Trans-Tasman Radiation Oncology Group Research Articles

Quality assurance audit: A prospective non‐randomised trial of chemotherapy and radiotherapy for osteolymphoma (TROG 99.04/ALLG LY02)*

A quality assurance (QA) audit of the Trans Tasman Radiation Oncology Group and Australasian Lymphoma and Leukaemia Group trial (TROG 99.04/ALLG LY02) began after accrual of 25 patients. The trial is a prospective non-randomized study of standard treatment for osteolymphoma. Data relating to informed consent, eligibility, chemotherapy and radiotherapy were reviewed. The audit showed a relatively low level of major variations from the protocol, with an overall rate of 3.6%. As this trial has accrued slowly over a long period, the concept of QA has also developed. Amendments were made to the protocol accordingly. In the future, QA procedures should be predetermined, conducted rapidly in real time, and appropriately funded in order to be relevant to the ongoing conduct of the trial.

Assuring high quality treatment delivery in clinical trials – Results from the Trans-Tasman Radiation Oncology Group (TROG) study 03.04 “RADAR” set-up accuracy study

Background and purpose A multi-centre clinical trial for prostate cancer patients provided an opportunity to introduce conformal radiotherapy with dose escalation. To verify adequate treatment accuracy prior to patient recruitment, centres submitted details of a set-up accuracy study (SUAS). We report the results of the SUAS, the variation in clinical practice and the strategies used to help centres improve treatment accuracy. Materials and methods The SUAS required each of the 24 participating centres to collect data on at least 10 pelvic patients imaged on a minimum of 20 occasions. Software was provided for data collection and analysis. Support to centres was provided through educational lectures, the trial quality assurance team and an information booklet. Results Only two centres had recently carried out a SUAS prior to the trial opening. Systematic errors were generally smaller than those previously reported in the literature. The questionnaire identified many differences in patient set-up protocols. As a result of participating in this QA activity more than 65% of centres improved their treatment delivery accuracy. Conclusions Conducting a pre-trial SUAS has led to improvement in treatment delivery accuracy in many centres. Treatment techniques and set-up accuracy varied greatly, demonstrating a need to ensure an on-going awareness for such studies in future trials and with the introduction of dose escalation or new technologies.

PSA response signatures – a powerful new prognostic indicator after radiation for prostate cancer?

Background We sought to determine whether inter-patient variations in pattern of PSA changes after radiation exist and, if so, are they prognostically significant. Methods In the Trans-Tasman Radiation Oncology Group (TROG) 96.01 randomized controlled trial, patients with T2b,c,3,4 N0 prostate cancer (PC) were randomised to 0, 3 or 6 months maximal androgen deprivation prior to 66 Gy to the prostate and seminal vesicles (XRT). Patterns of anatomical site of failure were one of the trial endpoints. Serial serum PSA’s were mandated at all follow-up visits. Pattern recognition software was developed to characterize PSA response “signatures” (PRS) after therapy in individual patients. Results By 2000, 270 eligible patients were randomised to radiation alone. Individual patient PSA values were observed to descend after radiation according to one of two characteristic “signatures”: single exponential (PRS Type 1), non-exponential (PRS Type 2). Compared to PRS Type 1, men with PRS Type 2 (50% of the group) had lower PSA nadir (nPSA) levels ( p < .0001), longer doubling times on relapse ( p = .006) and significantly lower rates of local (hazard ratio [HR]: 0.47, 95% confidence interval [0.30–0.75], p = .0014) and distant failure (HR: 0.25[0.13–0.46], p < .0001), death due to PC (HR: 0.20[0.10–0.42], p < .0001) and death due to any cause (HR: 0.37 [0.23–0.60], p < .0001). PRS retained its powerful prognostic significance in Cox models that incorporated all key pre-treatment covariates and nPSA. Conclusions PRS reflect the presence of tumor phenotypes that vary substantially in their clinical behavior and response to XRT. Molecular characterization is now necessary.

Time to biochemical failure and prostate-specific antigen doubling time as surrogates for prostate cancer-specific mortality: evidence from the TROG 96.01 randomised controlled trial

Surrogate endpoints for prostate cancer-specific mortality after curative primary treatment are not well established. We sought to assess time to biochemical failure (TTBF) and prostate-specific antigen doubling time (PSADT) after failure of curative treatment as candidates for this endpoint. PSA and survival data from the Trans-Tasman Radiation Oncology Group (TROG) 96.01 trial were used to assess surrogate candidates. Between June 28, 1996, and Feb 16, 2000, 802 eligible men with locally advanced prostate cancer were randomly allocated to prostatic irradiation alone, or to 3 or 6 months of maximum short-term androgen deprivation (STAD) before and during radiation. Successful surrogates were required to satisfy the Prentice criteria and to predict the trial finding. The TROG 96.01 trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12607000237482. 6 months of STAD was shown to significantly decrease prostate cancer-specific mortality compared with radiation alone, but 3 months of STAD did not result in a decrease. Relative to radiation alone, the hazard ratio of prostate cancer-specific mortality from randomisation was 0.95 (95% CI 0.63-1.41; p=0.79) in the 3-month STAD treatment arm and 0.56 (0.36-0.88; p=0.01) in the 6-month arm. PSADT predicted the trial finding and satisfied all four Prentice criteria at the cutpoints of less than 12 months and less than 15 months, with proportion of treatment effect ratios between 0.36 and 0.56. Time to biochemical failure was better than PSADT at predicting the trial finding and satisfying all four Prentice criteria at cutpoints of less than 1.5, less than 2, and less than 2.5 years, with proportion of treatment effect ratios between 0.45 and 0.64. This study provides proof of principle that TTBF and PSADT can be useful as surrogate endpoints for prostate cancer-specific mortality and offer potential to substantially reduce follow up in clinical trials. These endpoints now require assessment in multi-trial meta-analyses before use in clinical trials.

Weekly Carboplatin Reduces Toxicity During Synchronous Chemoradiotherapy for Merkel Cell Carcinoma of Skin

The toxicity of radiotherapy (RT) combined with weekly carboplatin and adjuvant carboplatin and etoposide was prospectively assessed in a group of patients with high-risk Stage I and II Merkel cell carcinoma of the skin. This regimen was compared with the Trans-Tasman Radiation Oncology Group 96:07 study, which used identical eligibility criteria but carboplatin and etoposide every 3 weeks during RT. Patients were eligible if they had disease localized to the primary site and lymph nodes, with high-risk features. RT was delivered to the primary site and lymph nodes to a dose of 50 Gy and weekly carboplatin (area under the curve of 2) was given during RT. This was followed by three cycles of carboplatin and etoposide. A total of 18 patients were entered into the study, and their data were compared with the data from 53 patients entered into the Trans-Tasman Radiation Oncology Group 96:07 study. Involved lymph nodes (Stage II) were present in 14 patients (77%). Treatment was completed as planned in 16 patients. The weekly carboplatin dose was delivered in 17 patients, and 15 were able to complete all three cycles of adjuvant carboplatin and etoposide. Grade 3 and 4 neutrophil toxicity occurred in 7 patients, but no cases of febrile neutropenia developed. Compared with the Trans-Tasman Radiation Oncology Group 96:07 protocol (19 of 53 cases of febrile neutropenia), the reduction in the febrile neutropenia rate (p = 0.003) and decrease in Grade 3 skin toxicity (p = 0.006) were highly statistically significant. The results of our study have shown that weekly carboplatin at this dosage is a safe way to deliver synchronous chemotherapy during RT for MCC and results in a marked reduction of febrile neutropenia and Grade 3 skin toxicity compared with the three weekly regimen.

A comparison of quality of life in patients with T3 rectal cancer receiving short course versus long course preoperative radiation. A Trans-Tasman Radiation Oncology Group Trial (TROG 01.04)

4097 Background: A randomised trial was conducted comparing the efficacy of short course (SC) and long course (LC) radiotherapy, prior to surgery in patients with resectable T3 rectal cancer. The impact of these treatments on quality of life (QL) was evaluated. Methods: QL was measured using the EORTC QLQ C-30 and QLQ C-38. Assessments were made in both groups at baseline, 1, 2, 3, 6, 9, 12 months. The C-30 global health/overall QL subscale was specified as the primary outcome. Mean change in QL scores from baseline for each domain, by arm was examined and pointwise differences compared using t-tests and p <0.01 for significance. Results: 326 patients were accrued from 27 Australasian centres. 287 were assessable for QL. Questionnaire completion at baseline, 1, 2, 3, 6, 9, 12 months was; 98%, 80%, 80%, 85%, 83%, 79%, 78% respectively. At baseline there were no between treatment differences for the C-30 or C-38. Global health/overall QL declined in both arms, particularly in the postoperative period (20 points). When compared with respect to the date of surgery, QL profiles were very similar with the exception that there was a trend for SC to be worse 4 months following surgery (difference = 13.2; p=0.036). Similar patterns pertained to fatigue, anorexia, pain and physical, role, social and sexual functioning. At 12 months most QL scores by treatment returned, on average, to within 10 points of their baseline value. Exceptions included sexual enjoyment and male sexual function (much worse) and future perspective (much better). At 12 months there were few between-treatment differences in change from baseline scores (none with p < 0.010). Conclusions: Preoperative radiotherapy and surgery adversely affect several aspects of QL. The most significant decline occurs in the post operative period. By 12 months most aspects of QL have returned close to baseline values with little difference between treatment groups. No significant financial relationships to disclose.

N2‐N3 neck nodal control without planned neck dissection for clinical/radiologic complete responders—Results of Trans Tasman Radiation Oncology Group Study 98.02

The aim of this study was to determine the incidence of isolated nodal failure in patients with N2/3 disease who achieved a complete clinical and radiological response (CR) at 12 weeks postchemoradiation, when no planned neck dissection was performed. We analyzed the nodal response and subsequent neck control of 102 patients with initial N2/3 disease treated on the Trans Tasman Radiation Oncology Group 98.02 study. With a median 4.3 years follow-up, the patterns of first failure in the CR patients were local 4%, local and nodal 2%, distant 28%, and locoregional plus distant (within 1 month) 6%. There were no patients who had only neck failure. Patients in this trial with N2/3 disease who obtained a clinical and radiological complete response to chemoradiation had a zero incidence of isolated neck failure without a planned neck dissection. The continued use of planned neck dissections in this patient subset cannot be justified.

Radiation therapists’ perspective on barriers to clinical trials research

This study investigates the barriers to the conduct of research as perceived by radiation therapists (RT) particularly with regards to their activity as part of collaborative clinical trials groups such as the Trans-Tasman Radiation Oncology Group. These were examined to identify solutions that might promote research by RT working within busy clinical services. In September to October 2005, surveys were sent to an RT Educator and RT Chiefs in four public hospitals in New South Wales, Australia, with a request to distribute and collect the surveys from RT employed at their centres. The overall response rate across these centres was 59% (78/133). Most of the respondents felt that their managers regarded research to be of high priority (79%) and that others in their workplace considered initiating and conducting research as important (79%). The RT considered lack of time during working hours to be the greatest barrier to research (87%). However, the RT felt that the availability of a research mentor would facilitate research in their workplace (90%). Based on our findings, the availability of structural support from radiation oncology centres may promote the clinical trials research participation of RT.

A prospective phase II study of adjuvant postoperative radiation therapy following nodal surgery in malignant melanoma—Trans Tasman Radiation Oncology Group (TROG) Study 96.06

A prospective phase II study of adjuvant postoperative radiation therapy following nodal surgery in malignant melanoma—Trans Tasman Radiation Oncology Group (TROG) Study 96.06

3007 ORAL Molecular profiles provide clinical meaningful outcome prediction in stage II colon cancer

To establish benchmark outcomes for combined modality treatment to be used in future prospective studies of osteolymphoma (primary bone lymphoma).In 1999, the Trans-Tasman Radiation Oncology Group (TROG) invited the Australasian Leukemia and Lymphoma Group (ALLG) to collaborate on a prospective study of limited chemotherapy and radiotherapy for osteolymphoma. The treatment was designed to maintain efficacy but limit the risk of subsequent pathological fractures. Patient assessment included both functional imaging and isotope bone scanning. Treatment included three cycles of CHOP chemotherapy and radiation to a dose of 45 Gy in 25 fractions using a shrinking field technique.The trial closed because of slow accrual after 33 patients had been entered. Accrual was noted to slow down after Rituximab became readily available in Australia. After a median follow-up of 4.3 years, the five-year overall survival and local control rates are estimated at 90% and 72% respectively. Three patients had fractures at presentation that persisted after treatment, one with recurrent lymphoma.Relatively high rates of survival were achieved but the number of local failures suggests that the dose of radiotherapy should remain higher than it is for other types of lymphoma. Disability after treatment due to pathological fracture was not seen.

4005 ORAL An open label randomized Phase II study of oral triple angiokinase inhibitor BIBF 1120 in Hormone Refractory Prostate Cancer (HRPC) patients who progressed after docetaxel

We sought to determine whether inter-patient variations in pattern of PSA changes after radiation exist and, if so, are they prognostically significant.In the Trans-Tasman Radiation Oncology Group (TROG) 96.01 randomized controlled trial, patients with T2b,c,3,4 N0 prostate cancer (PC) were randomised to 0, 3 or 6 months maximal androgen deprivation prior to 66 Gy to the prostate and seminal vesicles (XRT). Patterns of anatomical site of failure were one of the trial endpoints. Serial serum PSA’s were mandated at all follow-up visits. Pattern recognition software was developed to characterize PSA response “signatures” (PRS) after therapy in individual patients.By 2000, 270 eligible patients were randomised to radiation alone. Individual patient PSA values were observed to descend after radiation according to one of two characteristic “signatures”: single exponential (PRS Type 1), non-exponential (PRS Type 2). Compared to PRS Type 1, men with PRS Type 2 (50% of the group) had lower PSA nadir (nPSA) levels (p < .0001), longer doubling times on relapse (p = .006) and significantly lower rates of local (hazard ratio [HR]: 0.47, 95% confidence interval [0.30–0.75], p = .0014) and distant failure (HR: 0.25[0.13–0.46], p < .0001), death due to PC (HR: 0.20[0.10–0.42], p < .0001) and death due to any cause (HR: 0.37 [0.23–0.60], p < .0001). PRS retained its powerful prognostic significance in Cox models that incorporated all key pre-treatment covariates and nPSA.PRS reflect the presence of tumor phenotypes that vary substantially in their clinical behavior and response to XRT. Molecular characterization is now necessary.

3008 ORAL Acute adverse events in a randomised trial of short course versus long course preoperative radiotherapy for T3 adenocarcinoma of rectum: a Trans-Tasman Radiation Oncology Group trial (TROG 01.04)

3008 ORAL Acute adverse events in a randomised trial of short course versus long course preoperative radiotherapy for T3 adenocarcinoma of rectum: a Trans-Tasman Radiation Oncology Group trial (TROG 01.04)

A prospective phase II study of adjuvant postoperative radiation therapy following nodal surgery in malignant melanoma–Trans Tasman Radiation Oncology Group (TROG) Study 96.06

Background The role of adjuvant postoperative therapy after resection of localised malignant melanoma involving regional lymph nodes remains controversial. There are no randomised trials that confirm that postoperative radiation conveys a benefit in terms of regional control or survival. Methods Two hundred and thirty-four patients with melanoma involving lymph nodes were registered on a prospective study to evaluate the effect of postoperative radiation therapy. The regimen consisted of 48 Gy in 20 fractions to the nodal basin using recommended treatment guidelines for each of the major node sites. The primary endpoints were regional in-field relapse and late toxicity. Secondary endpoints were adjacent relapse, distant relapse, overall survival, progression-free survival and time to in-field progression. Results Adjuvant radiation therapy was well tolerated by all of the patients. As the first site of relapse, regional in-field relapses occurred in 16/234 patients (6.8%). The overall survival was 36% at 5 years. The progression-free survival and regional control rates were 27% and 91%, respectively, at 5 years. Patients with more than 2 nodes involved had a significantly worse outcome in terms of distant relapse, overall and progression-free survival. Conclusion We believe that adjuvant radiation therapy following nodal surgery could offer a possible benefit in terms of regional control. These results require confirmation in a randomised trial.

2525: An Australasian Leukaemia Lymphoma Group- Trans Tasman Radiation Oncology Group Prospective Multicentre Study of Limited Chemotherapy and Involved Field Radiotherapy (IFRT) for Clinical Stage I-II Hodgkin Lymphoma (HL)

2525: An Australasian Leukaemia Lymphoma Group- Trans Tasman Radiation Oncology Group Prospective Multicentre Study of Limited Chemotherapy and Involved Field Radiotherapy (IFRT) for Clinical Stage I-II Hodgkin Lymphoma (HL)

Efficacy and tolerability of concurrent weekly low dose cisplatin during radiation treatment of localised muscle invasive bladder transitional cell carcinoma: A report of two sequential Phase II studies from the Trans Tasman Radiation Oncology Group

Background and purpose To determine the feasibility, toxicity, and clinical effectiveness of concurrent weekly cisplatin chemotherapy in conjunction with definitive radiation in the treatment of localised muscle invasive bladder cancer. Patients and methods In January 1997 the Trans Tasman Radiation Oncology Group embarked on a Phase II study (TROG 97.01) of weekly cisplatin (35 mg/m 2 × 7 doses) plus radiation to a dose of 63 Gy over 7 weeks. Following an interim toxicity analysis, the dose intensity of cisplatin was reduced to 6 cycles and the radiation schedule changed to 64 Gy over 6.5 weeks leading to the second study (TROG 99.06). A total of 113 patients were enrolled. Results Acute grade 3 urinary toxicity occurred in 23% of the patients. Acute grade 4 pelvic toxicity was not seen. Thirty-eight patients (33%) experienced grade 3 or 4 cisplatin related toxicities with 15 patients (12%) requiring significant dose modification. The reduced dose intensity in Study 99.06 improved tolerability. Incidence of significant late morbidity was low (6%). Seventy-nine patients (70%) achieved complete remission at the 6 month cystoscopic assessment. Local invasive recurrence was seen in 11 of the 79 patients (14%). In 18 patients (16%) isolated superficial TCC/CIS were detected (6 months and beyond).The local control rate was 45% with a functional bladder being retained in 69 of the 113 patients (61%). RFS and DSS at 5 years were 33% and 50%, respectively. Conclusion Our two sequential Phase II studies have shown that concurrent chemoradiation using weekly cisplatin in the management of localised invasive bladder TCC is feasible and reasonably well tolerated. This approach is currently being investigated further in a randomised study.

Stage Is Not a Reliable Indicator of Tumor Volume in Non-small Cell Lung Cancer: A Preliminary Analysis of the Trans-Tasman Radiation Oncology Group 99-05 Database

Tumor volume has been shown to be a prognostic factor for the response of some tumors to radiotherapy. TNM stage has prognostic value for patients treated surgically for non-small cell lung cancer (NSCLC), but its value is less clear for patients treated by nonsurgical means. This may be because tumor size is not a consistent determinant of T stage or stage group. As part of the preliminary analyses for the Trans-Tasman Radiation Oncology Group 99-05 study, the authors performed this analysis to determine to what extent stage reflects tumor volume. In this prospective multicenter observational study, patients had to have histologically proven NSCLC, no evidence of disease beyond the primary site or thoracic lymph nodes, and been planned for radical radiotherapy with or without chemotherapy. Tumor volume measurements were based on computed tomography-based treatment planning images. Four hundred four patients were available for analysis. There was a strong correlation between (log) maximum tumor diameter and (log) tumor volume (r = 0.93, p < 0.001). Although there was a highly significant trend of increasing volume with increasing T stage and stage group, when tumors were categorized into four groups according to increasing volume, there was only 55% concordance with T stage and 67% concordance with stage group. There is limited correlation between tumor size and disease stage in patients with NSCLC. This justifies documentation and investigation of size as a potential prognostic factor independent of stage. Maximum tumor diameter may be an adequate substitute for volume as a measurement of size.

Stage Is Not a Reliable Indicator of Tumor Volume in Non-small Cell Lung Cancer: A Preliminary Analysis of the Trans-Tasman Radiation Oncology Group 99-05 Database

Stage Is Not a Reliable Indicator of Tumor Volume in Non-small Cell Lung Cancer: A Preliminary Analysis of the Trans-Tasman Radiation Oncology Group 99-05 Database

Whole brain irradiation following surgery or radiosurgery for solitary brain metastases: Mature results of a prematurely closed randomized Trans-Tasman Radiation Oncology Group trial (TROG 98.05)

We evaluated the effect of adjuvant whole brain irradiation (WBI) after surgery or radiosurgery for solitary brain metastases in a Phase III multicentre trial with randomization to 30-36 Gy WBI or observation. The study was closed early due to slow accrual after 19 patients (WBI 10, observation 9). There was no difference in CNS failure-free survival or overall survival between the arms. There was a trend to reduced CNS relapse with WBI (30% versus 78%, P = 0.12). Limited analysis of quality of life and neurocognitive function data revealed no evidence of difference between the arms. Our results are not inconsistent with two larger randomized trials and support the use of upfront WBI to decrease brain recurrence in this setting.

A comparative longitudinal quality of life study using the Spitzer quality of life index in a randomized multicenter phase III trial (FFCD 9102): chemoradiation followed by surgery compared with chemoradiation alone in locally advanced squamous resectable thoracic esophageal cancer

The aim of the study was to compare the longitudinal quality of life (QoL) between chemoradiation with or without surgery in patients with locally advanced squamous resectable esophageal cancer included in a randomized multicenter phase III trial (FFCD 9102). All patients with locally advanced resectable (T3-4 N0-1 M0) epidermoid or glandular esophageal cancer (n = 451) received induction chemoradiation. Responders (n = 259) were randomized between surgery (arm A) and continuation of chemoradiation (arm B). The Spitzer QoL Index was scored (0-10) at inclusion and at each follow-up, every 3 months during 2 years. QoL at baseline and longitudinal changes were respectively compared with univariate ANOVA and mixed-model analysis of variance for repeated measurements. The time interval between the follow-up was assessed and the same analyses were performed among survivors with 2 years of follow-up. The squamous histology was predominant in both arms. The mean QoL score decreased between baseline and the first follow-up and between the first and the second follow-ups. QoL scores at the first follow-up were comparatively worse in arm A than in arm B (7.52 versus 8.45, P < 0.01), whereas the longitudinal QoL study showed no difference between treatments (adjusted P = 0.26). Furthermore, the longitudinal QoL was not different (adjusted P = 0.23) among survivors with 2 years of follow-up. Among patients responding to induction chemoradiation, surgery and continuation of chemoradiation had the same impact on QoL in patients with locally advanced, resectable esophageal cancer although a significantly greater decrease in the Spitzer Index was observed in the postoperative period.

Prognostic Significance of [18F]-Misonidazole Positron Emission Tomography–Detected Tumor Hypoxia in Patients With Advanced Head and Neck Cancer Randomly Assigned to Chemoradiation With or Without Tirapazamine: A Substudy of Trans-Tasman Radiation Oncology Group Study 98.02

To determine the association between tumor hypoxia, treatment regimen, and locoregional failure (LRF) in patients with stage III or IV squamous cell carcinoma of the head and neck randomly assigned to radiotherapy (70 Gy in 35 fractions over 7 weeks) plus either tirapazamine and cisplatin in weeks 1, 4, and 7 and tirapazamine alone in weeks 2 and 3 (TPZ/CIS) or cisplatin and infusional fluorouracil during weeks 6 and 7 (chemoboost). Forty-five patients were enrolled onto a hypoxic imaging substudy of a larger randomized trial. Pretreatment and midtreatment [18F]-fluoromisonidazole positron emission tomography scans (FMISO-PET) were performed 2 hours after tracer administration, with qualitative scoring of uptake in both primary tumors and nodes. Thirty-two patients (71%) had detectable hypoxia in either or both primary and nodal disease. In patients who received chemoboost, one of 10 patients without hypoxia had LRF compared with eight of 13 patients with hypoxia; the risk of LRF was significantly higher in hypoxic patients (exact log-rank, P = .038; hazard ratio [HR] = 7.1). By contrast, in patients who received the TPZ/CIS regimen, only one of 19 patients with hypoxic tumors had LRF; risk of LRF was significantly higher in chemoboost patients (P = .001; HR = 15). Similarly, looking at the primary site alone, in patients with hypoxic primaries, zero of eight patients treated with TPZ/CIS experienced failure locally compared with six of nine patients treated with chemoboost (P = .011; HR = 0). Hypoxia on FMISO-PET imaging, in patients receiving a nontirapazamine-containing chemoradiotherapy regimen, is associated with a high risk of LRF. Our data provide the first clinical evidence to support the experimental observation that tirapazamine acts by specifically targeting hypoxic tumor cells.