Preoperative cisplatin, fluorouracil, and docetaxel with or without radiotherapy after poor early response to cisplatin and fluorouracil for resectable oesophageal adenocarcinoma (AGITG DOCTOR): results from a multicentre, randomised controlled phase II trial.

BACKGROUND: Patients with oesophageal/gastro-oesophageal junction adenocarcinoma (EAC) not showing early metabolic response (EMR) to chemotherapy have poorer survival and histological response rates <5%. We investigated whether tailoring neoadjuvant therapy can improve outcomes in these patients. PATIENTS AND METHODS: Patients with resectable EAC were enrolled and randomised into two single-arm, multicentre phase II trials. After induction cisplatin and 5-fluorouracil (CF), all were assessed by day 15 positron emission tomography (PET). Patients with an EMR [maximum standardised uptake values (SUVmax) ≥35% reduction from baseline to day 15 PET] received a second CF cycle then oesophagectomy. Non-responders were randomised 1 : 1 to two cycles of CF and docetaxel (DCF, n = 31) or DCF + 45 Gy radiotherapy (DCFRT, n = 35) then oesophagectomy. The primary end point was major histological response (<10% residual tumour) in the oesophagectomy specimen; secondary end points were overall survival (OS), progression-free survival (PFS), and locoregional recurrence (LR). RESULTS: Of 124 patients recruited, major histological response was achieved in 3/45 (7%) with EMR, 6/30 (20%) DCF, and 22/35 (63%) DCFRT patients. Grade 3/4 toxicities occurred in 12/45 (27%) EMR (CF), 13/31 (42%) DCF, and 25/35 (71%) DCFRT patients. No treatment-related deaths occurred. LR by 3 years was seen in 5/45 (11%) EMR, 10/31 (32%) DCF, and 4/35 (11%) DCFRT patients. PFS [95% confidence interval (CI)] at 36 months was 47% (31% to 61%) for EMR, 29% (15% to 45%) for DCF, and 46% (29% to 61%) for DCFRT patients. OS (95% CI) at 60 months was 53% (37% to 67%) for EMR, 31% (16% to 48%) for DCF, and 46% (29% to 61%) for DCFRT patients. CONCLUSIONS: EMR is associated with favourable OS, PFS, and low LR. For non-responders, the addition of docetaxel augmented histological response rates, but OS, PFS, and LR remained inferior compared with responders. DCFRT improved histological response and PFS/LR outcomes, matching the EMR group. Early PET/CT has the potential to tailor therapy for patients not showing an early response to chemotherapy. TRIAL REGISTRATION: ACTRN12609000665235.

Health professional's perspectives of the barriers and enablers to cancer care for Indigenous Australians.

To investigate health professionals' perspectives about factors that impede or facilitate cancer care for Indigenous people. Semi-structured interviews with 22 health professionals involved in Indigenous cancer care. Data were interpreted using an inductive thematic analysis approach. Participants presented their perspectives on a number of barriers and enablers to Indigenous cancer care. Barriers were related to challenges with communication, the health system and coordination of care, issues around individual and community priorities and views of cancer treatment and health professional judgement. Enablers to cancer care were related to the importance of trust and rapport as well as health care system and support factors. The findings highlighted the need for recording of Indigenous status in medical records and a coordinated approach to the provision of evidence-based and culturally appropriate cancer care. This could go some way to improving Indigenous patient's engagement with tertiary cancer care services.

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.

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.

Recombinant interferon-alpha2a plus 5-fluorouracil for the treatment of metastatic melanoma.

The therapy of metastatic melanoma is limited by poor responses to known chemotherapeutic agents. The report of Mulder et al. (Proc ASCO 1992; 11: 347) raised the possibility of the known interaction between 5-fluorouracil and interferon-alpha2a improving response rates in melanoma. This study was designed to examine the effects of 5-fluorouracil plus interferon-alpha2a alone without the confounding effects of dacarbazine. Doses were chosen based on the earlier study rather than the higher doses used in colon cancer. Therapy for metastatic melanoma with 5-fluorouracil and interferon-alpha2a is manageable in terms of toxicity. The major toxicities were lethargy, nausea/anorexia and flu-like symptoms. These were thought to be primarily attributable to interferon-alpha2a. Only one case of severe diarrhoea occurred. The response rate of 14% is similar to the reported results of interferon-alpha2a treatment alone. On these data, there is no evidence of synergy using this dose and schedule.

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.

Disposition of epirubicin after intraarterial administration in Lipiodol to patients with hepatocellular carcinoma.

Delivering emulsions of anthracycline drugs in Lipiodol, an iodinated poppy-seed oil, via the hepatic artery for the treatment of hepatocellular carcinoma (HCC) has become increasingly popular. However, investigations to determine the extent to which the Lipiodol sequesters the anthracycline in the liver have been limited. Concern has been expressed that such emulsions are not stable and that the anthracycline is, therefore, released rapidly into the circulation. We studied the pharmacokinetics of epirubicin (50 mg m-2) in five patients with nonresectable primary hepatocellular carcinoma after infusion of an epirubicin/Lipiodol emulsion via the hepatic artery. We used a reliable and specific high-performance liquid chromatography assay that allows quantitation of plasma concentrations of epirubicin, epirubicinol, epirubicin glucuronide, and epirubicin aglycone. Although a large interpatient variability in pharmacokinetics was observed, our results were similar to historical data after epirubicin intravenous therapy. Only the results from one patient provided evidence of significant retention of the drug in the liver. It would appear that more stable formulations of epirubicin/Lipiodol are required to increase the efficacy of this form of treatment. We suggest that pharmacokinetic studies should accompany clinical evaluation of emulsions of epirubicin/Lipiodol for the treatment of HCC.

Cisplatin-based therapy: a neurological and neuropsychological review.

The present paper reviews research in the area of the broad-spectrum chemotherapeutic agent cisplatin (cis-diamminedichloro-platinum II) and examines the implications for clinical neuropsychology arising from the neurological disruption associated with cisplatin-based therapy. The paper begins with a brief review of cisplatin treatment in terms other than survival alone, and examines the side-effects and the potential central nervous system (CNS) dysfunction in terms of neurological symptoms and concomitant implications for neuropsychology. Two main implications for clinical neuropsychology arising from cisplatin therapy are identified. First, cisplatin therapy impacts upon the psychological well-being of the patient, particularly during and in the months following treatment. It is suggested that during this time, a primary role for neuropsychology is to focus upon the monitoring and the active enhancement of the patient's social, psychological and spiritual resources. Second, with regard to neurocognitive changes, the review suggests that (1) neurocognitive assessment may not yield stable results within 8 months following treatment and (2) while perceptual, memory, attentional and executive dysfunction may be predicted following cisplatin treatment, little systematic research has been carried out to investigate such a possibility. Future research might profitably address this issue and also specifically examine the effects of low dosage cisplatin-based therapy and the effects of recently developed neuroprotective agents. Finally, there is some evidence to suggest that women may be more susceptible to neurotoxicity during cisplatin therapy, but no gender-related cognitive effects are reported in the cisplatin literature. Future research could usefully investigate gender differences in association with cisplatin chemotherapy.

Case report: lamivudine therapy for submassive hepatic necrosis due to reactivation of hepatitis B following chemotherapy.

This report describes the case of a 53-year-old woman who developed severe hepatitis following chemotherapy for breast carcinoma. The patient was hepatitis B surface antigen positive, e antigen negative and e antibody positive and had high levels of hepatitis B virus-DNA. Liver biopsy revealed submassive hepatic necrosis, consistent with reactivation of hepatitis B. Treatment with lamivudine resulted in rapid loss of hepatitis B virus-DNA, resolution of hepatitis and clinical recovery.

Survival after phase II treatment of advanced renal cell carcinoma with taxol or high-dose interleukin-2.

From 1986 to 1989, 71 patients with advanced renal cell carcinoma were treated at one institution with either the Phase II agent, taxol, or one of several high dose interleukin-2 (IL-2) protocols. As no responses to taxol were seen, that group may represent the natural history of renal cell carcinoma in a Phase II population. The results of treatment with IL-2 were examined against this background. Concurrently, 17 patients received taxol and 14 patients IL-2. An additional 40 patients subsequently received IL-2. Five taxol patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 were excluded from the comparison as similar patients were ineligible for the IL-2 studies. There were more patients in the IL-2 groups with non-liver/lung metastases and ECOG PS 0 than in the taxol group. Six (43%) of concurrent IL-2 patients responded [complete response (CR) = 14%; partial response (PR) = 29%]. The response rate for all IL-2-treated patients was 22% (CR +/- 7%, PR +/- 15%). The response rate to IL-2 was higher in cases with ECOG PS 0, time to treatment < 12 months, and no prior chemotherapy. The median time to progression for the concurrent IL-2 group was 4.5 months (4.0 months for all IL-2 patients) and 2.5 months for taxol patients. Median survival for concurrent IL-2 patients was 12.5 months (12 months for all IL-2 patients) and 10 months for taxol patients. Durable remissions resulted in a 21% overall survival at 40 months for all IL-2 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

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.