in Relation to Population Pharmacokinetics of Docetaxel

Purpose: Despite the extensive clinical experience with docetaxel, unpredictable interindividual variability in efficacy and toxicity remain important limitations associated with the use of this anticancer drug. Large interindividual pharmacokinetic variability has been associated with variation in toxicity profiles. Genetic polymorphisms in drug-metabolizing enzymes and drug transporters could possibly explain the observed pharmacokinetic variability. The aim of this study was therefore to investigate the influence of polymorphisms in the CYP3A and ABCB1 genes on the population pharmacokinetics of docetaxel. Experimental Design: Whole blood samples were obtained from patients with solid tumors and treated with docetaxel to quantify the exposure to docetaxel. DNA was collected to determine polymorphisms in the CYP3A and ABCB1 genes with DNA sequencing. A population pharmacokinetic analysis of docetaxel was done using nonlinear mixed-effect modeling. Results: In total, 92 patients were assessable for pharmacokinetic analysis of docetaxel. A three-compartmental model adequately described the pharmacokinetics of docetaxel. Several polymorphisms in the CYP3A and ABCB1 genes were found, with allele frequencies of 0.54% to 48.4%. The homozygous C1236T polymorphism in the ABCB1 gene (ABCB1*8) was significantly correlated with a decreased docetaxel clearance (−25%; P = 0.0039). No other relationships between polymorphisms and pharmacokinetic variables reached statistical significance. Furthermore, no relationship between haplotypes of CYP3A and ABCB1 and the pharmacokinetics could be identified. Conclusions: The polymorphism C1236T in the ABCB1 gene was significantly related to docetaxel clearance. Our current finding may provide a meaningful tool to explain interindividual differences in docetaxel treatment in daily practice.

Phase II study of 3-AP Triapine in patients with recurrent or metastatic head and neck squamous cell carcinoma

BACKGROUND Treatment options for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) are limited with response rates to cytotoxic chemotherapy of approximately 30% and median survival of 6 months. PATIENTS AND METHODS In a multicentre phase II study, 32 patients with recurrent or metastatic HNSCC received 3-AP Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone), an inhibitor of ribonucleotide reductase, 96 mg/m2, daily for 4 days every 14 days (one cycle). Eligibility criteria required Eastern Cooperative Oncology Group performance status (ECOG PS) of zero to two with a life expectancy of >3 months; one prior chemotherapy regimen was allowed. RESULTS Thirty patients were assessable for response and toxicity. Median age was 57 years (range 36-79) and median ECOG PS was one (range 0-2). Thirteen patients had previously been treated with chemotherapy. A total of 130 cycles were administered with a median number of cycles of 3.5 (range 1-8). Mild anaemia (40%), nausea (22%) and fatigue (22%) were commonly reported with G3 and G4 neutropenia documented in 22% and 22%, respectively. Overall response rate was 5.9% (95% confidence interval 0.2% to 28.7%). One patient achieved a partial response, eight had stable disease and 21 progressive disease. Median time to disease progression was 3.9 months. CONCLUSIONS 3-AP Triapine as a single agent, at this dose and schedule, is well tolerated but has only minor activity in the treatment of advanced HNSCC.

Phase Ib study of NGR-hTNF, a selective vascular targeting agent, administered at low doses in combination with doxorubicin to patients with advanced solid tumours

Background:Asparagine–glycine–arginine–human tumour necrosis factor (NGR–hTNF) is a vascular targeting agent exploiting a tumour-homing peptide (NGR) that selectively binds to aminopeptidase N/CD13, overexpressed on tumour blood vessels. Significant preclinical synergy was shown between low doses of NGR-TNF and doxorubicin.Methods:The primary aim of this phase I trial was to verify the safety of low-dose NGR–hTNF combined with doxorubicin in treating refractory/resistant solid tumours. Secondary objectives included pharmacokinetics (PKs), pharmacodynamics, and clinical activity. In all 15 patients received NGR–hTNF (0.2–0.4–0.8–1.6 μg m−2) and doxorubicin (60–75 mg m−2), both given intravenously every 3 weeks.Results:No dose-limiting toxicity occurred and the combination was well tolerated. Around two cases of neutropenic fevers, lasting 2 days, and two cases of cardiac ejection-fraction drops, one asymptomatic and the other symptomatic, were registered. Only 11% of the adverse events were related to NGR–hTNF and were short-lasting and mild-to-moderate in severity. There was no apparent PK interaction and the shedding of soluble TNF-receptors did not increase to 0.8 μg m−2. One partial response (7%), at dose level 0.8 μg m−2, and 10 stable diseases (66%), lasting for a median duration of 5.6 months, were observed.Conclusions:NGR–hTNF plus doxorubicin was administered safely and showed promising activity in patients pre-treated with anthracyclines. The dose level of 0.8 μg m−2 NGR–hTNF plus doxorubicin 75 mg m−2 was selected for phase II development.

18F-FLT PET During Radiotherapy or Chemoradiotherapy in Head and Neck Squamous Cell Carcinoma Is an Early Predictor of Outcome

This prospective study used sequential PET with the proliferation tracer 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) to monitor the early response to treatment of head and neck cancer and evaluated the association between PET parameters and clinical outcome. Methods: Forty-eight patients with head and neck cancer underwent 18F-FLT PET/CT before and during the second and fourth weeks of radiotherapy or chemoradiotherapy. Mean maximum standardized uptake values for the hottest voxel in the tumor and its 8 surrounding voxels in 1 transversal slice (SUVmax(9)) of the PET scans were calculated, as well as PET-segmented gross tumor volumes using visual delineation (GTVVIS) and operator-independent methods based on signal-to-background ratio (GTVSBR) and 50% isocontour of the maximum signal intensity (GTV50%). PET parameters were evaluated for correlations with outcome. Results: 18F-FLT uptake decreased significantly between consecutive scans. An SUVmax(9) decline ≥ 45% and a GTVVIS decrease ≥ median during the first 2 treatment weeks were associated with better 3-y disease-free survival (88% vs. 63%, P = 0.035, and 91% vs. 65%, P = 0.037, respectively). A GTVVIS decrease ≥ median in the fourth treatment week was also associated with better 3-y locoregional control (100% vs. 68%, P = 0.021). These correlations were most prominent in the subset of patients treated with chemoradiotherapy. Because of low 18F-FLT uptake levels during treatment, GTVSBR and GTV50% were unsuccessful in segmenting primary tumor volume. Conclusion: In head and neck cancer, a change in 18F-FLT uptake early during radiotherapy or chemoradiotherapy is a strong indicator for long-term outcome. 18F-FLT PET may thus aid in personalized patient management by steering treatment modifications during an early phase of therapy.

Polymorphisms in Endothelial Nitric Oxide Synthase (eNOS) and Vascular Endothelial Growth Factor (VEGF) Predict Sunitinib-Induced Hypertension

Hypertension is an important side effect of sunitinib treatment. In a retrospective study in 255 patients, single‐nucleotide polymorphisms (SNPs) in vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor (VEGFR)‐2, endothelin‐1 (ET‐1), and endothelium‐derived nitric oxide synthase (eNOS) were multivariately tested against hypertension grades and changes in systolic blood pressure (SBP), diastolic BP (DBP), and mean arterial BP (MAP). Next, the association between hypertension and survival in patients with metastatic renal cell cancer (mRCC) was studied. Greater elevations in SBP and MAP were associated with the presence of a haplotype in VEGFA (P = 0.014 and P = 0.036, respectively). The tendency to develop grade 3 hypertension was associated with this haplotype and also with a SNP in eNOS (P = 0.031 and P = 0.045, respectively). In mRCC patients, sunitinib‐induced hypertension was found to confer a survival benefit, with the mean overall survival being prolonged by 7.2 months (P = 0.035 and P = 0.026 for SBP and DBP elevations, respectively). Genetic polymorphisms in VEGFA and eNOS independently predict rise in BP and/or development of severe hypertension in sunitinib‐treated patients. Grade 3 hypertension was found to be an independent factor for overall survival in patients with mRCC.

Immunochemotherapy with interleukin-2, interferon- α and 5-fluorouracil for progressive metastatic renal cell carcinoma: a multicenter phase II study

In patients with metastatic renal cell carcinoma response rates of 7–26% have been achieved with immunotherapy. A high response rate of 48% in 35 patients has been reported for treatment with the combination of interferon-α (IFN-α), interleukin-2 (IL-2) and 5-fluorouracil (5-FU) (Atzpodien et al (1993 a) Eur J Cancer 29A: S6–8). We conducted a multicentre phase II study to confirm these results. Metastatic renal cell carcinoma patients were treated as outpatients with an 8-week treatment cycle. Recombinant human IL-2 20 MU m–2was administered subcutaneously (s.c.) three times a week (t.i.w) in weeks 1 and 4 and 5 MU m–2t.i.w. in weeks 2 and 3. Recombinant human IFN-α 2a 6 MU m–2was administered s.c. once in weeks 1 and 4 and t.i.w. in weeks 2 and 3, and 9 MU m–2t.i.w. in weeks 5–8. 5-FU (750 mg m–2) was given as a bolus injection intravenous once a week in weeks 5–8. The treatment cycle was repeated once in case of response or minor response. Fifty-two patients entered the study. All had undergone a nephrectomy and had progressive metastatic disease. The median WHO-performance status was 1, the median number of metastatic sites was 2 (range 1–5) and the median time between the diagnosis of the primary tumour and the start of treatment was 12.9 months (range 1–153). Among the 51 patients, including four patients with early progressive disease, who were evaluable for response, the response rate was 11.8% (95% confidence interval (CI) 2.9–20.7%), with no complete responses. Median duration of response was 8.3 (range 3.8–22.4+) months. Median survival was 16.5 (range 1.8–30.5+) months. Grade 3/4 toxicity (WHO) occurred in 29/52 (55.8%) of the patients in cycle 1 and in 6/16 (37.5%) of the patients in cycle 2. It consisted mainly of anorexia, fatigue, nausea, fever and leucocytopenia. We cannot confirm the high response rate in patients with metastatic renal cell carcinoma treated with the combination of IFN-α, IL-2 and 5-FU, as described by Atzpodien et al.

Functional MRI techniques demonstrate early vascular changes in renal cell cancer patients treated with sunitinib: a pilot study

Abstract Objective: To assess the early vascular effects of sunitinib in patients with renal cell carcinoma (RCC) with diffusion-weighted magnetic resonance imaging (DWI), dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and T2* perfusion MRI. Patients and methods: In 10 patients with abdominal RCC lesions, DWI, DCE-MRI and T2* perfusion MRI measurements at 3 Tesla were performed at baseline, 3 and 10 days after start of sunitinib. VEGF-A plasma levels were measured on days 0, 3 and 10. Results: DWI showed a significant increase in the apparent diffusion coefficient (×10−6 s/mm2) from baseline (mean 1158, range 814–2003) to day 3 (mean 1306, range 1008–2097, P = 0.015) followed by a decrease to baseline levels at day 10 (mean 1132, range 719–2005, P = 0.001). No significant changes were found in mean DCE-MRI parameters. T2* perfusion MRI showed a significant decrease in relative tumor blood volume (rBV) and relative tumor blood flow (rBF) at day 3 (rBV P = 0.037, rBF P = 0.018) and day 10 (rBV P = 0.006, rBF P = 0.009). VEGF-A plasma levels significantly increased after 10 days, but did not correlate with MRI parameters. Conclusions: Sunitinib induces antiangiogenic effects as measured by DWI and T2*-perfusion MRI, 3 and 10 days after the start of the initial treatment. DCE-MRI did not show significant changes. In the near future, early functional MRI-based evaluation can play an important role in tailoring treatment to the individual patient with RCC. Further investigation is warranted.

Short-term health-related quality of life and symptom control with docetaxel, cisplatin, 5-fluorouracil and cisplatin (TPF), 5-fluorouracil (PF) for induction in unresectable locoregionally advanced head and neck cancer patients (EORTC 24971/TAX 323)

Background:The EORTC 24971/TAX 323, a phase III study of 358 patients with unresectable locoregionally advanced squamous cell carcinoma of the head and neck, showed an improved progression-free and overall survival (OS) with less toxicity when docetaxel (T) was added to cisplatin and 5-fluorouracil (PF) for induction and given before radiotherapy (RT). The impact of the addition of docetaxel on patients’ health-related quality of life (HRQOL) and symptoms was investigated.Methods:HRQOL was assessed at baseline, at end of cycle 2, and 4, 6, and 9 months after completion of RT using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) and the EORTC QLQ Head and Neck Cancer-Specific Module (EORTC QLQ-H&N35). The primary HRQOL scale was global HRQOL per protocol.Results:Compliance to HRQOL assessments was 97% at baseline, but dropped to 54% by 6 months. Data were analysed up to 6 months. There was a trend towards improved global HRQOL during the treatment period. At 6 months after the end of RT, global HRQOL was higher in the TPF arm than in the PF arm, but the low compliance does not allow to draw definitive conclusions. Swallowing and coughing problems decreased more in the TPF arm than in the PF arm at the end of cycle 2, but to a limited extent.Conclusion:Induction chemotherapy with TPF before RT not only improves survival and reduces toxicity compared with PF but also seems to improve global HRQOL in a more sustainable manner.

Development of an imaging-guided CEA-pretargeted radionuclide treatment of advanced colorectal cancer: first clinical results

Background:Radiolabelled antibody targeting of cancer is limited by slow blood clearance. Pretargeting with a non-radiolabelled bispecific monoclonal antibody (bsMAb) followed by a rapidly clearing radiolabelled hapten peptide improves tumour localisation. The primary goals of this first pretargeting study in patients with the anti-CEACAM5 × anti-hapten (HSG) bsMAb, TF2, and the radiolabelled hapten-peptide, IMP288, were to assess optimal pretargeting conditions and safety in patients with metastatic colorectal cancer (CRC).Methods:Different dose schedules were studied in four cohorts of five patients: (1) shortening the interval between the bsMAb and peptide administration (5 days vs 1 day), (2) escalating the TF2 dose (from 75 to 150 mg), and (3) reducing the peptide dose (from 100 to 25 μg). After confirmation of tumour targeting by 111In-IMP288, patients were treated with a bsMAb/177Lu-IMP288 cycle.Results:Rapid and selective tumour targeting of the radiolabelled peptide was visualised within 1 h, with high tumour-to-tissue ratios (>20 at 24 h). Improved tumour targeting was achieved with a 1-day interval between the administration of the bsMAb and the peptide and with the 25-μg peptide dose. High 177Lu-IMP288 doses (2.5–7.4 GBq) were well tolerated, with some manageable TF2 infusion reactions, and transient grades 3–4 thrombocytopaenia in 10% of the patients who received 177Lu-IMP288.Conclusion:This phase I study demonstrates for the first time that pretargeting with bsMAb TF2 and radiolabelled IMP288 in patients with CEA-expressing CRC is feasible and safe. With this pretargeting method, tumours are specifically and rapidly targeted.