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.

BACKGROUND: The vascular disrupting agent combretastatin-A4-phosphate (CA4P) demonstrated antitumour activity in preclinical studies when combined with radiation. METHODS: Patients 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. RESULTS: Thirty-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. CONCLUSIONS: Radiotherapy 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.

Carbogen breathing increases prostate cancer oxygenation: a translational MRI study in murine xenografts and humans.

Hypoxia has been associated with poor local tumour control and relapse in many cancer sites, including carcinoma of the prostate. This translational study tests whether breathing carbogen gas improves the oxygenation of human prostate carcinoma xenografts in mice and in human patients with prostate cancer. A total of 23 DU145 tumour-bearing mice, 17 PC3 tumour-bearing mice and 17 human patients with prostate cancer were investigated. Intrinsic susceptibility-weighted MRI was performed before and during a period of carbogen gas breathing. Quantitative R(2)* pixel maps were produced for each tumour and at each time point and changes in R(2)* induced by carbogen were determined. There was a mean reduction in R(2)* of 6.4% (P=0.003) for DU145 xenografts and 5.8% (P=0.007) for PC3 xenografts. In all, 14 human subjects were evaluable; 64% had reductions in tumour R(2)* during carbogen inhalation with a mean reduction of 21.6% (P=0.0005). Decreases in prostate tumour R(2)* in both animal models and human patients as a result of carbogen inhalation suggests the presence of significant hypoxia. The finding that carbogen gas breathing improves prostate tumour oxygenation provides a rationale for testing the radiosensitising effects of combining carbogen gas breathing with radiotherapy in prostate cancer patients.

Positron emission tomography in oncology: a review.

Positron emission tomography is an evolving imaging tool that is becoming increasingly available for use in clinical practice. This overview will look at the current evidence for the use of positron emission tomography in imaging different tumour types and the different radiotracers that are either available or being evaluated in an investigational setting.

Human tumor blood flow is enhanced by nicotinamide and carbogen breathing.

Perfusion insufficiency and the resultant hypoxia are recognized as important mechanisms of resistance to anticancer therapy. Modification of the tumor microenvironment to increase perfusion and oxygenation of tumors may improve on the efficacy of these treatments. Using laser Doppler probes to measure microregional RBC flux, this study examines the influence of nicotinamide and carbogen on human tumor perfusion. Ten patients with advanced cancers were studied. Nicotinamide (80 mg/kg) was given p.o., and 60 min later, up to six probes were inserted into the tumor. Readings were taken for 1 h, followed by 10 min of carbogen breathing and 10 additional min of breathing room air. Results were compared with those from a similar group of eight control patients who were not given nicotinamide, but who breathed carbogen. In 44 microregions analyzed, 33 (73%) showed perfusion fluctuations of 50% or more, and 20 (44%) by 100% or more. This compared with the control group in whom 62% and 27% of microregions varied by 50% or more and 100% or more, respectively. Perfusion increases outweighed decreases by 30% with nicotinamide and 20% in the controls. On breathing carbogen, patients pretreated with nicotinamide showed an increase in tumor perfusion of 17% at 5 min and 22% at 10 min, compared with only 0% and 1% in the control group. Pretreatment with nicotinamide made little difference to the random blood flow fluctuations seen in controls. However, when carbogen was introduced, tumor perfusion increased compared with the control group. This may have important therapeutic implications by improving response to treatment and allowing better delivery of systemically administered agents.

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 LI's ( < 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.

The rationale for continuous, hyperfractionated, accelerated radiotherapy (CHART).

Continuous, hyperfractionated, accelerated radiotherapy (CHART) was devised to give the maximum chance of improving clinical radiotherapy and was based upon available radiobiological evidence. A pilot study, begun in 1985, has now included 210 patients. When comparison is made with previously treated cases, improved results have been seen in the two main groups included, that is, advanced head and neck and bronchial carcinomas. Multi-center randomized controlled clinical trials are planned.

Continuous, hyperfractionated, accelerated radiotherapy (CHART) in non-small cell carcinoma of the bronchus.

Between January 1985 and December 1988, 62 patients with locally advanced carcinoma of the bronchus were treated by radiotherapy using continuous, hyperfractionated, accelerated radiotherapy (CHART). With this regime on each of 12 consecutive days 3 fractions were given with a time interval of 6 hr between each. Initially a dose fraction of 1.4 Gy was used and a total of 50.4 Gy was achieved in 23 patients. As tolerance was good, the dose increment was raised to 1.5 Gy and the total to 54 Gy in the subsequent 39 patients. Esophagitis was the only immediate complication, and although most patients were reduced to a fluid diet for a period, recovery was complete and only one patient required endo-esophageal tube feeding for a short time. The results observed so far have been assessed against those in a previous trial of a radiosensitizer in cases similarly accepted for treatment. Complete regression, as observed radiologically, was achieved by 42%; this can be compared with 15% of the previously treated series. At 1 year the survival probability was 64% compared with a previous 44% and at 2 years 34% compared with a previous 12%. A randomized controlled clinical trial is now planned.

Radiation myelitis and survival in the radiotherapy of lung cancer.

A previous survey of patients who survived more than 6 months after radiotherapy for carcinoma of the bronchus using a 6 fraction regimen revealed a considerable incidence of radiation myelitis. In a further survey, in which the data bank has been increased from a total of 303 to 754 cases, analyses have confirmed that radiation myelitis occurs once a threshold dose of 33.5 Gy to the spinal cord has been reached. The incidence was positively related to the hemoglobin concentration, but not to the blood pressure at the time of radiotherapy. In the same group of patients survival was positively related to radiation dose, the hemoglobin concentration, and the systolic blood pressure. In other patients who were treated with 6 fractions, but who received a lower minimum tumor dose, either because this was planned or as a result of cord shielding, no relationship was shown between survival and radiation dose, hemoglobin concentration and systolic or pulse pressure. Radiosensitivity is dependent upon the oxygen concentration which, in normal tissues, is related to the hemoglobin concentration and in tumor to both the hemoglobin and the systolic blood pressure. The achievement of a threshold radiation dose appears essential before these prognostic factors become relevant.

Hemoglobin, radiation, morbidity and survival.

Analyses concerned with a group of patients treated by radiotherapy for carcinoma of the bronchus give evidence to support the view that oxygen tension at the time of radiation therapy is important both in determining tumor control and radiation morbidity.

Primary tumor control after radiotherapy for carcinoma of the bronchus.

The primary tumor control and the appearance of distant metastasis was observed closely in 62 patients entered into a randomized controlled trial of the radiosensitizing drug, misonidazole, in carcinoma of the bronchus. Sixty-one of the 62 patients are now dead; an autopsy examination was carried out in 42 (69%). Although survival was comparable to that observed in similar studies, tumor persisted or recurred at the primary site in 95% (58/61) while 39% (24/61) showed no evidence for distant metastasis. In these patients, improvement in the primary tumor control would be important in extending survival.

Continuous hyperfractionated accelerated radiotherapy (CHART) in localized cancer of the esophagus.

PURPOSE: To assess the efficacy and toxicity of continuous hyperfractionated accelerated radiotherapy (CHART) in locoregional control compared with a historical group of patients treated with conventionally fractionated radical radiotherapy. METHODS AND MATERIALS: Between 1985 and 1994, 54 patients with localized esophageal cancer were treated with CHART. Twenty-eight patients received CHART alone (54 Gy in 36 fractions over 12 consecutive days) and 15 were given intravenous mitomycin C and cisplatin on days 10 and 13, respectively. Eleven patients received 40.5 Gy in 27 fractions over 9 days, followed by a single high-dose-rate intraluminal brachytherapy insertion of 15 Gy at 1 cm. RESULTS: Acute toxicity was well tolerated and dysphagia was improved in 35 patients (65%), with 28 (52%) eating a normal diet by week 12. This compares with an improvement in dysphagia score in 72% of the conventionally treated group. The median duration of relief of dysphagia was 7.8 months (range 0-41.4) in the CHART group compared with 5.5 months (range 0-48) in the controls. Strictures developed in 29 patients (61%) and 18 were confirmed on biopsy to be due to recurrent disease. Median survival was 12 months (range 0.5-112) in the CHART group and 15 months (range 3.6-56) in the control patients. CONCLUSION: CHART is well tolerated and achieves a high rate of local control. Palliation in the short overall treatment time of esophageal cancer is an advantage in these patients whose median survival is only 12 months.

The relationship between tumor response and survival following radiotherapy for carcinoma of the bronchus.

Tumor response was closely observed in a randomized controlled trial of a radiosensitizing drug in the radiotherapy of carcinoma of the bronchus. The persistence of tumor cells in the sputum after treatment and the degree of regression measured radiologically at two months did not correlate with the subsequent course. However, total regression of tumor and time to regrowth both assessed radiologically showed a highly significant correlation with survival (P less than 0.0005).

Tumor cell kinetics, local tumor control, and accelerated radiotherapy: a preliminary report.

The local tumor control achieved in patients treated in a pilot study of continuous, hyperfractionated, accelerated radiotherapy has been related to the tumor cell kinetics evaluated by in vivo administration of bromodeoxyuridine and flow cytometry. In 42 of 50 patients with advanced squamous cell carcinomas in the head and neck region it was possible to sample the primary tumor prior to treatment. In three further cases, involved regional nodes were studied: in the remaining five, tissue was obtained subsequently either from a local recurrence or from a distant metastasis. Successful cell kinetic measurements were made in 38 (90%) of the 42 primary tumors. The median values of the labelling index, the duration of the DNA synthetic phase and, thus, the potential doubling time for all primaries were 7.1%, 9.8 hr, and 3.9 days, respectively. Complete regression was achieved in 28 (74%) of the primary tumors and in 23 (61%) this was maintained to the time of observation for this report. There was no significant influence of any of the cell kinetic parameters upon the immediate or longer term local tumor control. This result is compatible with the overcoming of cellular repopulation by the acceleration of radiotherapy.

Desmethylmisonidazole (Ro 05-9963): clinical pharmacokinetics after multiple oral administration.

The O-demethylated metabolite of misonidazole, Ro 05-9963, has been administered orally, prior to irradiation, to over 50 patients with malignant disease in order to assess the effectiveness of this compound as a hypoxic cell radiosensitizer. This paper reports the pharmacokinetic data observed in those patients who received multiple doses to a total of 12 gm-2. The mean time and magnitude of the peak plasma concentration was determined together with the plasma profile and half-life at the start and finish of each regime of 6, 20, 25 or so fractions. Half-life was independent of drug dose while peak plasma levels rose with increasing amount of drug given. The importance of urinary clearance for this polar drug is indicated by the figure of approximately 50% of administered dose excreted by this route over 24 hours, compared to less than 25% for misonidazole. It was also illustrated by the increased half-life shown by one patient who suffered renal failure during treatment. Peak plasma concentration appeared to be slightly later and were more variable than in the more ideal conditions of the normal volunteer study. In addition, this study confirmed the latter study's findings that absorption is rapid following oral administration of Ro 05-9963, yielding peak plasma levels nearly as high as those seen with misonidazole. Administration in capsules rather than aqueous solution lead to slower absorption, but the peak level did not change.

The morbidity of salvage surgery following conventional radiotherapy and continuous, hyperfractionated accelerated radiotherapy (CHART).

A comparison was made of the morbidity of surgery for loco-regional recurrence in patients with advanced cancer of the head and neck region following continuous hyperfractionated accelerated radiotherapy (CHART), after conventional radiotherapy, and also in a group following surgery only as the primary treatment. Post-surgical morbidity occurred in 14 (77%) of the 18 patients treated with CHART, of whom 11 (78%) required a further surgical procedure. In the conventional group, morbidity occurred in 14 (58%) of the 24 patients, of whom 9 (64%) required further surgery. Finally, in the surgical group morbidity occurred in 13 (48%) of the 27 patients, of whom 7 (54%) required further surgery. Because of the many factors that may influence the chance of morbidity and of the small number of cases, considered statistical analysis is not meaningful and there must be caution in the interpretation of results. When allowance is made for the greater frequency of more advanced tumors and for sites in the oropharynx and oral cavity, where procedures associated with greater risk of complication were performed, the morbidity seen after surgery was performed upon CHART patients appeared to be no greater than when conventional radiotherapy had been given. As expected, the surgery only group showed less morbidity than either of the radiotherapy groups.

The clinical testing of Ro 03-8799--pharmacokinetics, toxicology, tissue and tumor concentrations.

Ro 03-8799, a lipophilic nitroimidazole with a basic side chain, has now been administered intravenously to 69 patients. The elimination half-life in plasma was 5.1 hr and the plasma concentration at 30 min was 14.8 micrograms/ml standardized to a dose of 1 g per square meter of surface area. Immediate symptoms of malaise, heat, sweating and disorientation limit the amount of the drug which may be given on any one occasion. However, a dose of 750 mg per square meter of surface area may be given combined with daily radiotherapy. Our data suggest that when given with a 20 fraction course of radiotherapy, sensitization of hypoxic cells may be achieved equal to a 10-fold increase in the dose of misonidazole above that presently permitted.

Experience with CHART.

Continuous, hyperfractionated, accelerated radiotherapy (CHART) has been used at the Mount Vernon Cancer Treatment Center since January 1985. Patients with head and neck tumors and those with locally advanced non-oat cell carcinoma of the bronchus have formed the large majority of the 263 patients treated. Early reactions in the mucosae of the mouth and pharynx have been pronounced, but all have healed, while those in the skin have been less severe than with conventional radiotherapy. An unexpected late morbidity was radiation myelitis in four patients, but in other tissues including the skin, mucosae, the connective tissues, and the salivary glands, late changes appear reduced compared to those after conventional radiotherapy. In 92 patients with squamous cell carcinoma of the major sites in the head and neck region, of whom 71 were in Stages T3 and T4, a complete regression at the primary site and nodes was achieved in 90%. This can be compared with 62% in similar patients previously treated with curative intent at Mount Vernon between 1980 and 1985; the difference was maintained in follow-up (p = 0.003). Of 76 assessable patients with non-oat cell carcinoma of the bronchus, a complete radiological response has been achieved in 40%, compared to 12% in a retrospective group; again the difference has been maintained in follow up (p = 0.0001). A 1-year survival of 60% can be compared to 40% in the retrospective group and a 2-year survival of 29% compared to 12% (p = 0.01). With a reduction of permitted dose to the spinal cord, CHART gives promise for improvement in tumor control and a reduction in late morbidity. These promising results have led to multi-center randomized controlled clinical trials in carcinoma at the head and neck and in non-oat cell carcinoma of the bronchus. In these studies, CHART is being compared with conventional fractionated radiotherapy.

Concentrations achieved in human tumors after administration of misonidazole, SR-2508 and Ro 03-8799.

Misonidazole, SR-2508 and Ro 03-8799 have been given in sequence to patients before tumor sampling. Tumor concentrations of the three drugs have been measured and it has been possible to make prediction as to the likely advantage of the newer drugs over misonidazole. Based upon the three cases described here and 13 others given two drug combination, we suggest that in multifraction radiotherapy, both are likely to prove more than five times more efficient than misonidazole.

Continuous hyperfractionated accelerated radiotherapy in locally advanced carcinoma of the head and neck region.

Shortening of the overall duration of radiotherapy would reduce the possibility repopulation of tumor during treatment. Most clinical trials of such accelerated radiotherapy have incorporated a split course to improve normal tissue tolerance. Any interruption, however, even for the week-end, may allow repopulation to occur. A scheme of radiotherapy has been used during which treatment was given 3 times per day on each of 12 consecutive days without interruption for the week-end. In a pilot study a significant improvement in survival and local tumor control has been achieved in 48 patients with head and neck tumors when comparison was made with a previously treated group. A randomized controlled clinical trial is planned.