Angela Hong

Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial

BACKGROUND The use of radiotherapy after therapeutic lymphadenectomy for patients with melanoma at high risk of further lymph-node field and distant recurrence is controversial. Decisions for radiotherapy in this setting are made on the basis of retrospective, non-randomised studies. We did this randomised trial to assess the effect of adjuvant radiotherapy on lymph-node field control in patients who had undergone therapeutic lymphadenectomy for metastatic melanoma in regional lymph nodes. METHODS This randomised controlled trial included patients from 16 hospitals in Australia, New Zealand, the Netherlands, and Brazil. To be eligible for this trial, patients had to be at high risk of lymph-node field relapse, judged on the basis of number of nodes involved, extranodal spread, and maximum size of involved nodes. After lymphadenectomy, randomisation was done centrally by computer and patients assigned by telephone in a ratio of 1:1 to receive adjuvant radiotherapy of 48 Gy in 20 fractions or observation, with institution, lymph-node field, number of involved nodes, maximum node diameter, and extent of extranodal spread as minimisation factors. Participants, those giving treatment, and those assessing outcomes were not masked to treatment allocation. The primary endpoint was lymph-node field relapse (as a first relapse), analysed for all eligible patients. The study is registered at ClinicalTrials.gov, number NCT00287196. The trial is now closed and follow-up discontinued. FINDINGS 123 patients were randomly allocated to the adjuvant radiotherapy group and 127 to the observation group between March 20, 2002, and Sept 21, 2007. Two patients withdrew consent and 31 had a major eligibility infringement as decided by the independent data monitoring committee, resulting in 217 eligible for the primary analysis (109 in the adjuvant radiotherapy group and 108 in the observation group). Median follow-up was 40 months (IQR 27-55). Risk of lymph-node field relapse was significantly reduced in the adjuvant radiotherapy group compared with the observation group (20 relapses in the radiotherapy group vs 34 in the observation group, hazard ratio [HR] 0·56, 95% CI 0·32-0·98; p=0·041), but no differences were noted for relapse-free survival (70 vs 73 events, HR 0·91, 95% CI 0·65-1·26; p=0·56) or overall survival (59 vs 47 deaths, HR 1·37, 95% CI 0·94-2·01; p=0·12). The most common grade 3 and 4 adverse events were seroma (nine in the radiotherapy group vs 11 in the observation group), radiation dermatitis (19 in the radiotherapy group), and wound infection (three in the radiotherapy group vs seven in the observation group). INTERPRETATION Adjuvant radiotherapy improves lymph-node field control in patients at high risk of lymph-node field relapse after therapeutic lymphadenectomy for metastatic melanoma. Adjuvant radiotherapy should be discussed with patients at high risk of relapse after lymphadenectomy. FUNDING National Health and Medical Research Council of Australia, Cancer Australia, Melanoma Institute Australia, Cancer Council of South Australia.

Squamous cell carcinoma of the oropharynx in Australian males induced by human papillomavirus vaccine targets.

This study provides Australian data on the incidence of human papillomavirus (HPV)-related oropharyngeal cancer to aid the debate on extending the HPV vaccination programme to males. The HPV status for 302 oropharyngeal cancers diagnosed between 1987 and 2006 was determined by HPV E6-targeted multiplex real-time PCR/p16 immunohistochemistry. The overall HPV-positivity rate was 36% (94% types 16 and 18). HPV-related cancer increased from 19% (1987-1990) to 47% (2001-2005). HPV data used in conjunction with Australian cancer incidence data 2001-2005 showed that 1.56 cases of oropharyngeal cancer per 100,000 males per year were associated with HPV types targeted by the vaccine. Vaccinating males may substantially reduce the burden of oropharyngeal cancer in Australia.

Human papillomavirus predicts outcome in oropharyngeal cancer in patients treated primarily with surgery or radiation therapy

Objective:This study examines the prognostic significance of human papillomavirus (HPV) in patients with locally advanced oropharyngeal squamous cell carcinoma (SCC) treated primarily with surgery or definitive radiotherapy.Methods:One hundred and ninety-eight patients with Stage 3/4 SCC were followed up for recurrence in any form or death from any cause for between 1 and 235 months after diagnosis. HPV status was determined using HPV E6-targeted multiplex real-time PCR/p16 immunohistochemistry. Determinants of recurrence and mortality hazards were modelled using Coxs regression with censoring at follow-up dates.Results:Forty-two per cent of cancers were HPV-positive (87% type 16). HPV predicted loco-regional control, event-free survival and overall survival in multivariable analysis. Within the surgery with adjuvant radiotherapy (n=110), definitive radiotherapy-alone (n=24) and definitive radiotherapy with chemotherapy (n=47) groups, patients with HPV-positive cancers were one-third or less as likely to have loco-regional recurrence, an event or to die of any cause as those with HPV-negative cancers after adjusting for age, gender, tumour grade, AJCC stage and primary site. The 14 patients treated with surgery alone were considered too few for multivariable analysis.Conclusion:HPV status predicts better outcome in oropharyngeal cancer treated with surgery plus adjuvant radiotherapy as well as with definitive radiation therapy±chemotherapy.

Desmoplastic Neurotropic Melanoma : A Clinicopathologic Analysis of 128 Cases

Several studies have suggested that desmoplastic neurotropic melanoma (DNM) is associated with higher local recurrence rates than other types of melanoma. The authors investigated the local recurrence rates for patients with DNM after surgery alone or surgery followed by radiotherapy (RT).

Relationships between epidermal growth factor receptor expression and human papillomavirus status as markers of prognosis in oropharyngeal cancer

PURPOSE This study examines the prognostic significance of epidermal growth factor receptor (EGFR) expression in relation to human papillomavirus (HPV) status in oropharyngeal squamous cell carcinoma (SCC). MATERIALS AND METHODS Pathological diagnosis of 270 oropharyngeal SCCs was verified by the study pathologist; clinical details were extracted from institutional databases. Recurrence in any form or death from any cause was recorded for a median of 2.5 (range: 0-19.3) years after diagnosis. HPV status was determined by HPV E6-targeted multiplex real-time PCR/p16 immunohistochemistry; EGFR expression was evaluated by semiquantitative immunohistochemistry. Determinants of recurrence and mortality hazards were modelled using Cox regression with censoring at dates of last follow-up. RESULTS Thirty-seven percent of cancers were HPV-positive (91% type 16). HPV was a predictor of loco-regional recurrence, event-free and overall survival after adjustment for clinicopathological variables and EGFR. Patients with EGFR-positive cancers were 5-fold more likely to have loco-regional failure relative to those with EGFR-negative cancers. Patients with HPV-negative/EGFR-positive cancers had an adjusted 13-fold increased risk of having a loco-regional failure, an almost 4-fold increased risk of having an event and more than a 4-fold increased risk of dying of any cause relative to those with HPV-positive/EGFR-negative cancers. There was weak evidence that the effects of EGFR on outcome were limited to patients with HPV-negative cancers. CONCLUSIONS HPV and EGFR are independent prognostic markers in oropharyngeal SCC. Combining testing for HPV and EGFR appears to provide additional prognostic information.

En-bloc resection, extracorporeal irradiation, and re-implantation in limb salvage for bony malignancies

We treated 50 patients with bony malignancy by en-bloc resection, extracorporeal irradiation with 50 Gy and re-implantation of the bone segment. The mean survivor follow-up was 38 months (12 to 92) when 42 patients were alive and without disease. There were four recurrences. The functional results were good according to the Mankin score (17 excellent, 13 good, nine fair, three failures), the Musculoskeletal Tumour Society score (mean 77) and the Toronto Extremity Salvage score (mean 81). There was solid union, but bone resorption was seen in some cases. The dose of radiation was lethal to all cells and produced a dead autograft of perfect fit. Extracorporeal irradiation is a useful technique for limb salvage when there is reasonable residual bone stock. It allows effective re-attachment of tendons and produces a lasting biological reconstruction. There should be no risk of local recurrence or of radiotherapy-induced malignancy in the replanted bone.

Improving Management and Patient Care in Lentigo Maligna by Mapping With In Vivo Confocal Microscopy

IMPORTANCE Lentigo maligna (LM) is a clinical, pathologic, and therapeutic challenge with a higher risk of local recurrence than other types of melanoma correctly treated and also carries the cosmetically sensitive localization of head and neck. OBJECTIVE To determine whether in vivo reflectance confocal microscopy (RCM) mapping of difficult LM cases might alter patient care and management. DESIGN Analysis of LM and LM melanoma (LMM) in a series of patients with large facial lesions requiring complex reconstructive surgery and/or recurrent or poorly delineated lesions at any body sites were investigated. SETTINGS Two tertiary referral melanoma centers in Sydney, Australia. PARTICIPANTS Thirty-seven patients with LM (including 5 with LMM) were mapped with RCM. Fifteen patients had a recurrent LM, including 9 with multiple prior recurrences. The LM was classified amelanotic in 10 patients, lightly pigmented in 9, and partially pigmented in 18. INTERVENTIONS The RCM images were obtained in 4 radial directions (allowing for anatomic barriers) for LM margin delineation using an RCM LM score previously described by our research team. MAIN OUTCOME MEASURES Differences in the margin of LM as determined by RCM vs dermoscopy vs histopathologic analysis. RESULTS Seventeen of 29 patients (59%) with dermoscopically visible lesions had subclinical (RCM-identified) disease evident more than 5 mm beyond the dermoscopy margin (ie, beyond the excision margin recommended in published guidelines). The RCM mapping changed the management in 27 patients (73%): 11 patients had a major change in their surgical procedure, and 16 were offered radiotherapy or imiquimod treatment as a consequence of the RCM findings. Treatment was surgical in 17 of 37 patients. Surgical excision margins (based on the RCM mapping) were histopathologically involved in only 2 patients, each of whom had an LM lesion larger than 6 cm. CONCLUSIONS AND RELEVANCE In vivo RCM can provide valuable information facilitating optimal patient care management.

Whole brain radiotherapy after local treatment of brain metastases in melanoma patients--a randomised phase III trial.

BackgroundCerebral metastases are a common cause of death in patients with melanoma. Systemic drug treatment of these metastases is rarely effective, and where possible surgical resection and/or stereotactic radiosurgery (SRS) are the preferred treatment options. Treatment with adjuvant whole brain radiotherapy (WBRT) following neurosurgery and/or SRS is controversial. Proponents of WBRT report prolongation of intracranial control with reduced neurological events and better palliation. Opponents state melanoma is radioresistant; that WBRT yields no survival benefit and may impair neurocognitive function. These opinions are based largely on studies in other tumour types in which assessment of neurocognitive function has been incomplete.Methods/DesignThis trial is an international, prospective multi-centre, open-label, phase III randomised controlled trial comparing WBRT to observation following local treatment of intracranial melanoma metastases with surgery and/or SRS. Patients aged 18 years or older with 1-3 brain metastases excised and/or stereotactically irradiated and an ECOG status of 0-2 are eligible. Patients with leptomeningeal disease, or who have had previous WBRT or localised treatment for brain metastases are ineligible. WBRT prescription is at least 30 Gy in 10 fractions commenced within 8 weeks of surgery and/or SRS. Randomisation is stratified by the number of cerebral metastases, presence or absence of extracranial disease, treatment centre, sex, radiotherapy dose and patient age. The primary endpoint is the proportion of patients with distant intracranial failure as determined by MRI assessment at 12 months. Secondary end points include: survival, quality of life, performance status and neurocognitive function.DiscussionAccrual to previous trials for patients with brain metastases has been difficult, mainly due to referral bias for or against WBRT. This trial should provide the evidence that is currently lacking in treatment decision-making for patients with melanoma brain metastases. The trial is conducted by the Australia and New Zealand Melanoma Trials Group (ANZMTG-study 01-07), and the Trans Tasman Radiation Oncology Group (TROG) but international participation is encouraged. Twelve sites are open to date with 43 patients randomised as of the 31st March 2011. The target accrual is 200 patients.Trial registrationAustralia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12607000512426

Adjuvant radiotherapy and regional lymph node field control in melanoma patients after lymphadenectomy: Results of an intergroup randomized trial (ANZMTG 01.02/TROG 02.01)

LBA9084 Background: Adjuvant radiotherapy (RT) is an option for patients with isolated regional recurrence of melanoma considered to be at high risk of further regional recurrence after lymphadenectomy. This is the first completed study to assess the effects of RT on regional recurrence, survival, morbidity and quality of life (QOL) in these patients. METHODS Multicenter randomized study of patients with isolated regional recurrence at increased risk (>25%) of regional recurrence. Eligibile patients included ≥1 parotid, ≥ 2 cervical or axillary or ≥ 3 groin nodes or extra nodal spread of tumor or maximum metastatic node diameter ≥3cm in neck or axilla or ≥4cm in the groin. Patients were randomized to observation or regional nodal basin RT (48Gy in 20 fractions) after lymphadenectomy. Regional recurrence was the primary end point and morbidity, QOL, patterns of relapse, disease free and overall survival were secondary end points. The target sample size was 220 patients, which would enable a difference in 3 year regional relapse (cumulative incidence) rates of 30% versus 15% to be detected with a power of 80% (using a two sided logrank test at the 5% level of significance). RESULTS 250 pts were randomized from 16 centers from March 2002 to September 2007. There were 123 in the RT group and 127 in OBS group. 2 pts withdrew consent and 31 were excluded from analysis of the main objective following an independent blinded review of eligibility compliance by two reviewers. 227 pts were available for analysis of the main objective (109 RT, 108 OBS). Median follow-up was 27 mo. There was a statistically significant improvement in lymph node field control with radiotherapy, 20 RT pts and 34 OBS pts relapsed (HR 1.77 1.02-3.08 p=0.041). Median survival times were 2.6 years (RT) and 3.9 years (OBS) p=0.14. CONCLUSIONS Adjuvant RT improved regional control in melanoma patients at high risk of regional relapse after lymphadenectomy. An effect on survival was not demonstrated. No significant financial relationships to disclose.

The role of telomeres and telomerase in the pathology of human cancer and aging.

&NA; Cellular senescence, the state of permanent growth arrest, is the inevitable fate of replicating normal somatic cells. Postulated to underlie this finite replicative span is the physiology of telomeres, which constitute the ends of chromosomes. The repetitive sequences of these DNA‐protein complexes progressively shorten with each mitosis. When the critical length is bridged, telomeres trigger DNA repair and cell cycle checkpoint mechanisms that result in chromosomal fusions, cell cycle arrest, senescence and/or apoptosis. Should senescence be bypassed at such time, continued cell divisions in the face of dysfunctional telomeres and activated DNA repair machinery can result in the genomic instability favourable for oncogenesis. The longevity and malignant progression of the thus transformed cell requires coincident telomerase expression or other means to negate the constitutional telomeric loss. Practically then, telomeres and telomerase may represent plausible prognostic and screening cancer markers. Furthermore, if the argument is extended, with assumptions that telomeric attrition is indeed the basis of cellular senescence and that accumulation of the latter equates to aging at the organismal level, then telomeres may well explain the increased incidence of cancer with human aging.