Randomized Trial of Postoperative Radiation Therapy After Wide Excision of Neurotropic Melanoma of the Head and Neck (RTN2 Trial 01.09).

BACKGROUND: Cutaneous neurotropic melanoma (NM) of the head and neck (H&N) is prone to local relapse, possibly due to difficulties widely excising the tumor. This trial assessed radiation therapy (RT) to the primary site after local excision. METHODS: Participants from 15 international centers were randomized to observation or RT. The participants were required to have microscopically negative excision margins 5 mm wide or wider and no evidence of disease elsewhere. The primary outcome was time to local relapse. The secondary outcomes included time to any recurrence, overall survival (OS), and toxicity. RESULTS: The trial ceased prematurely due to slow recruitment and the COVID-19 pandemic. During 2009-2020, 50 participants were randomized: 23 to observation and 27 to RT. The most common NM subsites were scalp (32%), midface (22%), and lip (20%). The median depth of invasion was 5 mm, and desmoplasia observed in 69%. The median duration from randomization to last contact was 4.8 years. Four participants (8%) experienced local relapse as a first recurrence during the study period: 3 in the observation arm and 1 in the RT arm (hazard ratio [HR] 0.29; 95% confidence interval [CI] 0.03-2.76; p = 0.279). No statistically significant difference in time to any relapse or OS was observed. More than 6 months after randomization, grade 3 or greater toxicity was experienced by 10% of the participants in the observation arm and 12.5% of the participants in the RT arm of the study. CONCLUSION: Due to low accrual, the role of adjuvant RT for cutaneous NM of the H&N excised with microscopically negative margins 5 mm wide or wider remains undefined. Its routine use cannot be recommended. Local relapse might be less common than previously anticipated based on retrospective reports.

Inguinal and Ilio-inguinal Lymphadenectomy in Management of Palpable Melanoma Lymph Node Metastasis: A Long-Term Prospective Evaluation of Morbidity and Quality of Life.

PURPOSE: Prospective data are lacking on long-term morbidity of inguinal lymphadenectomy including the influence of extent of surgery, use of radiotherapy, and patient factors. The aim of this study is to evaluate the effects of these factors on patient outcome, quality of life (QOL), regional symptoms, and limb volumes after inguinal or ilio-inguinal lymphadenectomy for melanoma. METHODS: Analysis of the subgroup of patients with inguinal lymph node field relapse of melanoma, treated by inguinal or ilio-inguinal lymphadenectomy in the ANZMTG/TROG randomized trial of adjuvant radiotherapy versus observation. RESULTS: Sixty-nine patients, 46 having undergone inguinal and 23 ilio-inguinal lymphadenectomy, with median follow-up of 73 months were analyzed. Mean limb volume increased rapidly after surgery (7% by 3 months) and continued to increase for at least another 18 months. Patients with body mass index (BMI) ≥ 25 kg/m2 had greater limb volume increase than normal-weight patients (13.3% versus 6.9%, P = 0.030). QOL improved over the first 18 months, but despite initial improvement, regional symptoms persisted long term. Type of surgery (inguinal or ilio-inguinal lymphadenectomy) had no demonstrably significant effect on limb volume (9.9% versus 13.4%, P = 0.35), QOL (P = 0.68), or regional symptoms (P = 0.65). There was no difference in overall survival between inguinal and ilio-inguinal lymphadenectomy [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.40-1.40, P = 0.43]. CONCLUSIONS: Inguinal lymphadenectomy for melanoma is a potentially morbid procedure with significant increases in limb volume. Patients report reasonable QOL but may have ongoing regional symptoms. Overweight/obesity is associated with poorer QOL, increased limb volume, and regional symptoms.

Patterns of Failure Following Dose-escalated Chemoradiotherapy for Fluorodeoxyglucose Positron Emission Tomography Staged Squamous Cell Carcinoma of the Oesophagus.

AIMS: To analyse outcomes and patterns of failure following dose-escalated definitive chemoradiotherapy (CRT) for oesophageal squamous cell carcinoma using fluorodeoxyglucose positron emission tomography for staging and treatment planning. MATERIALS AND METHODS: A retrospective review of patients with oesophageal squamous cell carcinoma receiving definitive CRT to a dose of ≥56 Gy was conducted. Patient and tumour characteristics, treatment received and first sites of relapse were analysed. RESULTS: Between 2003 and 2014, 72 patients were treated with CRT to a median dose of 60 Gy (range 56-66 Gy). The median age was 63 years; most (61%) were stage III/IVa. The median follow-up was 57 months. Three year in-field control, relapse-free survival and overall survival was 64% (95% confidence interval 50-75%), 38% (95% confidence interval 27-50%) and 42% (95% confidence interval 30-53%), respectively. Of the 41 failures prior to death or at last follow-up date, isolated locoregional relapse occurred in 16 patients (22%) with isolated in-field recurrence in 11 patients (15%). Distant failure as first site of relapse was present in 25 patients (35%). No in-field failures occurred in the 11 patients with cT1-2, N0-1 tumours. The median survival for cT4 tumours was 8 months, with five of eight patients developing local progression within the first 6 months. CONCLUSIONS: Dose-escalated radiotherapy was associated with promising rates of in-field local control, with the exception of cT4 tumours. Distant failure remains a significant competing risk. Our data supports the need for current trials re-examining the role of dose escalation in the modern era.

Survival benefit and additional value of preoperative chemoradiotherapy in resectable gastric and gastro-oesophageal junction cancer: a direct and adjusted indirect comparison meta-analysis.

Several phase I/II studies of chemoradiotherapy for gastric cancer have reported promising results, but the significance of preoperative radiotherapy in addition to chemotherapy has not been proven. In this study, a systematic literature search was performed to capture survival and postoperative morbidity and mortality data in randomised clinical studies comparing preoperative (chemo)radiotherapy or chemotherapy versus surgery alone, or preoperative chemoradiotherapy versus chemotherapy for gastric and/or gastro-oesophageal junction (GOJ) cancer. Hazard ratios (HRs) for overall mortality were extracted from the original studies, individual patient data provided from the principal investigators of eligible studies or the earlier published meta-analysis. The incidences of postoperative morbidities and mortalities were also analysed. In total 18 studies were eligible and data were available from 14 of these. The meta-analysis on overall survival yielded HRs of 0.75 (95% CI 0.65-0.86, P < 0.001) for preoperative (chemo)radiotherapy and 0.83 (95% CI 0.67-1.01, P = 0.065) for preoperative chemotherapy when compared to surgery alone. Direct comparison between preoperative chemoradiotherapy and chemotherapy resulted in an HR of 0.71 (95% CI 0.45-1.12, P = 0.146). Combination of direct and adjusted indirect comparisons yielded an HR of 0.86 (95% CI 0.69-1.07, P = 0.171). No statistically significant differences were seen in the risk for postoperative morbidity or mortality between preoperative treatments and surgery alone, or preoperative (chemo)radiotherapy and chemotherapy. Preoperative (chemo)radiotherapy for gastric and GOJ cancer showed significant survival benefit over surgery alone. In comparisons between preoperative chemotherapy and (chemo)radiotherapy, there is a trend towards improved survival when adding radiotherapy, without increased postoperative morbidity or mortality.

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.

Lung cancer patients in Queensland suffer delays in receiving radiation therapy--but not as a result of distance.

AIM: To determine whether lung cancer radiation therapy waiting times in Queensland public hospitals are associated with distance of residence from the nearest treatment facility. METHODS: Retrospective analysis of radiation therapy waiting times of 1535 Queensland residents who were diagnosed with lung cancer from 2000 to 2004 and received radiation therapy as initial treatment at a public hospital. The effect of distance of residence from treatment centre on median waiting time was analysed by quantile regression controlling for sex, age, lung cancer histology, stage and therapeutic intent. RESULTS: The median waiting time from diagnosis to start of radiation therapy was 33 days for all patients. There was no significant difference (P = 0.141) in median waiting times in relation to distance of residence from a treatment centre. However, in most patients, waiting times were significantly longer than recommended by the Royal Australian and New Zealand College of Radiologists. Curative patients waited longer than palliative patients, while patients with earlier stage cancer waited longer than those with more advanced disease. CONCLUSION: Waiting times for radiation therapy among lung cancer patients in Queensland was not associated with distance from place of residence to the nearest public treatment facility. However, delays overall are excessive and are likely to worsen unless radiation treatment capabilities are enhanced to keep pace with population growth in Queensland.

Positron emission tomography and pathological evidence of response to neoadjuvant therapy in adenocarcinoma of the esophagus.

Our aim was to determine if fluorodeoxyglucose positron emission tomography (FDG-PET) could be correlated with a pathological response in patients with esophageal adenocarcinoma receiving neoadjuvant chemotherapy and/or chemoradiation therapy. Patients with resectable, histologically proven adenocarcinoma of the esophagus were entered in the study. Preoperative chemotherapy comprised two cycles of cisplatin and 5-fluorouracil. Radiation therapy commenced with the second cycle on day 22. FDG-PET images were obtained pre-treatment and on completion of intended neo-adjuvant treatment. Quantification was achieved by the calculation of both standardized uptake values (SUV) and tumor/liver ratios (TLR). Evidence of histopathological response was identified according to the Mandard tumor regression scoring system. There were 45 patients, 22 receiving neoadjuvant chemotherapy and 23 chemoradiation therapy. Forty patients underwent surgical resection. Seven patients (16%) had a histopathological response. The mean percentage change in SUV in the histological responders group was -56.8% (SD 29) and in the non-responders -27.8% (SD 32.1) (P = 0.035). The mean percentage change in TLR was -49.1% (SD 44.8) in the responders and in the non-responders -27.3% (SD 31.3) (P = 0.128). There was no difference between the two methods of assessment, however there was less variation with SUV. There was no correlation between the FDG-PET response and the histopathological response. Presently an FDG-PET scan performed 3-6 weeks after neoadjuvant therapy for adenocarcinoma of the esophagus should not be used as a marker of the potential result of the treatment. The optimal timing of a second FDG-PET remains unclear.

Outcomes from salvage esophagectomy post definitive chemoradiotherapy compared with resection following preoperative neoadjuvant chemoradiotherapy.

Chemoradiotherapy (CRT) as a definitive treatment for esophageal cancer, is being used with increasing frequency and as a result, surgeons will be required to assess more patients who have residual or recurrent local malignancy. This article aimed to assess outcomes after esophagectomy following definitive CRT (dCRT) and compare any difference between them and patients who had preoperative neoadjuvant CRT (nCRT) using a similar regimen of chemotherapy. From a prospective database the details of patients who had a resection following nCRT and dCRT were analyzed. The main therapeutic difference between the groups was the dose of radiotherapy (35 vs 60 Gy) and the timing of the resection following completion of the CRT (median 4 vs 28 weeks). Fourteen patients had an esophagectomy following a dCRT and 53 had one following a nCRT. Preoperatively, the dCRT group had worse respiratory function and more ECG abnormalities. Preoperative tumor length, pathological TNM staging and R0 resection rates were the same in both groups. Post resection, the dCRT group had greater morbidity than the nCRT group, spending longer in the intensive care unit (median 48 vs 24 h), more days in hospital (median 31 vs 13) and having more severe respiratory complications (37%vs 6%). The operative mortality was higher in the dCRT group (7%vs 0%). The three-year survival was 24% after dCRT. Patients selected for salvage esophagectomy following dCRT are a major challenge in postoperative care. However, some patients survive for a reasonable period of time, making resection a worthwhile option.

Radiotherapy for metastatic melanoma presenting in pregnancy.

We describe the study of a patient with metastatic melanoma to axillary nodes presenting during pregnancy. The factors considered in her management are discussed, including issues related to staging, the decision not to terminate the pregnancy and the relative efficacy and fetal toxicity of the available treatment options. An overview of the known effects of radiotherapy on the fetus is presented and the technical alterations that were used to decrease the toxicity of radiotherapy are discussed.

A phase I study of moderate-dose radiation therapy and weekly gemcitabine in patients with locally advanced non-small cell lung cancer not suitable for radical chemoradiation therapy.

AIMS: To describe the toxicity and response seen in patients receiving moderate-dose radiation therapy with concurrent weekly low-dose gemcitabine in the management of locally advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Eighteen patients with confirmed NSCLC were enrolled over a 17-month period from August 2000 until January 2002. All had localised disease but were considered unsuitable for curative therapy. Radiation therapy was given to a dose of 30 Gy in 15 fractions over 3 weeks. Gemcitabine was given weekly before and within 3 h of fractions 1, 6 and 11. The study was designed as a dose-escalation study, commencing at 100 mg/m2 and increasing at levels of 50 mg/m2, until the maximum tolerated dose (MTD) was reached. RESULTS: The MTD was regarded as being 150 mg/m2. The major acute toxicity observed was oesophagitis. Skin reactions were also reported. The overall response rate in all patients was 88%, with 44% achieving a complete response. CONCLUSION: The combination of gemcitabine and moderate-dose radiation therapy is feasible, and offers low toxicity and excellent response rates in patients with localised NSCLC not suitable for high-dose therapy.

Chemoradiation therapy is effective for the palliative treatment of malignant dysphagia.

Between 1993 and 2001, 106 patients with esophageal cancer were reviewed at a multidisciplinary clinic and treated with palliative intent by chemoradiation therapy. This study assesses the palliative benefit on dysphagia and documents the toxicity of this treatment. The study population comprised 72 men and 34 women with a median age of 69 years. Patients were treated with a median radiation dose of 35 Gy in 15 fractions with a concurrent single course of 5 FU-based chemotherapy. Dysphagia was measured at the beginning and completion of treatment and at monthly intervals until death, using a modified DeMeester (4-point) score. Treatment was well tolerated, with only 5% of patients failing to complete therapy. The treatment-related mortality was 6%. The median survival for the study population was 7 months. The median baseline score at presentation was 2 (difficulty with soft food). Following treatment, 49% of patients were assessed as having a dysphagia score of 0 (no dysphagia). Seventy-eight per cent had an improvement of at least one grade in their dysphagia score after treatment. Only 14% of patients showed no improvement with treatment. Fifty-one per cent maintained improved swallowing until the time of last follow-up or death. This single-institution study shows that chemoradiation therapy administered for the palliation of malignant dysphagia is well tolerated and produces a sustainable normalization in swallowing for almost half of all patients.

Use of oesophagogastroscopy to assess the response of oesophageal carcinoma to neoadjuvant therapy.

BACKGROUND: Approximately 25 per cent of patients with oesophageal cancer who undergo neoadjuvant chemoradiotherapy have no evidence of tumour in the resected specimen (complete pathological response). Those who do not respond have a poor 5-year survival compared with complete responders, regardless of whether or not they undergo surgery. Selecting for surgery only those who have a response to neoadjuvant therapy has the potential to improve overall survival as well as to rationalize the management of non-responders. This study assessed the accuracy of oesophagogastroscopy in this setting. METHODS: A prospective database of 804 patients undergoing oesophageal resection for carcinoma was reviewed. Endoscopic assessment of the response to neoadjuvant therapy in 100 consecutive patients was compared with the pathological assessment of response. The survival for each level of response was compared. RESULTS: At endoscopy 30 patients were considered to have had a complete response. This was confirmed pathologically in 15 patients. Survival was improved in those with a pathologically confirmed complete response (3-year survival rate 62.4 (s.e. 12.9) per cent) compared with non-responders (16.3 (s.e. 6.6) per cent). Those with microscopic residual disease also had an improved 3-year survival rate (46.3 (s.e. 12.2) per cent); however, oesophagogastroscopy failed to identify this subset. CONCLUSION: Oesophagogastroscopy may be useful in the assessment of tumour response to neoadjuvant therapy. However, owing to its poor accuracy patients should not be excluded from further therapeutic intervention on the basis of this assessment alone.

A prospective trial of short-fractionation radiotherapy for the palliation of liver metastases.

The purpose of this study was to prospectively examine the effectiveness and tolerability of a simple radiotherapy technique for the palliation of symptomatic liver metastases. Twenty-eight patients with symptomatic liver metastases were enrolled from seven centres, and received targeted (partial or whole) liver irradiation consisting of 10 Gy in two fractions over 2 days. Symptoms at baseline were hepatic pain (27 patients), abdominal distension (19), night sweats (12), nausea (18) and vomiting (eight). Twenty-two patients (76%) had failed previous treatment with chemotherapy, hormonal therapy and/or high-dose steroids. Symptoms and potential toxicities were prospectively assessed at the time of treatment, then 2, 6 and 10 weeks later. Individual symptom response rates were 53-66% at 2 weeks. Partial or complete global symptomatic responses were noted in 15 patients (54%) overall. The treatment was well tolerated with two patients (7%) experiencing grade 3 toxicity (one vomiting and one diarrhoea); however, four patients reported temporary worsening of pain shortly after treatment. This simple and well-tolerated treatment achieves useful palliation.

Radiation therapy following nodal surgery for melanoma: an analysis of late toxicity.

BACKGROUND: The role of adjuvant radiation therapy following resection of malignant melanoma involving regional lymph nodes remains controversial. There is no published randomized trial comparing surgery alone to surgery with postoperative radiation therapy that shows a benefit in terms of local control. Some retrospective studies, however, suggest that radiation given postoperatively reduces local recurrence. One of the obstacles to patients routinely being offered radiation therapy is the concern over the added late toxicity that may occur. The present article is a report of the first 130 patients of a prospective phase II multicentre study in Australia and New Zealand. METHODS: The study was aimed at patients who had had a resection of melanoma in regional nodes or in a regional node basin. The patients were given adjuvant radiation therapy to a recommended dose of 48 Gy in 20 fractions over 4 weeks using accepted radiation techniques for each of the major node sites. This report describes the late toxicity of the treatment received by these patients. RESULTS: The results of late toxicity experienced in the study were acceptable. CONCLUSION: The regimen of radiation therapy used could form the basis for the treatment arm of a randomized trial.

Early toxicity from preoperative radiotherapy with continuous infusion 5-fluorouracil for resectable adenocarcinoma of the rectum: a Phase II trial for the Trans-Tasman Radiation Oncology Group.

PURPOSE: To assess the toxicity and the efficacy of preoperative radiotherapy with continuous infusion 5-fluorouracil (5-FU) for locally advanced adenocarcinoma of the rectum. METHODS AND MATERIALS: Eligible patients had newly diagnosed localized adenocarcinoma of the rectum within 12 cm of the anal verge, Stage T3-4, and were suitable for curative resection. Eighty-two patients were treated with radiotherapy-50.4 Gy in 28 fractions in 5.6 weeks, given concurrently with continuous infusion 5-FU, using either 96-h/week infusion at 300 mg/m(2)/day or 7-days/week infusion at 225 mg/m(2)/day. RESULTS: The median age was 59 years (range, 27-87), and 67% of patients were male. Pretreatment stages of the rectal cancer were T3, 89% and resectable T4, 11%, with endorectal ultrasound confirmation in 67% of patients. Grade 3 acute toxicity occurred in 5 of 82 patients (6%; 95% confidence interval [CI], 2-14%). Types of surgical resection were anterior resection, 61%; abdominoperineal resection, 35%; and other procedures, 4%. There was no operative mortality. Anastomotic leakage after low anterior resection occurred in 3 of 50 patients (6%; 95% CI, 1-17%). The pathologic complete response rate was 16% (95% CI, 9-26%). Pathologic Stages T2 or less occurred in 51%. CONCLUSION: Preoperative radiotherapy with continuous infusion 5-FU for locally advanced rectal cancer is a safe regimen, with a significant downstaging effect. It does not seem to lead to a significant increase in serious surgical complications.

Localization of small esophageal cancers for radiation planning using endoscopic contrast injection: report on a series of eight cases.

Recently, Barrett's esophagus and early adenocarcinomas have been detected increasingly frequently in routine follow-up of patients with gastroesophageal reflux. Although surgery is the treatment of choice, some patients are medically unfit for esophagectomy and, in this case, the only alternative curative therapy is radical chemoradiation therapy. In addition, some patients who present with symptoms have small tumors that cannot be localized accurately using routine imaging techniques. This report describes a series of eight patients with small esophageal cancers in whom the tumors were successfully localized following endoscopic injection of contrast, and treated with chemoradiation therapy. The treatment was successful in seven patients. This method of tumor localization demonstrated that conventional techniques are mostly unreliable when applied to very early cancers.

Eligibility audits for the randomized neuropathic bone pain trial (TROG 96.05).

In February 1996 the Trans-Tasman Radiation Oncology Group (TROG) initiated a two-arm, multicentre, prospective randomized trial on radiotherapy for neuropathic pain due to bone metastases (TROG 96.05). This trial compares the response to a single 8-Gy fraction with 20 Gy in five fractions. The accrual target is 270 patients. In order to evaluate compliance with eligibility criteria after approximately 1 year of accrual, an independent audit of the first 42 randomized patients was commissioned. This found that only one of these patients did not have genuine neuropathic pain, but that this patient and seven others (19%) had infringements of other eligibility/exclusion criteria for the trial. Accordingly it was decided to continue the full audit up to 90 patients. This detected no further patients without genuine neuropathic pain, and found only one other eligibility infringement (1/48; 2%). It is concluded that this quality assurance (QA) measure undertaken early in the trial led to significantly improved clinician awareness of, and compliance with, eligibility/exclusion criteria. It also enabled an accurate comparison of outcome data for all randomized versus all eligible patients at the time of the preplanned first interim analysis at 90 patients. In view of the excellent compliance demonstrated in the second audit, a one-in-five sampling is proposed for future audits from centres that have already accrued at least five consecutive eligible patients. This is consistent with TROG QA guidelines now operational.