Results of a phase II pilot study of moderate dose radiotherapy for inoperable desmoid-type fibromatosis--an EORTC STBSG and ROG study (EORTC 62991-22998).

BACKGROUND: To determine the activity of radiotherapy in patients with inoperable desmoid-type fibromatosis (DF) a multicenter prospective phase II trial was carried out. MATERIALS AND METHODS: Patients with inoperable progressive disease of primary, recurrent or incompletely resected lesions received a dose of 56 Gy in 28 fractions. Follow-up MRI studies were carried out every 3 months for 2 years and thereafter every 6 months. The primary end point was local control rate at 3 years, estimated by a nonparametric method for interval-censored survival data. Secondary end points were objective tumor response, acute and late toxic effect. RESULTS: Forty-four patients (27 F/17 M) were enrolled from 2001 to 2008. Median age was 39.5 years. Main tumor sites included trunk 15 (34.1%) and extremities 27 (61.3%). Median follow-up was 4.8 years. The 3-year local control rate was 81.5% (90% one-sided confidence interval 74% to 100%). Best overall response during the first 3 years was complete response (CR) 6 (13.6%), partial response (PR) 16 (36.4%), stable disease 18 (40.9%), progressive disease 3 (6.8%) and nonassessable 1 (2.3%). Five patients developed new lesions. After 3 years, the response further improved in three patients: (CR 2, PR 1). Acute grade 3 side-effects were limited to skin, mucosal membranes and pain. Late toxic effect consisted of mild edema in 10 patients. CONCLUSIONS: Moderate dose radiotherapy is an effective treatment of patients with DF. Response after radiation therapy is slow with continuing regression seen even after 3 years.

Current standards for response evaluation by imaging techniques.

Response evaluation by means of response rates using radiological imaging techniques is well established and plays a pivotal role in the development of new anti-cancer agents. It is typically employed in phase II clinical trials and acts as a surrogate for patient benefit, thereby allowing potentially active agents to be fast tracked; at the same time, inactive agents can be discarded earlier, with fewer patients being exposed to them. Response evaluation has evolved over the past 25 years, and various imaging stipulations have been introduced to try and add some uniformity to the process and enable a comparison to be made between different studies. However, imaging still requires a well-defined anatomical lesion or lesions to be viewed and relies on the measurement of a reduction in tumour size during treatment as the basis for presumed clinical benefit. This implies a cytocidal mode of action of the agent under review, but over the past 5 years increasing numbers of new cytostatic agents have been developed, such as anti-angiogenesis agents and specific enzyme receptor antagonists, where the overall effect is to prevent new tumour cells from growing or developing rather than directly killing pre-existing tumour cells. Anatomical imaging alone is therefore inappropriate as the tumour would not necessarily be expected to reduce in size. Other surrogates of tumour growth and metabolism have to be utilised. Functional studies are therefore necessary; anatomical imaging modalities such as computed tomography (CT) and magnetic resonance imaging can be modified so that dynamic studies can be undertaken, and newer techniques such as positron emission tomography scanning can be employed. The latter has poor spatial resolution but when combined with CT it has the ability to measure function while the anatomical site is accurately determined. The aim now is to devise new response evaluation techniques and criteria incorporating functional imaging to enable accurate assessment of active new anti-cancer agents.

Radiologist review versus group peer review of claimed responses in a phase II study on high-dose ifosfamide in advanced soft tissue sarcomas of the adult: a study of the EORTC Soft Tissue and Bone Sarcoma Group.

The Soft Tissue and Bone Sarcoma Group (STBSG) of the EORTC ran a phase II study to assess the therapeutic activity of high-dose ifosfamide in patients with advanced soft tissue sarcomas by means of response rate (RR). Investigators claiming a response submitted the relevant chest radiographs (CXR) or scans to two other members of the STBSG for peer review. The reviewers completed a questionnaire indicating overall response or reasons for rejecting the claimed responses. An independent radiologist also reviewed the cases and he was blinded to the results of the peer review until the study was concluded. Twenty-two patients were reviewed by the radiologist and peer review, and the completed questionnaires were retrospectively reviewed. Two differences were noted, one partial responder (PR) was regarded as stable disease by the radiologist and one PR by peer review was determined a complete response by the radiologist. The radiologist found subsequent evidence of progressive disease in three patients who initially showed a PR, whilst the review group noted only one. This study suggests peer review in this tumor type is a satisfactory method of achieving an accurate, objective RR.

Results of an independent oncology review board of pivotal clinical trials of gemcitabine in non-small cell lung cancer.

Response rates reported in early phase II clinical trials are often not reproduced in subsequent larger or phase III studies. Independent review of claimed partial or complete responders to gemcitabine was undertaken in four pivotal, open-label phase II studies of advanced, non-small cell lung cancer (NSCLC) to provide accurate, consistent, reproducible response rates. Patients were chemonaive and had stage III or IV NSCLC. In three trials, gemcitabine (800 and 1250 mg/m2) was administered once-weekly for 3 weeks followed by a rest week. In the fourth, gemcitabine (90 mg/m2) was given twice-weekly for 3 weeks in every 4 weeks. The primary endpoint was response rate. Of the 374 evaluable patients, 114 (30%) were claimed as responders. Independent review reduced this to 79 (21%). The response range was reduced from 25-35 to 20-23% after validation; 95% confidence intervals did not overlap. Consistent application of response criteria by an independent panel significantly reduced response rates but produced greater consistency and reproducibility. These results confirm that gemcitabine is active against NSCLC. Subsequent larger-scale studies have produced comparable response rates, vindicating the use of independent review. Independent review is recommended for all trials using response rate as a primary endpoint.

Modern techniques in radiological imaging related to oncology.

BACKGROUND: Radiological imaging has existed for about 100 years and there have been significant advances in computer technology during the last 25 years. The ideal investigation should be non-invasive, repeatable, and have a sensitivity (detection of the lesion) and specificity (ability to predict the absence of disease) of 100%. TECHNIQUES: Recent advances in ultrasonography, computed tomography (CT) scanning and magnetic resonance imaging (MRI) have enabled a more accurate demonstration of anatomical structures and better spatial resolution. This has led to the detection of smaller lesions and faster scan times, and thus new or recurrent disease is demonstrated at an earlier stage and motion artefacts are reduced. Advances in imaging techniques have also enabled percutaneous manoeuvres, ranging from diagnostic biopsy of suspicious lesions to therapeutic stenting of malignant strictures, to be performed. Magnetic resonance spectroscopy (MRS) and positron emission tomography (PET) represent a different concept. They assess in vivo tissue metabolism and provide a physiological approach which allows comparison of normal and abnormal tissue, such as tumour. The measurement of certain metabolites or isotope tracers correlates with tumour metabolism, and the response to treatment can be predicted by quantitative changes. Thus, PET scanning and MRS will probably be valuable in assessing new chemotherapeutic agents in animals and patients in vivo. Patients likely to respond to a certain drug can be selected and further studies may help determine ideal dosing regimens. Lack of fine anatomical detail on PET images can be overcome by 'fusing' the 'slice' with the corresponding CT or MRI slice, allowing accurate anatomical and physiological information to be displayed. CONCLUSION: As more specific indicators of disease and the response to therapy become available, the combination of anatomical and functional imaging modalities will enable treatment to be undertaken at an earlier stage with the potential for increased survival.

Interpretation of duplex Doppler ultrasound in renal transplants in the early postoperative period.

A prospective study of duplex Doppler ultrasound in 29 renal transplants was undertaken to determine how to interpret Doppler findings in the immediate postoperative period. The study included intraoperative pulsed Doppler recordings from grafts immediately following release of vessel clamps. Subsequent follow-up studies were performed in the immediate postoperative period. Intraoperative Doppler appearances in the group as a whole were normal; there was a significant deterioration in Doppler appearances in the first 24-48 h of the postoperative period. In the absence of rejection subsequent Doppler appearances returned to normal. An abnormal Doppler appearance immediately following transplantation should be an expected result. If the Doppler fails to improve, or deteriorates having started to improve, rejection should be strongly suspected.

Pulmonary embolism, pulmonary hypertension, and choriocarcinoma.

A rare cause of pulmonary embolism and pulmonary artery hypertension in young women is choriocarcinoma growing in the pulmonary artery. This growth is reversible, and the disorder can be cured. We describe three patients with this feature who have been treated with appropriate high-risk chemotherapy and who are now in remission. Contrast-enhanced computed tomography can be used to identify major emboli, and progress of the disease can be monitored by serial ventilation/perfusion scans and measurement of serum human chorionic gonadotropin. Recognition of this rare syndrome is important because of the generally excellent outlook with appropriate treatment.

Mesenchymal hamartoma of the chest wall in infancy.

Two cases of mesenchymal hamartoma of the chest wall are presented. The clinical presentation, radiological and histological features of this rare tumour are discussed. The management, which may be conservative or surgical depends on the clinical symptoms, and this is also discussed.

Noninvasive monitoring of renal blood flow characteristics during acute renal failure in man.

Duplex Doppler ultrasound (DDU) was used to study the blood flow characteristics of the renal interlobar artery in 20 subjects with acute renal failure (ARF), 14 subjects with transient impairment of renal function and 23 control subjects with normal function. Renovascular resistance was assessed by pulsatility index (PI) and change in flow velocity by change in mean frequency shift (delta f). The 99% confidence intervals for PI in the three groups were 3.32-5.46, 1.58-2.34 and 0.99-1.33 respectively. Values for delta f were 0.2-0.38, 0.5-0.62 and 0.7-1.02 kHz respectively. Ten ARF patients recovered function, 99% confidence intervals for PI just prior to recovery were 0.9-1.48 and for delta f 0.52-1.02 kHz. There was increased renovascular resistance and reduced intrarenal blood flow velocity at the onset of ARF. These changes persisted during ARF; recovery of function occurred after they returned to normal. Similar, but less marked, changes were found in patients with a transient impairment of function.

Practical use of duplex Doppler analysis of the renal vasculature in critically ill patients.

Duplex doppler examination of blood flow in renal interlobar arteries was analysed in twelve critically ill patients before and during low-dose dopamine infusion (2 micrograms/kg/min). Renal vasodilatation and increased blood flow were observed with dopamine, confirming results with indirect or invasive techniques. The doppler ultrasound technique is entirely non-invasive, is simple and quick to carry out, provides instant results, and will allow tailoring of inotropic support in critically ill patients to provide optimum renal blood flow.