CHART revisited: a conservative approach for advanced head and neck cancer.

AIMS: To evaluate the long-term late adverse effects and treatment outcome in patients treated for advanced squamous cell carcinomas of the head and neck with continuous, hyperfractionated, accelerated radiation therapy (CHART). MATERIALS AND METHODS: One hundred and twenty-six consecutive patients were entered into a non-randomised study of CHART alone with salvage treatment reserved for locoregional recurrence. The primary end points were locoregional control and late treatment-related morbidity. Time-incidence curves and statistical comparisons were obtained by computing actuarial event-free intervals using the product-limit (Kaplan-Meier) method. The prevalence rate of adverse effects was calculated using yearly intervals. Patients have been followed over a 15-year period. RESULTS: The actuarial 12-year locoregional recurrence-free rate after radiotherapy alone was 46%, which was increased by 15% with the use of salvage treatment (hazard ratio for recurrence with CHART alone 1.23, confidence interval 1.017-1.494; P=0.033). Actuarial estimates of severe adverse effects at this time were: dysphagia 12% (grade 4); subcutaneous fibrosis 3%; xerostomia 15%. Ulcers of mucous membranes were observed in 18% of patients. As expected, the prevalence of events was lower than that calculated by the life-table method. CONCLUSIONS: Few, if any, studies have documented and reported on long-term adverse effects and treatment outcomes as in this pilot trial of CHART (median follow-up time of those alive at 5 years or more is 11 years and the maximum follow-up time is 18 years). The low level of moderate to severe long-term morbidity together with a good and maintained level of locoregional tumour control indicates that CHART achieves a therapeutic benefit in patients with advanced squamous cell carcinoma of the head and neck.

The prognosis of Hodgkin's disease in older adults.

This investigation was undertaken to assess the apparent poor survival of older patients with Hodgkin's disease. The clinical course of Hodgkin's disease in 136 patients, 60 to 79 years of age, was compared with that of 223 patients, 40 to 59 years of age. The patients registered from November 1977 through December 1983 had not been previously treated, and were treated at eight cancer centers. When the prognosis of all patients was examined by age, a definite change in the pattern of survival first appeared in the 60- to 69-year-old cohort. The entire older group (60 to 79 years) experienced twice the risk of dying from Hodgkin's disease and four times the risk of dying from other causes than did the younger group. In both groups, stage of disease was the strongest factor in predicting adjusted survival. Delay in treatment and advanced stage at presentation were not characteristic of Hodgkin's disease in older patients as has been postulated. Older patients responded to therapy with a similar complete remission rate (84% v 88% in the younger group, P = .24). From this study, we conclude that (1) Hodgkin's disease in the older adult does not have a different natural history, its major risk factors are similar to those known in other age groups, and thus should be amenable to existing therapeutic approaches; and (2) the prognosis of older patients with Hodgkin's disease has been obscured in previous studies by the inclusion of deaths due to other causes in survival estimates.

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.

Quality assurance in radiation therapy: European experience--present and future clinical efforts.

A high standard of radiotherapeutic practice must be sought in all phases of management of a patient with malignant disease. Radiation therapy must be appropriately chosen and integrated with surgery, cytotoxic chemotherapy and all other modes of treatment. The most suitable technique with a dose, fractionation and time regime must be devised and executed with technical and personal care. Follow-up to truly assess tumor control and morbidity is essential so as to guide the management of future patients. To achieve this in Europe great reliance is placed upon the training and qualification of the therapist and staff. In England a Fellowship of the Royal College of Radiologists in radiation therapy is regarded as essential for appointment as a permanent consultant within the Health Service. A high examination standard is set with pass rates ranging from 10 to 30%. High standards are applied to the professional qualifications for radiation physicists, nurses and technical staff. Most radiotherapy centers and departments have been visited by the Royal College in order to determine if the standard of staffing and equipment justifies inclusion in the list of training departments. There is, unfortunately, no control of continuing education of the consultant once appointed. In the countries belonging to the European economic union, a new Diploma in Radiation Therapy has been established to be a standard for consultant practice through all the countries included. In a few multi-center trials in the United Kingdom members of the central organization visit centers to look at the case notes and compare them with the material submitted from the trial center. This effort at monitoring clinical trials is only just beginning in the United Kingdom. The European Organization for Research and Treatment of Cancer has recently initiated a quality control study in some of the centers included in the Radiotherapy Group. A preliminary report has just appeared on the results of the clinical and dosimetric studies in 8 centers placed in 5 European countries. This first European effort appears to have been successful and further details will become available. These initiatives through research may well lead to wider studies of quality assurance in radiation therapy within Europe.

A review of hypoxic cell radiosensitization.

Despite an enormous laboratory and clinical effort, advance in patient care has not yet been achieved by hypoxic cell radiosensitization. The reasons for this are considered and suggestions made as to the future direction of work in this important field.

Keynote address: hypoxic cell sensitizers: clinical developments.

"Tumours having small islands of cells should be radiosensitive, and those having large masses, radioresistant. This was found to be the case and there is a ready explanation for this: the outside cells are close to blood vessels and will thus be well supplied with oxygen, whilst the inside cells are not well placed in this respect. Now it is known that cells well supplied with oxygen are radiosensitive, compared to the same cells deprived of oxygen; it is therefore likely that for this reason, variation in blood supply, that the outside cells are more easily destroyed than those within."

Normobaric oxygen as a sensitizer of hypoxic tumor cells.

A series of experiments have been performed to determine the relative radiosensitivities of a mouse mammary tumor (CA NT) irradiated in 100% normobaric oxygen or in air, using clinically relevant dose-fractionation schedules. The results demonstrate that normobaric oxygen is a potent radiosensitizer, its effect being more marked with smaller size fractions. Enhancement ratios (ER) of 1.23 to 1.45 were obtained. By contrast, no significant benefit was seen with single doses (ER = 1.05 +/- 0.14). The degree of radiosensitization with oxygen, in these fractionated regimens, is greater than that reported for the chemical radiosensitizer, misonidazole. It therefore seems appropriate to re-examine the clinical potential of normobaric oxygen and to consider how the conditions of normobaric radiotherapy achieved in the laboratory can be translated to man.

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.

The uptake of the radiosensitizing compound Ro 03-8799 (Pimonidazole) in human tumors.

The nitroimidazole, Ro 03-8799, has proved unique among the drugs tested as chemical hypoxic cell radiosensitizers because of the preferential concentration which has been observed in tumors. Our accumulation of experience has allowed new analyses to be performed upon 127 samples from 39 patients; 47 samples of normal tissue were also obtained from 26 of these patients. Tissue sampling was performed usually between 20 and 30 minutes after initiation of infusion of Ro 03-8799. By expressing results as tumor: plasma ratios, difficulties in comparison because of differing doses and body sizes, together with a variation in the actual time of sampling, have been avoided. A small portion of each specimen which was analyzed for drug concentration was also examined histologically to give an impression of the percentage of the specimen occupied by tumor cells. Analyses have shown that the average tumor concentration is approximately twice that of normal tissues which have been sampled and four times that in plasma. In 38 breast tumor samples, the concentration of drug varied directly as the proportion occupied by tumor cells. The highest tumor: plasma ratios were seen in samples taken from some samples of malignant melanoma. These findings confirm that a greater potency can be expected for this drug as a radiosensitizer because of its ability to enter tumor cells in high concentration. In drug development programs for chemical sensitizing and cytotoxic agents, drugs which show this phenomenon should be explored.

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.