Randomized double-blind trial of amifostine versus placebo for radiation-induced xerostomia in patients with head and neck cancer.

INTRODUCTION: The role of the radioprotector amifostine in ameliorating radiotherapy side effects in head and neck squamous cell carcinoma (HNSCC) is controversial. This trial aimed to determine whether pretreatment with amifostine reduced the incidence of Radiation Therapy Oncology Group grade ≥2 acute and late xerostomia in patients receiving definitive or adjuvant radiotherapy for HNSCC, without reducing tumour control or survival. METHODS: Between 14 September 2001 and 8 November 2004, 44 Royal Adelaide Hospital patients were randomized double-blind to receive amifostine (200 mg/m2 IV) or placebo (normal saline IV) 5 days/week, prior to standard radiotherapy (60-70 Gy), each having ≥75% of the parotids treated to ≥40 Gy. Side effects were assessed weekly during treatment, at 3 and 5 months after radiotherapy, then every 6 months until disease progression or death. RESULTS: The accrual target was 200 patients over 4-5 years, but the trial closed prematurely when only 44 patients had been randomized after 3 years. Of 41 evaluable patients, 80% (16/20) in the amifostine arm had grade ≥2 acute radiation salivary toxicity versus 76% (16/21) in the placebo arm (P = 1.00). The rate of grade ≥2 late radiation salivary toxicity at 12 months was 66% in the amifostine arm and 82% in the placebo arm (estimated hazard ratio 1.61, 95% confidence interval 0.74-3.49, P = 0.22). Other toxicities tended to be worse in the amifostine arm: acute grade 3-4 skin 35% vs 5% and mucous membrane 40% vs 5%; grade ≥2 vomiting 35% vs 5%, hypocalcaemia 25% vs 5% and fatigue 85% vs 33%, with only the latter retaining statistical significance after adjusting for multiple comparisons. There were no significant differences in failure-free (P = 0.70) or overall survival (P = 0.86), with estimated 4-year rates of 48% vs 54% and 49% vs 59% for the amifostine vs placebo arms respectively. CONCLUSION: There was no clear evidence that pretreatment with amifostine made any difference to the incidence of grade ≥2 acute or late xerostomia. Other toxicity tended to be more severe with amifostine. There was no effect on failure-free or overall survival. Acknowledging the low statistical power, these results do not support the use of IV amifostine pre-radiotherapy in HNSCC.

Intensity-modulated radiotherapy for nasopharyngeal carcinoma: clinical correlation of dose to the pharyngo-esophageal axis and dysphagia.

PURPOSE: The aim of this study was to quantify the dose delivered to the pharyngo-esophageal axis using different intensity-modulated radiation therapy (IMRT) techniques for treatment of nasopharyngeal carcinoma and to correlate this with acute swallowing toxicity. METHODS AND MATERIALS: The study population consisted of 28 patients treated with IMRT between February 2002 and August 2005: 20 with whole field IMRT (WF-IMRT) and 8 with IMRT fields junctioned with an anterior neck field with central shielding (j-IMRT). Dose to the pharyngo-esophageal axis was measured using dose-volume histograms. Acute swallowing toxicity was assessed by review of dysphagia grade during treatment and enteral feeding requirements. RESULTS: The mean pharyngo-esophageal dose was 55.2 Gy in the WF-IMRT group and 27.2 Gy in the j-IMRT group, p < 0.001. Ninety-five percent (19/20) of the WF-IMRT group developed Grade 3 dysphagia compared with 62.5% (5/8) of the j-IMRT group, p = 0.06. Feeding tube duration was a median of 38 days for the WF-IMRT group compared with 6 days for the j-IMRT group, p = 0.04. CONCLUSIONS: Clinical vigilance must be maintained when introducing new technology to ensure that unanticipated adverse effects do not result. Although newer planning systems can reduce the dose to the pharyngo-esophageal axis with WF-IMRT, the j-IMRT technique is preferred at least in patients with no gross disease in the lower neck.

Patients with multiple myeloma treated with thalidomide: evaluation of clinical parameters, cytokines,angiogenic markers, mast cells and marrow CD57+ cytotoxic T cells as predictors of outcome.

BACKGROUND AND OBJECTIVES: In vitro studies suggest that thalidomide has an immunoregulatory role and alters the marrow microenvironment. We assessed laboratory and clinical parameters in patients with myeloma treated with thalidomide as potential prognostic markers and looked for changes with therapy. DESIGN AND METHODS: Seventy-five patients with relapsed/refractory myeloma received thalidomide in a phase II trial. Serial samples of platelet-poor plasma and bone marrow were tested for angiogenic cytokines including vascular endothelial growth factor (VEGF), marrow microvessel-density (MVD), mast cells and CD57+ cell expression. The effects of these parameters on response rate (RR), progression-free survival (PFS) and overall survival (OS) were analyzed. RESULTS: Elevated baseline VEGF predicted for a superior RR (p=0.018) and PFS. Elevated CD57+ cells also predicted superior PFS (p=0.012). MVD did not predict for RR, PFS or OS, but MVD and VEGF fell significantly in responders. Multivariate analysis identified that inferior OS was associated with age >65 years (p=0.017), raised lactate dehydrogenase (p=0.001), raised hepatocyte growth factor levels (p=0.012) and low pre-treatment CD57+ cells (p<0.001). INTERPRETATION AND CONCLUSIONS: Our findings support the suggestion that thalidomide has anti-angiogenic and immunomodulatory effects in myeloma. The preferred method for assessing angiogenesis is plasma VEGF levels and the assessment of CD57+ cells for patients with myeloma receiving novel immunomodulatory drugs should be further investigated.

Prognostic factors predictive of response and survival to a modified FOLFOX regimen: importance of an increased neutrophil count.

PURPOSE: The aim of this study was to identify prognostic indicators of survival and response in a homogeneous population of chemotherapy-naive patients treated with oxaliplatin as part of 3 successive trials. PATIENTS AND METHODS: Patient data were derived from 3 successive phase II trials evaluating modifications of the FOLFOX4 (oxaliplatin/5-fluorouracil/leucovorin) regimen. Clinical and laboratory prognostic factors were identified from the literature. Multifactor analyses stratified by treatment cohort were performed to identify independent prognostic factors for progression-free survival (PFS), overall survival (OS), and response rate. RESULTS: One hundred thirty-four patients were enrolled across all 3 studies. Reduced PFS (n = 128) was associated with patients with the following characteristics: no previous surgery (P = 0.003); previous adjuvant chemotherapy (P = 0.015); > 1 organ involvement (P = 0.001); baseline absolute neutrophil count (ANC) > or = upper limit of normal (P = 0.001); and time from diagnosis to metastases < 9 months (P = 0.043). Poor OS (n = 128) was associated with patients with the following characteristics: performance status > 1 (P < 0.001); > 1 organ involvement (P = 0.018); and baseline ANC > or = upper limit of normal (P < 0.001). Response rate was related to previous surgery (P = 0.017) and performance status (P = 0.02). CONCLUSION: This analysis has identified the additional prognostic importance of an increased ANC for PFS and OS. Further consideration needs to be given to include markers of systemic inflammation such as ANC as well as relevant cytokine levels in a larger cohort of identically treated patients.

A multicenter phase II trial of thalidomide and celecoxib for patients with relapsed and refractory multiple myeloma.

Preclinical data indicates that cyclooxygenase-2 (COX-2) inhibition impairs plasma cell growth and potentially synergizes with thalidomide. We performed a trial in previously treated patients with myeloma using thalidomide up to a maximum dose of 800 mg/d with celecoxib (400 mg bid). Outcomes were compared with a prior trial of thalidomide. Sixty-six patients with median age of 67 (range, 43-85) received a median dose of thalidomide and celecoxib of 400 and 800 mg/d, respectively, with median durations of treatment of 27 and 13 weeks, respectively. The most common toxicities associated with premature discontinuation of celecoxib (n = 30 of 53, 57%) were fluid retention and deterioration of renal function. Overall response rate (RR) was 42% and with 20 months median follow-up; the actuarial median progression-free survival and overall survival were 6.8 and 21.4 months, respectively. Unlike our prior study, age >65 years was not predictive of inferior RR due to improvement in RR in older patients with the combination (37% versus 15%, P = 0.08). The RR was superior in patients who received a total dose of celecoxib exceeding 40 g in the first 8 weeks of therapy (62% versus 30%, P = 0.021). Progression-free survival and overall survival were also improved. Other predictors for inferior progression-free survival were age >65 years (P = 0.016) and elevated beta(2)-microglobulin (P = 0.017). This study provides evidence that the addition of high-dose celecoxib adds to the antimyeloma activity of thalidomide but this comes with unacceptable toxicity. Future studies should use newer COX-2 inhibitors with thalidomide, or their respective derivatives.

Nipple aspiration and ductal lavage in women with a germline BRCA1 or BRCA2 mutation.

INTRODUCTION: The aim of this study was to collect serial samples of nipple aspirate (NA) and ductal lavage (DL) fluid from women with germline BRCA1/2 mutations in order to create a biorepository for use in identifying biomarkers of breast cancer risk. METHODS: Between March 2003 and February 2005, 52 women with germline BRCA1 or BRCA2 mutations (median age 43 years, range 27 to 65 years) were scheduled for six-monthly NA, DL and venesection. DL was attempted for all NA fluid-yielding (FY) and any non-FY ducts that could be located at each visit. RESULTS: Twenty-seven (52%) women were postmenopausal, predominantly (19/27) from risk reducing bilateral salpingo-oophorectomy (BSO). FY ducts were identified in 60% of all women, 76% of premenopausal women versus 44% of postmenopausal (P = 0.026). Eighty-five percent of women had successful DL. Success was most likely in women with FY ducts (FY 94% versus non-FY 71% (P = 0.049). DL samples were more likely to be cellular if collected from FY ducts (FY 68% versus non-FY 43%; P = 0.037). Total cell counts were associated with FY status (FY median cell count 30,996, range 0 to >1,000,000 versus non-FY median cell count 0, range 0 to 173,577; P = 0.002). Four women (8%) had ducts with severe atypia with or without additional ducts with mild epithelial atypia; seven others had ducts with mild atypia alone (11/52 (21%) in total). Median total cell count was greater from ducts with atypia (105,870, range 1920 to >1,000,000) than those with no atypia (174, 0 to >1,000,000; P

The 'QUAD SHOT'--a phase II study of palliative radiotherapy for incurable head and neck cancer.

BACKGROUND AND PURPOSE: The primary objective of this study was to estimate the rate of tumour response to a cyclical hypofractionated palliative radiotherapy regimen (QUAD SHOT) in previously untreated patients with incurable squamous cell carcinoma of the head and neck. Secondary objectives were to prospectively evaluate toxicity, quality of life (QoL) and survival in these patients. PATIENTS AND METHODS: The QUAD SHOT consisted of 14 Gy in four fractions, given twice a day and at least 6h apart, for 2 consecutive days. This regimen was repeated at 4 weekly intervals for a further two courses if there was no tumour progression. The QoL tool used was an abbreviation of the EORTC QLQ-C30. RESULTS: Thirty eligible patients (29 Stage IV, 20 performance status 2-3) had at least one treatment and 16 patients completed all three cycles. Sixteen patients (53%) had an objective response (2CR, 14PR) and a further seven had stable disease. Median overall survival was 5.7 months, median progression free survival was 3.1 months. The treatment was very well tolerated, with improved QoL in 11 of 25 evaluable patients (44%). CONCLUSION: The QUAD SHOT regimen is an effective palliative treatment with minimal toxicity and a good response rate, which impacts positively on patients' QoL.

Intraoperative radiotherapy in women with early breast cancer treated by breast-conserving therapy.

BACKGROUND: Previous studies demonstrated the feasibility of intraoperative radiotherapy (IORT) to the primary tumour bed using a miniature electron beam driven X-ray source for early breast cancer. This study aimed to evaluate the feasibility of IORT as a tumour bed boost after whole breast irradiation (WBI) in breast conserving therapy. METHODS: This was a single-arm prospective trial for women with breast cancer measuring <3 cm. After breast-conserving surgery, a single IORT dose of 5 Gray (Gy) prescribed to 10 mm from the applicator surface was delivered to the breast tissues using 50 kV X-ray followed by standard WBI. The feasibility rate of protocol therapy was defined as the percentage of all women who completed both IORT and WBI. A desirable completion rate was >90%. The protocol therapy would be considered unsuitable for further development if the completion rate was <75% or severe acute toxicity occurred in >15% of women who received IORT. RESULTS: Sixty patients were recruited for the study. IORT and WBI were delivered in 58 and 55 patients, respectively. Thus, the feasibility rates of IORT alone and both IORT and WBI were 97% (95% confidence interval (CI), 89-99%) and 92% (95% CI, 83-97%), respectively. A severe surgical complication or grade 3 or 4 acute radiation toxicity were identified in 10% (6/58) of women who had IORT. CONCLUSION: Tumour bed boost using IORT in women with early breast cancer treated with conservative surgery and WBI was shown to be feasibly consistent with previous studies.

Phase II study of autologous stem cell transplant using busulfan-melphalan chemotherapy-only conditioning followed by interferon for relapsed poor prognosis follicular non-Hodgkin lymphoma.

Alpha interferon has proven efficacy in prolonging remissions in patients with follicular non-Hodgkin lymphoma (NHL) when given concurrently with or after conventional-dose anthracycline-based chemotherapy, but there are limited data on its use after myeloablative conditioning. We prospectively evaluated the toxicity and efficacy of interferon given thrice weekly for up to 5 years post-engraftment in patients with relapsed follicular NHL undergoing autologous stem cell transplant using busulfan-melphalan conditioning. Thirty-seven patients were enrolled in this Australasian Leukaemia & Lymphoma Group study and transplanted between 1995 and 1999. Only one patient had received prior rituximab. Two patients died of transplant-related toxicity; 28 of the remainder commenced interferon, but it was discontinued prematurely in most patients due to toxicity (mainly fatigue and depression) or relapse. While the majority of patients (29/36 evaluable: 81%) achieved a complete remission based on clinical and CT scan criteria post-transplant, most relapsed relatively early, with a median progression-free survival of 2.4 years. The overall survival at 7 years was 49%. Eight patients (22%), however, remain alive a median of 9.3 years post-transplant, having never relapsed, and another six patients (16%) remain alive in durable remission after salvage therapy. These results demonstrate that interferon is poorly tolerated post-autograft and hence is unlikely to positively contribute to patient outcome. Long-term follow-up demonstrates that autografting may result in durable remissions in a meaningful minority of patients with relapsed follicular NHL.

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

BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) tubes have largely replaced nasogastric tubes (NGTs) for nutritional support of patients with head and neck cancer undergoing curative (chemo) radiotherapy without any good scientific basis. METHODS: A prospective study was conducted to compare PEG tubes and NGTs in terms of nutritional outcomes, complications, patient satisfaction, and cost. RESULTS: There were 32 PEG and 73 NGT patients. PEG patients sustained significantly less weight loss at 6 weeks post-treatment (median 0.8 kg gain vs 3.7 kg loss, p < .001), but had a high insertion site infection rate (41%), longer median duration of use (146 vs 57 days, p < .001), and more grade 3 dysphagia in disease-free survivors at 6 months (25% vs 8%, p = .07). Patient self-assessed general physical condition and overall quality of life scores were similar in both groups. Overall costs were significantly higher for PEG patients. CONCLUSION: PEG tube use should be selective, not routine, in this patient population.

Malignant ureteral obstruction: outcomes after intervention. Have things changed?

PURPOSE: We reviewed the clinical outcome for patients who underwent decompression of malignant ureteral obstruction by analyzing potential prognostic factors, technical success, complication rates and days spent in hospital. MATERIALS AND METHODS: Retrospective analysis of 102 patients who underwent decompression for malignant ureteral obstruction from 1991 to 2003 was performed. Data on overall survival, prognostic factors, technical failure, complications and days of hospitalization after decompression were examined. RESULTS: Median overall survival was 6.8 months (95% CI 4.8-9.3) and the overall survival rate at 12 months was 29% (95% CI 21%-39%). Univariate analyses found inferior overall survival associated with patients having metastases (p=0.041), undergoing nephrostomy (p=0.046), prior treatment for cancer (p=0.024) and diagnosis of malignant ureteral obstruction in previously established malignancy (p=0.043). After multivariate analysis poor prognostic factors were presence of metastases (p=0.020) and diagnosis of malignant ureteral obstruction in previously established malignancy (p=0.039). Unfavorable cohorts with 3 or 4 unfavorable baseline risk factors had an inferior overall survival (p=0.008) with 12-month overall survival rates of 12% to 19%. Initial decompression of malignant ureteral obstruction failed in 6% of patients (95% CI 2%-12%) and complications were experienced by 53% (95% CI 43%-63%). Patients were more likely to experience a complication if they had therapy after decompression (p=0.03). The median percentage of their remaining lifetime spent in hospital was 17.4% (range 0.21% to 100%). CONCLUSIONS: The overall survival of patients with malignant ureteral obstruction remains poor. Prognostic factors for decreased overall survival and prolonged hospital stay have been identified. Although the technical success of decompression has improved the subsequent complication rate is still high.

Clinical impact of, and prognostic stratification by, F-18 FDG PET/CT in head and neck mucosal squamous cell carcinoma.

BACKGROUND: The aim of this study was to determine prospectively the incremental value of positron emission tomography/computed tomography (PET/CT) over conventional assessment (clinical examination and CT/MRI imaging). METHODS: All patients undergoing (18)F-fluorodeoxyglucose (FDG)-PET/CT for primary head and neck mucosal squamous cell carcinoma between January 2002 and December 2003 (inclusive) were included in this study provided they had undergone contemporaneous conventional assessment of the head and neck region and had 12 months minimum follow-up. RESULTS: Seventy-six patients underwent 100 PET/CT scans. The majority of patients (74%) were treated with definitive (chemo)radiotherapy. Median follow-up time was 28 months. PET/CT led to a TNM classification alteration in 34% (12/35), a change in radiotherapy planning technique and/or dose in 29% (10/35), and altered treatment response assessment in 43% (13/30). A complete metabolic response was predictive of overall survival (p = .037). CONCLUSION: Our results support incorporation of PET/CT into the management paradigm of head and neck mucosal squamous cell carcinoma.

Relationship of hepatic functional imaging to irinotecan pharmacokinetics and genetic parameters of drug elimination.

PURPOSE: The marked variability of irinotecan (Ir) clearance warrants individualized dosing based on hepatic drug handling. The aims of this trial were to identify parameters from functional hepatic nuclear imaging (HNI) that correlate with (1) Ir pharmacology, and (2) single-nucleotide polymorphisms (SNPs) for the ABCB1 (P-glycoprotein) and UGT-1A1 genes, known to influence Ir handling. METHODS: Patients underwent genotyping for ABCB1 SNPs and UTUGT-1A1*28 carriage and HNI with 99mTc-DIDA (acetanilidoiminodiacetic acid)/99mTc-DISIDA (disofenin) and MIBI (99mTc-sestamibi) scans, probes for biliary transport proteins ABCC1 and -2, and ABCB1 function. HNI data were analyzed by noncompartmental and deconvolutional analysis to provide hepatic extraction and biliary excretion parameters. Patients received Ir, fluorouracil, and folinic acid using a weekly x2, every-3-weeks schedule. Plasma was taken for Ir and SN-38 analysis on day 1, cycle 1. RESULTS: Of the 21 patients accrued, Ir pharmacokinetics data were obtained from 16 patients. 99mTc-DIDA/DISIDA percent retention at 1 hour (1-hour RET) correlated to baseline serum bilirubin (P = .008). Both 99mTc-DIDA/DISIDA and MIBI 1-hour RET correlated with SN-38 area under the curve (AUC; P < .01). On multiple regression analysis, SN-38 AUC = -215 + 18.68 x bilirubin + 4.27 x MIBI 1-hour RET (P = .009, R2 = 44.2%). HNI parameters did not correlate with Ir toxicity or UGT1A1*28 carriage. MIBI excretion was prolonged in patients with the ABCB1 exon 26 TT variant allele relative to wild-type (P = .015). CONCLUSION: Functional imaging of hepatic uptake and excretory pathways may have potential to predict Ir pharmacokinetics. Evaluation of a larger cohort as well as polymorphisms in other biliary transporters and UGT1A1 alleles is warranted.