The safety, feasibility, and efficacy of an 18-week exercise intervention for adults with primary brain cancer - the BRACE study.

PURPOSE: To determine the safety, feasibility, and potential effect of an 18-week exercise intervention for adults with primary brain cancer. MATERIALS AND METHODS: Eligible patients were 12-26-weeks post-radiotherapy for brain cancer. The individually-prescribed weekly exercise was ≥150-minutes of moderate-intensity exercise, including two resistance-training sessions. The intervention was deemed "safe" if exercise-related, serious adverse events (SAE) were experienced by <10% of participants, and feasible if recruitment, retention, and adherence rates were ≥75%, and ≥75% compliance rates were achieved in ≥75% of weeks. Patient-reported and objectively-measured outcomes were assessed at baseline, mid-intervention, end-intervention, and 6-month follow-up, using generalized estimating equations. RESULTS: Twelve participants enrolled (51 ± 19.5 years, 5 females). There were no exercise-related SAEs. The intervention was feasible (recruitment:80%, retention:92%, adherence:83%). Participants completed a median of 172.8 (min:77.5, max:560.8) minutes of physical activity per week. 17% met the compliance outcome threshold for ≥75% of the intervention. Improvements in quality of life (mean change (95% CI): 7.9 units (1.9, 13.8)), functional well-being (4.3 units (1.4, 7.2)), depression (-2.0 units (-3.8, -0.2)), activity (112.8 min (42.1, 183.4)), fitness (56.4 meters (20.4, 92.5)), balance (4.9 s (0.9, 9.0)), and lower-body strength (15.2 kg (9.3, 21.1)) were observed end-intervention. CONCLUSION: Preliminary evidence support that exercise is safe and beneficial to the quality of life and functional outcomes for people with brain cancer.Registration: ACTRN12617001577303.

The BRAin Cancer and Exercise (BRACE) study highlights the need for regular monitoring of disease- and treatment-related side effects which may present as barriers to exercise.Exercise prescription should be modified according to the presence and severity of disease- and treatment-related barriers.Adverse events observed, such as dizziness, highlight the importance of supervised exercise for people with brain cancer.If supervision is not possible, then exercise modes with low risk of harm from falls are recommended (e.g., walking, machine-based resistance training).

Resilience and ongoing quality care for cancer clinical trials during COVID-19: Experience from a tertiary hospital in Australia.

BACKGROUND: The COVID-19 pandemic has forced rapid system-wide changes to be implemented within cancer care at an alarming pace. Clinical trials are a key element of comprehensive cancer care. Ensuring the continuing safe conduct of cancer clinical trials in the context of a pandemic is challenging. METHODS: We aimed to describe the COVID-19 pandemic response of a Cancer Care Clinical Research Unit (CRU) of a tertiary hospital in Queensland, Australia. We used a mixed methods approach for this case study. Emailed directives from CRU managers to all CRU staff sharing were qualitatively analysed and mapped against our unit activities over longitudinal time points. Data from patient recruitment and protocol deviations were analysed using descriptive statistics. RESULTS: Mapping activity from 11 March to 30 September 2020 revealed rapid change during the first 2 weeks. Four key strategies to accommodate change were identified: supporting patients and families, introduction of telehealth, accessing investigational product, and social distancing. Early in the pandemic we recognised that our core key stakeholders were integral to our response. When compared to the previous 12 months, our recruitment numbers dropped markedly in early phases of the response but recovered over time, as we accommodated internal and external impacts. CONCLUSION: Our experience of agility as a necessity, adapting to support patients, and managing both clinical research activity and sponsors during the height of the pandemic response is presented here in order to inform future disaster response planning by clinical trial organisations.

A prospective study investigating the efficacy and toxicity of definitive ChemoRadiation and ImmunOtherapy (CRIO) in locally and/or regionally advanced unresectable cutaneous squamous cell carcinoma.

BACKGROUND: Patients with unresectable advanced cutaneous squamous cell carcinoma (cSCC) are generally treated with palliative intent. Immune checkpoint blockade has significant activity in the palliative setting in patients with recurrent or metastatic cSCC. This single arm phase 2 prospective study aims to investigate the combination of curative intent chemoradiation and durvalumab (anti-PD-L1 checkpoint inhibitor) for this patient cohort. METHODS: Patients with unresectable locally and or regionally advanced pathologically confirmed cSCC (stage III-IVa) deemed fit for CRIO by consensus of the Multidisciplinary meeting will be eligible. In the first stage of a two-stage minimax design, we aim to recruit a total of 15 patients. If fewer than 7 patients achieved a complete response in the first stage, we will conclude the treatment is not more effective than standard treatment. The co-primary endpoints of CRIO are the safety of treatment (acute and late toxicities) and the rate of complete response. Secondary endpoints would include overall survival, progression free survival, and locoregional control. Translational research endpoints including biomarkers (CD73, CD39, PD-1, PD-L1) will also be explored utilising multiplex immunohistochemistry on tumour biopsy samples obtained prior to commencing treatment and during treatment (week 2). In addition, the utility of CXCR-4 PET/CT scan will be explored. DISCUSSION: CRIO is a novel trial evaluating the combination of curative intent chemoradiotherapy with concurrent and adjuvant durvalumab for patients with unresectable stage III-IVa cSCC. TRIAL REGISTRATION: Trial registered with the Australian New Zealand Clinical Trial Registry (ACTRN12618001573246).

Improving guideline sensitivity and specificity for the identification of proactive gastrostomy placement in patients with head and neck cancer.

BACKGROUND: Swallowing and nutrition guidelines for patients with head and neck cancer are available for identification of proactive gastrostomy placement in patients with high nutritional risk. The purpose of this study was to investigate improvements to the validity of these guidelines. METHODS: A multivariate analysis was fitted to the original dataset (n = 501) to examine the variables that may predict gastrostomy placement (eg, tumor site, treatment, sex, and age). Using these factors, the high risk category was modified and retrospectively validated in the same cohort to provide new measures of sensitivity and specificity. RESULTS: The following were positive predictors of gastrostomy placement: T3 (p = .01), T4 (p < .001), and chemoradiotherapy (p < .001). Laryngeal (p = .02) and skin cancer (p < .001) were negative predictors. Modification of the high risk definition improved sensitivity to 58% and maintained specificity at 92%. CONCLUSION: Minor modifications to the high risk definition in the guidelines have improved the guideline sensitivity for future use. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1163-E1171, 2016.

Natural oil-based emulsion containing allantoin versus aqueous cream for managing radiation-induced skin reactions in patients with cancer: a phase 3, double-blind, randomized, controlled trial.

PURPOSE: To investigate the effects of a natural oil-based emulsion containing allantoin versus aqueous cream for preventing and managing radiation-induced skin reactions. METHODS AND MATERIALS: A total of 174 patients were randomized and participated in the study. Patients received either cream 1 (the natural oil-based emulsion containing allantoin) or cream 2 (aqueous cream). Skin toxicity, pain, itching, and skin-related quality of life scores were collected for up to 4 weeks after radiation treatment. RESULTS: Patients who received cream 1 had a significantly lower average level of Common Terminology Criteria for Adverse Events at week 3 (P<.05) but had statistically higher average levels of skin toxicity at weeks 7, 8, and 9 (all P<.001). Similar results were observed when skin toxicity was analyzed by grades. With regards to pain, patients in the cream 2 group had a significantly higher average level of worst pain (P<.05) and itching (P=.046) compared with the cream 1 group at week 3; however, these differences were not observed at other weeks. In addition, there was a strong trend for cream 2 to reduce the incidence of grade 2 or more skin toxicity in comparison with cream 1 (P=.056). Overall, more participants in the cream 1 group were required to use another topical treatment at weeks 8 (P=.049) and 9 (P=.01). CONCLUSION: The natural oil-based emulsion containing allantoin seems to have similar effects for managing skin toxicity compared with aqueous cream up to week 5; however, it becomes significantly less effective at later weeks into the radiation treatment and beyond treatment completion (week 6 and beyond). There were no major differences in pain, itching, and skin-related quality of life. In light of these results, clinicians and patients can base their decision on costs and preferences. Overall, aqueous cream seems to be a more preferred option.

Cutaneous carcinoma of the head and neck with clinical features of perineural infiltration treated with radiotherapy.

AIMS: To review the outcome of patients with non-melanomatous carcinoma of the skin of the head and neck with perineural infiltration (PNI) with clinical features treated with radiotherapy. MATERIALS AND METHODS: Between 1991 and 2004, 56 patients with non-melanomatous skin carcinoma with PNI with clinical features were identified from the institution's oncology database. All patients had radiotherapy as either definitive or adjuvant treatment. The factors that affected outcome were analysed. The primary end point was the 5 year relapse-free survival (RFS) from the time of diagnosis of PNI. RESULTS: The overall 5 year RFS for the whole group was 48%. Squamous histology had a more unfavourable outcome than basal cell histology (5 year RFS: 39% versus 80%; P = 0.07). Tumours located in the distribution of the cranial nerves V1 and V2 had a worse outcome than tumours at other sites (5 year RFS: 33% versus 72%, P = 0.056). Those with multiple cranial nerve involvement did worse than those with single nerve involvement (27% versus 62%, P = 0.1). The pattern of relapse was predominantly local (87%), with a low rate (15%) of successful salvage. CONCLUSION: Radiotherapy with or without surgery is curative in about half head and neck cutaneous non-melanomatous carcinomas with clinical PNI. The frequent local failure suggests that improvements in local treatment are required.

The impact of preradiation residual disease volume on time to locoregional failure in cutaneous Merkel cell carcinoma--a TROG substudy.

PURPOSE: This study evaluated the impact of margin status and gross residual disease in patients treated with chemoradiation therapy for high-risk stage I and II Merkel cell cancer (MCC). METHODS AND MATERIALS: Data were pooled from 3 prospective trials in which patients were treated with 50 Gy in 25 fractions to the primary lesion and draining lymph nodes and 2 schedules of carboplatin based chemotherapy. Time to locoregional failure was analyzed according to the burden of disease at the time of radiation therapy, comparing patients with negative margins, involved margins, or macroscopic disease. RESULTS: Analysis was performed on 88 patients, of whom 9 had microscopically positive resection margins and 26 had macroscopic residual disease. The majority of gross disease was confined to nodal regions. The 5-year time to locoregional failure, time to distant failure, time to progression, and disease-specific survival rates for the whole group were 73%, 69%, 62%, and 66% respectively. The hazard ratio for macroscopic disease at the primary site or the nodes was 1.25 (95% confidence interval 0.57-2.77), P=.58. CONCLUSIONS: No statistically significant differences in time to locoregional failure were identified between patients with negative margins and those with microscopic or gross residual disease. These results must, however, be interpreted with caution because of the limited sample size.

Decreased hospital stay and significant cost savings after routine use of prophylactic gastrostomy for high-risk patients with head and neck cancer receiving chemoradiotherapy at a tertiary cancer institution.

BACKGROUND: Evidence-based nutritional and swallowing guidelines were developed to identify patients at high risk of developing malnutrition during chemoradiation for head and neck cancer. These guidelines recommended a prophylactic gastrostomy and were actively implemented at our institution in January 2007. This study assesses the effect of this policy change on patient outcomes. METHODS: This retrospective cohort study was carried out for the years before (2005) and after (2007) implementation of these guidelines. RESULTS: In all, 165 patients were treated with radical chemoradiation for head and neck cancer at our institution in the years 2005 and 2007. Gastrostomy tube complications were low. Patients in 2007 had significantly fewer hospital admissions, unexpected admissions, and a shorter mean duration of hospital stay in comparison with those in 2005. CONCLUSIONS: Prophylactic gastrostomy tubes in patients with high-risk head and neck cancer resulted in a significant decrease in hospital admissions and length of stay, and led to increased bed availability.

Validated swallowing and nutrition guidelines for patients with head and neck cancer: identification of high-risk patients for proactive gastrostomy.

BACKGROUND: The "Swallowing and Nutrition Guidelines for Patients with Head and Neck Cancer" were developed to guide early identification and management of dysphagia and nutritional risk before, during, and after cancer treatment. The purpose of this study was to validate these guidelines. METHODS: Patients attending a Combined Head and Neck Clinic at a major tertiary hospital in 2007 to 2008 were assessed using the guidelines, with high-risk category patients recommended for proactive gastrostomy. Data were collected on guideline adherence, gastrostomy tube insertion, and weight. Sensitivity, specificity, and positive predictive value were calculated for validation. RESULTS: Proactive gastrostomy tubes were inserted in 173 of 501 patients (25%). Overall guideline adherence was 87%. High-risk category adherence was 75%. Validation outcomes were sensitivity 54%, specificity 93%, and positive predictive value 82%. CONCLUSION: The risk categories in the guidelines are valid to assist early identification of swallowing and nutritional risk and guide decision-making on proactive gastrostomy tube insertion.

A double-blind randomised controlled trial of a natural oil-based emulsion (Moogoo Udder Cream®) containing allantoin versus aqueous cream for managing radiation-induced skin reactions in patients with cancer.

BACKGROUND: Radiation-induced skin reaction (RISR) is one of the most common and distressing side effects of radiotherapy in patients with cancer. It is featured with swelling, redness, itching, pain, breaks in skin, discomfort, and a burning sensation. There is a lack of convincing evidence supporting any single practice in the prevention or management of RISR. METHODS/DESIGNS: This double-blinded randomised controlled trial aims to investigate the effects of a natural oil-based emulsion containing allantoin (as known as Moogoo Udder Cream®) versus aqueous cream in reducing RISR, improving pain, itching and quality of life in this patient group. One group will receive Moogoo Udder Cream®. Another group will receive aqueous cream. Outcome measures will be collected using patient self-administered questionnaire, interviewer administered questionnaire and clinician assessment at commencement of radiotherapy, weekly during radiotherapy, and four weeks after the completion of radiotherapy. DISCUSSION: Despite advances of radiologic advances and supportive care, RISR are still not well managed. There is a lack of efficacious interventions in managing RISR. While anecdotal evidence suggests that Moogoo Udder Cream® may be effective in managing RISR, research is needed to substantiate this claim. This paper presents the design of a double blind randomised controlled trial that will evaluate the effects of Moogoo Udder Cream® versus aqueous cream for managing in RISR in patients with cancer. TRIAL REGISTRATION: ACTRN 12612000568819.

Tubular breast carcinoma: an argument against treatment de-escalation.

PURPOSE: To evaluate the role of adjuvant radiotherapy in management of patients with tubular carcinoma of the breast. METHODS: One hundred seventy-eight patients treated for tubular carcinoma were identified from the Queensland Radium Institute database. A retrospective review of medical records identified 115 patients meeting eligibility criteria: breast-conserving surgery for a histological diagnosis of tubular carcinoma, minimum follow up of 12 months and adequate medical records. RESULTS: Median follow up was 64 months. There were no significant differences between patient characteristics treated with and without radiotherapy. Median age at diagnosis was 54 (36-78) years. Ninety-five percent tumours were T1 and four patients had positive axillary lymph nodes. Of 94 patients treated with adjuvant radiotherapy, one developed local relapse. Five of 21 patients who did not have adjuvant radiotherapy failed locally. Five-year relapse-free survival with and without radiotherapy was 100 and 89%, respectively (hazard ratio for radiotherapy: 0.06; 95% confidence interval 0.01-0.32, P = 0.001). CONCLUSION: Radiotherapy has a significant impact on relapse-free survival in patients treated with breast-conserving surgery for tubular carcinoma.

Perineural infiltration of cutaneous squamous cell carcinoma and basal cell carcinoma without clinical features.

PURPOSE: To review the factors that influence outcome and patterns of relapse in patients with cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) with perineural infiltration (PNI) without clinical or radiologic features, treated with surgery and radiotherapy. METHODS AND MATERIALS: Between 1991 and 2004, 222 patients with SCC or BCC with PNI on pathologic examination but without clinical or radiologic PNI features were identified. Charts were reviewed retrospectively and relevant data collected. All patients were treated with curative intent; all had radiotherapy, and most had surgery. The primary endpoint was 5-year relapse-free survival from the time of diagnosis. RESULTS: Patients with SCC did significantly worse than those with BCC (5-year relapse-free survival, 78% vs. 91%; p < 0.01). Squamous cell carcinoma with PNI at recurrence did significantly worse than de novo in terms of 5-year local failure (40% vs. 19%; p < 0.01) and regional relapse (29% vs. 5%; p < 0.01). Depth of invasion was also a significant factor. Of the PNI-specific factors for SCC, focal PNI did significantly better than more-extensive PNI, but involved nerve diameter or presence of PNI at the periphery of the tumor were not significant factors. CONCLUSIONS: Radiotherapy in conjunction with surgery offers an acceptable outcome for cutaneous SCC and BCC with PNI. This study suggests that focal PNI is not an adverse feature.

Factors influencing relapse-free survival in Merkel cell carcinoma of the lower limb--a review of 60 cases.

PURPOSE: Factors affecting relapse-free survival (RFS) in patients with Merkel cell carcinoma (MCC) of the lower limb were reviewed. METHODS AND MATERIALS: The records of 60 patients from 1986 to 2005 with a diagnosis of MCC of the lower limb or buttock were retrospectively reviewed. The patients were treated with curative intent with surgery, radiation, or chemotherapy. RESULTS: The 5-year overall survival, disease-specific survival, and RFS were 53%, 61%, and 20%, respectively. Factors influencing RFS were analyzed using univariate analysis. It appeared that recurrent disease worsened RFS (p = 0.03) and the addition of any radiotherapy improved RFS (p <0.001), as did radiotherapy to the inguinal nodes (p = 0.01) or primary site and inguinal nodes (p = 0.003). Age, surgical margins, and stage were not statistically significant. On multivariate analysis, the only significant factor was the addition of radiotherapy (hazard ratio = 0.51 p = 0.03). CONCLUSION: The addition of radiotherapy improves RFS compared with surgery alone. Elective treatment should be given to the inguinal nodes to reduce the risk of relapse.

Is radiotherapy a good adjuvant strategy for men with a history of cryptorchism and stage I seminoma?

PURPOSE: Men with cryptorchism can have aberrant abdominopelvic lymph node (LN) drainage or a different natural history if they develop Stage I seminoma. If so, the nodal echelons for metastases will not be reliable, and adjuvant radiotherapy (RT) would not be an ideal strategy. METHODS AND MATERIALS: Two prospectively maintained oncology databases were reviewed for men with a history of testicular seminoma and cryptorchidism. The primary endpoint was the 5-year relapse-free rate. RESULTS: A total of 23 men were identified, most (n = 13) had had a tumor in a scrotal location after orchiopexy. After orchiectomy, 5 men were managed with surveillance, and 18 underwent RT to a median dose of 25 Gy (range, 20-30 Gy). All the radiation fields included the para-aortic LNs, and 13 included the ipsilateral pelvic LNs. After a median follow-up of 64 months (range, 2-148), 2 patients developed a relapse. One did so 4 months into a surveillance program in the para-aortic and ipsilateral pelvic LNs, sites that would have been treated had he undergone RT. The other patient developed a relapse in the contralateral testis 46 months after having undergone RT. It is likely that the latter patient had a metachronous primary rather than a relapse; hence, the 5-year relapse-free rate was 80% for surveillance and 100% for RT. Both patients underwent successful salvage treatment, and all patients were disease free and alive at the last follow-up visit. CONCLUSION: A history of cryptorchism does not appear to confer a greater risk of relapse for men with Stage I seminoma managed with radiotherapy. RT, surveillance, and adjuvant carboplatin chemotherapy are treatment options for these patients.

Radiotherapy for perineural invasion in cutaneous head and neck carcinomas: toward a risk-adapted treatment approach.

BACKGROUND: We retrospectively reviewed outcomes in patients treated with radiotherapy (RT) for cutaneous head and neck carcinoma with perineural invasion (PNI), with the aim of developing risk-adapted treatment guidelines. METHODS: A total of 118 patients were treated with RT between April 1992 and July 2000. Ninety-seven patients had PNI discovered through histology (pPNI) and 21 patients had symptoms/signs of PNI (cPNI). All received RT (median dose, 55 Gy; range, 17-74): 114 postoperatively and 4 definitively. Median follow-up was 84 months (range, 4-201). RESULTS: The 5-year local control (LC) rates were 90% with pPNI and 57% with cPNI (p < .0001). The pPNI and cPNI groups also differed in relapse-free survival (76% vs 46%, p = .003), disease-specific survival (90% vs 76%, p = .002), and overall survival (69% vs 57%, p = .03). pPNI patients with BCC histology (n = 42) had better LC (97% vs 84%, p = .02) than pPNI SCC (n = 55). CONCLUSION: Surgery plus RT provides a high rate of LC in patients with pPNI, particularly those with BCC. Therapeutic improvements are needed for patients with cPNI.

Weekly carboplatin reduces toxicity during synchronous chemoradiotherapy for Merkel cell carcinoma of skin.

PURPOSE: 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 AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Predictors of acute grade 4 swallowing toxicity in patients with stages III and IV squamous carcinoma of the head and neck treated with radiotherapy alone.

PURPOSE: The purpose of the study was to investigate the predictive factors for acute grade 4 swallowing toxicity in an attempt to identify which patients may benefit from early intervention with enteral feeding during curative radiation treatment for localised Stages 3-4 squamous cell carcinoma of the head and neck. It was hypothesised that craniocaudal length of the treatment field to the upper neck and pharynx would correlate with grade 4 swallowing toxicity due to the increased volume of pharynx irradiated. PATIENTS AND METHODS: Toxicity data were collected prospectively as part of a phase III randomised trial (TROG 91:01) that assigned patients to either conventional (CRT) or accelerated radiotherapy (ART). Patients were randomly assigned to either CRT, using a single 2 Gy per day to a dose of 70 Gy in 35 fractions in 49 days or to ART, using 1.8 Gy twice a day to a dose of 59.4 Gy in 33 fractions in 24 days. Treatment allocation was stratified for site and stage. Accrual commenced in 1991 and the trial was closed in 1998 when the target of 350 patients was reached. Potential factors were analysed that predicted for Grade IV swallowing toxicity. RESULTS: The treatment field lengths >82mm for the second phase increased the probability of requiring intervention with percutaneous endoscopic gastrostomy (PEG) or Nasogastric tube (NGT). The probability of grade 4 swallowing was 36% if the phase 2 treatment length was >82mm vs 16% for less < or = 82mm(p=0.0001). A predictive enteral grading score (PEG score) was derived using the Cox regression coefficients: Field length of the boost volume >82mm scored 3 points, Stage grouping greater than 1 scored 1 point, altered fractionation scored 2 points, ECOG greater than 1 scored 1 point. The PEG score was 45% if the score was 6 and 19% if the score was <6 (p=0.0). CONCLUSIONS: More attention needs to be focused on developing robust dose and volume constraints for the pharyngeal mucosa and the musculature in order to reduce the need for enteral feeding. Patients with PEG score of 6 or greater are at high risk of requiring enteral feeding during radiation treatment and should be considered for prophylactic PEG or NG feeding.

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) x 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.

Does chemotherapy improve survival in high-risk stage I and II Merkel cell carcinoma of the skin?

PURPOSE: The effectiveness of synchronous carboplatin, etoposide, and radiation therapy in improving survival was evaluated by comparison of a matched set of historic control subjects with patients treated in a prospective Phase II study that used synchronous chemotherapy and radiation and adjuvant chemotherapy. PATIENTS AND METHODS: Patients were included in the analysis if they had disease localized to the primary site and nodes, and they were required to have at least one of the following high-risk features: recurrence after initial therapy, involved nodes, primary size greater than 1 cm, or gross residual disease after surgery. All patients who received chemotherapy were treated in a standardized fashion as part of a Phase II study (Trans-Tasman Radiation Oncology Group TROG 96:07) from 1997 to 2001. Radiation was delivered to the primary site and nodes to a dose of 50 Gy in 25 fractions over 5 weeks, and synchronous carboplatin (AUC 4.5) and etoposide, 80 mg/m(2) i.v. on Days 1 to 3, were given in Weeks 1, 4, 7, and 10. The historic group represents a single institution's experience from 1988 to 1996 and was treated with surgery and radiation alone, and patients were included if they fulfilled the eligibility criteria of TROG 96:07. Patients with occult cutaneous disease were not included for the purpose of this analysis. Because of imbalances in the prognostic variables between the two treatment groups, comparisons were made by application of Cox's proportional hazard modeling. Overall survival, disease-specific survival, locoregional control, and distant control were used as endpoints for the study. RESULTS: Of the 102 patients who had high-risk Stage I and II disease, 40 were treated with chemotherapy (TROG 96:07) and 62 were treated without chemotherapy (historic control subjects). When Cox's proportional hazards modeling was applied, the only significant factors for overall survival were recurrent disease, age, and the presence of residual disease. For disease-specific survival, recurrent disease was the only significant factor. Primary site on the lower limb had an adverse effect on locoregional control. For distant control, the only significant factor was residual disease. CONCLUSIONS: The multivariate analysis suggests chemotherapy has no effect on survival, but because of the wide confidence limits, a chemotherapy effect cannot be excluded. A study of this size is inadequately powered to detect small improvements in survival, and a larger randomized study remains the only way to truly confirm whether chemotherapy improves the results in high-risk MCC.

High-risk Merkel cell carcinoma of the skin treated with synchronous carboplatin/etoposide and radiation: a Trans-Tasman Radiation Oncology Group Study--TROG 96:07.

PURPOSE: The effectiveness of synchronous carboplatin, etoposide, and radiation therapy was prospectively assessed in a group of patients with high-risk Merkel cell carcinoma (MCC) of the skin. PATIENTS AND METHODS: Patients were eligible if they had disease localized to the primary site and nodes, and were required to have at least one of the following high risk features: recurrence after initial therapy, involved nodes, primary tumor size greater than 1 cm, gross residual disease after surgery, or occult primary with nodes. Radiation was delivered to the primary site and nodes to a dose of 50 Gy in 25 fractions over 5 weeks and synchronous carboplatin (area under the curve, 4.5) and intravenous etoposide 80 mg/m2 days 1 to 3 was given in weeks 1, 4, 7, and 10. The median age of the group was 67 (range, 43-86) years, and there were 39 males and 14 females. Involved nodes (stage II) were present in 33 cases (62%). The sites involved were head and neck (22 patients), occult primary (13 patients), upper limb (eight patients), lower limb (eight patients), and trunk (two patients). RESULTS: Fifty-three patients were entered between 1996 and 2001. The median potential follow-up was 48 months. There were no treatment related deaths. The 3-year overall survival, locoregional control, and distant control were 76%, 75%, and 76%, respectively. Tumor site and the presence of nodes were factors that were predictive for local control and survival. Multivariate analysis indicated that the major factor influencing survival was the presence of nodes; however, this was not a significant factor in locoregional control. CONCLUSION: High levels of locoregional control and survival have been achieved with the addition of chemotherapy to radiation treatment for high-risk MCC of the skin. The role of chemoradiotherapy for high-risk MCC warrants further investigation.