Detection of genomic mutations in blood and urine free circulating tumour DNA in patients with inoperable and metastatic lung adenocarcinoma harbouring an EGFR mutation in tissue: a UK pilot study.

The development of methodologies to analyse circulating tumour DNA (ctDNA) in the blood or urine of cancer patients provides an invaluable resource that can be used for diagnosis and prognosis and to evaluate response to treatments. Lung cancer has seen in the last years a revolution in treatment strategy with the use of several classes of EGFR inhibitors. However, almost invariably, resistance to such therapies appears. In this paper, we describe a pilot, longitudinal study with 20 patients with confirmed EGFR mutations in tissue biopsy for lung cancer. The objective of the study was to determine whether ctDNA from plasma and/or urine could be used to monitor the EGFR mutational status of patients with confirmed EGFR mutation-positive non-small cell lung cancer (NSCLC) during treatment with EGFR inhibitors. Blood and urine were collected monthly over periods ranging from 6 to 16 months. CtDNA was analysed in each patient for the presence of several known mutations that predispose to resistance to EGFR inhibitors. We have proven that serial monitoring of ctDNA from both plasma and urine is feasible and that patients are willing to participate in this process. We have also shown that longitudinal ctDNA monitoring may detect resistance mutations before the development of radiological and clinical disease progression.

Immunotherapy-related adverse events in real-world patients with advanced non-small cell lung cancer on chemoimmunotherapy: a Spinnaker study sub-analysis.

Background: The Spinnaker study evaluated survival outcomes and prognostic factors in patients with advanced non-small-cell lung cancer receiving first-line chemoimmunotherapy in the real world. This sub-analysis assessed the immunotherapy-related adverse effects (irAEs) seen in this cohort, their impact on overall survival (OS) and progression-free survival (PFS), and related clinical factors. Methods: The Spinnaker study was a retrospective multicentre observational cohort study of patients treated with first-line pembrolizumab plus platinum-based chemotherapy in six United Kingdom and one Swiss oncology centres. Data were collected on patient characteristics, survival outcomes, frequency and severity of irAEs, and peripheral immune-inflammatory blood markers, including the neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII). Results: A total of 308 patients were included; 132 (43%) experienced any grade irAE, 100 (32%) Grade 1-2, and 49 (16%) Grade 3-4 irAEs. The median OS in patients with any grade irAES was significantly longer (17.5 months [95% CI, 13.4-21.6 months]) than those without (10.1 months [95% CI, 8.3-12.0 months]) (p<0.001), either if Grade 1-2 (p=0.003) or Grade 3-4 irAEs (p=0.042). The median PFS in patients with any grade irAEs was significantly longer (10.1 months [95% CI, 9.0-11.2 months]) than those without (6.1 months [95% CI, 5.2-7.1 months]) (p<0.001), either if Grade 1-2 (p=0.011) or Grade 3-4 irAEs (p=0.036). A higher rate of irAEs of any grade and specifically Grade 1-2 irAEs correlated with NLR <4 (p=0.013 and p=0.018), SII <1,440 (p=0.029 ad p=0.039), response to treatment (p=0.001 and p=0.034), a higher rate of treatment discontinuation (p<0.00001 and p=0.041), and the NHS-Lung prognostic classes (p=0.002 and p=0.008). Conclusions: These results confirm survival outcome benefits in patients with irAEs and suggest a higher likelihood of Grade 1-2 irAEs in patients with lower NLR or SII values or according to the NHS-Lung score.

The Effects of GCSF Primary Prophylaxis on Survival Outcomes and Toxicity in Patients with Advanced Non-Small Cell Lung Cancer on First-Line Chemoimmunotherapy: A Sub-Analysis of the Spinnaker Study.

GCSF prophylaxis is recommended in patients on chemotherapy with a >20% risk of febrile neutropenia and is to be considered if there is an intermediate risk of 10−20%. GCSF has been suggested as a possible adjunct to immunotherapy due to increased peripheral neutrophil recruitment and PD-L1 expression on neutrophils with GCSF use and greater tumour volume decrease with higher tumour GCSF expression. However, its potential to increase neutrophil counts and, thus, NLR values, could subsequently confer poorer prognoses on patients with advanced NSCLC. This analysis follows on from the retrospective multicentre observational cohort Spinnaker study on advanced NSCLC patients. The primary endpoints were OS and PFS. The secondary endpoints were the frequency and severity of AEs and irAEs. Patient information, including GCSF use and NLR values, was collected. A secondary comparison with matched follow-up duration was also undertaken. Three hundred and eight patients were included. Median OS was 13.4 months in patients given GCSF and 12.6 months in those not (p = 0.948). Median PFS was 7.3 months in patients given GCSF and 8.4 months in those not (p = 0.369). A total of 56% of patients receiving GCSF had Grade 1−2 AEs compared to 35% who did not receive GCSF (p = 0.004). Following an assessment with matched follow-up, 41% of patients given GCSF experienced Grade 1−2 irAEs compared to 23% of those not given GCSF (p = 0.023). GCSF prophylaxis use did not significantly affect overall or progression-free survival. Patients given GCSF prophylaxis were more likely to experience Grade 1−2 adverse effects and Grade 1−2 immunotherapy-related adverse effects.

Protocol for a prospective observational cohort study collecting data on demographics, symptoms and biomarkers in people with mesothelioma (ASSESS-meso).

INTRODUCTION: Mesothelioma is a heterogeneous disease that can be challenging to monitor and prognosticate. ASSESS-meso is a multicentre, prospective, longitudinal observational cohort study of patients with mesothelioma. The primary aim is to describe different clinical phenotypes and investigate predictive and prognostic factors, including biomarkers from blood and pleural fluid. The secondary aim is to provide a resource for future trials and substudies. METHODS AND ANALYSIS: We aim to recruit 700 patients with a histological, cytological or clinicopathological diagnosis of mesothelioma, at any anatomical site (pleural, peritoneal, pericardial, etc). Longitudinal data will be collected, including clinical information, radiological investigations, blood tests and patient-reported outcome measures for breathlessness, chest pain and sweats. Preplanned analyses will use Cox proportional hazards method to evaluate factors associated with survival, linear and logistic regression models to investigate associations with symptoms, and analysis of variance modelling to explore changes in symptoms over time. ETHICS AND DISSEMINATION: Ethical approval has been granted by the Research Ethics Committee South West-Central Bristol (17-SW-0019) and Health Research Authority (IRAS ID 220360). A study steering committee has been established and results will be published OpenAccess in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN: 61861764.

Concept: A randomised multicentre trial of first line chemotherapy comparing three weekly cabazitaxel versus weekly paclitaxel in HER2 negative metastatic breast cancer.

BACKGROUND: Paclitaxel is commonly used as first-line chemotherapy for HER2-negative metastatic breast cancer (MBC) patients. However, with response rates of 21.5-53.7% and significant risk of peripheral neuropathy, there is need for better chemotherapy. PATIENTS AND METHODS: This open-label phase II/III trial randomised HER2-negative MBC patients 1:1 to either 6 cycles of three-weekly cabazitaxel (25 mg/m2), or, weekly paclitaxel (80 mg/m2) over 18 weeks. The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (ORR), time to response (TTR), overall survival (OS), safety and tolerability and quality of life (QoL). RESULTS: 158 patients were recruited. Comparing cabazitaxel to paclitaxel, median PFS was 6.7 vs 5.8 months (HR 0.87; 80%CI 0.70-1.08, P = 0.4). There was no difference in median OS (20.6 vs 18.2 months, HR 1.00; 95%CI 0.69-1.45, P = 0.99), ORR (41.8% vs 36.7%) or TTR (HR 1.09; 95%CI 0.68-1.75, P = 0.7). Grade ≥3 adverse events occurred in 41.8% on cabazitaxel and 46.8% on paclitaxel; the most common being neutropenia (16.5%) and febrile neutropenia (12.7%) cabazitaxel and neutropenia (8.9%) and lung infection (7.6%) paclitaxel. Peripheral neuropathy of any grade occurred in 54.5% paclitaxel vs 16.5% cabazitaxel. Mean EQ-5D-5L single index utility score (+0.05; 95%CI 0.004-0.09, P = 0.03) and visual analogue scale score (+7.7; 95%CI 3.1-12.3, P = 0.001) were higher in cabazitaxel vs paclitaxel. CONCLUSIONS: Three-weekly cabazitaxel in HER2-negative MBC does not significantly improve PFS compared to weekly paclitaxel, although it has a lower risk of peripheral neuropathy with better patient reported QoL outcomes. It is well tolerated and requires fewer hospital visits.

A trial of intra-pleural bacterial immunotherapy in malignant pleural mesothelioma (TILT) - a randomised feasibility study using the trial within a cohort (TwiC) methodology.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive thoracic malignancy with a poor prognosis. Systemic immunotherapy is an effective frontline treatment for MPM, and there is a scientific rationale supporting the possible efficacy of local, i.e. intra-pleural immune modulators. Trial of intra-pleural bacterial immunotherapy (TILT) investigated the feasibility of performing a randomised trial of intra-pleural bacterial immunotherapy in people with MPM, using the trials within cohorts (TwiC) methodology. METHODS: TILT was a multicentre, three-armed, randomised, feasibility TwiC of intra-pleural OK432, BCG, or usual care in people with MPM. Eligible participants were identified from within the ASSESS-meso study, a prospective, longitudinal, observational cohort study, and were randomly selected to be offered a single dose of OK432 or BCG, via an indwelling pleural catheter. The primary outcome was feasibility, evaluated against prespecified recruitment, attrition and data completeness targets. The acceptability of trial processes and interventions was assessed during qualitative interviews with participants and family members at the end of the trial. TILT was registered prospectively on the European Clinical Trials Registry (EudraCT number 2016-004,727-23) and the ISRCTN Register on 04 December 2017. RESULTS: Seven participants were randomised from a planned sample size of 12; thus, the 66% recruitment rate target was not met. Two participants withdrew after randomisation, breaching the pre-stated attrition threshold of 10%. It was not possible to maintain blinding of control participants, which negated a fundamental tenet of the TwiC design. The trial processes and methodology were generally acceptable to participants and relatives, despite several recipients of intra-pleural bacterial agents experiencing significant local and systemic inflammatory responses. CONCLUSION: It was possible to design a clinical trial of an investigational medicinal product based on the TwiC design and to obtain the necessary regulatory approvals. However, whilst acceptable to participants and relatives, the TwiC design was not a feasible method of investigating intra-pleural bacterial immunotherapy in people with MPM. Future trials investigating this topic should consider the eligibility constraints and recruitment difficulties encountered. TRIAL REGISTRATION: TILT was registered prospectively on the European Clinical Trials Registry (EudraCT number 2016-004727-23 ) and the ISRCTN Register ( 10432197 ) on 04 December 2017.

Efficacy outcomes and prognostic factors from real-world patients with advanced non-small-cell lung cancer treated with first-line chemoimmunotherapy: The Spinnaker retrospective study.

BACKGROUND: Efficacy outcomes and prognostic factors of real-world patients with advanced non-small cell lung cancer (aNSCLC) treated with first-line chemoimmunotherapy are still limited. PATIENTS AND METHODS: In the retrospective Spinnaker study, data was collected from patients in six United Kingdom and one Swiss oncology centres with first-line pembrolizumab plus platinum-based chemotherapy. Efficacy outcomes and potential prognostic factors were estimated aiming at developing a prognostic model. RESULTS: Three-hundred-eight patients were included, 32% ≥ 70 years, with ≥ 3 metastatic sites in 33%, brain or liver metastases in 10% and 12%, respectively. With a median follow-up of 18.0 months (mo.) (range, 15.9-20.1), median overall survival (OS) and progression-free survival (PFS) were 12.7 mo. (range, 10.2-15.2), and 8.0 mo. (range, 7.1-8.8), respectively. The neutrophils-to-lymphocytes ratio (NLR) and systemic immune-inflammatory index (SII) (i.e., NLR × platelet count) were both significantly higher in ECOG PS 1 (p = 0.0147 and p = 0.0018, respectively), underweight or normal body mass index (p = 0.0456 and p = 0.0062, respectively), ≥3 metastatic sites (p = 0.0069 and p = 0.112), pretreatment steroids (p = 0.0019 and p = 0.0017). By MVA, the number of metastatic sites ≥ 3 (p < 0.001 and p = 0.002), squamous histology (p = 0.033 and p = 0.013) and SII ≥ 1444 (p = 0.031 and p = 0.009, respectively) were associated with both worse OS and PFS and led to a highly discriminating three-class risk prognostic model. CONCLUSION: Real-world PFS with chemoimmunotherapy in aNSCLC patients is similar to that reported in clinical trials. A high number of metastatic sites, squamous histology and high SII are adverse prognostic factors that might contribute to a clinically useful prognostic model.

Prognostic effect of body mass index in patients with advanced NSCLC treated with chemoimmunotherapy combinations.

INTRODUCTION: It has been recognized that increasing body mass index (BMI) is associated with improved outcome from immune checkpoint inhibitors (ICIs) in patients with various malignancies including non-small cell lung cancer (NSCLC). However, it is unclear whether baseline BMI may influence outcomes from first-line chemoimmunotherapy combinations. METHODS: In this international multicenter study, we evaluated the association between baseline BMI, progression-free survival (PFS) and overall survival (OS) in a cohort of patients with stage IV NSCLC consecutively treated with first-line chemoimmunotherapy combinations. BMI was categorized according to WHO criteria. RESULTS: Among the 853 included patients, 5.3% were underweight; 46.4% were of normal weight; 33.8% were overweight; and 14.5% were obese. Overweight and obese patients were more likely aged ≥70 years (p=0.00085), never smokers (p<0.0001), with better baseline Eastern Cooperative Oncology Group-Performance Status (p=0.0127), and had lower prevalence of central nervous system (p=0.0002) and liver metastases (p=0.0395). Univariable analyses showed a significant difference in the median OS across underweight (15.5 months), normal weight (14.6 months), overweight (20.9 months), and obese (16.8 months) patients (log-rank: p=0.045, log rank test for trend: p=0.131), while no difference was found with respect to the median PFS (log-rank for trend: p=0.510). Neither OS nor PFS was significantly associated with baseline BMI on multivariable analysis. CONCLUSIONS: In contrast to what was observed in the context of chemotherapy-free ICI-based regimens, baseline BMI does not affect clinical outcomes from chemoimmunotherapy combinations in patients with advanced NSCLC.

Protocol for a mixed-method study to inform the feasibility of undertaking a large-scale multicentre study comparing the clinical and patient-reported outcomes of oncoplastic breast conservation as an alternative to mastectomy with or without immediate breast reconstruction in women unsuitable for standard breast-conserving surgery (the ANTHEM Feasibility Study).

INTRODUCTION: Approximately 40% of the 55 000 women diagnosed with breast cancer each year in the UK undergo mastectomy because they are considered unsuitable for standard breast-conserving surgery (BCS) due to tumour size or multiple tumour foci. Mastectomy can significantly impact women's quality of life, and only one in four women currently undergo immediate breast reconstruction (IBR).Level 2 oncoplastic breast-conserving surgery (OPBCS) combines removing the cancer with a range of plastic surgical volume replacement (eg, local perforator flaps) and volume displacement techniques (eg, therapeutic mammaplasty) that can extend the role of BCS and may allow some women not suitable for standard BCS to avoid mastectomy. High-quality research to determine whether OPBCS offers a safe and effective alternative to mastectomy±IBR is currently lacking. Preliminary work is needed to ensure a future large-scale study is feasible and well designed and addresses questions important to patients and the National Health Service. METHODS AND ANALYSIS: Mixed methods will be used to inform feasibility and design of a future large-scale study comparing the clinical effectiveness and cost-effectiveness of OPBCS and mastectomy±IBR. It will have four parts: (1) a National Practice Questionnaire to determine current practice and provision of oncoplastic breast and reconstructive surgery in the UK; (2) a pilot multicentre prospective cohort study to explore the proportion of patients choosing OPBCS versus mastectomy, the proportion in OPBCS is successful and clinical and patient-reported outcomes of different techniques at 3 and 12 months postsurgery; (3) a qualitative interview study to explore patients' attitudes to different procedures, rationale for decision-making and perceptions of outcomes; and (4) design of the future study.All centres offering OPBCS and mastectomy in the UK will be invited to participate. Recruitment is planned to commence winter 2020 and continue for 12 months. ETHICS AND DISSEMINATION: The study has ethical approval from the Wales Research Ethics Committee 6 National Research Ethics Service (REC Ref 20/WA/0225). Results will be presented at national and international meetings and published in peer-reviewed journals. We will work with patients to develop lay summaries and share these through patient groups and breast cancer charities. TRIAL REGISTRATION NUMBER: ISRCTN18238549.

Zoledronic acid in the management of mesothelioma - a feasibility study (Zol-A Trial): study protocol for a randomised controlled trial.

BACKGROUND: Nitrogen containing bisphosphonates such as zoledronic acid (ZA) are known to contain certain anti-cancer properties. These have been investigated in the past in various cancers such as breast, prostate and colon. ZA in particular has shown promising results in pre-clinical studies. We propose a multicentre double-blind randomised controlled feasibility study to assess the recruitment and acceptability of ZA/placebo alongside chemotherapy in malignant pleural mesothelioma (MPM). METHODS: Patients will be recruited for a 13-month period from October 2016 to November 2017. Eligible patients will be identified via the regional mesothelioma multidisciplinary team meeting. Those who receive chemotherapy will be randomised to receive either ZA or placebo alongside their chemotherapy. Those who decline chemotherapy will be offered to join the trial on the non-randomised open-labelled arm of the trial. Patients will receive a maximum of six cycles of ZA/placebo, at three-weekly cycles. All patients will be followed up for six months from randomisation. Semi-structured interviews to gather data on acceptability of trial procedures, tolerability of ZA and other relevant information will take place after the participants have completed their six cycles of treatment. For a better understanding about non-participation in mesothelioma trials we also aim to interview those who decline to take part in the trial. DISCUSSION: The qualitative and quantitative data gathered in this feasibility trial will hopefully pave the way to designing a robust full phase III trial to investigate the potential synergistic effect of ZA and current standard treatment for MPM, cisplatin-pemetrexed combination chemotherapy. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN45536692 . Registered on 9 August 2016. EudraCT no. 2015-004433-26.

Synergistic antitumour effects of rapamycin and oncolytic reovirus.

There are currently numerous oncolytic viruses undergoing clinical trial evaluation in cancer patients and one agent, Talimogene laherparepvec, has been approved for the treatment of malignant melanoma. This progress highlights the huge clinical potential of this treatment modality, and the focus is now combining these agents with conventional anticancer treatments or agents that enhance viral replication, and thereby oncolysis, in the tumour microenvironment. We evaluated the combination of reovirus with rapamycin in B16F10 cell, a murine model of malignant melanoma, based on potential mechanisms by which mTOR inhibitors might enhance viral oncolysis. Rapamycin was not immunomodulatory in that it had no effect on the generation of an antireovirus-neutralising antibody response in C57/black 6 mice. The cell cycle effects of reovirus (increase G0/G1 fraction) were unaffected by concomitant or sequential exposure of rapamycin. However, rapamycin attenuated viral replication if given prior or concomitantly with reovirus and similarly reduced reovirus-induced apoptotic cell death Annexin V/PI and caspase 3/7 activation studies. We found clear evidence of synergistic antitumour effects of the combination both in vitro and in vivo, which was sequence dependent only in the in vitro setting. In conclusion, we have demonstrated synergistic antitumour efficacy of reovirus and rapamycin combination.

Prophylactic radiotherapy for the prevention of procedure-tract metastases after surgical and large-bore pleural procedures in malignant pleural mesothelioma (SMART): a multicentre, open-label, phase 3, randomised controlled trial.

BACKGROUND: The use of prophylactic radiotherapy to prevent procedure-tract metastases (PTMs) in malignant pleural mesothelioma remains controversial, and clinical practice varies worldwide. We aimed to compare prophylactic radiotherapy with deferred radiotherapy (given only when a PTM developed) in a suitably powered trial. METHODS: We did a multicentre, open-label, phase 3, randomised controlled trial in 22 UK hospitals of patients with histocytologically proven mesothelioma who had undergone large-bore pleural interventions in the 35 days prior to recruitment. Eligible patients were randomised (1:1), using a computer-generated sequence, to receive immediate radiotherapy (21 Gy in three fractions within 42 days of the pleural intervention) or deferred radiotherapy (same dose given within 35 days of PTM diagnosis). Randomisation was minimised by histological subtype, surgical versus non-surgical procedure, and pleural procedure (indwelling pleural catheter vs other). The primary outcome was the incidence of PTM within 7 cm of the site of pleural intervention within 12 months from randomisation, assessed in the intention-to-treat population. This trial is registered with ISRCTN, number ISRCTN72767336. FINDINGS: Between Dec 23, 2011, and Aug 4, 2014, we randomised 203 patients to receive immediate radiotherapy (n=102) or deferred radiotherapy (n=101). The patients were well matched at baseline. No significant difference was seen in PTM incidence in the immediate and deferred radiotherapy groups (nine [9%] vs 16 [16%]; odds ratio 0·51 [95% CI 0·19-1·32]; p=0·14). The only serious adverse event related to a PTM or radiotherapy was development of a painful PTM within the radiotherapy field that required hospital admission for symptom control in one patient who received immediate radiotherapy. Common adverse events of immediate radiotherapy were skin toxicity (grade 1 in 50 [54%] and grade 2 in four [4%] of 92 patients vs grade 1 in three [60%] and grade 2 in two [40%] of five patients in the deferred radiotherapy group who received radiotherapy for a PTM) and tiredness or lethargy (36 [39%] in the immediate radiotherapy group vs two [40%] in the deferred radiotherapy group) within 3 months of receiving radiotherapy. INTERPRETATION: Routine use of prophylactic radiotherapy in all patients with mesothelioma after large-bore thoracic interventions is not justified. FUNDING: Research for Patient Benefit Programme from the UK National Institute for Health Research.

The impact of the 21-gene assay on adjuvant treatment decisions in oestrogen receptor-positive early breast cancer: a prospective study.

BACKGROUND: International guidelines, including NICE, recommend using the 21-gene Recurrence Score assay for guiding adjuvant treatment decisions in ER+, HER2-negative early breast cancer (BC). We investigated the impact of adding this assay to standard pathological tests on clinicians'/patients' treatment decisions and on patients' decisional conflict in the United Kingdom. METHODS: In this prospective multicentre study, eligibility criteria included: ER+ HER2-negative BC (N0/Nmic for patients ⩽50 years; ⩽3 positive lymph nodes for patients >50 years) and being fit for chemotherapy. Physicians'/patients' treatment choices and patients' decisional conflict were recorded pre- and post testing. RESULTS: The analysis included 137 patients. Overall, adjuvant treatment recommendations changed in 40.7% of patients, with the direction of the change consistent with the Recurrence Score results (net decrease in chemotherapy recommendation rate in low Recurrence Score patients and net increase in high Recurrence Score patients). Patients' choices were generally consistent with physicians' recommendations. Post-testing, patients' decisional conflict decreased significantly (P<0.0001). In the 67 patients meeting the NICE criteria for testing, the recommendation change rate was 49.3%. CONCLUSIONS: Recurrence Score testing significantly influenced treatment recommendations overall and in the subgroup of patients meeting the NICE criteria, suggesting that this test could substantially alter treatment patterns in the United Kingdom.

REO-10: a phase I study of intravenous reovirus and docetaxel in patients with advanced cancer.

PURPOSE: REOLYSIN (Oncolytics Biotech) consists of a wild-type oncolytic reovirus, which has selective cytotoxicity for tumor cells while sparing normal cells. In a phase I study as a single agent, repeated infusions of reovirus were safe with evidence of antitumor activity. Preclinical studies indicate potential for synergy between reovirus and chemotherapeutic agents. A multicenter, phase I dose escalation study was designed to assess the safety of combining reovirus with docetaxel chemotherapy in patients with advanced cancer. EXPERIMENTAL DESIGN: Patients received 75 mg/m(2) docetaxel (day 1) and escalating doses of reovirus up to 3 × 10(10) TCID(50) (days 1-5) every 3 weeks. RESULTS: Twenty-five patients were enrolled, and 24 patients were exposed to treatment, with 23 completing at least one cycle and 16 suitable for response assessment. Dose-limiting toxicity of grade 4 neutropenia was seen in one patient, but the maximum tolerated dose was not reached. Antitumor activity was seen with one complete response and three partial responses. A disease control rate (combined complete response, partial response, and stable disease) of 88% was observed. Immunohistochemical analysis of reovirus protein expression was observed in posttreatment tumor biopsies from three patients. CONCLUSION: The combination of reovirus and docetaxel is safe, with evidence of objective disease response, and warrants further evaluation in a phase II study at a recommended schedule of docetaxel (75 mg/m(2), three times weekly) and reovirus (3 × 10(10) TCID(50), days 1-5, every 3 weeks).