Michele I. Saunders

The value of pretreatment cell kinetic parameters as predictors for radiotherapy outcome in head and neck cancer: a multicenter analysis.

PURPOSEnThe aim of this study was to assess the potential of pre-treatment cell kinetic parameters to predict outcome in head and neck cancer patients treated by conventional radiotherapy.nnnMATERIALS AND METHODSnData from 11 different centers were pooled. Inclusion criteria were such that the patients received radiotherapy alone, and that the radiotherapy was given in an overall time of at least 6 weeks with a dose of at least 60 Gy. All patients received a tracer dose of either iododeoxyuridine (IdUrd) or bromodeoxyuridine (BrdUrd) intravenously prior to treatment and a tumor biopsy was taken several hours later. The cell kinetic parameters labeling index (LI), DNA synthesis time (Ts) and potential doubling time (Tpot) were subsequently calculated from flow cytometry data, obtained on the biopsies using antibodies against I/BrdUrd incorporated into DNA. Each center carried out their own flow cytometry analysis.nnnRESULTSnFrom the 11 centers, a total of 476 patients conforming to the inclusion criteria were analyzed. Median values for overall time and total dose were 49 days and 69 Gy, respectively. Fifty one percent of patients had local recurrences and 53% patients had died, the majority from their disease. Median follow-up was 20 months; being 30 months for surviving patients. Multivariate analysis revealed that T-stage, maximum tumor diameter, differentiation grade, N-stage, tumor localization and overall time correlated with locoregional control, in decreasing order of significance. For the cell kinetic parameters, univariate analysis showed that only LI was significantly associated with local control (P=0.02), with higher values correlating with a worse outcome. Ts showed some evidence that patients with longer values did worse, but this was not significant (P=0.06). Tpot showed no trend (P=0.8). When assessing survival in a univariate analysis, neither LI nor Tpot associated with outcome (P=0.4, 0.4, respectively). Surprisingly, Ts did correlate with survival, with longer values being worse (P=0.02). In the multivariate analysis of local control, LI lost its significance (P=0.16).nnnCONCLUSIONSnThe only pretreatment kinetic parameter for which some evidence was found for an association with local control (the best end-point for testing the present hypothesis) was LI, not Tpot, and this evidence disappeared in a multivariate analysis. It therefore appears that pretreatment cell kinetic measurements carried out using flow cytometry, only provide a relatively weak predictor of outcome after radiotherapy in head and neck cancer.

Phase Ib trial of radiotherapy in combination with combretastatin-A4-phosphate in patients with non-small-cell lung cancer, prostate adenocarcinoma, and squamous cell carcinoma of the head and neck

BACKGROUNDnThe vascular disrupting agent combretastatin-A4-phosphate (CA4P) demonstrated antitumour activity in preclinical studies when combined with radiation.nnnMETHODSnPatients with non-small-cell lung cancer (NSCLC), prostate adenocarcinoma, and squamous cell carcinoma of the head and neck (SCCHN) received 27 Gy in 6 fractions treating twice weekly over 3 weeks, 55 Gy in 20 fractions over 4 weeks, and 66 Gy in 33 fractions over 6 weeks respectively. CA4P was escalated from 50 mg/m2 to 63 mg/m2. CA4P exposure was further increased from one to three to six doses. Patients with SCCHN received cetuximab in addition.nnnRESULTSnThirty-nine patients received 121 doses of CA4P. Dose-limiting toxic effects (DLTs) of reversible ataxia and oculomotor nerve palsy occurred in two patients with prostate cancer receiving weekly CA4P at 63 mg/m2. DLT of cardiac ischaemia occurred in two patients with SCCHN at a weekly dose of 50 mg/m2 in combination with cetuximab. Three patients developed grade 3 hypertension. Responses were seen in 7 of 18 patients with NSCLC. At 3 years, 3 of 18 patients with prostate cancer had prostate-specific antigen relapse.nnnCONCLUSIONSnRadiotherapy with CA4P appears well tolerated in most patients. The combination of CA4P, cetuximab, and radiotherapy needs further scrutiny before it can be recommended for clinical studies.BACKGROUNDnThe vascular disrupting agent combretastatin-A4-phosphate (CA4P) demonstrated antitumour activity in preclinical studies when combined with radiation.nnnMETHODSnPatients with non-small-cell lung cancer (NSCLC), prostate adenocarcinoma, and squamous cell carcinoma of the head and neck (SCCHN) received 27 Gy in 6 fractions treating twice weekly over 3 weeks, 55 Gy in 20 fractions over 4 weeks, and 66 Gy in 33 fractions over 6 weeks respectively. CA4P was escalated from 50 mg/m2 to 63 mg/m2. CA4P exposure was further increased from one to three to six doses. Patients with SCCHN received cetuximab in addition.nnnRESULTSnThirty-nine patients received 121 doses of CA4P. Dose-limiting toxic effects (DLTs) of reversible ataxia and oculomotor nerve palsy occurred in two patients with prostate cancer receiving weekly CA4P at 63 mg/m2. DLT of cardiac ischaemia occurred in two patients with SCCHN at a weekly dose of 50 mg/m2 in combination with cetuximab. Three patients developed grade 3 hypertension. Responses were seen in 7 of 18 patients with NSCLC. At 3 years, 3 of 18 patients with prostate cancer had prostate-specific antigen relapse.nnnCONCLUSIONSnRadiotherapy with CA4P appears well tolerated in most patients. The combination of CA4P, cetuximab, and radiotherapy needs further scrutiny before it can be recommended for clinical studies.

Antivascular effects of neoadjuvant androgen deprivation for prostate cancer: an in vivo human study using susceptibility and relaxivity dynamic MRI.

PURPOSEnThe antivascular effects of androgen deprivation have been investigated in animal models; however, there has been minimal investigation in human prostate cancer. This study tested the hypothesis that androgen deprivation causes significant reductions in human prostate tumor blood flow and the induction of hypoxia at a magnitude and in a time scale relevant to the neoadjuvant setting before radiotherapy.nnnMETHODS AND MATERIALSnTwenty patients were examined, each with five multi-parameter magnetic resonance imaging scans: two scans before the commencement of androgen suppression, one scan after 1 month of hormone treatment, and two further scans after 3 months of therapy. Quantitative parametric maps of the prostate informing on relative blood flow (rBF), relative blood volume (rBV), vascular permeability (transfer constant [K(trans)]), leakage space (v(e)) and blood oxygenation (intrinsic relaxivity [R(2)∗]) were calculated.nnnRESULTSnTumor blood volume and blood flow decreased by 83% and 79%, respectively, in the first month (p < 0.0001), with 74% of patients showing significant changes. The proportion of individual patients who achieved significant changes in T1 kinetic parameter values after 3 months of androgen deprivation for tumor measurements was 68% for K(trans) and 53% for v(e) By 3 months, significant increases in R(2)∗ had occurred in prostate tumor, with a rise of 41.1% (p < 0.0001).nnnCONCLUSIONSnAndrogen deprivation induces profound vascular collapse within 1 month of starting treatment. Increased R(2)∗ in regions of prostate cancer and a decrease in blood volume suggest a reduction in tumor oxygenation.

The potential advantages of 18FDG PET/CT-based target volume delineation in radiotherapy planning of head and neck cancer

PURPOSEnThis study investigated two fixed threshold methods to delineate the target volume using (18)FDG PET/CT before and during a course of radical radiotherapy in locally advanced squamous cell carcinoma of the head and neck.nnnMATERIALS AND METHODSnPatients were enrolled into the study between March 2006 and May 2008. (18)FDG PET/CT scans were carried out 72h prior to the start of radiotherapy and then at 10, 44 and 66Gy. Functional volumes were delineated according to the SUV Cut Off (SUVCO) (2.5, 3.0, 3.5, and 4.0bwg/ml) and percentage of the SUVmax (30%, 35%, 40%, 45%, and 50%) thresholds. The background (18)FDG uptake and the SUVmax within the volumes were also assessed.nnnRESULTSnPrimary and lymph node volumes for the eight patients significantly reduced with each increase in the delineation threshold (for example 2.5-3.0bwg/ml SUVCO) compared to the baseline threshold at each imaging point. There was a significant reduction in the volume (p⩽0.0001-0.01) after 36Gy compared to the 0Gy by the SUVCO method. There was a negative correlation between the SUVmax within the primary and lymph node volumes and delivered radiation dose (p⩽0.0001-0.011) but no difference in the SUV within the background reference region. The volumes delineated by the PTSUVmax method increased with the increase in the delivered radiation dose after 36Gy because the SUVmax within the region of interest used to define the edge of the volume was equal or less than the background (18)FDG uptake and the software was unable to effectively differentiate between tumour and background uptake.nnnCONCLUSIONSnThe changes in the target volumes delineated by the SUVCO method were less susceptible to background (18)FDG uptake compared to those delineated by the PTSUVmax and may be more helpful in radiotherapy planning. The best method and threshold have still to be determined within institutions, both nationally and internationally.

DIRECT COMPARISON OF BROMODEOXYURIDINE AND KI-67 LABELLING INDICES IN HUMAN TUMOURS

Direct comparison of bromodeoxyuridine (BrdUrd) and Ki‐67 labelling indices was achieved by selecting similar areas from serial sections of human tumours. Fifteen patients were selected who had been administered BrdUrd in vivo and both proliferation markers were assessed by immunohistochemistry. The data show a good correlation between both BrdUrd LI and MIB‐1 LI and Tpot (calculated using the flow cytometry derived duration of S phase) and MIB‐1 LI. The contribution of BrdUrd LI to growth fraction varied as a function of proliferation characteristics. In tumours with a high LI, the number of DNA synthesizing cells represented half the growth fraction, whilst in tumours with lower LIs (<10%) the ratio of DNA precursor labelled cells as a function of growth fraction fell to between 10% and 20%. Tpot showed a linear correlation with MIB‐1/BrdUrd ratio with a slope approaching unity. It was apparent that both intra‐ and interpatient variation in proliferation index was greater for BrdUrd labelling than for MIB‐1 expression.

[64Cu]diacetyl-bis(N4-methyl-thiosemicarbazone) — a radiotracer for tumor hypoxia

Positron emission tomography scanning using the radiotracer-labeled copper (II)-diacetyl-bis(N(4)-methylthiosemicarbazone) has been proposed as a noninvasive method for evaluating tumor hypoxia. Tumor hypoxia results in a more aggressive tumor phenotype together with resistance to both radiotherapy and chemotherapy. A noninvasive technique for evaluation of tumor hypoxia is not currently available. Validation of this technique would provide clinicians with a tool for determining the most appropriate cancer therapy, prognostic information, and subvolume delineation for the radiotherapy dose escalation to the radioresistant hypoxic regions within a tumor. This review article describes the background to the development of this tracer, its proposed retention mechanism, biodistribution dosimetry and the preclinical and clinical studies to date. It outlines the potential use of this radiotracer for imaging in the field of oncology.

Quantitative helical dynamic contrast enhanced computed tomography assessment of the spatial variation in whole tumour blood volume with radiotherapy in lung cancer

We aim to assess the spatial distribution of blood volume (BV) in whole lung tumours in patients undergoing radiotherapy using helical dynamic contrast enhanced computed tomography (DCE-CT), and to determine whether conventional single level, or whole tumour measurements is more representative of the vascular effects of radiotherapy. Following ethical approval and informed consent, 15 patients with histologically proven non-small cell lung cancer underwent paired helical DCE-CT studies at baseline to assess repeatability, and after two fractions of radiotherapy (9 Gy total dose). Tumour BV was calculated for individual contiguous 10mm axial slices, and for the entire tumour volume on a pixel-per-pixel basis. Baseline tumour BV was heterogeneous varying by 15.33%+/-17.11 between adjacent 10mm axial slices. Within subject coefficient of variation was 36.72% with conventional single tumour level evaluation, and 13.62% with whole tumour measurements. Following radiotherapy, one patient had an increase in BV greater than baseline variation (derived from the 95% limits of change) using single level evaluation; in contrast, seven patients had an increase in BV when the whole tumour was assessed. As a group, following radiotherapy, mean BV increased by 17.27% (paired t-test, p=0.20) with single level evaluation and 19.26% (p=0.049) with whole tumour assessment. Tumour BV measured using DCE-CT is spatially heterogeneous. Given the slice-by-slice variation in blood volume, our results demonstrate that whole tumour DCE-CT measurements are more repeatable, and may be a better predictor of vascular changes following therapy, compared to conventional single tumour level evaluations.