Prognostic stratification of HPV-associated oropharyngeal cancer based on CD103+ immune cell abundance in patients treated on TROG 12.01 and De-ESCALaTE randomized trials.

BACKGROUND: High CD103+ intratumoral immune cell (ITIC) abundance is associated with better prognosis in unselected patients with human papilloma virus-associated oropharyngeal squamous cell carcinoma (HPV-associated OPSCC) treated with cisplatin and radiotherapy (CIS/RT). Substituting cetuximab (CETUX) for CIS with RT in HPV-associated OPSCC resulted in inferior efficacy. Our aim was to determine whether quantification of CD103 ITIC could be used to identify a population of HPV-associated OPSCC with superior prognosis. PATIENTS AND METHODS: We pooled data from the TROG 12.01 and De-ESCALaTE randomized trials that compared CETUX/70GyRT with CIS/70GyRT in low-risk HPV-associated OPSCC: American Joint Committee on Cancer 7 stage III (excluding T1-2N1) or stage IV (excluding N2b-c if smoking history >10 pack-years and/or distant metastases), including all patients with available tumor samples. The primary endpoint was failure-free survival (FFS) in patients receiving CETUX/RT comparing CD103+ ITIC high (≥30%) versus low (<30%). High and low CD103 were compared using Cox regression adjusting for age, stage and trial. RESULTS: Tumor samples were available in 159/182 patients on TROG 12.01 and 145/334 on De-ESCALaTE. CD103+ ITIC abundance was high in 27% of patients. The median follow-up was 3.2 years. The 3-year FFS in patients treated with CETUX/RT was 93% [95% confidence interval (CI) 79% to 98%] in high CD103 and 74% (95% CI 63% to 81%) in low CD103 [adjusted hazard ratio = 0.22 (95% CI 0.12-0.41), P < 0.001]. The 3-year overall survival in patients treated with CETUX/RT was 100% in high CD103 and 86% (95% CI 76% to 92%) in low CD103, P < 0.001. In patients treated with CIS/RT, there was no significant difference in FFS. CONCLUSIONS: CD103+ ITIC expression separates CETUX/RT-treated low-risk HPV-associated OPSCC into excellent and poor prognosis subgroups. The high CD103 population is a rational target for de-intensification trials.

Identification of an excellent prognosis subset of human papillomavirus-associated oropharyngeal cancer patients by quantification of intratumoral CD103+ immune cell abundance.

BACKGROUND: Accurate prognostic stratification of human papillomavirus-associated oropharyngeal cancers (HPV+OPSCC) is required to identify patients potentially suitable for treatment deintensification. We evaluated the prognostic significance of CD103, a surface marker associated with tissue-resident memory T cells (TRMs), in two independent cohorts of patients with HPV+OPSCC. PATIENTS AND METHODS: The abundance and distribution of CD103+ immune cells were quantified using immunohistochemistry in a cohort of 189 HPV+OPSCC patients treated with curative intent and correlated with outcome. Findings were then validated in an independent cohort comprising 177 HPV+OPSCCs using univariable and multivariable analysis. Intratumoral CD103+ immune cells were characterized by multispectral fluorescence immunohistochemistry and gene expression analysis. RESULTS: High intratumoral abundance of CD103+ immune cells using a ≥30% cut-off was found in 19.8% of tumors in the training cohort of HPV+OPSCC patients and associated with excellent prognosis for overall survival (OS) with adjusted hazard ratio (HR) of 0.13 [95% confidence interval (CI) 0.02-0.94, P = 0.004]. In the independent cohort of HPV+OPSCCs, 20.4% had high intratumoral CD103+ abundance and an adjusted HR for OS of 0.16 (95% CI 0.02-1.22, P = 0.02). Five year OS of patients with high intratumoral CD103 was 100% across both cohorts. The C-statistic for the multivariate prognostic model with stage and age was significantly improved in both cohorts with the addition of intratumoral CD103+ cell abundance. On the basis of spatial location, co-expression of CD8 and CD69, and gene expression profiles, intratumoral CD103+ cells were consistent with TRMs. CONCLUSION: Quantification of intratumoral CD103+ immune cell abundance provides prognostic information beyond that provided by clinical parameters such as TNM-staging, identifying a population of low risk HPV+OPSCC patients who are good candidates for trials of deintensification strategies.

Olfactory neuroblastoma: 14-year experience at an Australian tertiary centre and the role for longer-term surveillance.

BACKGROUND: Olfactory neuroblastoma is a rare sinonasal malignancy, with poorly defined treatment protocols. Management at a tertiary centre was retrospectively evaluated to inform future treatment and follow up. METHODS: Cases treated with curative intent (2000-2014) were included. Data were collected, and overall and disease-free survival rates were calculated. RESULTS: Eleven cases were identified, with a median follow up of 87 months. One patient was Kadish stage A, one was stage B, eight were stage C and one was stage D. The latter patient underwent chemoradiotherapy alone. The remaining patients proceeded to: endoscopic-assisted wide local excision (n = 2), anterior craniofacial resection (n = 4) or endoscopic craniofacial resection (n = 4). No patients had primary nodal disease or elective neck treatment. One patient had neoadjuvant chemoradiation. Six patients had post-operative radiotherapy; three received adjuvant chemotherapy. Two patients had late cervical node failure, and proceeded to neck dissection and post-operative radiotherapy. Two patients had late local recurrence. Ten-year overall and disease-free survival rates were 68.2 and 46.7 per cent, respectively. CONCLUSION: Longer-term follow up is supported given the incidence of late regional and local recurrence. Prophylactic treatment of cervical nodes in locally advanced disease is an area for further investigation.

Phase II study of single-agent panitumumab in patients with incurable cutaneous squamous cell carcinoma.

BACKGROUND: Although advanced cutaneous squamous cell carcinoma (CSCC) is quite common, there are few prospective trials regarding its optimal management. This study evaluated the efficacy and safety of single-agent panitumumab in the treatment of patients with CSCC not suitable for local therapy. PATIENTS AND METHODS: Sixteen patients received single-agent panitumumab at a dose of 6 mg/kg repeated every 2 weeks for a minimum of three cycles and continued until progression, a maximum of nine cycles or dose-limiting toxicity. The primary end point was the best overall response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) criteria. Secondary end points included evaluation of safety, toxicity and progression-free survival (PFS). RESULTS: Between May 2010 and May 2012, 16 patients were recruited. Fourteen patients were male and the median age was 68 years. Fifteen patients had locoregionally advanced or recurrent disease with 14 patients receiving previous radiotherapy and 7 receiving previous cytotoxic chemotherapy. The best ORR [partial (PR) or complete response (CR)] was 31% (3/16 PR, 2/16 CR) with a further 6 of 16 patients achieving SD. The median PFS and overall survival were 8 and 11 months respectively. Grade 3 or 4 events were observed in five patients (four being skin toxicity) with one patient ceasing due to skin toxicity. With a median follow-up of 24 months, 10 patients died due to progressive disease, 6 are alive, one patient with no evidence of disease at the time of analysis. CONCLUSIONS: Single-agent panitumumab is safe and effective in the management of patients with advanced CSCC even in a previously extensively pre-treated cohort.

T-category remains an important prognostic factor for oropharyngeal carcinoma in the era of human papillomavirus.

AIMS: To determine prognostic factors for locoregional relapse (LRR), distant relapse and all-cause death in a contemporary cohort of locoregionally advanced oropharyngeal squamous cell carcinoma (OSCC) treated with definitive chemoradiotherapy or radiotherapy alone. MATERIALS AND METHODS: OSCC patients treated with definitive radiotherapy between 2005 and 2010 were identified from a prospective head and neck database. Patient age, gender, smoking history, human papillomavirus (HPV) status, T- and N-category, lowest involved nodal level and gross tumour volume of the primary (GTV-p) and nodal (GTV-n) disease were analysed in relation to LRR, distant relapse and death by way of univariate and multivariate analysis. RESULTS: In total, 130 patients were identified, 88 HPV positive, with a median follow-up of 42 months. On multivariate analysis HPV status was a significant predictor of LRR (hazard ratio 0.15; 95% confidence interval 0.05-0.51) and death (hazard ratio 0.29; 95% confidence interval 0.14-0.59) but not distant relapse (hazard ratio 0.53, 95% confidence interval 0.22-1.27). Increasing T-category was associated with a higher risk of LRR (hazard ratio 1.80 for T3/4 versus T1/2; 95% confidence interval 1.08-2.99), death (hazard ratio 1.37, 95% confidence interval 1.06-1.77) and distant relapse (hazard ratio 1.35; 95% confidence interval 1.00-1.83). Increasing GTV-p was associated with increased risk of distant relapse and death. N3 disease and low neck nodes were significant for LRR, distant relapse and death on univariate analysis only. CONCLUSION: Tumour HPV status was the strongest predictor of LRR and death. T-category is more predictive of distant relapse and may provide additional prognostic value for LRR and death when accounting for HPV status.

Dental management of patients irradiated for head and neck cancer.

Patients undergoing radiation therapy as either primary, adjuvant, combination therapy or palliative management of head and neck malignancies are prone to a range of dental complications. Strategies for prevention and management of such complications may be controversial. This article aims to highlight the current understanding and management of the dental needs for patients before, during and after radiation therapy.

Human papillomavirus modifies the prognostic significance of T stage and possibly N stage in tonsillar cancer.

BACKGROUND: Despite the association with more advanced nodal stage, patients with human papillomavirus (HPV) positive oropharyngeal cancers have better outcomes. We examined whether the HPV can modify the effect of known prognostic factors in tonsillar cancer. PATIENTS AND METHODS: A total of 489 patients from 10 centres were followed up for recurrence or death for a median of 3.2 years. Determinants of the rate of locoregional recurrence, death from tonsillar cancer and overall survival were modelled using Cox regression. RESULTS: The prognostic value of T and N stages were modified by HPV as indicated by statistically significant interaction terms. After adjusting for age, gender and treatment, T stage appeared relevant only for HPV-positive cancers (where a higher T stage was associated with worse outcomes). There was some evidence that N stage was a more relevant prognostic factor for HPV-negative than -positive cancers. There was no evidence that the HPV modifies the effect of age, gender or grade on outcomes. CONCLUSIONS: This study suggests that the prognostic significance of the conventional staging system in tonsillar cancer is modified by HPV.

Distinct patterns of stomatitis with concurrent cetuximab and radiotherapy for head and neck squamous cell carcinoma.

To describe the distinct patterns of severe anterior stomatitis seen with concurrent cetuximab and radiotherapy (RT) compared to chemoRT or altered fractionation RT (AFRT) and explore potential associations with clinical and dosimetric parameters. We reviewed acute toxicity data from 42 patients receiving cetuximab-RT and a matched cohort of 36 patients receiving chemoRT or AFRT. The occurrence of grade ≥3 oral toxicities was analysed with respect to clinical (age, gender, smoking/alcohol history, tumour subsite, grade of acneiform rash) and dosimetric parameters. Cetuximab-RT patients experienced higher rates of grade ≥3 cheilitis (26% vs 6%, p=0.01) and anterior stomatitis (38% vs 6%, p=0.002), despite these structures receiving low RT doses (median maximum dose to lips 9.3 Gy, anterior oral cavity 20 Gy). Multivariable analyses identified increasing severity of acneiform rash as the strongest predictor of grade ≥3 cheilitis whilst increasing RT dose was weakly correlated. A trend was observed for increasing pack years of smoking on univariate analysis only. The combination of cetuximab and low doses of RT to the anterior oral cavity has resulted in a distinctive pattern of cheilitis and anterior stomatitis in our patients. Further exploration of this phenomenon may yield additional insights into the interaction of cetuximab with RT in non-target tissues.

Predicting regional control based on pretreatment nodal size in squamous cell carcinoma of the head and neck treated with chemoradiotherapy: a clinician's guide.

The aim of this study was to determine the regional control rate with concurrent chemoradiotherapy (CRT) based on pretreatment nodal size in mucosal head and neck squamous cell carcinoma (HNSCC) in patients who achieved a complete response (CR) at the primary site by 12 weeks post-treatment. Between December 1997 and November 2003, 117 patients with node-positive HNSCC were treated with concurrent CRT, with 108 (92%) achieving a CR at the primary site by 12 weeks. There were 93 males (86%), median age 55 (37-79) years and the most common primary site was the oropharynx (65%). Patients were divided into three subgroups: or=6.1 cm 8 (7%). All patients received concurrent platinum-based chemotherapy and the median radiation dose was 70 Gy (60-72 Gy). The 3-year regional control rate based on pretreatment nodal size was or=6.1 cm 50% (95%CI 15-77%) (P = 0.001). The 3-year regional control rate based on pre-treatment nodal size was or=6.1 cm 50% (95%CI 15-77%) (P = 0.001). These results provide a quantitative guide for the clinician as to the likelihood of regional control based on pretreatment nodal size following CRT in patients who achieve a CR at the primary site by 12 weeks post-treatment.

Randomized study of percutaneous endoscopic gastrostomy versus nasogastric tubes for enteral feeding in head and neck cancer patients treated with (chemo)radiation.

Percutaneous endoscopic gastrostomy (PEG) tubes have largely replaced nasogastric tubes (NGT) for nutritional support of patients with head and neck cancer undergoing curative (chemo)radiotherapy without any good scientific basis. A randomized trial was conducted to compare PEG tubes and NGT in terms of nutritional outcomes, complications, patient satisfaction and cost. The study was closed early because of poor accrual, predominantly due to patients' reluctance to be randomized. There were 33 patients eligible for analysis. Nutritional support with both tubes was good. There were no significant differences in overall complication rates, chest infection rates or in patients' assessment of their overall quality of life. The cost of a PEG tube was 10 times that of an NGT. The duration of use of PEG tubes was significantly longer, a median 139 days compared with a median 66 days for NGT. We found no evidence to support the routine use of PEG tubes over NGT in this patient group.

Parotid-sparing radiotherapy: does it really reduce xerostomia?

AIMS: Parotid-sparing radiotherapy (PSRT) was introduced for patients with selected head and neck cancer requiring bilateral upper-neck irradiation at our centre in 2000. The aim of this study was to compare the subjective degree of xerostomia in patients treated with PSRT between January 2000 and June 2003 with patients treated using conventional techniques (radiotherapy) over the same period. MATERIALS AND METHODS: Eligible patients were required to have completed treatment 6 months previously and be recurrence-free at the time of interview. PSRT was defined as conformal radiotherapy, in which the mean dose to at least one parotid gland was 33 Gy or less, as determined by the dose-volume histogram. Patients receiving radiotherapy were treated with standard parallel-opposed fields, such that both parotids received a minimum of 40 Gy. Xerostomia was assessed using a validated questionnaire containing six questions with a rating between 0 and 10. Lower scores indicated less difficulty with xerostomia. RESULTS: Thirty-eight eligible patients treated with PSRT were identified: 25 with oropharyngeal cancer and 13 with nasopharyngeal cancer (NPC). The mean overall questionnaire score (Q1-5) for this group was 4.20 (standard error = 0.33). Forty-four patients (24 oropharyngeal, 21 NPC) treated with radiotherapy over the same period were eligible. The mean overall questionnaire score (Q1-5) for this group was 5.86 (standard error = 0.35). The difference in mean overall scores between the two groups of patients was statistically significant (P < 0.001), as were the scores for four of the six individual questions. CONCLUSION: These results suggest that PSRT offers improved long-term xerostomia-related quality of life compared with conventional radiotherapy.

Clinical verification of the superiority of the current International Union Against Cancer staging criteria in an Australian population of patients with nasopharyngeal carcinoma.

The purpose of this study is to assess the prognostic abilities of the fourth and fifth edition International Union Against Cancer (UICC) staging systems for nasopharyngeal carcinoma (NPC) in Australian patients. All patients planned for curative treatment at the Peter MacCallum Cancer Centre from April 1985 to December 1999 were included in this study. There were 181 patients eligible for this study. The median follow up was 7.6 years. Histological subgroups were World Health Organization (WHO) 1 (23), WHO 2 (12), and WHO 3 (146). Presentation with stage IV disease was 83% by UICC fourth edition staging and 34% by UICC fifth edition staging. The 5 years failure-free survival (FFS) rates for stage 1, 2, 3 and 4 disease by the fourth edition was 77, 100, 93, and 49% respectively,and by the fifth edition was 85, 76, 57 and 36%, respectively. The 5 years overall survival (OS) for stage 1, 2, 3, and 4 disease by the fourth edition was 77, 100, 100 and 61%; respectively, and by the fifth edition was 85, 82, 67 and 53%, respectively. Stage 4 patients by the fourth edition were reclassified as stages 2, 3 and 4 by the fifth edition with hazard ratios of 0.77, 1.01 and 1.79, respectively. In multifactor analysis, the fifth edition staging system was significantly related to FFS and OS after allowing for the fourth edition (FFS: P = 0.002; OS: P = 0.005), but the fourth edition was not significantly related to FFS or OS after allowing for the fifth edition (FFS: P = 0.96; OS: P = 0.96). This study confirms the prognostic superiority of the fifth edition UICC staging system over the fourth edition staging system in an Australian NPC population.

Combined modality treatment using concurrent radiotherapy and pharmacologically-guided carboplatin for inoperable and incompletely resected non-small cell lung cancer.

BACKGROUND: In our previous randomised trial, radiotherapy (RT) was given concurrently with carboplatin 350 mg/m(2). We wanted to show that the safety and efficacy of the drug could be improved by pharmacologically-guided dosing based on renal function. PATIENTS AND METHODS: Patients were eligible if they had unresectable or incompletely resected NSCLC, good performance status (ECOG 0-2), weight loss < 10%, no distant metastases and adequate haematology and biochemistry. Radiotherapy was given to the primary site and regional lymph nodes to a total dose of 60 Gy in 30 fractions over 6 weeks. Two cycles of carboplatin were given in divided doses of 1-h infusions daily for 5 days before RT weeks 1 and 6. A total plasma AUC of 7 mg/ml per minute per cycle was targeted. The total dose was calculated by using Calvert or Chatelut formulae. RESULTS: Forty-nine patients were treated. Patient characteristics included: 78% male; mean age 66 (range: 38--78); 80% stage 3A or 3B; incomplete resection in six patients. The median dose of carboplatin administered per cycle was 850 mg (range 435--1650); 89% of patients received a higher carboplatin dose compared with BSA-calculated dose (mean increase 41%). Forty-two patients (86%) completed treatment as planned. Myelosuppression > or = grade 3 occurred in 14 patients (29%) (one patient died of pneumonia while neutropenic); two patients developed > or = grade 3 acute oesophagitis and two patients had > or = grade 3 acute pulmonary toxicity. Late pulmonary toxicity > or = grade 3 occurred in two patients. The mean potential follow-up time was 2.7 years. The estimated proportion of patients alive and free of local or distant progression at 1 year was 42% and the median survival duration was 16 months (95% CI: 11--21 months). CONCLUSIONS: Radical chest irradiation can be combined with two cycles of pharmacologically-guided full-dose carboplatin, however because our study demonstrated significant haematologic toxicity, we recommend carboplatin dosing according to renal function at less than full dose (i.e. AUC 6 mg/ml per minute per cycle).

Changing acute renal failure treatment from intermittent hemodialysis to continuous hemofiltration: impact on azotemic control.

BACKGROUND: Continuous renal replacement therapy is increasingly used in the management of acute renal failure in critically ill patients. The advantages of continuous renal replacement therapy (CRRT) over intermittent hemodialysis (IHD), however, are not yet fully documented. In particular, it is unknown whether continuous veno-venous hemodiafiltration (CVVHDF) provides better control of azotemia than IHD. OBJECTIVES: To study the effect on azotemic control of changing acute renal failure treatment from IHD to CVVHDF. SETTINGS: Tertiary intensive care unit. PATIENTS: Forty seven consecutive critically ill patients with multiorgan failure and acute renal failure treated with IHD and 47 similar patients treated with CVVHDF. METHODS: Analysis of daily morning urea and creatinine concentrations over the period of renal replacement therapy in the ICU. Statistical comparison of data. RESULTS: The two groups of patients were comparable for mean age (55 years for IHD vs. 60 years for CVVHDF; NS) and number of failing organs prior to therapy (mean of 4.2 for IHD vs. 3.7 for CVVHDF; NS). Severity of illness at admission as assessed by APACHE II score, however, was greater for patients receiving CVVHDF (29.4 vs 25.7; p<0.003). CVVHDF was associated with a significantly lower plasma urea (p < 0.0001) and serum creatinine (p < 0.01) level at 24 hours of treatment despite similar levels at the start of therapy Throughout the duration of therapy, mean urea levels (35.0 mmol/L for IHD vs 23.4 mmol/L for CVVHDF) and mean serum creatinine levels (513 micromoles/L for IHD and 263 micromoles/L for CVVHDF) showed significantly (p <0.0001) better control of uremia with CRRT. CONCLUSIONS: Changing the form of renal replacement therapy from intermittent hemodialysis to continuous hemofiltration is associated with improved control of azotemia. The superior adequacy of small solute clearance achieved during CVVHDF provides additional support for its preferential use in the management of acute renal failure in the ICU.