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.

Heads Up: a pilot trial of a psychological intervention to improve nutrition in head and neck cancer patients undergoing radiotherapy.

Malnutrition in head and neck cancer (HNC) patients is common and associated with poorer radiotherapy outcomes including increased mortality. This pilot trial investigates the feasibility and effectiveness of a psychological intervention to improve nutritional status, depression and mortality in HNC patients undergoing radiotherapy. Fifty-nine intervention patients received motivational interviewing and cognitive behavioural therapy compared to 70 historical controls who received treatment as usual. Participants were assessed for nutrition, depression and mortality. There were no significant differences between groups in nutritional status, depression or mortality. Subgroup analyses among patients at greater nutritional risk (cancers of the oral cavity, pharynx, larynx) revealed a potentially clinically important reduction on the PG-SGA and lower mortality (31% of controls vs. 16% intervention; P = 0.03) in favour of the intervention condition. Potential benefits in nutritional status and in mortality in this pilot trial of a psychological intervention among HNC patients at high nutritional risk suggest that a larger randomised controlled trial is warranted.

The GOFURTGO Study: AGITG phase II study of fixed dose rate gemcitabine-oxaliplatin integrated with concomitant 5FU and 3-D conformal radiotherapy for the treatment of localised pancreatic cancer.

BACKGROUND: Locally advanced inoperable pancreatic cancer (LAPC) has a poor prognosis. By increasing intensity of systemic therapy combined with an established safe chemoradiation technique, our intention was to enhance the outcomes of LAPC. In preparation for phase III evaluation, the feasibility and efficacy of our candidate regimen gemcitabine-oxaliplatin chemotherapy with sandwich 5-fluorouracil (5FU) and three-dimensional conformal radiotherapy (3DCRT) needs to be established. METHODS: A total of 48 patients with inoperable LAPC without metastases were given gemcitabine (1000 mg m(-2) d1 + d15 q28) and oxaliplatin (100 mg m(-2) d2 + d16 q28) in induction (one cycle) and consolidation (three cycles), and 5FU 200 mg m(-2) per day over 6 weeks during 3DCRT 54 Gy. RESULTS: Median duration of sustained local control (LC) was 15.8 months, progression-free survival (PFS) was 11.0 months, and overall survival was 15.7 months. Survival rates for 1, 2, and 3 years were 70.2%, 21.3%, and 12.8%, respectively. Global quality of life did not significantly decline from baseline during treatment, which was associated with modest treatment-related toxicity. CONCLUSION: Fixed-dose gemcitabine and oxaliplatin, combined with an effective and safe regimen of 5FU and 3DCRT radiotherapy, was feasible and reasonably tolerated. The observed improved duration of LC and PFS with more intensive therapy over previous trials may be due to patient selection, but suggest that further evaluation in phase III trials is warranted.

Impact of radiation therapy on acute toxicity in breast conservation therapy for early breast cancer.

AIMS: To document the acute toxicity experienced by women receiving radiation therapy as part of breast-conservation therapy (BCT) for early breast cancer. MATERIALS AND METHODS: A retrospective review was undertaken of the medical records of 234 consecutive women managed with radiation therapy for BCT over a 2-year period. A policy of formal acute toxicity documentation was present during this period with descriptive measures as well as the Radiation Therapy Oncology Group (RTOG) acute toxicity scoring system. Cutaneous moist desquamation, peak RTOG score, breast oedema and chemotherapy dose intensity were end points assessed. Patient and treatment characteristics were investigated for their association with study end points using Chi-squared and logistic regression analyses. RESULTS: A total of 223 (95%) of women had data available for analysis. All women were treated with tangential fields on megavoltage linear accelerators. Eighty-three (37.2%) women had systemic chemotherapy either delivered simultaneously in 58 and sequentially in 25. Moist desquamation occurred in 70 (31.4%) women; principally in the inframammary fold only in 43 (19.3%). Only 12 (5.4%) had a confluent moist reaction. Two hundred and ten (94%) women had a peak RTOG skin grade of 2 or less. Breast oedema was evident at treatment end in 46 (20.5%). On univariate analysis, physical factors, such as patient weight (P<0.001) and breast size (P<0.001), were significantly associated with moist desquamation, as were the volume of breast resected (P=0.02) and the use of chemotherapy (P=0.03). Only the physical factors remained significant on multivariate analysis. The presence of breast oedema was associated with surgical factors such as post-operative oedema (P<0.001) and infective complications (P<0.001). The use of concurrent chemoradiotherapy did not affect chemotherapy dose intensity, nor did the presence of moist desquamation increase the risk of febrile complications in chemotherapy-related neutropenia. CONCLUSION: This study confirms the relatively low incidence of significant acute toxicity experienced by women during radiation therapy as part of BCT. These study data should assist surgeons and women in the decision-making process for BCT.

Relapse patterns after chemo-radiation for carcinoma of the oesophagus.

AIM: The detailed review of patterns of failure in this report was undertaken to identify the continuing obstacles to the successful management of oesophageal cancer, and to establish whether there is a case to compare definitive chemo-radiation (Def-CR) and surgery for patients with squamous cancer in a randomized controlled trial. MATERIALS AND METHODS: First and subsequent sites of failure were reviewed in 274 patients treated with Def-CR using two cycles of cisplatin, infusional fluorouracil and 60 Gy; and 92 patients with limited chemo-radiation (CR), using one cycle and 35 Gy, followed by surgery (CR-Surg). All were treated on prospective non-randomized trials run by the Trans-Tasman Radiation Oncology Group between 1985 and 1999. Failure patterns were analysed using competing risks methodology, and pre-treatment variables predicting survival were identified by proportional hazards modelling. RESULTS: Site, stage, performance status and gender were independently predictive of survival following Def-CR. Local failure was evident in 42.3% of patients, but distant failure in isolation occurred in an additional 18.1%. Lowest rates of local and distant failure at 5 years (29.9% and 26%) occurred in patients with squamous cancer (SCC) located in the upper-third, whose 5-year survival was also the most favourable (49.2%). Survival was least favourable in patients with adenocarcinoma (AC) in the lower two-thirds (18.1%) due to higher rates of local (51.5%) and distant (36.1%) failure. Local failure occurred in 31.5% of patients undergoing CR-Surg but distant failure in isolation was observed in a further 34.7%. Outcomes were least favourable in patients with AC of the lower-third in whom 57.7% failed distantly and 5-year survival was 3.8%. Response to pre-operative chemo-radiation was also strongly predictive of outcome. Patients with no residual cancer in the resection specimen had the lowest rates of local (0%) and distant (16.7%) failure and the best survival (64.9%). Survival in patients with residual cancer in nodes, however, was extremely poor (3.5%) with distant failure occurring in 66.7%. CONCLUSION: The concurrent administration of chemotherapy with radiotherapy seems to have improved loco-regional control and has exposed distant failure as an obstacle to further improvements in outcome. Site, histological subtype, gender and response to chemo-radiation may predict biological differences in oesophageal cancer (OC) that influence outcome. A good case for a randomized comparison between Def-CR and CR-Surg in patients with SCC in the lower two-thirds exists.

Comparison of prostate set-up accuracy and margins with off-line bony anatomy corrections and online implanted fiducial-based corrections.

The aim of the study was to determine prostate set-up accuracy and set-up margins with off-line bony anatomy-based imaging protocols, compared with online implanted fiducial marker-based imaging with daily corrections. Eleven patients were treated with implanted prostate fiducial markers and online set-up corrections. Pretreatment orthogonal electronic portal images were acquired to determine couch shifts and verification images were acquired during treatment to measure residual set-up error. The prostate set-up errors that would result from skin marker set-up, off-line bony anatomy-based protocols and online fiducial marker-based corrections were determined. Set-up margins were calculated for each set-up technique using the percentage of encompassed isocentres and a margin recipe. The prostate systematic set-up errors in the medial-lateral, superior-inferior and anterior-posterior directions for skin marker set-up were 2.2, 3.6 and 4.5 mm (1 standard deviation). For our bony anatomy-based off-line protocol the prostate systematic set-up errors were 1.6, 2.5 and 4.4 mm. For the online fiducial based set-up the results were 0.5, 1.4 and 1.4 mm. A prostate systematic error of 10.2 mm was uncorrected by the off-line bone protocol in one patient. Set-up margins calculated to encompass 98% of prostate set-up shifts were 11-14 mm with bone off-line set-up and 4-7 mm with online fiducial markers. Margins from the van Herk margin recipe were generally 1-2 mm smaller. Bony anatomy-based set-up protocols improve the group prostate set-up error compared with skin marks; however, large prostate systematic errors can remain undetected or systematic errors increased for individual patients. The margin required for set-up errors was found to be 10-15 mm unless implanted fiducial markers are available for treatment guidance.

Assessment of a daily online implanted fiducial marker-guided prostate radiotherapy process.

The aims of this study were to investigate whether intrafraction prostate motion can affect the accuracy of online prostate positioning using implanted fiducial markers and to determine the effect of prostate rotations on the accuracy of the software-predicted set-up correction shifts. Eleven patients were treated with implanted prostate fiducial markers and online set-up corrections. Orthogonal electronic portal images were acquired to determine couch shifts before treatment. Verification images were also acquired during treatment to assess whether intrafraction motion had occurred. A limitation of the online image registration software is that it does not allow for in-plane prostate rotations (evident on lateral portal images) when aligning marker positions. The accuracy of couch shifts was assessed by repeating the registration measurements with separate software that incorporates full in-plane prostate rotations. Additional treatment time required for online positioning was also measured. For the patient group, the overall postalignment systematic prostate errors were less than 1.5 mm (1 standard deviation) in all directions (range 0.2-3.9 mm). The random prostate errors ranged from 0.8 to 3.3 mm (1 standard deviation). One patient exhibited intrafraction prostate motion, resulting in a postalignment prostate set-up error of more than 10 mm for one fraction. In 14 of 35 fractions, the postalignment prostate set-up error was greater than 5 mm in the anterior-posterior direction for this patient. Maximum prostate rotations measured from the lateral images varied from 2 degrees to 20 degrees for the patients. The differences between set-up shifts determined by the online software without in-plane rotations to align markers, and with rotations applied, was less than 1 mm (root mean square), with a maximum difference of 4.1 mm. Intrafraction prostate motion was found to reduce the effectiveness of the online set-up for one of the patients. A larger study is required to determine the magnitude of this problem for the patient population. The inability in the current software to incorporate in-plane prostate rotations is a limitation that should not introduce large errors, provided that the treatment isocentre is positioned near the centre of the prostate.

Absence of adverse early quality of life outcomes of radiation therapy in breast conservation therapy for early breast cancer.

The New South Wales Breast Radiation Oncology Group has completed a prospective multicentre study of the impact of radiation therapy (RT) on acute toxicity and quality of life (QoL) in women with early breast cancer treated with breast conservation therapy. The patient group received adjuvant breast tangential RT after wide local excision of breast cancer. Acute toxicity and cosmesis was assessed quantitatively and qualitatively. European Organization of Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-30) and Perceived Adjustment to Chronic Illness Scale (PACIS) were the QoL instruments used. Of 175 women, 34.3% described lethargy leading to a significant disruption to normal activity during RT. At week 6, this had reduced to 7.5% reporting significant lethargy. No negative effects on QoL were noted over the time period of RT; EORTC demonstrated no difference (P = 0.79). PACIS recorded a significant improvement in functioning (P < 0.001) from baseline to week 6. Univariate analysis on potential predictive patient, tumour and treatment factors demonstrated an association of baseline pre-RT breast discomfort with worse lethargy (P = 0.03), EORTC (P < 0.01) and PACIS (P < 0.01) measures. This study confirms the minimal impact of RT on patient functioning at 6 weeks post-treatment.

Why a breast boost should remain a controversial aspect of routine breast conservation management in Australia and New Zealand in 2002.

Two randomized trials have recently shown a statistically significant improvement in local control when a boost is employed in the conservative treatment of early breast cancer. However, unresolved issues of cost effectiveness, potentially increased toxicity and the inability to automatically generalize these results to Australian and New Zealand practice remain. In view of these unresolved controversies, the St George and Wollongong hospitals breast boost trial (SGW trial) will continue to recruit.

All delays before radiotherapy risk progression of Merkel cell carcinoma.

Prolonged waiting times for radiotherapy have resulted in many centres assigning priorities to various patient or diagnostic groups. A high risk of progression on a waiting list is one factor that would reasonably influence the priority. The present descriptive study of 27 patients with Merkel cell carcinoma (MCC) found that a median wait of 24 days for radiotherapy is associated with a high risk of progression. Eleven (41%) of 27 patients developed progressive disease, including five (45%) of 11 patients waiting for adjuvant radiotherapy. Patients treated adjuvantly also had longer waiting times prior to their initial radiotherapy consultation (median 41 days), which may have contributed to the rate of progression. Merkel cell carcinoma is an aggressive but curable malignancy and appropriate management should include efforts to minimize all potential delays prior to the commencement of radiotherapy.

Pilot study of high-frequency ultrasound to assess cutaneous oedema in the conservatively managed breast.

Cutaneous oedema is a relatively frequent complication in patients treated conservatively for breast cancer. The factors that contribute to this complication have not been precisely determined. We performed a pilot study to assess the usefulness of high-frequency ultrasound as a quantitative measure of cutaneous oedema. Eleven patients undergoing breast-conserving therapy for breast cancer were studied. Both the treated and untreated breasts were examined. Total cutaneous thickness provided a useful measure of cutaneous oedema. The treated breast was significantly thicker than the untreated breast (P < 0.001). The medial aspect of the breast was thicker than the lateral aspect in both the treated and untreated breast (P < 0.001). The increase in cutaneous thickness predated radiotherapy in those patients who had undergone an axillary dissection. Intrapatient variation in skin thickness was much less than interpatient variation in skin thickness (coefficient of variation 6.4% vs. 18.2% for the untreated breast; coefficient of variation 13.9% vs. 30.9% for the treated breast). Increasing cutaneous thickness was associated with decreasing cutaneous echodensity. We were unable to derive quantitative estimates of echodensity. Cutaneous oedema is an important outcome variable following conservative treatment of breast cancer. High-frequency ultrasound is able to quantify this accurately. It can readily detect changes invisible to the naked eye. High-frequency ultrasound should enable the effects of different treatment options (e.g., extent of surgery, radiotherapy, and chemotherapy) on cutaneous oedema to be differentiated and for the time course of oedema to be accurately characterised.