James W. Denham

Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial

BACKGROUND Resection remains the best treatment for carcinoma of the oesophagus in terms of local control, but local recurrence and distant metastasis remain an issue after surgery. We aimed to assess whether a short preoperative chemoradiotherapy regimen improves outcomes for patients with resectable oesophageal cancer. METHODS 128 patients were randomly assigned to surgery alone and 128 patients to surgery after 80 mg/m(2) cisplatin on day 1, 800 mg/m(2) fluorouracil on days 1-4, with concurrent radiotherapy of 35 Gy given in 15 fractions. The primary endpoint was progression-free survival. Secondary endpoints were overall survival, tumour response, toxic effects, patterns of failure, and quality of life. Analysis was done by intention to treat. FINDINGS Neither progression-free survival nor overall survival differed between groups (hazard ratio [HR] 0.82 [95% CI 0.61-1.10] and 0.89 [0.67-1.19], respectively). The chemoradiotherapy-and-surgery group had more complete resections with clear margins than did the surgery-alone group (103 of 128 [80%] vs 76 of 128 [59%], p=0.0002), and had fewer positive lymph nodes (44 of 103 [43%] vs 69 of 103 [67%], p=0.003). Subgroup analysis showed that patients with squamous-cell tumours had better progression-free survival with chemoradiotherapy than did those with non-squamous tumours (HR 0.47 [0.25-0.86] vs 1.02 [0.72-1.44]). However, the trial was underpowered to determine the real magnitude of benefit in this subgroup. INTERPRETATION Preoperative chemoradiotherapy with cisplatin and fluorouracil does not significantly improve progression-free or overall survival for patients with resectable oesophageal cancer compared with surgery alone. However, further assessment is warranted of the role of chemoradiotherapy in patients with squamous-cell tumours.

Influence of Androgen Suppression Therapy for Prostate Cancer on the Frequency and Timing of Fatal Myocardial Infarctions

PURPOSE We evaluated whether the timing of fatal myocardial infarction (MI) was influenced by the administration of androgen suppression therapy (AST). PATIENTS AND METHODS The study cohort comprised 1,372 men who were enrolled onto three randomized trials between February 1995 and June 2001. In the three trials, the men were randomly assigned to receive radiation therapy with 0 versus 3 versus 6, 3 versus 8, or 0 versus 6 months of AST. Fine and Grays regression was used to determine the clinical factors associated with the time to fatal MI, and estimates of time to fatal MI were calculated using a cumulative incidence method. When comparing the cumulative incidence estimates using Grays k-sample P values, increased weight was ascribed to the earlier data because recovery of testosterone is expected for most men within 2 years after short-course AST. RESULTS Men age 65 years or older who received 6 months of AST experienced shorter times to fatal MIs compared with men in this age group who did not receive AST (P = .017) and men younger than 65 years (P = .016). No significant difference (P = .97) was observed in the time to fatal MIs in men age 65 years or older who received 6 to 8 months of AST compared with 3 months of AST. CONCLUSION The use of AST is associated with earlier onset of fatal MIs in men age 65 years or older who are treated for 6 months compared with men who are not treated with AST.

The radiotherapeutic injury--a complex 'wound'.

Radiotherapeutic normal tissue injury can be viewed as two simultaneously ongoing and interacting processes. The first has many features in common with the healing of traumatic wounds. The second is a set of transient or permanent alterations of cellular and extracellular components within the irradiated volume. In contrast to physical trauma, fractionated radiation therapy produces a series of repeated insults to tissues that undergo significant changes during the course of radiotherapy. Normal tissue responses are also influenced by rate of dose accumulation and other factors that relate to the radiation therapy schedule. This article reviews the principles of organised normal tissue responses during and after radiation therapy, the effect of radiation therapy on these responses, as well as some of the mechanisms underlying the development of recognisable injury. Important clinical implications relevant to these processes are also discussed.

Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial

BACKGROUND The TROG 96.01 trial assessed whether 3-month and 6-month short-term neoadjuvant androgen deprivation therapy (NADT) decreases clinical progression and mortality after radiotherapy for locally advanced prostate cancer. Here we report the 10-year results. METHODS Between June, 1996, and February, 2000, 818 men with T2b, T2c, T3, and T4 N0 M0 prostate cancers were randomly assigned to receive radiotherapy alone, 3 months of NADT plus radiotherapy, or 6 months of NADT plus radiotherapy. The radiotherapy dose for all groups was 66 Gy, delivered to the prostate and seminal vesicles (excluding pelvic nodes) in 33 fractions of 2 Gy per day (excluding weekends) over 6·5-7·0 weeks. NADT consisted of 3·6 mg goserelin given subcutaneously every month and 250 mg flutamide given orally three times a day. NADT began 2 months before radiotherapy for the 3-month NADT group and 5 months before radiotherapy for the 6-month NADT group. Primary endpoints were prostate-cancer-specific mortality and all-cause mortality. Treatment allocation was open label and randomisation was done with a minimisation technique according to age, clinical stage, tumour grade, and initial prostate-specific antigen concentration (PSA). Analysis was by intention-to-treat. The trial has been closed to follow-up and all main endpoint analyses are completed. The trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12607000237482. FINDINGS 802 men were eligible for analysis (270 in the radiotherapy alone group, 265 in the 3-month NADT group, and 267 in the 6-month NADT group) after a median follow-up of 10·6 years (IQR 6·9-11·6). Compared with radiotherapy alone, 3 months of NADT decreased the cumulative incidence of PSA progression (adjusted hazard ratio 0·72, 95% CI 0·57-0·90; p=0·003) and local progression (0·49, 0·33-0·73; p=0·0005), and improved event-free survival (0·63, 0·52-0·77; p<0·0001). 6 months of NADT further reduced PSA progression (0·57, 0·46-0·72; p<0·0001) and local progression (0·45, 0·30-0·66; p=0·0001), and led to a greater improvement in event-free survival (0·51, 0·42-0·61, p<0·0001), compared with radiotherapy alone. 3-month NADT had no effect on distant progression (0·89, 0·60-1·31; p=0·550), prostate cancer-specific mortality (0·86, 0·60-1·23; p=0·398), or all-cause mortality (0·84, 0·65-1·08; p=0·180), compared with radiotherapy alone. By contrast, 6-month NADT decreased distant progression (0·49, 0·31-0·76; p=0·001), prostate cancer-specific mortality (0·49, 0·32-0·74; p=0·0008), and all-cause mortality (0·63, 0·48-0·83; p=0·0008), compared with radiotherapy alone. Treatment-related morbidity was not increased with NADT within the first 5 years after randomisation. INTERPRETATION 6 months of neoadjuvant androgen deprivation combined radiotherapy is an effective treatment option for locally advanced prostate cancer, particularly in men without nodal metastases or pre-existing metabolic comorbidities that could be exacerbated by prolonged androgen deprivation. FUNDING Australian Government National Health and Medical Research Council, Hunter Medical Research Institute, AstraZeneca, and Schering-Plough.

Tirapazamine, Cisplatin, and Radiation Versus Fluorouracil, Cisplatin, and Radiation in Patients With Locally Advanced Head and Neck Cancer: A Randomized Phase II Trial of the Trans-Tasman Radiation Oncology Group (TROG 98.02)

PURPOSE To select one of two chemoradiotherapy regimens for locally advanced squamous cell carcinoma (SCC) of the head and neck as the experimental arm for the next Trans-Tasman Radiation Oncology Group phase III trial. PATIENTS AND METHODS One hundred twenty-two previously untreated patients with stage III/IV SCC of the head and neck were randomized to receive definitive radiotherapy (70 Gy in 7 weeks) concurrently with either cisplatin (75 mg/m(2)) plus tirapazamine (290 mg/m(2)/d) on day 2 of weeks 1, 4, and 7, and tirapazamine alone (160 mg/m(2)/d) on days 1, 3, and 5 of weeks 2 and 3 (TPZ/CIS), or cisplatin (50 mg/m(2)) on day 1 and infusional fluorouracil (360 mg/m(2)/d) on days 1 through 5 of weeks 6 and 7 (chemoboost). RESULTS Three-year failure-free survival rates were 55% with TPZ/CIS (95% CI, 39% to 70%) and 44% with chemoboost (95% CI, 30% to 60%; log-rank P = .16). Three-year locoregional failure-free rates were 84% in the TPZ/CIS arm (95% CI, 71% to 92%) and 66% in the chemoboost arm (95% CI, 51% to 79%; P = .069). More febrile neutropenia and grade 3 or 4 late mucous membrane toxicity were observed with TPZ/CIS, while acute skin radiation reaction was more severe and prolonged with chemoboost. Compliance with protocol treatment was satisfactory on both arms. CONCLUSION Both regimens are feasible and are associated with significant but acceptable toxicity profiles in the cooperative group setting. Based on the promising efficacy seen in this trial, TPZ/CIS is being evaluated in a large phase III trial.

An Atlas-Based Electron Density Mapping Method for Magnetic Resonance Imaging (MRI)-Alone Treatment Planning and Adaptive MRI-Based Prostate Radiation Therapy

PURPOSE Prostate radiation therapy dose planning directly on magnetic resonance imaging (MRI) scans would reduce costs and uncertainties due to multimodality image registration. Adaptive planning using a combined MRI-linear accelerator approach will also require dose calculations to be performed using MRI data. The aim of this work was to develop an atlas-based method to map realistic electron densities to MRI scans for dose calculations and digitally reconstructed radiograph (DRR) generation. METHODS AND MATERIALS Whole-pelvis MRI and CT scan data were collected from 39 prostate patients. Scans from 2 patients showed significantly different anatomy from that of the remaining patient population, and these patients were excluded. A whole-pelvis MRI atlas was generated based on the manually delineated MRI scans. In addition, a conjugate electron-density atlas was generated from the coregistered computed tomography (CT)-MRI scans. Pseudo-CT scans for each patient were automatically generated by global and nonrigid registration of the MRI atlas to the patient MRI scan, followed by application of the same transformations to the electron-density atlas. Comparisons were made between organ segmentations by using the Dice similarity coefficient (DSC) and point dose calculations for 26 patients on planning CT and pseudo-CT scans. RESULTS The agreement between pseudo-CT and planning CT was quantified by differences in the point dose at isocenter and distance to agreement in corresponding voxels. Dose differences were found to be less than 2%. Chi-squared values indicated that the planning CT and pseudo-CT dose distributions were equivalent. No significant differences (p > 0.9) were found between CT and pseudo-CT Hounsfield units for organs of interest. Mean ± standard deviation DSC scores for the atlas-based segmentation of the pelvic bones were 0.79 ± 0.12, 0.70 ± 0.14 for the prostate, 0.64 ± 0.16 for the bladder, and 0.63 ± 0.16 for the rectum. CONCLUSIONS The electron-density atlas method provides the ability to automatically define organs and map realistic electron densities to MRI scans for radiotherapy dose planning and DRR generation. This method provides the necessary tools for MRI-alone treatment planning and adaptive MRI-based prostate radiation therapy.

Do acute mucosal reactions lead to consequential late reactions in patients with head and neck cancer

BACKGROUND AND PURPOSE The relationship between acute and late mucosal reactions remains ill defined but is of considerable relevance to efforts to produce therapeutic gains through the use of altered fractionation schemes and concurrent chemotherapy. We therefore investigated whether acute mucosal reactions in patients treated with an accelerated and a conventionally fractionated radiotherapy regime predicted the severity of late mucosal reactions. PATIENTS AND METHODS The study population consisted of 191 patients randomised on a prospective trial comparing conventional fractionation at 2 Gy/fraction per day, 70 Gy over 47 days with an accelerated regimen of 59.4 Gy, 1.8 Gy b.i.d over 24 days for Stage III-IV carcinoma of the head and neck. Acute and late mucosal reactions were scored according to RTOG/EORTC criteria and analyzed using multiple regression techniques. RESULTS The duration of time spent by patients at the acute confluent mucositis grade 3 level was inversely related to the time to onset of the reaction for both fractionation schedules. Time to onset was more rapid for patients treated on the accelerated schedule but time spent at the reaction grade did not differ significantly between the schedules. After correction for treatment and patient related factors, anatomical site (oral cavity/oropharynx versus hypopharynx/larynx) and increasing duration of confluent mucositis emerged as independent predictors of the hazard of late mucosal reactions with the latter effect being more pronounced in the accelerated treatment arm. The expected reduction in late mucosal effects in the accelerated fractionation arm, predicted by the LQ model for late effects was identified only in patients whose acute confluent mucosal reactions lasted less than 20 days. CONCLUSIONS The presence of individual patient susceptibility factors that determine the severity of acute mucosal reactions is suggested. A link between severe and prolonged acute reactions and the risk of developing late mucosal reactions that is independent of biological dose, has also been found. Purpose designed prospective studies of these issues are necessary.

Normal tissue effects: reporting and analysis.

Any effective cancer therapy developed to date is associated with a spectrum of normal tissue effects of varying incidence and severity. With an increasing number of novel therapeutic approaches undergoing clinical testing and an increased effort to optimize the established treatment modalities, methods for reliable quantification of normal tissue effects have become a key element in advancing cancer care. Here, we present a review of many of the issues involved in reporting and analyzing clinical normal tissue effect data. A distinction is introduced between explorative (science-driven) and pragmatic (patient-centered) studies. The desirable properties of criteria for reporting and grading toxicity are discussed from a biological and clinical perspective. Validation of toxicity criteria and the statistical issues involved in analyzing this type of data are presented with special emphasis on descriptors of the time evolution of toxicity. Finally, we discuss surrogate markers for late effects, mechanistic studies, and the design of clinical studies with normal tissue endpoints as a primary outcome. It is concluded that a consensus is required on guidelines for the reporting of normal tissue effects to improve the comparability of published reports on treatment outcome.

Micronuclei in Cytokinesis-blocked Lymphocytes of Cancer Patients Following Fractionated Partial-body Radiotherapy

We applied the cytokinesis-block micronucleus assay to measure chromosome damage in lymphocytes of 11 cancer patients undergoing fractionated partial-body irradiation. Measurements performed before, during and after cessation of radiotherapy showed a dose-related increase in micronucleus frequency in each of the patients studied. When the results for micronucleus frequency (Y) were plotted against the estimated equivalent whole-body dose (X) the dose-response relationship obtained was Y = 75.8X + 49.5 (r = 0.783, P less than 0.0001). A general decline in MN frequency was observed during the post-treatment period down to 57 per cent (+/- 10) after 12 months but there was considerable variation between individuals. The advantages and disadvantages of the application of the cytokinesis-block micronucleus assay as a biological dosimeter for lymphocytes irradiated in vivo are discussed.

Patterns of treatment failure and prognostic factors associated with the treatment of esophageal carcinoma with chemotherapy and radiotherapy either as sole treatment or followed by surgery .

PURPOSE The records of patients with esophageal cancer who were treated with a combined modality therapy were reviewed to determine the effects of simultaneously administered chemotherapy and radiotherapy (RT) at sites of recurrence and the relationship between treatment outcome and clinicopathologic variables. PATIENTS AND METHODS One hundred seventeen patients were treated with fluorouracil (800 mg/m2) [corrected] and cisplatin (80 mg/m2) combined with either 36 Gy (36 patients) or 54 to 60 Gy (35 patients) of RT as sole therapy. Forty-six patients underwent surgery after they had received chemotherapy and 36 Gy of RT as initial treatment. Patients with either squamous cell cancer (SCC) or adenocarcinoma were included. RESULTS Complete endoscopic regression after an initial 36 Gy of RT and chemotherapy occurred in more than 50% of patients and in both tumor types. Relief of dysphagia accompanied tumor regression. Forty-two tumors were resected, and 11 showed a complete histologic response. Significant associations were demonstrated between enhanced survival and a diagnosis of SCC, a complete endoscopic response to initial chemotherapy and RT, and a tumor length of less than 5 cm. Multivariate analyses suggested that tumor length and complete endoscopic response were independent prognostic variables. The survival rate of patients treated by resection or radical-dosage RT was not significantly different. CONCLUSIONS The relief of dysphagia demonstrates the palliative value of chemotherapy and RT in both tumor types. The similar survival rates of patients with SCC or adenocarcinoma treated either surgically or with high-dose combined therapy (54 to 60 Gy) emphasize the need to evaluate the role of surgery and combined treatment in randomized studies.