Survival outcomes after delayed cytoreduction surgery following neoadjuvant chemotherapy in advanced epithelial ovarian cancer.

OBJECTIVE: Interval cytoreduction following neoadjuvant chemotherapy is a well-recognized treatment alternative to primary debulking surgery in the treatment of advanced epithelial ovarian cancer where patient and/or disease factors prevent complete macroscopic disease resection to be achieved. More recently, the strain of the global COVID-19 pandemic on hospital resources has forced many units to alter the timing of interval surgery and extend the number of neoadjuvant chemotherapy cycles. In order to support this paradigm shift and provide more accurate counseling during these unprecedented times, we investigated the survival outcomes in advanced epithelial ovarian cancer patients with the intent of maximal cytoreduction following neoadjuvant chemotherapy with respect to timing of surgery and degree of cytoreduction. METHODS: A retrospective review of all patients aged 18 years and above with FIGO (2014) stage III/IV epithelial ovarian cancer treated with neoadjuvant chemotherapy and the intention of interval cytoreduction surgery between January 2008 and December 2017 was conducted. Overall and progression-free survival outcomes were analyzed and compared with patients who only received chemotherapy. Outcome measures were correlated with the number of neoadjuvant chemotherapy cycles and amount of residual disease following surgery. RESULTS: Six hundred and seventy-one patients (median age 67 (range 20-91) years) were included in the study with 572 patients treated with neoadjuvant chemotherapy and surgery and 99 patients with chemotherapy only. There was no difference in the proportion of patients in whom complete cytoreduction was achieved based on number of cycles of neoadjuvant chemotherapy (2-4 cycles: 67.7%, n=337/498); ≥5 cycles: 62.2%, n=46/74). Patients undergoing cytoreduction surgery after neoadjuvant chemotherapy had a median 5-year progression-free and overall survival of 24 and 38 months, respectively. No significant difference in overall survival between surgical groups was observed (interval cytoreduction: 41 months vs delayed cytoreduction: 43 months, p=0.52). Those who achieved complete cytoreduction to R0 (no macroscopic disease) had a significant median overall survival advantage compared with those with any macroscopic residual disease (R0: 49-51 months vs R<1: 22-39 months, p<0.001 vs R≥1: 23-26 months, p<0.001). CONCLUSIONS: Survival outcomes do not appear to be worse for patients treated with neoadjuvant chemotherapy if cytoreduction surgery is delayed beyond three cycles. In advanced epithelial ovarian cancer patients the imperative to achieve complete surgical cytoreduction remains gold standard, irrespective of surgical timing, for best survival benefit.

Chemotherapy compliance in high-risk Merkel cell carcinoma treated with chemoradiotherapy.

OBJECTIVE: To evaluate chemotherapy (CT) compliance in patients treated with chemoradiotherapy (CRT) for high-risk Merkel cell cancer (MCC). METHODS: Data from three prospective clinical trials in high-risk MCC performed by the Trans-Tasman Radiation Oncology Group were included in this analysis. Patients were treated with one of two carboplatin-based CT schedules and standardised radiotherapy (RT) to the primary site and nodes to a dose of 50-60 Gy in 25-30 fractions. Patients' baseline characteristics were analysed using χ2 tests to determine compliance factors for completing CT. A Cox univariate analysis was performed to assess the impact of CT compliance on time to locoregional failure, time-to-distant failure, time-to-recurrence and time-to-death. RESULTS: A total of 88 patients were identified, with a median follow up of 38.5 months. Of these, 75 (85%) completed CT (median age 64.2 years, range 62.0-66.4), while 13 did not (median age 72 years, range 68.1-75.9), P = 0.006. Women comprised 18/75 patients who completed CT and 7/13 patients who did not complete it (P = 0.03). Performance status, site, stage, surgical margins, RT dose and toxicity did not impact on their CT compliance. At 5 years, 26% of patients had locoregional relapse, 26% had distant failure and 34% had died. CONCLUSIONS: In this small cohort of patients treated with CRT for high-risk MCC, older age and female sex were associated with failure to complete CT. Severe acute skin and haematological toxicity did not correlate with failure to complete CT.

The shift toward neo-adjuvant chemotherapy and interval debulking surgery for management of advanced ovarian and related cancers in a population-based setting: Impact on clinical outcomes.

OBJECTIVES: The aim of this study was to determine the proportion of patients with advanced ovarian and related cancers (EOC+RC), treated with neoadjuvant chemotherapy and interval debulking surgery (NACT - IDS), and to determine if there was any relationship with optimal cytoreduction rates and overall survival (OS) in a state-wide gynaecologic oncology service over time. METHODS: A retrospective review was undertaken using a population-based database of patients with stages 3 and 4 EOC+RC treated from 1982 till 2013 at the Queensland Centre for Gynaecological Cancer (QCGC). The proportion of patients treated with NACT - IDS compared with primary debulking surgery (PDS) was determined and compared with debulking rates and with the moving five-year OS probability. RESULTS: From 1982-2013, 2601 patients with advanced EOC+RC were managed at QCGC. No patients received NACT - IDS till 1995 when the first two patients received this treatment, rising to 55% of patients in 2013. Surgical cytoreduction rates to no macroscopic residual (R0) were achieved 32% of the time by 2006, rising to 48% in 2009, and 62% in 2013. Despite the increase in utilisation of NACT - IDS, our unit has noted a continued rise in the OS probability at five years to 45%. CONCLUSIONS: The increasing utilisation of NACT - IDS in the setting of a large centralised clinical service has been associated with increasing rates of optimal cytoreduction and survival rates have continued to rise in excess of those achieved in the trials reported to date.

Analysis of prognostic variables, development of predictive models, and stratification of risk groups in surgically treated FIGO early-stage (IA-IIA) carcinoma cervix.

OBJECTIVES: The objectives of the study were to evaluate clinicopathologic prognostic variables in surgically treated International Federation of Obstetrics and Gynecology early-stage (IA-IIA) cervical cancer, develop prognostic models, and note the role of adjuvant treatment, patterns of failure, and salvage survival (SS) in each group. METHODS: Records of 542 patients who received primary surgical treatment for International Federation of Obstetrics and Gynecology (IA-IIA) cervical cancer were reviewed. Ninety-eight patients who relapsed after primary treatment were identified and matched for stage and age with a control group. Clinicopathologic prognostic variables were identified and used to develop a prognostic model with 3 risk groups for overall survival (OS) and relapse-free survival (RFS). The roles of adjuvant treatment, relapse sites, and SS were also noted in the groups. RESULTS: The 5-year OS was 70% for the whole group, 97% in the control group, and 44% in the relapse group. There was a statistically significant decrease in survival in patients 70 years or older, those with positive lymphovascular space invasion (LVSI), and in patients with positive LVSI and increasing depth of invasion in both univariate and multivariate analyses (P < 0.001). Positive lymph node status and tumor size of 31 mm or greater showed only a trend toward lower OS and RFS, respectively, in multivariate analysis. An additive model using regression coefficients from multivariate Cox model stratified patients into low-, medium-, and high-risk groups. Relapse-free survival and OS were significantly different in all 3 groups (P < 0.001). Salvage survival was better in low-risk group relative to medium- and high-risk groups, (P = 0.05) as well as between the medium- and high-risk groups (P = 0.03). More distant and locoregional relapses were noted in the medium- and high-risk groups, and SS was better with a local versus locoregional or distant recurrence (P < 0.001). CONCLUSIONS: In this study, age 70 years or older and positive LVSI were found to be statistically significant prognostic factors for both OS and RFS. Positive lymph nodes status showed only a trend toward lower OS. Positive LVSI status had significant adverse prognostic effects on RFS and OS in tumors with increasing depth of invasion. Additive prognostic model helps identify predictors and stratify patients into low-, medium-, and high-risk groups for survival. Many of these factors can be identified preoperatively and may assist in decision to offer primary surgery or alternative therapies in patients with potentially operable cervix cancer. Prognostic model can be used as a tool to design clinical trials and select the group of patients who are the appropriate target for a trial.

Effect of lifestyle factors and hormone therapy on heart function by serial echocardiography in postmenopausal women.

BACKGROUND: There is conflicting information on the effects of oestrogen on the heart in women, especially those using postmenopausal hormone therapy. Whilst some studies reported a beneficial effect, others showed adverse outcomes. The interplay of lifestyle factors and type/timing of therapy remains to be clarified. AIM: The aim of this study was to determine the effects of lifestyle and hormone therapy on heart function and structure in postmenopausal women. METHOD: As part of a large longitudinal study of women randomly recruited from an urban population, the study assessed 410 suitable women by echocardiography in Year 1 and Year 5 of the study by two independent cardiologists. RESULTS: In lifestyle characteristics, the difference in age and body mass (as markers of cardiovascular risk) was in favour of never-users versus hormone therapy-users. Using an arbitrary cut-off > or =15% change for an effect, we found lifestyle factors had minimal effect on the two measured parameters - ejection fraction, left ventricular mass. Effects of hormone therapy were variable and mixed; greatest effect was found for an 'early start' of hormone therapy with oestrogen-only preparation - the risk of reduced ejection fraction was decreased [hazard ratio (HR) 0.42, confidence interval = 0.17-1.03, P = 0.06] and risk of increased left ventricular mass was increased (HR 2.21, 1.09-4.49, P = 0.03). CONCLUSION: Our findings add to the evidence that oestrogen given to postmenopausal women has a mixed effect on the heart, with effect best shown when started early.

Persistence and malignant sequelae of gestational trophoblastic disease: Clinical presentation, diagnosis, treatment and outcome.

BACKGROUND: The major concern in gestational trophoblastic disease is management of persistent disease and malignant sequelae. However, prediction of response to treatment is difficult and methods used controversial. AIM AND METHODS: To evaluate the usefulness of clinical presentation, methods of diagnosis and categorisation of risk in determining clinical outcomes, by analysis of a database of 705 registered patients collected over 30 years. RESULTS: From the database, there were 97 patients who developed persistent disease and malignant sequelae on the basis of defined criteria - 80.4% had molar pregnancy and 19.6% non-molar pregnancy. Vaginal bleeding was not a common presentation; 59.8% had no clinical symptoms. According to protocol, monitoring by serial human chorion gonadotrophin (HCG) levels followed by imaging screen was used in all patients; histology was also available in 41.2% from hysterectomy and curettage specimens. There were 16 of 76 patients with persisting disease who had metastases (21.1%), and 2 of 20 patients with choriocarcinoma who had an antecedent molar pregnancy (10.0%). Based on five risk factors, 25 patients were categorised as 'high risk' and assigned to receive multi-drug chemotherapy. There were two deaths (2.1% for all malignant sequelae); both were from molar pregnancies. One patient failed to respond and the other suffered a complication of intensive chemotherapy. CONCLUSION: Serial HCG levels remain the best monitor to determine therapeutic response. Categorisation of 'high risk' by five factors is useful in treatment. Albeit a small series, clinical outcome is favourable with a five-year survival of 89.7%.

Analysis of risk factors for persistent gestational trophoblastic disease.

SETTING: Persistent disease is a serious consequence of molar pregnancies. Its early detection is critical to effective chemotherapy. Therefore, determination of risk becomes an important clinical decision. OBJECTIVES: To determine the relative risk of persistent disease in a cohort of patients with partial and complete molar pregnancies by analysis of five factors derived from a database using multivariate analysis. RESULTS: Of 686 patients, 78 developed persistent disease which required treatment (rate of 11.3%). Risk was markedly increased when serum human chorionic gonadotrophin (HCG) failed to reach negative by 12 weeks after evacuation [hazard ratio (HR) = 120.78, P < 0.001]. Risk was markedly decreased when the interval from last pregnancy exceeded 12 months (HR = 0.24, P = 0.005). Other factors such as patient's age, stage of gestation and serum HCG level at presentation were not found to be strongly associated with risk of persistent disease. CONCLUSION: These findings support the application of the following two factors in risk prediction for molar pregnancies: > 12 weeks to become HCG negative and interval from last pregnancy < 12 months. They will contribute to a greater awareness of persistent disease and assist in early detection and effective chemotherapy.

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.

Disease-free survival after vaginal vault brachytherapy versus observation for patients with node-negative intermediate-risk endometrial adenocarcinoma.

PURPOSE: To compare the disease-free survival (DFS) of patients with surgical stage 1, intermediate-risk endometrial adenocarcinoma (EAC) treated with primary surgery with or without adjuvant vaginal vault brachytherapy (VVBT). PATIENTS AND METHODS: A retrospective chart review identified 575 patients with stage 1B, 1C or 2A endometrial cancer who had surgery between 1990 and 2004. All patients were surgically staged and 259 patients received postoperative VVBT. The date and site of first recurrence were considered the primary statistical endpoints and were analysed by univariate and multivariate Cox models. Subgroups of patients stratified by substage and grade were created and Log-rank tests using vaginal recurrence as the endpoint were calculated within these groups. RESULTS: After a mean follow-up period of 72 months (95%-confidence interval (CI): 68 to 75 months) a total of 43 (7.5%) patients developed recurrence. Multivariate analysis demonstrated that increasing patient's age at diagnosis and stage 1C or 2A disease were independent risk factors for recurrence whereas the grade of differentiation and the type of treatment (surgery alone vs. surgery followed by postoperative VVBT) were not associated with a change in DFS. Analysis within the subgroups stratified by substage and grade did not even reveal a trend towards improved local control with VVBT. CONCLUSION: Postoperative VVBT was not associated with a measurable reduction in the risk of recurrence in surgical stage 1, intermediate-risk endometrial cancer.

Prospective analysis of the utility of 18-FDG PET in Merkel cell carcinoma of the skin: A Trans Tasman Radiation Oncology Group Study, TROG 09:03.

INTRODUCTION: TROG 09.03 prospectively studied the utility of Fluorine-18 Fluorodeoxyglucose (18-FDG) PET in the management of Merkel cell carcinoma of skin. METHODS: Following consent and registration, a pre-treatment FDG-PET/CT was performed. Sites of avid disease were confirmed by cytology where practicable. Following surgery, patients with AJCCv7 Stages IIA-IIIB disease were treated with chemo-radiotherapy and reassessed with a post-treatment PET. RESULTS: Fifty-eight subjects (45 males and 13 females, median age 68 years) were enrolled between 2011 and 2015, 43 patients of whom went on to receive chemo-radiotherapy. An occult primary was present in 22 (37.9%), T1 in 22 (37.9%) and T2 disease in 14 (24.1%). Nodal disease was present in 69% of cases. Fifty per cent of subjects had gross residual disease at the primary site and/or nodal site at the time of registration. 18-FDG PET/CT had a sensitivity of 94.74% (95% CI 82-99.3%) and a specificity of 88.24% (95% CI 63.56-98.54). The positive predictive value was 94.74% (83.01-98.51) and the negative predictive value was 88.24% (95% CI 65.81-96.69). The pre-treatment PET influenced a treatment decision in 27.6% of cases. Upstaging occurred in 15 (25.9%), with no down staging. Other diseases were identified in 4 (6.9%) patients. Univariate analysis failed to demonstrate that pre-treatment SUV levels or a negative post-treatment PET had any impact on overall survival. PET staged patients had 89% 3-year in-field loco-regional control and 76% 3-year overall survival. CONCLUSION: Staging 18-FDG-PET significantly influenced treatment decisions in approximately one-third of cases of MCC and should be considered in the routine pre-treatment work-up. Post-treatment PET was not found to be prognostic. Funding through the Medicare Benefits Schedule needs to be considered for high risk MCC.

Locally advanced tonsillar squamous cell carcinoma: Treatment approach revisited.

AIMS: The purpose of this study was to review the treatment policy for locally advanced stage III and IV squamous cell carcinoma (SCC) of the tonsil at the Princess Alexandra Hospital Head and Neck Unit, Brisbane, Australia. MATERIALS AND METHODS: The records of 148 patients with curable stage III and IV SCC of the tonsil were reviewed from the years 1992 to 2004 inclusive. During this period, patients were treated with surgery and postoperative radiotherapy and only offered definitive radiation if they were medically or surgically inoperable. There were 102 patients treated with surgery +/- postoperative radiotherapy (group 1) and 46 patients treated with definitive radiotherapy +/- chemotherapy (group 2). The endpoints of locoregional control (LRC), disease specific survival (DSS), and overall survival (OS) were studied and prognostic factors were investigated with univariate and multivariate analyses. RESULTS: The 5-year OS, DSS, and LRC were 57%, 69%, and 84%, respectively. Univariate analyses showed that patients in group 1 had a superior OS (69% vs. 41%, P = .007), a trend toward improvement in LRC (88% vs. 73%, P = .08), and a nonsignificant improvement in DSS (75% vs. 56%, P = .14). There was a greater percentage of patients with an Eastern Cooperative Oncology Group (ECOG) score of 2 or less in group 1, suggesting selection bias toward the surgical group. Multivariate analyses, which adjusted for known prognostic factors, showed that treatment group was significant for OS but not for LRC or DSS. CONCLUSIONS: Surgery and postoperative radiotherapy continues to provide a superior outcome in locally advanced tonsil SCC in patients with surgically resectable disease, good ECOG performance status, and medically operable.

Prognostic importance of preoperative CA-125 in International Federation of Gynecology and Obstetrics stage I epithelial ovarian cancer: an Australian multicenter study.

PURPOSE: To evaluate the prognostic significance of preoperative CA-125 levels on overall survival of patients with International Federation of Gynecology and Obstetrics (FIGO) stage I epithelial ovarian cancer (EOC). PATIENTS AND METHODS: Data from 518 patients with FIGO stage I EOC treated in seven gynecologic oncology centers throughout Australia between 1990 and 2002 were analyzed. Patients with borderline tumors and nonepithelial ovarian carcinomas were excluded, as were women in whom CA-125 had not been determined preoperatively. Preoperative CA-125 levels were studied in surgically staged and incompletely staged patients and compared with prognostic factors, such as substage, grade, and histologic type. Multivariate Cox models were calculated. RESULTS: CA-125 levels more than 30 U/mL were associated with higher grade, substage 1B and 1C, nonmucinous histologic type, and older age. In univariate analysis, higher histologic grade, the absence of surgical staging, and preoperative CA-125 levels more than 30 U/mL were associated with impaired survival. Multivariate analysis identified histologic grade, preoperative CA-125, and surgical staging as independent predictors for survival. In the subgroup of completely surgically staged patients, the 5-year overall survival rate was 82% (95% CI, 76% to 88%) for patients with CA-125 levels more than 30 U/mL and 95% (95% CI, 90% to 99%) for patients with CA-125 levels of 30 U/mL or less (P = .028). In the group of incompletely staged patients, the 5-year survival rates were similar for patients with elevated and normal serum CA-125 levels. CONCLUSION: Complete surgical staging, histologic grade, and preoperative serum CA-125 levels are independent prognostic factors and should be included in the decision making for chemotherapy.

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.

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.

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.

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.

The effect of anaemia on efficacy and normal tissue toxicity following radiotherapy for locally advanced squamous cell carcinoma of the head and neck.

PURPOSE: The aims of this analysis were to determine the effect of anaemia on loco-regional control, relapse-free survival, cause-specific survival, overall survival, and acute and late radiation therapy toxicity in patients with Stage III and IV squamous cell carcinoma of the head and neck treated with radiotherapy. PATIENTS AND METHODS: Between 1991 and 1998, 350 patients were randomly assigned to either conventional radiotherapy, (70 Gy in 35 fractions in 49 days) or to accelerated radiotherapy (59.4 Gy in 33 fractions in 24 days). Patients were divided into two groups according to their haemoglobin level: a normal haemoglobin group (>/=13 g/dl in males, >/=12 g/dl in females) and a low haemoglobin group (<13 g/dl in males, <12 g/dl in females). The influence of anaemia on cause-specific survival and the development of confluent mucositis independent of other variables was tested using Cox proportional hazards model. RESULTS: Of 350 patients recruited to the trial, 238 had haemoglobin measurements and were eligible for inclusion in this secondary analysis. One hundred and ninety-three were considered to have normal haemoglobin, and 45 patients were considered to be anaemic. There were significant differences between the groups in loco-regional control, relapse-free survival, cause-specific survival and overall survival, with hazards ratios of 0.56 (95% confidence interval (CI) 0.34-0.94), 0.57 (95% CI 0.35-0.92), 0.49 (95% CI 0.29-0.85) and 0.43 (95% CI 0.26-0.70) in favour of the normal haemoglobin group. Using Cox proportional hazards modelling, haemoglobin level was a significant predictor of cause-specific survival in addition to disease site, stage, and Eastern Cooperative Oncology Group status. There were no statistically significant differences between the groups in the development of acute or late reactions. CONCLUSION: Significant reductions in loco-regional control, disease-free survival, cause-specific survival and overall survival occur in the presence of anaemia. No significant differences in normal tissue toxicity have been identified in this analysis.

A Phase III study on the efficacy of topical aloe vera gel on irradiated breast tissue.

The aim of the study was to see if topical aloe vera gel would be beneficial in reducing the identified skin side-effects of radiation therapy, including erythema, pain, itching, dry desquamation, and moist desquamation, when compared with aqueous cream. The secondary aim was to assess the effect of other factors known to predict severity of radiation skin reaction, ie, breast size, smoking habit, and one or more drainages of lymphocele after surgery, on other skin side effects. A Phase III study was conducted involving 225 patients with breast cancer after lumpectomy or partial mastectomy, who required a course of radiation therapy using tangential fields. Patients were randomized to either topical aloe vera gel or topical aqueous cream to be applied 3 times per day throughout and for 2 weeks after completion of radiation treatment. Weekly skin assessments were performed by nursing staff. Aqueous cream was significantly better than aloe vera gel in reducing dry desquamation and pain related to treatment. Subjects with D cup or larger size breasts experienced significantly more erythema, regardless of treatment arm. For subjects who had undergone lymphocele drainage, the aloe vera group experienced significantly more pain than the aqueous cream group. Within the aqueous cream arm, smokers were significantly more likely to experience itching within the treatment field than were nonsmokers. Within the aloe vera arm, subjects who had undergone one or more lymphocele drainages after surgery were significantly more likely to experience erythema and itching within the treatment field than those who did not have drainage. In this study, aloe vera gel did not significantly reduce radiation-induced skin side effects. Aqueous cream was useful in reducing dry desquamation and pain related to radiation therapy.

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.