Percentage grade 4 tumour predicts outcome for prostate adenocarcinoma in needle biopsies from patients with advanced disease: 10-year data from the TROG 03.04 RADAR trial.

Previous reports have shown that quantification of high tumour grade is of prognostic significance for patients with prostate cancer. In particular, percent Gleason pattern 4 (GP4) has been shown to predict outcome in several studies, although conflicting results have also been reported. A major issue with these studies is that they rely on surrogate markers of outcome rather than patient survival. We have investigated the prognostic predictive value of quantifying GP4 in a series of prostatic biopsies containing Gleason score 3+4=7 and 4+3=7 tumours. It was found that the length of GP4 tumour determined from the measurement of all biopsy cores from a single patient, percent GP4 present and absolute GP4 were all significantly associated with distant progression of tumour, all-cause mortality and cancer-specific mortality over a 10-year follow-up period. Assessment of the relative prognostic significance showed that these parameters outperformed division of cases according to Gleason score (3+4=7 versus 4+3=7). International Society of Urological Pathology (ISUP) Grade Groups currently divide these tumours, according to Gleason grading guidelines, into grade 2 (3+4=7) and grade 3 (4+3=7). Our results indicate that this simple classification results in the loss of important prognostic information. In view of this we would recommend that ISUP Grade Groups 2 and 3 be amalgamated as grade 2 tumour with the percentage of GP4 carcinoma being appended to the final grade, e.g., 3+4=7 carcinoma with 40% pattern 4 tumour would be classified as ISUP Grade Group 2 (40%).

Interfraction patient motion and implant displacement in prostate high dose rate brachytherapy.

PURPOSE: To quantify movement of prostate cancer patients undergoing treatment, using an in-house developed motion sensor in order to determine a relationship between patient movement and high dose rate (HDR) brachytherapy implant displacement. METHODS: An electronic motion sensor was developed based on a three axis accelerometer. HDR brachytherapy treatment for prostate is delivered at this institution in two fractions 24 h apart and 22 patients were monitored for movement over the interval between fractions. The motion sensors functioned as inclinometers, monitoring inclination of both thighs, and the inclination and roll of the abdomen. The implanted HDR brachytherapy catheter set was assessed for displacement relative to fiducial markers in the prostate. Angle measurements and angle differences over a 2 s time base were binned, and the standard deviations of the resulting frequency distributions used as a metric for patient motion in each monitored axis. These parameters were correlated to measured catheter displacement using regression modeling. RESULTS: The mean implant displacement was 12.6 mm in the caudal direction. A mean of 19.95 h data was recorded for the patient cohort. Patients generally moved through a limited range of angles with a mean of the exception of two patients who spent in excess of 2 h lying on their side. When tested for a relationship between movement in any of the four monitored axes and the implant displacement, none was significant. CONCLUSIONS: It is not likely that patient movement influences HDR prostate implant displacement. There may be benefits to patient comfort if nursing protocols were relaxed to allow patients greater freedom to move while the implant is in situ.

Thermoluminescence dosimetry for in-vivo verification of high dose rate brachytherapy for prostate cancer.

It was the aim of the study to verify dose delivered in urethra and rectum during High Dose Rate brachytherapy boost (HDRBB) of prostate cancer patients. During the first fraction of HDRBB measurement catheters were placed in the urethra and rectum of prostate cancer patients. These contained LiF:Mg,Ti Thermoluminescence Dosimetry (TLD) rods of 1 mm diameter, with up to 11 detectors positioned every 16 mm separated by radio-opaque markers. A Lorentzian peak function was used to fit the data. Measurements from 50 patients were evaluated and measured doses were compared with predictions from the treatment planning system (Plato Vs 13.5 to 14.1). Prospective urinary and rectal toxicity scores were collected following treatment. In more than 90% of cases, the Lorentzian peak function provided a good fit to both experimental and planning urethral data (r2 > 0.9). In general there was good agreement between measured and predicted doses with the average difference between measured and planned maximum dose being 0.1 Gy. No significant association between dose and any clinical endpoints was observed in 43 patients available for clinical evaluation. An average inferior shift of 2 mm between the plan and the measurement performed approximately 1 hour after the planning CT scan was found for the dose distribution in the cohort of patients for the urethra measurements. Rectal measurements proved to be more difficult to interpret as there is more variability of TLD position between planning and treatment. TLD in-vivo measurements are easily performed in urethra and rectum during HDR brachytherapy of prostate patients. They verify the delivery and provide information about the dose delivered to critical structures. The latter may be of particular interest if higher doses are to be given per fraction such as in HDR monotherapy.

Simple nontoxic treatment of advanced metastatic seminoma with carboplatin.

Between 1982 and 1986, 34 patients with advanced metastatic seminoma were treated with four to six courses of single-agent carboplatin administered at 400 mg/m2 every 4 weeks either on an outpatient basis or during 24-hour admissions. Patients with raised serum alphafetoprotein (AFP) or with multiple (more than three) lung metastases were excluded since these features may indicate a nonseminomatous component. In this series 20 patients were previously untreated except for orchiectomy, and 14 patients had received prior radiotherapy restricted to infradiaphragmatic nodal areas. Treatment was extremely well tolerated. No patient suffered renal damage, neurotoxicity, or ototoxicity, and there were no episodes of neutropenic septicemia, thrombocytopenic hemorrhage, or bruising. The actuarial 2-year survival was 94% (95% confidence intervals, 83% to 100%) with follow-up of 12 to 46 months from completion of carboplatin (mean, 26 months). The actuarial chance of remaining alive and free from progressive disease at 2 years was 80% (95% confidence intervals, 66% to 94%). Of six patients who relapsed, five are currently in remission 9 to 18 months after completion of salvage treatment. This level of antitumor activity is equivalent to that seen with aggressive combination regimens. Single-agent carboplatin should be considered the treatment of choice for advanced stages of malignant seminoma when limitation of toxicity is considered important; however, the rarity, especially of extranodal metastases from seminoma, leads to the need for further investigation using this approach.

Optimal planning target volume for stage I testicular seminoma: A Medical Research Council randomized trial. Medical Research Council Testicular Tumor Working Group.

PURPOSE: To compare relapse rates and toxicity associated with para-aortic (PA) strip or PA and ipsilateral iliac lymph node irradiation (dogleg [DL] field) (30 Gy/15 fractions/3 weeks) for stage I testicular seminoma. PATIENTS AND METHODS: Between July 1989 and May 1993, 478 men with testicular seminoma stage I (T1 to T3; no ipsilateral inguinoscrotal operation before orchiectomy) were randomized (PA, 236 patients; DL, 242 patients). RESULTS: Median follow-up time is 4.5 years. Eighteen relapses, nine in each treatment group, have occurred 4 to 35 months after radiotherapy; among these, four were pelvic relapses, all occurring after PA radiotherapy. However, the 95% confidence interval (CI) for the difference in pelvic relapse rates excludes differences of more than 4%. The 3-year relapse-free survival was 96% (95% CI, 94% to 99%) after PA radiotherapy and 96.6% (95% CI, 94% to 99%) after DL (difference, 0.6%; 95% confidence limits, -3.4%, +4.6%). One patient (PA field) has died from seminoma. Survival at 3 years was 99.3% for PA and 100% for DL radiotherapy. Acute toxicity (nausea, vomiting, leukopenia) was less frequent and less pronounced in patients in the PA arm. Within the first 18 months of follow-up, the sperm counts were significantly higher after PA than after DL irradiation. CONCLUSION: In patients with testicular seminoma stage I (T1 to T3) and with undisturbed lymphatic drainage, adjuvant radiotherapy confined to the PA lymph nodes is associated with reduced hematologic, gastrointestinal, and gonadal toxicity, but with a higher risk of pelvic recurrence, compared with DL radiotherapy. The recurrence rate is low with either treatment. PA radiotherapy is recommended as standard treatment in these patients.

Efficacy of high-dose palliative radiotherapy for localised, castration-resistant prostate cancer.

AIMS: There are limited outcome data after radiotherapy treatment for clinically localised, castration-resistant prostate cancer. We report our single institution experience on patient outcomes in this group using high-dose palliative radiotherapy (HDPRT). MATERIALS AND METHODS: A retrospective review of patient hospital records was conducted in prostate cancer patients treated with palliative intent radiotherapy and restricted to those who had castration-resistant disease, no evidence of regional or distant disease and who received a local radiotherapy dose equivalent to 40 Gy or greater. RESULTS: Fifty-one patients met the study criteria, 88% of these had high-risk disease at initial diagnosis. The median time to delivery of HDPRT was 66 months and the median follow-up from HDPRT was 54 months. Grade 3 or worse toxicity was experienced in 8%. The estimated freedom from local failure, cause-specific survival and overall survival at 5 years were 81, 65 and 35%, respectively. Local procedures were a significant contributor to local morbidity, with the most common procedure a transurethral resection of the prostate (27% patients). Only two patients died from complications of local failure. CONCLUSION: HDPRT was well tolerated and provided a high rate of local control in a clinically localised castration-resistant prostate cancer population. Although prostate cancer remained the most frequent cause of death, some patients had extended survival without evidence of disease progression.

The development of practice standards for radiation oncology in Australia: a tripartite approach.

In many areas of health care, practice standards have become an accepted method for professions to assess and improve the quality of care delivery. The aim of this work is to present the development of practice standards for radiation oncology in Australia, highlighting critical points and lessons learned. Following a review of radiotherapy services in Australia, a multidisciplinary group with support from the Australian Government developed practice standards for radiation oncology in Australia. The standards were produced in a multistep process including a nationwide survey of radiotherapy centres and piloting of the standards in a representative subset of all Australian radiotherapy centres. The standards are grouped into three sections: Facility management (covering staffing, data management, equipment and processes); Treatment planning and delivery (providing more detailed guidance on prescription, planning and delivery); Safety and quality management (including radiation safety, incident monitoring and clinical trials participation). Each of the 16 standards contains specific criteria, a commentary and suggestions for the evidence required to demonstrate compliance. The development of the standards was challenging and time consuming, but the collaborative efforts of the professions resulted in standards applicable throughout Australia and possibly further afield.

Validation of International Society of Urological Pathology (ISUP) grading for prostatic adenocarcinoma in thin core biopsies using TROG 03.04 'RADAR' trial clinical data.

In 2014 a consensus conference convened by the International Society of Urological Pathology (ISUP) adopted amendments to the criteria for Gleason grading and scoring (GS) for prostatic adenocarcinoma. The meeting defined a modified grading system based on 5 grading categories (grade 1, GS 3+3; grade 2, GS 3+4; grade 3, GS 4+3; grade 4, GS 8; grade 5, GS 9-10). In this study we have evaluated the prognostic significance of ISUP grading in 496 patients enrolled in the TROG 03.04 RADAR Trial. There were 19 grade 1, 118 grade 2, 193 grade 3, 88 grade 4 and 79 grade 5 tumours in the series, with follow-up for a minimum of 6.5 years. On follow-up 76 patients experienced distant progression of disease, 171 prostate specific antigen (PSA) progression and 39 prostate cancer deaths. In contrast to the 2005 modified Gleason system (MGS), the hazards of the distant and PSA progression endpoints, relative to grade 2, were significantly greater for grades 3, 4 and 5 of the 2014 ISUP grading scheme. Comparison of predictive ability utilising Harrell's concordance index, showed 2014 ISUP grading to significantly out-perform 2005 MGS grading for each of the three clinical endpoints.

A dose-controlled study of 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP) in the treatment of patients with painful bone metastases.

One hundred and fourteen patients with painful bone metastases participated in this randomised, dose-controlled study of the efficacy and safety of 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP), a systemically administered radiopharmaceutical. Fifty-five patients received single doses of 0.5 mCi/kg and 59 patients received single doses of 1.0 mCi/kg. Treatment with 153-Sm-EDTMP produced improvement from baseline in all patient-rated efficacy assessments, including degree of pain, level of daytime discomfort, quality of sleep and pain relief. During the first 4 weeks after dose administration, when the patients evaluated efficacy daily, there were statistically significant changes from baseline with the 1.0 mCi/kg dose but not with the 0.5 mCi/kg dose. The difference between doses in visual analogue pain scores was statistically significant at week 4 (P = 0.0476). Among subsets of patients examined, female patients with breast cancer receiving 1.0 mCi/kg had the most noticeable improvement. The physicians judged that approximately half of the patients in each dose group were experiencing some degree of pain relief by week 2. This value increased to 55% for the 0.5 mCi/kg group and 70% for the 1.0 mCi/kg group at week 4. More patients in the higher dose group (54%) than in the lower dose group (44%) completed the 16-week study. A predictable level of dose-related marrow suppression was the only toxicity associated with 153Sm-EDTMP treatment. Values for platelets and WBCs reached nadirs at 3 or 4 weeks with both doses and recovered by 8 weeks. Even at their lowest point, the values were generally higher than those associated with infectious or haemorrhagic complications. Myelotoxicity was no greater in female patients than in male patients. Long-term follow-up revealed longer survival among breast cancer patients who had received the higher dose than among those who had received the lower dose. The results suggest that the 1.0 mCi/kg dose of 153Sm-EDTMP is safe and effective for the treatment of painful bone metastases.

Radiotherapy after chemotherapy for metastatic seminoma--a diminishing role. MRC Testicular Tumour Working Party.

In a retrospective study, data from 302 patients with metastatic testicular seminoma treated with chemotherapy between 1978 and 1990 in 10 European centres were analysed to evaluate the role, if any, of postchemotherapy treatment with irradiation. The primary endpoint of this study was the progression-free survival rate after chemotherapy with or without additional radiotherapy. This was related to the type of primary chemotherapy, sites and sizes of pre- and postchemotherapy masses, the extent of surgical resection after chemotherapy and the use of radiotherapy. 174 patients had residual disease at the end of chemotherapy. The most important prognostic factors for progression were the presence of any visceral metastases or raised LDH prechemotherapy, and the presence of residual disease at visceral sites after chemotherapy. Approximately half the patients with residual masses underwent postchemotherapy radiotherapy, with selection based predominantly on institutional practice. In patients receiving platinum-based chemotherapy, no significant difference was detected in progression-free survival whether or not radiotherapy was employed. Patients receiving BEP (bleomycin, etoposide and cisplatin) had a progression-free survival rate of 88% (95% CI, 80-96%) uninfluenced by postchemotherapy radiotherapy. In patients with residual masses confined to the abdomen after platinum-based chemotherapy, the absolute benefit to radiotherapy was estimated to be 2.3%. The potential benefit of postchemotherapy radiotherapy is minimal, and so it is concluded that the use of adjuvant radiotherapy to residual masses after platinum-based chemotherapy for metastatic seminoma is unnecessary.

Reversible changes in radiation response induced by all-trans retinoic acid.

PURPOSE: The aim was to establish a model of reversible radiosensitization in human tumor cell lines by all-trans retinoic acid without influencing cell cycle or differentiation. METHODS AND MATERIALS: Three human carcinoma cell lines (one bladder and two lung lines) were incubated in medium containing delipidized serum with or without varying concentrations of all-trans retinoic acid for a range of time periods, and their acute response to radiation measured by clonogenic assay. Cell phenotype was monitored using growth rates, morphology, and intermediate filament expression. RESULTS: Two of the three cell lines (those in which cell kill was predominantly through reparable damage beta in control cultures) showed an increase in radiosensitivity with retinoic acid, at a concentration with no discernable effect on phenotype (10(-7) M). No significant change in alpha values was observed. The values for beta increased from 0.057 to 0.109 and from 0.039 to 0.075, corresponding to dose modification factors of 1.59 and 1.67. When retinoic acid was removed prior to irradiation, cell survival returned to control levels by 48 h. CONCLUSION: Radiosensitization occurred at retinoic acid concentrations that did not otherwise perturb the cells; the effect may be due to inhibition of DNA repair in cells usually competent at repair. The model provides a method of altering radiosensitivity in selected cell lines without genetic mutation, which may enable investigation of DNA repair mechanisms.

Hemibody irradiation in lymphomas and related malignancies.

Between 1979 and 1984, 34 patients with advanced lymphoma or leukemia resistant to other treatments have been treated with single or sequential hemibody irradiation (HBI). Good symptomatic relief was obtained in the majority of patients, with minimal acute toxicity. Disease regression occurred in the majority of patients and was maintained in those achieving a complete remission. Stage III disease and 'good risk' histology predicted a good outcome. Marrow toxicity was marked only in those patients with marrow involvement. HBI is recommended as a worthwhile palliative treatment particularly in nodal nodular disease.

A randomized trial of hypofractionated schedules of palliative radiotherapy in the management of bladder carcinoma: results of medical research council trial BA09.

PURPOSE: To compare the efficacy and toxicity of two hypofractionated radiotherapy schedules for the improvement of local symptoms from muscle-invasive bladder cancer. METHODS AND MATERIALS: A multicenter randomized trial was conducted comparing the efficacy and toxicity of two radiotherapy schedules (35 Gy in 10 fractions and 21 Gy in 3 fractions) for symptomatic improvement in patients considered unsuitable for curative treatment through disease stage or comorbidity. The primary outcome measures were overall symptomatic improvement of bladder-related symptoms at 3 months and changes in bladder- and bowel-related symptoms from pretreatment to end-of-treatment and 3-month assessments. Overall symptomatic improvement was defined prospectively as the improvement in one bladder-related symptom of at least one grade at 3 months, with no deterioration in any other bladder-related symptom. RESULTS: Five hundred patients were recruited, but data on symptomatic improvement at 3 months was only available on 272 patients. Of these, 68% achieved symptomatic improvement (71% for 35 Gy, 64% for 21 Gy), with no evidence of a difference in efficacy or toxicity between the two arms. There was no evidence of a difference in survival between the two schedules (hazard ratio [HR] = 0.99, 95% CI 0.82-1.21, p = 0. 933). CONCLUSION: This is the largest prospective trial to date in the palliative treatment of bladder cancer, and provides baseline data against which other results may be compared. The use of 21 Gy in 3 fractions appears as effective as 35 Gy in 10 fractions, although modest differences in survival, symptomatic improvement rates, and toxicity can not be reliably excluded.

Radiosensitivity related to neuroendocrine and endodermal differentiation in lung carcinoma lines.

A panel of human lung carcinoma lines was studied with respect to hormone production and intermediate filament expression to distinguish between endodermal and neuroendocrine differentiation. An index of the degree of neuroendocrine differentiation of each line was derived from the presence or absence of hormone production, cytokeratins, neurofilaments and an embryonic endodermal cell marker, which allowed identification of three groups showing high, intermediate or low neuroendocrine expression. This grouping correlated well with the in vitro radiosensitivity of the lines, those expressing pure neuroendocrine features being significantly more radiosensitive than those with an endodermal phenotype, with the intermediate group having intermediate sensitivity. Use of such an index might predict those patients likely to benefit from the use of radiotherapy in their management.

Chemotherapy and radiotherapy in advanced testicular non-seminoma. 2. Results of treatment.

Between 1976 and 1981, 63 patients with Stage II-IV testicular non-seminoma were treated by chemotherapy followed 4-6 weeks later by involved field radiotherapy. Of this group, 58 (92.1%) are alive and tumour-free, one patient died post-operatively and four of uncontrolled disease. There were no deaths from drug-induced neutropenic sepsis. During the same period a second group of 53 patients who had received radiotherapy were given chemotherapy for recurrent disease. Of this group, 38 (71.7%) are alive and tumour-free, eight died of uncontrolled malignancy, six from drug-related complications and one from a myocardial infarct. In patients receiving elective post-chemotherapy irradiation, tumour volume exerted little influence on treatment outcome, the disease-free survival rates for small volume and bulky disease being 100% and 87.2%, respectively. Conversely, in patients receiving chemotherapy after prior irradiation there was a significant difference; 96.7% and 43.4%, respectively (p less than 0.001). Of the 63 patients in the drug-irradiation protocol group 23 (36.5%) had residual masses excised. In 18 patients (78.2%) the excised tissue showed either fibrosis or mature teratoma. Despite the excellent survival figures for patients receiving post-chemotherapy irradiation the value of this approach cannot be assumed, although the slight difference between small and bulky presentations suggests that radiotherapy may have contributed to the therapeutic result.

Identification of intermediate-risk prostate cancer patients treated with radiotherapy suitable for neoadjuvant hormone studies.

We undertook a retrospective review of patients presenting with apparently localised prostatic carcinoma to a single practitioner for consideration of radiation therapy to clarify the characteristics of those patients who might benefit from the use of neo-adjuvant androgen deprivation. Of 133 patients referred between January 1989 and June 1994, 85 were considered suitable for radical therapy, of whom 31 were treated with hormone therapy prior to radiotherapy, frequently on the basis of an elevated PSA. Increasing PSA levels (p = 0.0016) and Gleason grade (p = 0.026) were independent variables for relapse. It was possible to define three prognostic groups of patients, on the basis of initial PSA and Gleason grade. Those of intermediate risk (PSA < 10 micrograms/l, Gleason score 8-10; PSA 10-25 micrograms/l, Gleason 5-7 or 8-10; PSA > 25 micrograms/l, Gleason score 2-4) had a superior duration of disease-free survival if given initial hormone therapy. This group of patients is potentially the most likely to benefit from such an approach and should be enrolled in prospective randomised studies of neoadjuvant androgen deprivation.

The acute in vitro and in vivo radiosensitivity of human lung tumour lines.

Eleven human lung tumour lines have been established in xenograft or tissue culture, and the responses to acute irradiation of the 10 lines which cloned in soft agar were assayed. In vitro radiosensitivity was evaluated using the multitarget and linear quadratic models of cell survival and the surviving fraction at 2 Gy. Significant differences in the response of the different cell types were found, the large-cell phenotype exhibiting radioresistance, and small-cell carcinomas and adenocarcinomas being radiosensitive. No differences in the capacity of the different tumour types to repair radiation damage were demonstrated. In vivo and spheroid response was modified by the effects of hypoxia and cell-contact phenomena. The results suggested that hyperfractionation would be useful in the clinical management of adenocarcinoma and small-cell carcinoma.

Chemotherapy and radiotherapy for advanced testicular non-seminoma. I. The influence of sequence and timing of drugs and radiation on the appearance of normal tissue damage.

Acute and delayed normal tissue damage has been investigated in 63 advanced stage testicular non-seminoma patients receiving elective involved-field irradiation after chemotherapy and in 53 patients who had chemotherapy given for relapse after prior irradiation. The risk of death from complications due to chemotherapy was 0% and 9.4% (p less than 0.025) in the two groups respectively. Gastro-intestinal damage and/or subcutaneous fibrosis was present in 12.6% and 24.5% of patients respectively, although only three patients have serious persisting disability. In patients receiving 35-45 Gy to the retroperitoneum the incidence of normal tissue damage was 0% and 25% (p less than 0.001), respectively. In addition to the sequence in which chemotherapy and radiotherapy was delivered, the time interval between completion of radiotherapy and start of chemotherapy was important with 6/6 patients receiving drugs within 2 months of irradiation developing fibrosis. Abdominal surgery appeared not to influence the risk of damage. Of nine patients receiving drugs after infradiaphragmatic and supra-diaphragmatic irradiation two died of neutropenic sepsis.

The dose-rate effect in human tumour cells.

The radiation response of 12 cell lines derived from a variety of human tumours has been investigated over the dose-rate range from 150 to 1.6 cGy/min. As the dose rate was lowered, the amount of sparing varied widely; in 2 cell lines it was zero, in the other cell lines the dose required for 10(-2) survival ranged up to twice the value at high dose rate. Low dose-rate irradiation discriminates better than high dose rate between tumour cell lines of differing radiosensitivity. The data are equally well fitted by two mathematical models of the dose-rate effect: the LPL model of Curtis and the Incomplete Repair model of Thames. Analysis by the LPL model leads to the conclusion that the theoretical radiosensitivity in the total absence of repair was rather similar among the 7 cell lines on which this analysis was possible. What differs among these cell lines is the extent of repair and/or the probability of direct infliction of a non-repairable lesion. Recovery from radiation damage was also examined by split-dose experiments in a total of 17 human tumour cell lines. Half-time values ranged from 0.36 to 2.3 h and there was a systematic tendency for split-dose halving times to be longer than those derived from analysis of the dose-rate effect. This could imply that cellular recovery is a two-component process, low dose-rate sparing being dominated by the faster component. The extent of low dose-rate sparing shows some tendency to correlate with the magnitude of split-dose recovery; in our view the former is the more reliable measure of cellular recovery. The clinical implication of these studies is that some human tumour types may be well treated by hyperfractionation or low dose-rate irradiation, while for others these may be poor therapeutic strategies.

Fundamental bases of combined therapy in lung cancer: cell resistance to chemotherapy and radiotherapy.

This overview briefly examines the mechanisms of drug resistance in lung cancer, including multidrug resistance and its atypical phenotypes, the role of cytoplasmic protectors such as glutathione, and resistance at the level of the DNA through topoisomerases, gene amplification or mutation, and DNA repair. Understanding of radioresistance is less advanced, but resistance may arise through limitation of the amount of DNA damage inflicted or by its subsequent modification by intracellular protectors or DNA repair. The mechanisms of radioresistance are generally distinct from those of chemoresistance providing a rationale for the use of combined modality therapy.