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This phase I study was conducted to evaluate the safety and Maximum Tolerated Dose of PENAO (4-(N-(S-penicillaminylacetyl)amino)-phenylarsonous acid), a second-generation organic arsenical with anti-mitochondrial activity, when given as a continuous intravenous infusion (CIVI), in patients with advanced solid tumours. Eligibility criteria for this trial included age ≥ 18 years, advanced solid tumour, ECOG Performance Status ≤ 1 and adequate organ function. PENAO was administered by CIVI, with dose levels initially increased by infusion duration in a 21-day cycle at a fixed daily dose and then increased daily dose. Standard dose-limiting toxicity (DLT) definitions were used in a “3 + 3” design. Patients had regular monitoring of toxicity and efficacy. Pharmacokinetic assays of serum and urine As were performed. Twenty-six patients were treated across 8 dose levels. The only dose-limiting toxicity (DLT) observed was fatigue, that occurred in one patient treated at the highest dose level of 9 mg/m2/day. No significant organ toxicity or objective responses were observed, although there were two patients with stable disease lasting up to 7 months. Pharmacokinetic analysis unexpectedly indicated a half-life of 9–19 days, invalidating the CIVI dosing resulting in discontinuation of the study before the RP2D was defined. PENAO was administered by CIVI at dose levels up to 9 mg/m2/day with only one DLT noted. Pharmacokinetic studies invalidated the rationale for continuous dosing and led to discontinuation of the trial without defining a RP2D. Future clinical development of PENAO will use intermittent dosing schedule, alone and in combination with rapamycin.

Patients with cancer are at increased risk for infection, but the relative morbidity and mortality of all infections is not well understood. The objectives of this study were to determine the prevalence, incidence, time-trends and risk of mortality of infections associated with hospital admissions in patients with haematological- and solid-tumour malignancies over 11 years. A retrospective, longitudinal cohort study of inpatient admissions between 1 January 2007 and 31 December 2017 at the Peter MacCallum Cancer Centre was conducted using administratively coded and patient demographics data. Descriptive analyses, autoregressive integrated moving average, Kaplan-Meier and Cox regression modelling were applied. Of 45,116 inpatient hospitalisations consisting of 3033 haematological malignancy (HM), 18,372 solid tumour neoplasm (STN) patients and 953 autologous haematopoietic stem cell transplantation recipients, 67%, 29% and 88% were coded with ≥ 1 infection, respectively. Gastrointestinal tract and bloodstream infections were observed with the highest incidence, and bloodstream infection rates increased significantly over time in both HM- and STN-cohorts. Inpatient length of stay was significantly higher in exposed patients with coded infection compared to unexposed in HM- and STN-cohorts (22 versus 4 days [p

Background The role of FDG-PET/CT imaging in assessing response to immunotherapy in advanced cutaneous squamous cell carcinoma (CSCC) is unknown. This study compared complete metabolic response (CMR) rates by FDG-PET and RECIST1.1 via CT or MRI in patients on cemiplimab for > 10 months. Methods This was a single-centre retrospective study of 15 patients treated with cemiplimab for advanced CSCC who had CT/MRI and FDG-PET/CT at > 10 months to assess metabolic treatment response. The median age was 73 years (range 55–84) and 93% were male. RECIST1.1 and PERCIST1.0 tumor responses were evaluated by blinded readers. Results Seventy-three percent (11/15) (95%CI 44.9, 92.2%) achieved a CMR on PET. Of these 11, on RECIST1.1 there was one complete response, 9 partial responses and one stable disease. Conclusions In patients on cemiplimab for > 10 months, there was discordance between CR rates on FDG-PET versus RECIST1.1. FDG-PET/CT may have utility for clarifying depth of response in patients treated with immunotherapy for CSCC.

To report 5-year outcomes of a prospective registry study investigating posttherapy FDG PET/CT in women with locally advanced cervical cancer. A secondary analysis assessing the prognostic significance of HPV infection was performed. Patients underwent definitive chemoradiation followed by a single FDG PET/CT scan for response assessment. A complete metabolic response (CMR) was defined as no evidence of FDG-avid disease. Patients were dichotomized according to HPV infection status into a ‘higher-risk’ group and a ‘lower-risk’ group, with the higher-risk group comprising those with alpha-7 strain HPV (subtypes 18, 39 and 45) and those who were HPV-negative and the lower-risk group comprising those with alpha-9 strain HPV (subtypes 16, 31, 33, 52 and 58) and those with mixed strains. Survival outcomes, patterns of failure and salvage therapy outcomes were investigated for their association with metabolic response and HPV status. In 105 patients the median prospective follow-up was 5.2 years. The 5-year cancer-specific, overall and progression-free survival rates in patients with a CMR were 97 %, 93 % and 86 %, respectively. In patients without a CMR, the corresponding 5-year survival rates were 36 %, 22 % and 0 % respectively (p

Background: Human papillomavirus (HPV) infection is a powerful prognostic biomarker in a subset of head and neck squamous cell carcinomas, specifically oropharyngeal cancers. However, the role of HPV in non-oropharyngeal sites, such as the larynx, remains unconfirmed. Methods: We evaluated a cohort of 324 laryngeal squamous cell carcinoma (LSCC) patients for the expression of p16INK4A (p16) protein by immunohistochemistry (IHC) and for high-risk HPV E6 and E7 mRNA transcripts by RNA in situ hybridisation (ISH). p16 expression and HPV status were correlated with clinicopathological features and outcomes. Results: Of 307 patients assessable for p16 IHC, 20 (6.5%) were p16 positive. Females and node-positive patients were more likely to be p16 positive (P

PR-104 is a "pre-prodrug" designed to be activated to a dinitrobenzamide nitrogen mustard cytotoxin by nitroreduction in hypoxic regions of tumors. This study was conducted to establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and pharmacokinetics (PK) of PR-104 in patients with advanced solid tumors.Patients with solid tumors refractory or not amenable to conventional treatment were evaluated in a dose-escalation trial of PR-104 administered as a 1-h intravenous (IV) infusion every 3 weeks. The plasma PK of PR-104 and its primary metabolite, PR-104A, were evaluated.Twenty-seven patients received a median of two cycles of PR-104 in doses ranging from 135 to 1,400 mg/m(2). The MTD of PR-104 as a single-dose infusion every 3 weeks was established as 1,100 mg/m(2). One of six patients treated at 1,100 mg/m(2) experienced DLT of grade 3 fatigue. Above the MTD, the DLTs at 1,400 mg/m(2) were febrile neutropenia and infection with normal absolute neutrophil count. No objective responses were observed, although reductions in tumor size were observed in patients treated at dosesor = 550 mg/m(2). The plasma PK of PR-104 demonstrated rapid conversion to PR-104A, with approximately dose-linear PK of both species.PR-104 was well tolerated at a dose of 1,100 mg/m(2) administered as an IV infusion every 3 weeks. The area under the PR-104A plasma concentration-time curve at this dose exceeded that required for activity in human tumor cell cultures and xenograft models. The recommended dose of PR-104 as a single agent for phase II trials is 1,100 mg/m(2) and further trials are underway.

Paclitaxel, when combined with carboplatin, exhibits a platelet-sparing effect. Paclitaxel is formulated in Cremophor EL (CrEL), which has been shown in preclinical models to reduce haematological toxicity from radiotherapy and chemotherapy. We sought to determine the effect of a 3-h infusion of 20 ml/m2 (equivalent to 175 mg/m2 paclitaxel) CrEL on myelosuppression following carboplatin chemotherapy, and the effect of CrEL on carboplatin pharmacokinetics.A total of 16 patients with locally advanced or metastatic cancer were randomized to receive either CrEL or saline over 3 h prior to carboplatin (area under the curve, AUC, 5-7). Each patient was subsequently crossed over to the other treatment. Blood samples were collected at selected time-points for estimation of platinum AUC and 24-h platinum levels. Full blood counts were obtained three times per week.Of the 16 patients randomized, 15 were evaluable. Myelosuppression was measured by percentage fall at nadir and nadir levels. No significant differences were obtained when comparing CrEL and saline with respect to the above end-points after adjusting for multiple testing. There was no evidence to indicate that CrEL altered the pharmacokinetics of carboplatin.CrEL at this dose and schedule does not appear to be a major contributory factor to the platelet-sparing effect of paclitaxel when combined with carboplatin, nor does it alter the pharmacokinetics of carboplatin.

To compare glomerular filtration rate measured by technetium-99m ([Tc(99m)]) DTPA clearance with estimated creatinine clearance (CrCl) (Cockcroft and Gault (CG) method) in patients with serum creatinine (Scr) levels0.06 mmol l(-1), and determine the effect of rounding serum creatinine to 0.06 mmol l(-1). Patients with serum creatinine values0.06 mmol l(-1) at the time of [Tc(99m)] clearance determination were identified. Creatinine clearance was calculated by the CG method using both actual and rounded Scr values. A total of 419 adults had GFR measured by technetium-99m diethyl triamine penta-acetic acid ([Tc(99m)] DTPA) clearance. Out of this group, 26 patients had a serum creatinine value0.06 mmol l(-1). The CG estimates of renal function using actual serum creatinine resulted in an overall overestimation of 12.9% when compared to [Tc(99m)] DTPA clearance. When the value of serum creatinine was rounded to 0.06 mmol l(-1), the formula underestimated renal function by -7.0%. Analysis of estimated creatinine clearance for different levels of renal function showed significant differences to [Tc(99m)] DTPA clearance. Rounding up of serum creatinine to 0.06 mmol l(-1) improved the predictive ability of the CG method for the patients with [Tc(99m)] DTPA clearance/=100 ml min(-1), but worsened the effect in those100 ml min(-1). This work indicates that when bedside estimates of renal function are calculated using the CG formula actual Scr should be used first to estimate CrCl. If the resultant CrCl is/=100 ml min(-1), then the Scr should be rounded up to 0.06 mmol l(-1) and CrCl recalculated. Further assessment of this approach is warranted in a larger cohort of patients.

Squamous cell carcinoma (SCC) of the head and neck (H&N) represents a major international health problem. The overwhelming majority of H&N cancers are strongly associated with tobacco use, and the intense global marketing of tobacco products suggests that it is unlikely there will be a decrease in H&N cancer incidence in the near future. Ongoing advances in surgical techniques continue to diminish treatment-related morbidity for patients with advanced disease. New developments in radiation and chemotherapy suggest that nonoperative treatment strategies will increasingly accomplish effective disease control, particularly with the refinement of concurrent chemoradiotherapy regimens and the use of new molecular agents which modulate H&N tumor growth. In this article, we highlight selected advances in surgery, radiation, and chemoradiation, which hold particular promise for the future of H&N cancer therapy. The evolution of surgical techniques includes the increasing use of selective neck dissection, the use of conservation techniques in the management of selected laryngeal and hypopharyngeal tumors, the use of free tissue transfer for optimal reconstruction and the increased availability of expertise in combined surgical approaches for tumors of the skull base. Altered radiation fractionation has evolved to a mature state of knowledge in recent years based primarily on clinical trials performed in patients with advanced H&N cancer. A major current challenge involves how to best interdigitate optimal radiation fractionation with concurrent chemotherapy regimens in H&N cancer. Among a series of new molecular agents under active investigation in H&N cancer, two specific examples with high promise are discussed, which exploit tumor hypoxia (tirapazamine) and overexpression of the epidermal growth factor receptor (EGFR inhibitors), respectively. These and other stepwise advances are contributing to the gradual reduction in global mortality rates for H&N cancer patients observed over the last decade, as well as to diminishing the adverse impact on patient quality of life that commonly accompanies treatment for this complex tumor site.

The use of high-dose chemotherapy for metastatic breast cancer has been an area of recent interest and the role of such treatment in the management of metastatic breast cancer is still to be defined. Multiple studies have suggested that such treatment can be given with minimal morbidity and mortality. We describe two cases of life-threatening interstitial pneumonitis, following high-dose chemotherapy (HDT) with cyclophosphamide, thiotepa and docetaxel with stem cell rescue given for metastatic breast cancer. The available relevant literature is reviewed.

This phase I study was designed to determine the optimal dosages of a novel repetitive high-dose therapy regimen for patients with metastatic breast cancer (MBC). The planned treatment was three cycles of high-dose cyclophosphamide, thiotepa and docetaxel delivered every 35 days with progressive dose-escalation in successive cohorts. Each cycle was supported by peripheral blood progenitor cells (PBPC) and filgrastim. Eighteen patients were entered into this trial. Of the planned 54 treatment cycles, 44 were delivered and 11 patients completed all three cycles. The dose-limiting toxicities were interstitial pneumonitis and mucositis with moderately severe diarrhea (n = 3) and rash (n = 3). There were no treatment-related deaths. Of the 17 patients with evaluable disease, 16 patients responded with six patients achieving a complete remission and an additional four patients achieving no detectable disease (negative re-staging including PET scan) but a persistently abnormal bone scan. At a median follow-up of 12 months, median progression-free survival was 11 months with the median overall survival not reached. The recommended doses for phase II/III studies are cyclophosphamide (4 g/m2), thiotepa (300 mg/m2) and docetaxel (100 mg/m2). Bone Marrow Transplantation (2000) 26, 955–961.

The objectives of this phase I trial were to determine the maximally tolerated doses of the combination of epirubicin and paclitaxel with and without G-CSF (granulocyte colony stimulating factor) support and to investigate whether epirubicin pharmacokinetics are altered by paclitaxel. Patients with advanced cancer, performance status 0-2, and a normal left ventricular ejection fraction who had received up to 1 prior chemotherapy regimen were treated with epirubicin followed by a 3-hour infusion of paclitaxel repeated every 3 weeks. Dose levels studied were (paclitaxel/epirubicin) 155/75, 175/75, 175/90, 200/90 mg/m2 without G-CSF and 175/90 mg/m2 with G-CSF. Thirty-five patients were entered and all were assessable for toxicity. The dose-limiting dose level was 175 mg/m2 paclitaxel and 90 mg/m2 epirubicin with limiting toxicities of febrile neutropenia, diarrhea and esophagitis. The addition of G-CSF did not allow escalation of epirubicin. No significant cardiac toxicity was observed. Epirubicin pharmacokinetics were studied during the first 2 cycles in 6 patients, who were randomized to receive 1 cycle with no interval between the completion of the epirubicin and the commencement of the paclitaxel infusion and the other cycle with a 72-hour interval between the drugs. There was no substantial effect of paclitaxel on epirubicin or epirubicinol pharmacokinetics, although there was a marginal increase in glucoronidation. In conclusion, paclitaxel 175 mg/m2 and epirubicin 75 mg/m2 is recommended for phase II and III studies.

The effects of 4-demethoxydaunorubicin (idarubicin, IDA) and MX2, a new morpholino-anthracycline, on up-regulation of the MDR1 gene in the low-level multidrug resistant (MDR) cell line CEM/A7R were compared at similar concentrations (IC10, IC50and IC90) over a short time exposure (4 and 24 h). The chemosensitivity of each drug was determined by a 3-day cell growth inhibition assay. Compared with epirubicin (EPI), IDA and MX2 were 17- and eightfold more effective in the CEM/A7R line respectively. No cross-resistance to 5-FU was seen in the CEM/A7R line. Verapamil (5 μM) and PSC 833 (1 μM), which dramatically reversed resistance to EPI in the CEM/A7R line, had no sensitizing effect on the resistance of this line to MX2, but slightly decreased resistance to IDA. The sensitivity to 5-FU was unchanged by these modulators. The induction of MDR1 mRNA expression by IDA, MX2 and 5-FU was analysed by Northern blotting and semiquantitatively assessed by scanning Northern blots on a phosphorimager. The relative level of MDR1 expression was expressed as a ratio of MDR1 mRNA to the internal RNA control glyceraldehyde-3-phosphate dehydrogenase (GAPDH). IDA, MX2 and 5-FU differentially up-regulated MDR1 mRNA in the CEM/A7R line in a dose-dependent manner. Both IDA and MX2 induced MDR1 expression within 4 h. 5-FU up-regulated MDR1 expression only when drug exposure was prolonged to 24 h. Based on MRK 16 binding, flow cytometric analysis of P-glycoprotein (Pgp) expression paralleled the increase in MDR1 mRNA levels. For the three anthracyclines, the increase in MDR1 expression was stable in cells grown in the absence of drug for more than 3 weeks after drug treatment. The induction of MDR1 expression by 5-FU was transient, associated with a rapid decrease in the increased Pgp levels which returned to baseline 72 h after the removal of 5-FU. This study demonstrates that MDR1 expression can be induced by analogues of anthracyclies not pumped by Pgp, and that this induction appears to be stable despite a 3-week drug-free period. © 1999 Cancer Research Campaign