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Background. Sinonasal undifferentiated carcino- ma (SNUC) is an uncommon malignancy associated with poor prognosis. The optimal treatment approach for SNUC has not been established was performed. Methods. A retrospective review of all patients with SNUC seenatthePeterMacCallumCancerCentreovera12-yearperiod. Results. Ten patients with SNUC were identified, with nine having locally advanced disease (T4). Seven were treated with three cycles of platinum and 5-fluorouracil followed by radiation with two cycles of concurrent platinum. In these seven patients, the 2-year progress on-free survival was 43% (95% CI, 11% to 82%) and the 2-year overall survival was 64% (95% CI, 23% to 91%). One patient with a T1N0 nasal cavity tumor treated with radiation alone has not had a relapse. Two patients who were treated with initial surgical resection, prior to referral to our institution, received postoperative radiation, but they subse- quently had relapses and died. Conclusion. Induction chemotherapy followed by concur- rent chemoradiation is a promising treatment strategy for SNUC. A 2004 Wiley Periodicals, Inc. Head Neck 26: 435-441, 2004

The purpose of this study was to evaluate the local control, pattern of recurrence, overall survival, and prognostic factors of patients with squamous cell carcinoma (SCC), adenocarcinoma, and undifferentiated carcinoma of the paranasal sinuses (PNS) and nasal cavity (NC) presenting to our center for curative treatment over a 10-year period.Between 1991 and 2000, 60 patients with SCC (n = 32), adenocarcinoma (n = 25), and undifferentiated carcinoma (n = 3) of the PNS or NC were identified. Forty patients received surgery and postoperative radiotherapy, four surgery alone; 11, radiotherapy alone; three radical radiotherapy after surgical recurrence; one, chemoradiotherapy and surgery; and one, induction chemotherapy followed by radiotherapy.Forty-seven patients (78%) were seen with T3-4 disease; however, most (92%) were node negative on initial assessment. The predominant failure pattern was local disease persistence or recurrence. The estimated 2- and 5-year local control rates were 63% and 49%, respectively. Orbital and neural invasion significantly affected local control. The estimated 2- and 5 year overall survival rates were 57% and 40%, respectively.Local failure remains the dominant cause for poor outcome in this group of patients. Because of the proximity of critical normal structures, the ability to perform adequate surgery and to deliver effective radiotherapy is limited in many cases. The use of postoperative concurrent chemoradiotherapy warrants further investigation.

Objective Paclitaxel is most commonly infused over 3 hs rather than the original schedule of 24 h as the briefer infusion duration results in greater convenience, similar efficacy, significantly less myelosuppression, and less cost. While differences in toxicity between 3- and 24-h infusions are well described, there is little information about the effect of modest prolongation of infusion duration, which is often employed in patients who develop hypersensitivity reactions. To assess whether prolonging a 3-h infusion significantly increases the degree of neutropenia, we reviewed our data from a randomized, crossover trial of 3-h versus 6-h versus 24-h regimens of paclitaxel. Methods Results from 12 patients who were randomized to receive one 3-h, one 6-h and one 24-h infusion of paclitaxel in varied sequences during their first three cycles of treatment were analysed. The blood counts were monitored closely throughout each cycle of treatment. Results Crossover trial methodology was used to assess the differences in the degree of neutropenia caused by the three different infusion regimens. The 24-h infusion regimen resulted in significantly worse neutropenia than the 3- or 6-h infusion regimens. There was no statistically significant difference between the 3- and 6-h infusion regimens with respect to all endpoints. The estimated mean difference in the duration of grade 3 or 4 neutropenia between the 3- and 6-h infusion regimens (6 h − 3-h) was 1.1 day (95% CI: −0.9, 3.2), and for grade 4 neutropenia, the estimated mean difference in the duration was 0.8 day (95% CI: −0.4, 2.0). Conclusion Increasing the duration of paclitaxel infusions from 3 to 6 h does not result in a statistically significant increase in the degree of neutropenia. Any additional neutropenia is likely to be of brief duration.

The optimal chemoradiation regimen for stage III non-small cell lung cancer (NSCLC) has not been determined. In this phase I/II study, the use of twice-weekly paclitaxel concomitant with weekly cisplatin and thoracic radiotherapy (RT) was evaluated. Patients with stage III NSCLC (without pleural effusion or cervical lymphadenopathy) were treated with thoracic RT (60 Gy in 30 fractions over 6 weeks) with concurrent weekly cisplatin 20 mg/m(2) and escalating doses of twice-weekly paclitaxel (starting dose of paclitaxel of 20 mg/m(2) increased in increments of 5 mg/m(2)) in successive cohorts of three to six patients until two or more patients experienced dose limiting toxicities (DLTs) at a particular dose level. All patients were planned to be given a further two cycles of consolidation chemotherapy consisting of paclitaxel 175 mg/m(2) and carboplatin AUC 5 after completion of RT. Twenty-five patients were enrolled in this study from two institutions. At a dose of paclitaxel 35 mg/m(2), two of four treated patients had DLTs (1 grade 3 oesophagitis and pulmonary toxicity; 1 grade 3 oesophagitis and infection). The recommended dose was therefore determined to be 30 mg/m(2) and a total of 15 patients were enrolled in an expanded cohort at this level. The overall response rate for all patients was 64% (95% CI: 43-82%). The estimated median survival was 23.6 months with an estimated 1-year and 2-year survival of 72 and 49%, respectively. Paclitaxel can be safely given twice-weekly at a dose of 30 mg/m(2) in combination with weekly cisplatin (20 mg/m(2)) and thoracic RT (60 Gy), and this regimen has significant activity in stage III NSCLC.

Incidence: Nasopharyngeal cancer (NPC) is a rare disease in Caucasians and is commonly WHO Type 1 (squamous cell carcinoma) histology. NPC is endemic in southern China (the Guangdong Province), Hong Kong and Taiwan, and is usually WHO Type 3 (undifferentiated) histology. These differing patient cohorts and different staging systems have hampered the rate of progress in optimizing the management of NPC patients. Changing demographics: Melbourne's population demographics have changed significantly since 1985. Our NPC population currently bridges the endemic and non-endemic populations. Treatment: There have been major improvements in radiation therapy techniques. The optimal conformal radiation technique(s) to be used if IMRT is not available is discussed. Concurrent chemotherapy and radiation therapy (chemoradiation) is the current standard of treatment in NPC. The role of additional sequential chemotherapy is controversial. A randomized trial comparing induction chemotherapy and chemoradiation versus chemoradiation alone would be very informative.

The prognostic significance of extracranial distant metastasis detected by positron emission tomography (PET) was investigated in patients with non-small cell lung cancer (NSCLC). Forty-two patients staged with 18F-fluorodeoxyglucose-PET-detected distant metastasis before planned surgery (n = 7) or radical radiotherapy (RT)/chemoradiotherapy (n = 35) for NSCLC were identified from a prospective database. The influence of metastasis number and other prognostic factors was investigated using Cox's regression analysis. Treatment after PET included surgery (n = 2), radical RT (n = 5), palliative RT (n = 25), chemotherapy (n = 8) or supportive care (n = 2). All but 4 patients had died by the last follow-up. Median survival was 9 months overall, 12 months for 27 patients with single PET-detected metastasis and 5 months for 15 patients with > 1 metastasis (p = 0.009). It was found that the Eastern Cooperative Oncology Group performance status (p = 0.027) but not pre-PET stage, weight loss or metastasis site correlated with survival. PET-detected metastatic tumor burden appeared to influence survival and should be evaluated as a prognostic factor in NSCLC.

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.

In the article that accompanies this editorial, Janssens et al report the outcome results of a phase III trial of accelerated radiotherapy with carbogen and nicotinamide (ARCON) versus accelerated radiotherapy alone in the treatment of 345 patients with stages T2 to T4, any nodal stage, M0 laryngeal cancer. Despite the sound biologic rationale for accelerated radiotherapy plus carbogen and nicotinamide (ARCON) and the promising results from a large preceding nonrandomized study, no evidence of a therapeutic gain was seen in the definitive phase III trial. Specifically, no significant differences were observed in laryngeal preservation rates, disease-free survival, overall survival, treatment-related toxicity, or functional outcomes. The authors did note an improved regional nodal complete response rate in the ARCON arm as assessed clinically, but this did not translate into any improvement in disease-free survival after “salvage” neck dissection. Unfortunately, both the article and the protocol are unclear as to whether a neck dissection was stipulated for patients who failed to achieve a regional complete response by a certain time after treatment. If this was the case, the required neck dissection would normally be considered part of the definitive treatment package, and patients undergoing surgery would not be scored as having sustained a regional failure. In a translational research substudy involving 79 patients, the investigators estimated the hypoxic fraction of tumor cells in biopsies of the primary tumor by using pimonidazole staining. They reported that regional (but not local) control was significantly improved by treatment with ARCON in patients with more hypoxic primary tumors (defined as 2.6% pimonidazole staining) but not in patients with better oxygenated tumors. However, this conclusion is based on small numbers of neck failures and appears to take no account of the original neck node classification of these patients. It can therefore be considered no more than a hypothesisgenerating observation. Although these findings are consistent with the notion that any benefit from a hypoxia-targeting therapy will be restricted to the population with demonstrable hypoxia, an important caveat is that they did not actually assess hypoxia in the nodes. The hypoxia status of the primary and nodes has been reported to be discordant in studies that used hypoxic positron emission tomography (PET) imaging. ARCON is the latest in the growing list of interventions targeting hypoxia that have failed to realize their predicted potential in the treatment of unselected populations of patients with head and neck cancers. Strategies thathavepreviouslybeensubjectedtorandomizedclinical trials includehyperbaricoxygen, hypoxiccell radiosensitizers(misonidazole, etanidazole, and nimorazole), fast neutron therapy, concurrent chemotherapy with mitomycin C, and the hypoxic cell cytotoxin tirapazamine. Although a recent meta-analysis of trials of hypoxic modification did show a small but significant survival benefit, only nimorazole has entered clinical practice, and then only in Denmark, in combination with radiation without chemotherapy. It is an axiom of rational targeted therapy that the intervention can be successful only if the target is present and cure limiting. In the case of therapies targeting hypoxia, this requires not only that tumors harbor hypoxic clonogenic cells before treatment, but also that effective reoxygenation does not occur during treatment. Another important consideration as to whether hypoxia is cure limiting, at least for oropharyngeal tumors, is a tumor’s human papillomavirus (HPV) status. Recent data suggest that HPV-associated oropharyngeal cancers have a similarly high incidence of hypoxia compared with HPVnegative head and neck cancers but nonetheless retain their favorable prognosis. Furthermore, there are data from exploratory analyses of three randomized trials of hypoxia-targeting therapies that suggest that any benefit from these therapies may be restricted to patients with HPV-negative tumors. Several strategies have been used to detect tumor hypoxia before treatment, albeit with inconsistent correlations with outcome. These include oxygen electrode measurements, histochemical markers, plasma markers, functional imaging, and gene expression profiling. Use of such tests may enlarge the patient population potentially able to benefit from hypoxiatargeted therapy. Retrospective analyses of the Danish Head and Neck Cancer Study (DAHANCA) 5 trial have suggested that some of these tests may be predictive of benefit from nimorazole, and we have previously reported that patients with PETimageable hypoxia may benefit from tirapazamine. Nevertheless, such approaches have not been incorporated into phase III trials, at least in part because of the lack of a validated, reproducible test of tumor hypoxia that has been demonstrated to be suitable for use in multi-institutional clinical trials. The efficiency of reoxygenation during treatment is more difficult to measure and interpret. There are limited data from three small [18F]-misonidazole PET imaging studies about the persistence of hypoxia during treatment and correlation with outcome. It is noteworthy that in the Trans Tasman Radiation Oncology Group JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 15 MAY 2

Results of ZD0473 in platinum-pretreated ovarian cancer: analysis according to platinum free interval. Resistance to platinum-containing regimens can develop in many women, with ovarian cancer and may lead to relapse in > 80% of patients. ZD0473 is a new-generation platinum agent that, in preclinical studies, shows evidence of antitumour activity and overcomes platinum-resistance mechanisms. This Phase 11 trial has evaluated the efficacy and tolerability of ZD0473 in second-line ovarian cancer patients. Patients received ZD0473 120 mg/m(2) (1-h iv infusion, day 1 q 3-weeks); the starting dose was increased to 150 mg/m2 after a safety review. We report here on results when patients are divided into four cohorts depending upon whether they were considered platinum- resistant or -sensitive. Patients were placed into one of 3 cohorts if they were platinum resistant (relapsed/progressed 26 weeks (sensitive). Ninety-four patients were recruited to the trial (59 resistant, 35 sensitive; median age 58 [range 27-75] years; 86 with performance status [PSI less than or equal to1). Forty- nine patients received a starting dose of 120 mg/m(2), of which 15 escalated to 150 mg/m(2), and 45 received a starting dose of 150 mg/m(2). Overall, the median number of treatment cycles received was 3 (range 1-8). Grade 3/4 thrombocytopenia was the most common haematological adverse event occurring in 62% of patients overall. Grade 3/4 lethargy, vomiting and nausea were the most common non-haematological toxicities. No clinically significant oto-, nephro- or neurotoxicity was observed. Overall response rates for all platinum-resistant and - sensitive patients were 8.3% and 32.4%, respectively. Stable disease occurred in 17 resistant and 15 sensitive patients.

A phase II trial of ZD0473 in platinum-pretreated ovarian cancer. The primary aim of this phase 11 trial was to assess the antitumour activity of ZD0473 in ovarian cancer patients who had failed initial platinum-based therapy. Patients (n = 94) were classified as either platinum-sensitive (n = 35) or platinum-resistant (n = 59) depending on whether they had relapsed or progressed within 26 weeks of completing first-line platinum-based chemotherapy. Patients initially received 120 mg/m(2) ZD0473 as a 1-h intravenous (i.v.) infusion on day I of a 3-week cycle. If well tolerated, the dose could be escalated to 150 mg/m(2). Few patients (9%) withdrew because of treatment-related adverse events and no clinically significant oto-, nephro- or neurotoxicity was observed. Objective response rates for platinum-resistant and sensitive patients were 8.3 and 32.4%, respectively, and clinical benefit was observed in 76.5% of the sensitive patients. Median time to progression was 57 and 180 days, and median time to death was 242 and 402 days, for resistant and sensitive patients, respectively. In conclusion, ZD0473 has a manageable toxicity profile and encouraging activity in platinum-sensitive ovarian cancer patients.

The aim of this study was to determine the toxicity, response rate, failure-free survival, and overall survival in a treatment program comprising continuous infusion carboplatin, short infusion 5-fluorouracil (5-FU) and radiotherapy for localized carcinoma of the thoracic esophagus. To be eligible, patients were required to have Karnofsky performance status greater than or equal to 60, adequate organ function, and have received no prior therapy. Planned radiation dose was 50 Gy in 25 fractions over 5 weeks. 5-FU was to be administered commencing days 1 and 29 of radiotherapy, and given at a dose of I g/m 2 /d for 4 days as a continuous infusion. Carboplatin was to commence on day 1 of radiotherapy and be given throughout the period of radiation as a continuous infusion. The starting dose of carboplatin was 28 mg/m 2 /d. The protocol specified a 25% dose reduction of carboplatin if more than two of the first six patients experienced dose-limiting toxicity (DLT). DLT was defined as grade IV neutropenia lasting more than 7 days, grade IV thrombocytopenia, or any grade IV nonhematologic toxicity. All 23 patients in the study received protocol radiotherapy, except one who was given an extra 10 Gy. Seven patients received carboplatin at 28 mg/m 2 /d and 16 received 21 mg/m 2 /d, Hematologic DLTs were experienced by all of the seven patients receiving the higher dose. No patients in the low-dose group experienced hematologic DLTs, and only 2 of 16 ceased chemotherapy early because of myelosuppression. Three patients in the low-dose group experienced grade IV esophagitis but were able to complete protocol radiotherapy. Apart from esophagitis, nonhematologic toxicity was generally moderate or mild. Six patients had thrombosis complicating the central venous catheters. Endoscopy was performed in 21 patients (91%), with an overall complete response rate of 65% (CI: 43-84%) for the whole group or 71% (CI: 48-89%) for the endoscopically evaluated group. Estimated median failure-free survival time was 8.9 months (CI: 7.1-12.9), and estimated median overall survival time was 21.4 months (CI: 9.6-35.4). Carboplatin at 21 mg/m 2 /d as a continuous infusion may be given safely in combination with short infusional 5-FU and radiotherapy for localized carcinoma of the esophagus. This combination has resulted in response data comparable to that of larger studies of cisplatin-containing regimens and warrants further study, ideally in a phase III randomized controlled trial.

PURPOSE: To determine the efficacy and safety of epirubicin, cisplatin, and infusional fluorouracil (5-FU) chemotherapy followed by radiation with concurrent cisplatin in patients with locally and/or regionally advanced nasopharyngeal cancer. PATIENTS AND METHODS: Thirty-five patients were treated with three cycles of induction chemotherapy with epirubicin 50 mg/m2 and cisplatin 75 mg/m2 combined with continuous-infusion 5-FU 200 mg/m2 daily for 9 weeks, followed by concurrent chemoradiation of 60 Gy in 2-Gy fractions with cisplatin 20 mg/m2 daily for 5 days in weeks 1 and 6. RESULTS: Median age was 43 years, 74% had World Health Organization type III histology, and 91% had stage IV disease (International Union Against Cancer, ed 4). All patients received three cycles of induction chemotherapy, and 97% completed chemoradiation. The estimated 4-year progression-free survival rate was 81% (95% CI, 59% to 93%), and the estimated 4-year overall survival rate was 90% (95% CI, 74% to 97%). Only two patients have had a locoregional relapse by the close-out date despite the use of only 60 Gy. Induction chemotherapy was well tolerated, with 11% grade 3 or 4 stomatitis, 26% grade 3 vomiting, and no episodes of febrile neutropenia. Acute toxicities of chemoradiation were as follows: 23% grade 3 or 4 vomiting, 6% febrile neutropenia, 31% grade 3 mucositis, and 23% grade 3 skin toxicity. The most prevalent grade 3 late effects were xerostomia and hearing loss. CONCLUSION: This regimen was well tolerated, can be delivered as planned, and has resulted in excellent locoregional disease control and survival in patients with locally advanced nasopharyngeal cancer.

Traditionally, following high-dose therapy (HDT), unmanipulated autologous PBPC are infused. Alternatively, purified CD34+ cells can now be obtained by immunomagnetic separation using the CliniMACS device. Limited data currently exist examining hemopoietic recovery with such cells.Ten patients with advanced breast cancer had PBPC mobilized with docetaxel (100 mg/m2) and G-CSF (10 microg/kg per day), harvested and processed using the CliniMACS CD34-selection device and equally divided into three aliquots for cryopreservation. Unmanipulated 'back-up' cells were also collected on a separate day of the same mobilization, divided into three and cryopreserved. Patients subsequently received three cycles of HDT with cyclophosphamide (4 g/m2), thiotepa (300 mg/m2) and paclitaxel (175 mg/m2). The intent was for patients to receive CD34-selected cells to support each of the three cycles of HDT (i.e., 1/3 for each cycle). If, however, hemopoietic recovery was delayed after Cycle 1, 1/3 of the unmanipulated cells were infused following Cycle 2 and the remaining CD34-selected cells (2/3) were used to support Cycle 3.PBPC from 10 patients underwent CD34-selection with a resulting median purity of 93% (range: 76-98%) and yield of 62% (range: 16-93%). Of the 10 patients, only two were able to be supported with CD34-selected cells for all three cycles of HDT. The remaining eight patients required unmanipulated 'back-up' cells to support Cycle 2. Three patients also required infusion of 'back-up' unmanipulated cells because of persistent neutropenia (n = 1) or thrombocytopenia (n = 2) following cycles initially supported by CD34-selected cells. The median number of CD34-selected cells (x 10(6)/kg) infused per cycle was 1.5 (0.7-2.6) (n = 20) and unselected cells was 1.7 (1.4-2.8) (n = 10). Comparing hemopoietic recovery between cycles of HDT supported by CD34-selected (n = 20) and unmanipulated cells (n = 10) there was a significant slowing with the CD34-selected cells; time to ANC1.0 = 13 days versus 10 days, platelets20 = 17 days versus 13 days,50 = 25 versus 17 days (all P values0.001). There was no correlation between the dose of CD34-selected cells infused and neutrophil/platelet recovery.We have demonstrated that, although unmanipulated PBPC achieve rapid hemopoietic recovery (at modest CD34 doses ofor = 2.8 x 10(6)/kg), CliniMACS-selected CD34+ cells (in the doses utilized in this study ofor = 2.6 x 10(6)/kg) result in significantly prolonged recovery.

Background Inducible T cell Co-Stimulator (ICOS), a member of the CD28/B7/CTLA immunoglobulin receptor superfamily, is expressed on T cells after engagement with cognate antigen and activation. ICOS provides a co-stimulatory signal augmenting T cell proliferation, cytokine production, cytotoxic function and survival. GSK3359609 is a humanized IgG4 antibody selected for its potent binding agonist activity against human ICOS. Rationale for targeting ICOS with GSK33359609 as a monotherapy and in combination with other cancer immunotherapies such as pembrolizumab is supported by preclinical evidence. Methods INDUCE-1 is a first in human study evaluating safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity of GSK3359609 administered as an intravenous (IV) infusion once every three weeks (Q3W) alone (Part 1) and in combination with 200 mg pembrolizumab (Q3W IV infusion) or other immunotherapy (Part 2) in approximately 304 adult patients. In the dose escalation phase, eligible patients are required to have selected, relapsed/refractory solid tumors. Accelerated titration design is planned for the first 3 dose levels in Part 1, with 1 patient enrolled at each dose level; modified toxicity probability interval method will inform on subsequent dose escalation decisions (minimum 3 patients per dose level), and maximum tolerated dose or maximum administered dose determination. In the expansion phase, cohorts may be defined by factors such as tumor histology, biomarker features, or prior treatment. More than one GSK3359609 dose level may be evaluated in a single expansion cohort by patient random assignment. Tumor biopsies (before and on-treatment) are optional in escalation and required in expansion to provide biomarker data that may inform on optimal dose selection as well as mechanistic understanding of GSK3359609 activity. Immune-related Response Evaluation Criteria in Solid Tumors will be the primary measure of clinical activity. As of 12 January 2017, no dose limiting toxicities (DLT) were observed in the first 2 dose levels of GSK3359609 monotherapy; dose level 3 cohort enrollment is completed and under observation for DLTs. ClinicalTrials.gov identifier: NCT02723955 Study is funded by GlaxoSmithKline and is in collaboration with Merck & Co, Inc Citation Format: Eric Angevin, Todd M. Bauer, Catherine E. Ellis, Hui Gan, Rigel Hall, Aaron Hansen, Axel Hoos, Roxanne C. Jewell, Jessica Katz, Juan Martin-Liberal, Michele Maio, Patrick A. Mayes, Jolly Mazumdar, Michael Millward, Danny Rischin, Jan H. Schellens, Sapna Yadavilli, Helen Zhou. INDUCE-1: a phase I open-label study of GSK3359609, an ICOS agonist antibody, administered alone and in combination with pembrolizumab in patients with selected, advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT039. doi:10.1158/1538-7445.AM2017-CT039

TPS6090 Background: Approximately half of patients (pts) with HNSCC are diagnosed with locally advanced disease and treated with surgery or concomitant chemoradiotherapy (CRT) with cisplatin. Unfortunately, disease recurs in 40% to 60% of patients. The PD-l inhibitor pembro is approved for recurrent/metastatic HNSCC. CRT has immunomodulatory effects; preclinical data suggest that efficacy can be improved by adding pembro. The phase 3 KEYNOTE-412 trial (NCT03040999) will explore if CRT + pembro can improve outcomes of pts with LA-HNSCC. Methods: Adult pts with newly diagnosed, pathologically proven, treatment-naive LA-HNSCC will be enrolled. Study population will include p16-negative HNSCC (any T3-T4 or any N2a-N3 [AJCC 7th edition]) and p16-positive oropharyngeal cancer (any T4 or any N3). Other eligibility criteria: measurable disease per RECIST v1.1 by blinded independent central review (BICR), provision of tumor sample for biomarker analyses, ECOG PS 0 or 1, and eligible for definitive CRT but not considered for primary surgery. Pts will be randomly assigned 1:1 to receive either pembro 200 mg every 3 weeks (Q3W) plus CRT, which includes radiotherapy (RT; accelerated [70 Gy, six 2 Gy fractions/wk] or standard [70 Gy, five 2 Gy fractions/week] fractionation) plus cisplatin 100 mg/m2 Q3W for 3 cycles only, or placebo Q3W plus CRT. Pts will be stratified by RT regimen, tumor site/p16 status, and disease stage. Treatment will continue until centrally confirmed disease progression, unacceptable AEs, decision to withdraw by pt or investigator, or completion of 17 doses of pembro/placebo. Disease status will be evaluated by CT or MRI 12 weeks after end of CRT, every 4 months during the next 2 years, and then every 6 months during years 3-5. Pts will be evaluated for neck dissection at 12 weeks after CRT. AEs will be monitored and graded using CTCAE v4.0 throughout the trial and for 30 days (90 days for serious AEs) after end of treatment. Primary efficacy end point is event-free survival per RECIST v1.1 by BICR. Key secondary end points: overall survival, quality of life, and safety and tolerability of pembro. Approximately 780 pts will be enrolled. Clinical trial information: NCT03040999.

6008 Background: We report on the first multi-centre randomized phase III trial of post-operative radiotherapy (PORT) vs post-operative chemo-RT (CRT) in high-risk cutaneous squamous cell carcinoma of the head and neck (cSCCHN) (NCT00193895). Methods: The primary objective was to determine whether there was a freedom from loco-regional relapse (FLRR) difference between patients randomly assigned to 60-66Gy (6-6.5 weeks) with or without weekly carboplatin (AUC 2) following resection of gross disease. Patients were stratified to high-risk nodal (either extracapsular nodal extension, intra-parotid nodal disease of any size or number, cervical nodal disease with ≥2 nodes or largest node > 3cm) or high-risk primary (T3-T4 or in-transit metastases). Patients with both features were stratified to the high-risk nodal group. Secondary objectives included disease-free survival (DFS), overall survival (OS) and acute & late toxicity (CTCAE V3). Results: 321 patients were randomly assigned between 2005-2014, with 11 not commencing treatment protocol due to disease progression or withdrawal of consent. Of the 310 patients commencing treatment protocol (157 RT and 153 CRT), 230 (74%) had high-risk nodal, 70 (22%) high-risk primary and 10 (3%) both. Median follow up was 60 months, median RT dose was 60Gy and 85% randomised to CRT completed 6 cycles of carboplatin. The 2- & 5-year FLRR (95% CI) for the RT arm was 88% (83-93%)/83% (77-90%) and for CRT 89% (84-94%)/87% (81-93%) (HR 0.85; 95%CI [0.46-1.55]; p = 0.59). The 2- & 5 year DFS (95% CI) for the RT arm was 78% (72-85%)/67% (60-76%) and for CRT 83% (77-89%)/73% (66-81%) (HR 0.85; 95%CI [0.55-1.29]; p = 0.43). The 2- & 5 year OS (95% CI) for the RT arm was 88% (83-93%)/76% (69-84%) and for CRT 88% (83-94%)/79% (72-86%) (HR 0.95; 95%CI [0.58-1.57]; p = 0.84). 134 (43%) experienced Grade 3/4 skin toxicity; 49% RT, 37% CRT (p = 0.039). 12 (3.9%) experienced Grade 3/4 subcutaneous fibrosis; 2.5% RT, 5.2% CRT. Conclusions: While surgery and PORT provided excellent FLRR with acceptable toxicity, the addition of weekly carboplatin did not improve outcomes in high-risk cSCCHN. Clinical trial information: NCT00193895.

TPS3113 Background: Inducible T cell Co-Stimulator (ICOS), a member of the CD28/B7/CTLA-4 receptor superfamily expressed on T cells after engagement with cognate antigen and activation, provides a co-stimulatory signal augmenting T cell proliferation, survival and cytokine production. GSK3359609 is a humanized IgG4 antibody selected for its potent agonist activity against human ICOS. The unique mechanistic profile of an ICOS agonist antibody, such as GSK3359609, offers an opportunity to investigate the antitumor potential of targeting a T cell co-stimulator alone and in combination with other cancer immunotherapies such as pembrolizumab. Methods: INDUCE-1 is a first- in-human study evaluating safety, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity of GSK3359609 administered as an intravenous (IV) infusion once every 3 weeks (Q3W) alone (Part 1) and in combination with 200 mg pembrolizumab (Q3W IV infusion) or other immunotherapy (Part 2) in approximately 304 adult patients. In dose escalation, eligible patients are required to have selected relapsed/refractory solid tumors. Primary objective is to determine safety, tolerability, and maximum tolerated or administered dose. Modified toxicity probability interval method will inform dose escalation decisions (minimum 3 patients per dose level [DL]). In expansion, cohorts may be defined by factors such as tumor histology, biomarker features, or prior treatment. More than one GSK3359609 DL may be evaluated in an expansion cohort by random assignment. Blood immunophenotyping is monitored in all patients; tumor biopsies (before and on-treatment) are optional in escalation and required in expansion to provide biomarker data that may inform on optimal dose selection as well as mechanistic understanding of GSK3359609. Efficacy measures are every 9 weeks and are according to immune-related RECIST. As of 7 Feb 2017, the first 3 monotherapy DL cohorts completed without dose limiting toxicities; DL 4 enrollment is ongoing. Study is funded by GlaxoSmithKline and is in collaboration with Merck & Co., Inc. Clinical trial information: NCT02723955.

Background DNA hypermethylation is reported as a frequent event and prognostic marker in head and neck squamous cell carcinomas (HNSCC). Methylation has been commonly assessed with non-quantitative methodologies, such as methylation-specific PCR (MSP). We investigated previously reported hypermethylated genes with quantitative methodology in oral tongue squamous cell carcinomas (OTSCC). Results The methylation status of 12 genes in 115 OTSCC samples was assessed by one or more of three quantitative analyses: methylation sensitive high resolution melting (MS-HRM), sensitive-melting analysis after real time-methylation specific PCR (SMART-MSP), and bisulfite pyrosequencing. In contrast to much of the literature, either no or infrequent locus-specific methylation was identified by MS-HRM for DAPK1, RASSF1A, MGMT, MLH1, APC, CDH1, CDH13, BRCA1, ERCC1, and ATM. The most frequently methylated loci were RUNX3 (18/108 methylated) and ABO (22/107 methylated). Interrogation of the Cancer Genome Atlas (TCGA) HNSCC cohort confirmed the frequency of significant methylation for the loci investigated. Heterogeneous methylation of RUNX3 (18/108) and ABO (22/107) detected by MS-HRM, conferred significantly worse survival (P = 0.01, and P = 0.03). However, following quantification of methylation levels using pyrosequencing, only four tumors had significant quantities (>15%) of RUNX3 methylation which correlated with a worse patient outcome (P

The acute and late toxicities of synchronous carboplatin, etoposide, and radiation therapy were prospectively assessed in a group of patients with high-risk Merkel cell carcinoma of the skin.Forty patients from six different centers throughout Australia were entered into a Phase II study under the auspices of the Trans-Tasman Radiation Oncology Group. The trial was activated in 1996 and continues to accrue. Patients are eligible if they have disease localized to the primary site and nodes and are required to have at least one of the following high-risk features: recurrence after initial therapy, involved nodes, primary size greater than 1 cm, gross residual disease after surgery, or occult primary with nodes. Radiation was delivered to the primary site and nodes to a dose of 50 Gy in 25 fractions over 5 weeks, and synchronous carboplatin (area under curve [AUC] 4.5) and etoposide (80 mg/M(2) i.v.) were given on days 1-3 during weeks 1, 4, 7, and 10. The median age of the group was 67 years (43-78).The median duration of follow-up was 22 months (2-45). There were no treatment-related deaths. Grade 3 or 4 skin toxicity occurred in 63% of patients (95% CI 48, 78). The most serious acute effect was on neutrophils with Grade 3 or 4 (neutrophils1 x 10(9)/L), occurring in 60% (95% CI 45, 75) of cases. Complications from neutropenia (fever and sepsis) occurred in 16 patients (40% of cases). The median time for neutropenic complications was 27 days (9-35), and 10/16 (62%) cases of neutropenic fever occurred after the second cycle of chemotherapy. The probability of Grade 3 or 4 late effects on platelets (50 x 10(9)/L) and hemoglobin (8 g/dl) was 10% (95% CI 1, 20) and 6% (95% CI 2, 15), respectively. Of the 40 patients, 35 were able to complete 4 cycles of chemotherapy. There were no factors predictive for neutropenic toxicity at a p value0.05.The protocol has acceptable toxicity, and the treatment has been deliverable in a multi-institutional trial setting. Neutropenia is likely to occur with synchronous carboplatin/etoposide and radiation in this population of patients. The risk of a febrile neutropenia was greatest at the time of the second cycle of chemotherapy, when there was moist desquamation of skin or mucosal membranes that provided a portal for infection. This should be considered in the design of subsequent protocols with chemoradiotherapy.

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. (C) 2001 Elsevier Science Inc.

Objective. In view of the significant activity of topotecan in ovarian cancer with dose-limiting toxicity (DLT) of myelosuppression, we evaluated the addition of topotecan to carboplatin and paclitaxel with peripheral blood progenitor cell (PBPC) support. Methods. Patients with previously untreated stage IIIC or IV ovarian cancer with macroscopic residual disease following primary debulking surgery were eligible. Patients received two cycles of carboplatin AUC=5 and 175 mg/m 2 of paclitaxel with collection of PBPCs after the second cycle. Patients subsequently received three cycles of high-dose therapy (HDT) with topotecan on a daily ×5 schedule, paclitaxel (250 mg/m 2 over 24 h), and carboplatin (AUC = 12–16). Results. Nineteen patients with a median age of 49 years (range 21–63) were enrolled and topotecan was escalated in 6 patient cohorts up to a dose of 4.5 mg/m 2 /day. Fifty-two of the planned 57 treatment cycles were delivered with no treatment-related deaths. Neutrophil and platelet recovery was rapid and the interval between HDT was 28 days. Febrile neutropenia occurred following 57% of all HDT cycles. DLTs of mucositis and diarrhea were observed at topotecan (4.5 mg/m 2 /day), paclitaxel (250 mg/m 2 ) and carboplatin (AUC = 12). The protocol was subsequently modified to administer topotecan (2.5 mg/m 2 /day) with carboplatin (AUC = 16); however, 2 patients developed grade 4 diarrhea (1 with grade 3 mucositis and 1 with grade 4 mucositis). The clinical CR rate was 73% (14/19) with an overall clinical response rate of 95% (18/19). Of the 14 patients with a CCR, 13 of these underwent a second-look laparotomy with 8 (61%) achieving a pthological CR. With a median follow-up of 28 months (range 11–40 months), the median PFS is 36 months and OS has not been reached. Conclusion. When combined with carboplatin (AUC = 12) and paclitaxel (250 mg/m 2 ), the recommended topotecan dose is 3.5 mg/m 2 /day for 5 days. This outpatient HDT regimen combines three of the most active drugs in ovarian cancer with acceptable toxicity and promising activity.

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.

PURPOSE: To determine the maximum-tolerated dose of tirapazamine when combined with cisplatin and radiation in patients with T3/4 and/or N2/3 squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: The starting schedule was conventionally fractionated radiotherapy (70 Gy in 7 weeks) with concomitant cisplatin 75 mg/m2 and tirapazamine 290 mg/m2 (before cisplatin) in weeks 1, 4, and 7 and tirapazamine alone 160 mg/m2 three times a week in weeks 2, 3, 5, and 6. Positron emission tomography scans for tumor hypoxia (18F misonidazole) were performed before and during radiotherapy. RESULTS: We treated 16 patients with predominantly oropharyngeal primary tumors, including 10 patients with T4 or N3 disease. Febrile neutropenia occurred toward the end of radiotherapy in three out of six patients treated on the initial dose level. Two of these patients also developed grade 4 acute radiation reactions. Another 10 patients were treated with the same doses, but the week 5 and week 6 tirapazamine doses were omitted. This resulted in less neutropenia and only one dose-limiting toxicity (DLT) (febrile neutropenia), and eight out of 10 patients completed treatment without any dose omissions. In these 10 patients, the acute radiation toxicities were not obviously enhanced compared with chemoradiotherapy regimens using concurrent platinum and fluorouracil. 18F misonidazole scans detected hypoxia in 14 of 15 patients at baseline, with only one patient having detectable hypoxia at the end of treatment. With a median follow-up of 2.7 years, the 3-year failure-free survival rate was 69% (SE, 12%), the 3-year local progression-free rate was 88% (SE, 8%), and the 3-year overall survival rate was 69% (SE, 12%). CONCLUSION: DLT was due unexpectedly to febrile neutropenia, which could be overcome by omitting tirapazamine in weeks 5 and 6. The combination of tirapazamine, cisplatin, and radiotherapy resulted in remarkably good and durable clinical responses in patients with very advanced head and neck cancers. It warrants further investigation.

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.

Initial trials of paclitaxel and doxorubicin in advanced breast cancer yielded high response rates but significant cardiac toxicity was observed. In this phase II trial we investigated the efficacy and safety of paclitaxel combined with epirubicin. Patients with advanced breast cancer, performance status 0–2, measurable disease, and a normal left ventricular ejection fraction, who may have received adjuvant chemotherapy were treated with epirubicin 75 mg m–2followed by a 3-h infusion of paclitaxel 175 mg m–2repeated every 3 weeks. Forty-three eligible patients were treated at six centres. 67% patients received the maximum of six cycles. The response rate was 54% (95% CI 38–69%), 12% CR and 42% PR. Estimated median progression-free survival was 6.9 months (95% CI 5.4–10.0) and estimated median overall survival was 17.9 months (95% CI 14.2–25.7). Four patients had a decrease in the left ventricular ejection fraction (LVEF) of ≥20% of baseline value, and in two patients the LVEF decreased to below the lower limit of normal, but no patient developed clinical evidence of cardiac failure. Grade 4 neutropenia occurred in 56% cycles, but only 4% of cycles were complicated by febrile neutropenia. Grade 3 or 4 non-haematologic toxicity was uncommon. In conclusion, paclitaxel 175 mg m–2and epirubicin 75 mg m–2is a well tolerated, promising regimen for the treatment of advanced breast cancer. © 2000 Cancer Research Campaign

The aim of this study was to review our experience with a treatment regimen that combined conventionally fractionated radiation therapy (70 Gy over 7 weeks) with chemotherapy (cisplatin and fluorouracil), given concurrently in the last 2 weeks of radiation therapy in patients with previously untreated advanced squamous cell cancer of the head and neck region.Twenty-eight patients, all but two having UICC stage IV disease, were treated at the Peter MacCallum Cancer Institute between November 1995 and April 1998. Planned chemotherapy consisted initially of continuous infusion at 10 mg/m(2) per day of cisplatin and 400 mg/m(2) per day of fluorouracil on days 1-5 of weeks 6 and 7 of a conventionally fractionated course of radiotherapy. After the first 14 patients, the dose of fluorouracil was reduced to 360 mg/m(2) per day because of acute toxicity.36.8 months), with an estimated 50% surviving at 2 years (CI, 29-71%). Sixteen patients (57%) developed confluent mucositis and 11 (39%) developed patchy mucositis. The median duration of mucositis for these 27 patients was 1.5 months. Seventeen patients (61%) required nutritional support for a median duration of 1.4 months. Fourteen patients (50%) had grade three skin reactions, and 12 (43%) had one or more other significant (Grade 3) toxicities, predominantly infective. Grade 3 late toxicity has been observed in three patients to date (three xerostomia, including one with severe depression), and one patient had chronic ulceration of the oral tongue (grade 4). This chemoradiation regimen achieved an excellent complete response rate and good locoregional control at 2 years in patients with a poor initial prognosis. Acute toxicity was significant but manageable. The regimen offers an alternative to surgery and postoperative radiation therapy in locally advanced head and neck cancer.

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

Objective. To provide an overview of the known pharmacological activity of the solvent for pacli taxel, Cremophor, and the implications for therapy with paclitaxel. Data Sources. Following an outline of the chemistry of Cremophor and its potential to cause hypersensitivity, we present a summary of our own results from studies on the effect of Cremophor as an MDR modulator. Data Extraction. The pharmacokinetic inter actions of paclitaxel and Cremophor are discussed, with reference to our own preclinical and clinical studies of Cremophor, and literature reports of altered drug disposition following combination therapy with paclitaxel are examined. Data Synthesis. Cremophor is not an inert solubiliser. Cremophor may contribute to drug interactions by altering drug disposition, and it has the ability to modulate multidrug resistance. As a consequence of the presence of Cremophor in the paclitaxel formulation, the use of paclitaxel should be considered as the administration of two agents.

We investigated the relationship between hypoxia, human papillomavirus (HPV) status and outcome in head and neck squamous cell carcinoma.Patients with stage III and IV head and neck squamous cell carcinoma treated on phase I and II chemoradiation trials with 70-Gy radiation combined with tirapazamine/cisplatin or cisplatin/fluorouracil (5FU), hypoxic imaging using [18F]-misonidazole positron emission tomography and known HPV status (by p16 immunohistochemistry) were included in this sub-study. Separate analyses were conducted to consider the impact of tirapazamine on HPV-negative tumours in the phase II trial.Both p16-positive oropharyngeal tumours and p16-negative head and neck squamous cell carcinoma tumours had a high prevalence of tumour hypoxia; 14/19 (74%) and 35/44 (80%), respectively. The distribution of hypoxia (primary, nodal) was similar. On phase II, trial patients with p16-negative hypoxic tumours had worse loco-regional control with cisplatin and 5FU compared with tirapazamine and cisplatin (P 0.001) and worse failure-free survival (hazard ratio = 5.18; 95% confidence interval, 1.98-13.55; P = 0.001). Only 1 out of 14 p16-positive patients on the phase II trial experienced loco-regional failure.Hypoxia, as assessed by [18F]-misonidazole positron emission tomography, is frequently present in both p16-positive and negative head and neck cancer. Further research is required to determine whether hypoxic imaging can be used to predict benefit from hypoxia-targeting therapies in patients with p16-negative tumours.

CDKN2A (p16) disruption is reported as a frequent event in head and neck squamous cell carcinomas that confers poor prognosis. We investigated the frequency of different potential mechanisms of CDKN2A inactivation in oral tongue squamous cell carcinomas (OTSCC) and their impact on patient outcome. From a cohort of 153 OTSCC patients, 131 formalin fixed paraffin embedded blocks of pre-treatment primary tumours were suitable for further molecular analysis. We assessed CDKN2A (p16) levels by immunohistochemistry (IHC), promoter methylation status by methylation-sensitive high resolution melting, mutation status by Sanger sequencing, gene copy number variation by fluorescence in situ hybridisation, and correlated these with patient outcome. We found that the majority of OTSCC did not overexpress p16 (110/116, 95%), assessed by IHC. The frequency of CDKN2A mutations was 20% (21/103), homozygous loss was 7% (7/97), hemizygous loss 31% (30/97), and promoter methylation was 18% (20/113). We found no evidence of these mechanisms in 24/106 (23%) p16 IHC negative tumours. No significant correlation was identified between any potential mechanism of CDKN2A inactivation and clinical features, including smoking status and age. There was a non-significant trend for worse overall survival for p16 IHC negative patients versus positive patients (HR = 1.81, 95% CI = 0.44-7.47, p = 0.40). No relationship was found between mechanisms of CDKN2A disruption and patient outcome. In conclusion, we demonstrate that CDKN2A alteration is a frequent event in OTSCC tumourigenesis. However, no correlation was identified between different potential mechanisms of CDKN2A disruption and clinical characteristics or patient outcome.

The discovery that the human papilloma virus (HPV) is associated with a high and increasing percentage of oropharyngeal squamous cell carcinomas (SCCs) is among the most significant advances in the field of head and neck oncology. HPV-positive oropharyngeal cancer (HPVOPC) has clinical, etiologic, pathologic, and molecular features that distinguish it from HPV-negative disease. Increasingly, HPVOPC is being diagnosed in clinical practice because of the easy availability of p16 immunohistochemistry, a surrogate marker of HPV. The superior prognosis of HPVOPC has led to a reexamination of treatment approaches, and clinical trials are currently investigating strategies to deintensify treatment to reduce acute and late toxicity while preserving efficacy. This is of particular interest in low-risk patients. Unfortunately, patients with HPV-negative tumors still have high rates of locoregional failure and more efficacious treatments are required. This review of oropharyngeal SCC focuses on current and investigational treatment strategies in patients with both HPV-positive and HPV-negative oropharyngeal SCC.

Cyclophosphamide was widely used as a single agent prior to the advent of platinum-based regimens for epithelial ovarian cancer, and, in combination with platinum, prior to the adoption of platinum and paclitaxel as standard first-line therapy. As cyclophosphamide currently has no defined role in ovarian cancer we aimed to assess its activity in women with recurrent disease.A retrospective review was conducted of patients from three centers in Melbourne, Australia who had received oral cyclophosphamide treatment for recurrent ovarian cancer. The primary end-point was response rate to oral cyclophosphamide (150 mg p.o. day 1-14) based on Gynecologic Cancer InterGroup (GCIG) CA125 and/or Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Secondary end-points included overall and progression-free survival and toxicity.In all, 26 patients were identified and 23 patients were evaluable for response. The median number of prior chemotherapy regimens was three (range 1-6). The response rate to oral cyclophosphamide was 44% with 10 of the 23 patients achieving a partial response (PR) based on GCIG (CA125) criteria. The median number of cycles received was three (range 1-16). Cyclophosphamide showed activity both in patients with platinum-sensitive (seven of 13 PR) and resistant or refractory disease (three of 10 PR). There was no grade 3 or 4 toxicity but two patients ceased cyclophosphamide due to less severe non-hematological toxicity.Single agent oral cyclophosphamide is active and well tolerated in recurrent ovarian cancer. Further investigation of oral cyclophosphamide in patients with platinum-sensitive and platinum-resistant disease is warranted.

The primary purpose of this study was to review the efficacy of unilateral treatment of lateralized tonsil primaries, in particular whether laterality of the primary is a more powerful determinant of contralateral neck failure than advanced ipsilateral nodal classification.A retrospective study of all patients with tonsillar cancer treated with curative intent between January 1990 and December 2002 was performed.There were 167 patients, 76% men, median age 58 years, 86% current or ex-smokers. The majority of patients (58%) had stage IV disease. Five-year local, nodal, locoregional, and distant failure rates were 14%, 4%, 18%, and 8%, respectively. Of the 58 patients treated unilaterally, 33% had N2a, N2b, or N3 nodal disease. There were no contralateral nodal failures in the unilaterally treated group.These results support the potential use of unilateral radiation therapy (RT) for lateralized tonsil primaries even with advanced ipsilateral nodal disease.

A 53-year-old man presented with a 6-month history of mild hoarseness, with no associated pain, dysphagia, or stridor. At nasoendoscopy, a lesion was detected involving the whole length of the left vocal cord, with abnormal mucosa also seen in the right ventricle ( Fig 1 ). The left vocal cord movement was impaired. There were no palpable neck nodes. Biopsy under anesthesia revealed moderately differentiated squamous cell carcinoma. He was a current smoker of 30 cigarettes per day (45 pack-year smoking history), and he consumed four standard drinks of alcohol per day. His Eastern Cooperative Oncology Group performance status was 1, and he had no significant comorbidities. Radiologic review of his outside computed tomography scan noted that it was of poor quality, and a magnetic resonance imaging scan was recommended, which showed low-volume T4a disease based on focal thyroid cartilage penetration ( Fig 2 ). A positron emission tomography (PET) scan revealed no evidence of nodal or distant metastasis.

Background Paclitaxel (Taxol) is a new drug with efficacy against a variety of malignant tumors. The clinical formulation of paclitaxel contains 50% Cremophor EL, a polyethoxylated castor oil vehicle (carrier) that can reverse multidrug resistance (MDR) mediated by P-glycoprotein. Three-hour intravenous infusions of paclitaxel can yield end-of-infusion plasma Cremophor concentrations of 1 microL/mL or more, which are sufficient to reverse MDR in vitro by at least 50%. Despite extensive clinical use, the pharmacokinetics of Cremophor have not been described. Purpose We studied the pharmacokinetics of Cremophor in patients with ovarian cancer who were undergoing treatment with paclitaxel to determine whether plasma Cremophor concentrations achieved during and following 3-, 6-, and 24-hour drug infusions were similar to those shown to modulate MDR in vitro. Methods Eleven patients with previously treated (i.e., with platinum-containing chemotherapy regimens) ovarian cancer were randomly assigned to receive one 3-hour, one 6-hour, and one 24-hour infusion of paclitaxel in varied sequences during their first three cycles of treatment with this drug. Blood samples were collected both during and following the three infusion periods, and Cremophor concentrations in these samples were measured by use of a bioassay based on the ability of Cremophor in plasma samples to reverse cellular resistance to daunorubicin in vitro. Results Ten patients were treated with paclitaxel at a dose level of 175 mg/m2, and one patient was treated at a dose level of 135 mg/m2. At the 175-mg/m2 dose level, peak plasma Cremophor concentrations of 1 microL/mL or more were achieved in eight of 10 patients during both the 3-hour and the 6-hour infusions; with the 24-hour infusion, only one patient achieved a peak plasma Cremophor concentration of 1 microL/mL or more. The eight patients who achieved plasma Cremophor concentrations of 1 microL/mL during the 3-hour infusion were above this level 30 minutes into the infusion; the total time that the plasma concentration was greater than 1 microL/mL was 8.9 +/- 5.0 hours (mean +/- standard deviation; range, 4.1-15.6 hours). For the eight patients who achieved plasma Cremophor concentrations of 1 microL/mL during the 6-hour infusion, the total time that the concentration was greater than 1 microL/mL was 10.2 +/- 9.0 hours (range, 0.3-21.9 hours). The patient who received paclitaxel at a dose of 135 mg/m2 achieved a peak plasma Cremophor concentration of 1 microL/mL or more only during the 3-hour infusion. Conclusions Paclitaxel infusions of 3 and 6 hours can result in sustained plasma Cremophor concentrations sufficient for substantial reversal of P-glycoprotein-mediated MDR in vitro. These plasma Cremophor concentrations are not achieved during 24-hour infusions of paclitaxel.

PURPOSE To determine the antitumor activity and toxicity of paclitaxel administered as a 3-hour infusion in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Fifty-one patients with advanced measurable or assessable NSCLC and performance status 0 to 2 who had not received prior chemotherapy were treated with paclitaxel 175 mg/m2 over 3 hours with premedication. Cycles were repeated every 3 weeks for a maximum of nine cycles. Most patients had prior radiotherapy (57%), extrathoracic metastatic disease (65%), and measurable disease (75%). Twenty-two percent had previously untreated stage III disease. RESULTS The objective response rate was five of 51 (10%; 95% confidence interval, 3% to 21%). No subgroup with a higher response rate could be identified. There were no complete responses (CRs) and all responses lasted less than 5 months. Treatment was well tolerated with brief World Health Organization (WHO) grade IV neutropenia in only 16% of patients. Grade III/IV myalgia/athralgia occurred in 22% of patients. No significant hypersensitivity reactions occurred. CONCLUSION The antitumor activity of this dose and schedule appears inferior to that reported in previously published phase II trials in NSCLC that used higher doses of paclitaxel infused over 24 hours, although confidence intervals for response overlap. Determining the optimal dose and schedule for using paclitaxel in NSCLC requires further investigation, and these results should caution against using shorter infusions outside appropriate clinical trials.

e23158Background: Tumor hypoxia is associated with resistance to chemotherapy and radiotherapy. Recurrent/metastatic squamous cell carcinomas of the head and neck & skin (SCCHN/SCCS) and non-small ...

TPS6105Background: R/M SCCHN/SCCS have a poor prognosis. Molecularly targeted EGFR therapies provide some clinical benefit but are limited by systemic on-target side effects such as rash and diarrh...

Summary Objectives To investigate the tolerability and feasibility of induction gemcitabine and carboplatin chemotherapy followed by radiotherapy with concurrent cisplatin in patients with locally advanced nasopharyngeal carcinoma. Patients and methods Twenty-eight patients with previously untreated non-keratinising nasopharyngeal carcinoma, with stage IIb to IV disease were enroled to receive three cycles of carboplatin AUC 5 and gemcitabine 1 g/m 2 day 1 and 8 every 21-days, followed by 70 Gy of radiotherapy with concurrent cisplatin 20 mg/m 2 /day for 5 days of weeks 1, 4 and 7. Results 26/28 (93.0%) patients received all three cycles of induction chemotherapy. All 27 patients who commenced chemoradiotherapy received 70 Gy in 35 fractions of radiotherapy with at least two cycles of concurrent cisplatin. The three-year time to locoregional failure rate was 92.9% (95% CI: 75.5–98.2%) and the three-year overall survival rate was 89.3% (95% CI: 71.6–96.5%). Induction chemotherapy was well tolerated with 5/28 (17.9%) patients experiencing grade 3 non-haematological toxicities and no reported episodes of febrile neutropenia or grade 4 toxicity. For the 27 patients who received radiotherapy, no acute grade 4 radiation toxicities and only 2/27 (7.4%) late grade 4 radiation adverse events were observed. Conclusion The use of induction carboplatin and gemcitabine followed by chemoradiotherapy is feasible, with acceptable toxicity, and is a promising regimen for the treatment of locally advanced nasopharyngeal carcinoma.

For many cancers, tumour hypoxia is an adverse prognostic factor, and increases chemoradiation resistance; its importance in non-small cell lung cancer (NSCLC) is unproven. This study evaluated tumoural hypoxia using fluoroazomycin arabinoside ((18) F-FAZA) positron emission tomography (PET) scans among patients with locoregionally advanced NSCLC treated with definitive chemoradiation.Patients with stage IIIA-IIIB NSCLC underwent (18) F-FAZA PET scans and (18) F-2-deoxyglucose (FDG)-PET scans within 4 weeks of commencing and 8 weeks following conventionally-fractionated concurrent platinum-based chemoradiation (60 Gy). Intra-lesional hypoxic volumes of the primary and nodal masses were compared with FDG-PET metabolic volumes. Baseline tumoural hypoxia was correlated with disease free survival (DFS).Seventeen patients underwent pre-treatment (18) F-FAZA PET and FDG-PET scans. Intra-lesional hypoxia was identified on 11 scans (65%). Baseline lesional hypoxic volumes were consistently smaller than FDG-PET volumes (P = 0.012). There was no statistical difference between the mean FDG-PET volumes in patients with or without baseline hypoxia (P = 0.38). Eight patients with baseline hypoxia had post treatment (18) F-FAZA scans and 6 of these (75%) had resolution of imageable hypoxia following chemoradiation. The DFS was not significantly different between the hypoxic or non-hypoxic groups (median 0.8 years and 1.3 years respectively, P = 0.42).Intra-lesional hypoxia, as detected by (18) F-FAZA PET, was present in 65% of patients with locally-advanced NSCLC and resolved in the majority of patients following chemoradiation. Larger studies are required to evaluate the prognostic significance of the presence and resolution of hypoxia assessed by PET in NSCLC.

Health literacy is the capacity to seek, understand and utilise health information to make informed health decisions. Suboptimal health literacy has been linked to poor health outcomes. This study assessed health literacy in patients treated for head and neck or lung cancer and associations between health literacy and demographic factors and distress levels.Consecutive English-speaking patients were approached at Peter MacCallum Cancer Centre. Face-to-face interviews were conducted. Health literacy was assessed using the Shortened Test of Functional Health Literacy in Adults (S-TOFHLA) and Health Literacy Management Scale (HeLMS). Distress was assessed by the Distress Thermometer.Response rate was 73 % (n = 93). Using S-TOFHLA, prevalence of inadequate and marginal health literacy was 5.4 and 6.5 % respectively, and both groups were associated with older age (p = 0.043) and low education level (p = 0.009). Specific assessment of S-TOFHLA revealed that 70 % could not interpret prescription labels. HeLMS reported that 17 % had health literacy difficulties. Low scores on domains of HeLMS were associated with lower education level (p0.05) but younger age (p0.05). Distress was not associated with S-TOFHLA scores but related to low scores in two domains of HeLMS (p0.05).Using two different measures, a substantial proportion of patients have poor health literacy abilities and may experience difficulties in accessing health services.

Summary Objectives Novel therapies are required for patients with recurrent or metastatic oral tongue squamous cell carcinoma (OTSCC). Fibroblast Growth Factor Receptor 1 ( FGFR1 ) amplification frequently occurs in squamous cell carcinoma of the lung and represents a novel druggable therapeutic target in this and other malignancies. This study examined the frequency and clinical associations of FGFR1 amplification in OTSCC. Materials and methods The frequency of FGFR1 amplification determined by fluorescence in situ hybridization was evaluated in a cohort of 123 OTSCC patients. Associations of FGFR1 amplification with clinical characteristics and outcome were determined. Results FGFR1 gene amplification was present in 9.3% (10/107) of cases and was significantly associated with smoking status ( P = 0.03). FGFR1 amplification was seen more commonly in males (9/10 amplified cases male, P = 0.16) and there were no associations with age, stage, T stage, nodal status, alcohol history or performance status (all P > 0.05). Outcome was not significantly different between FGFR1 amplified and non-amplified patients. Conclusions Copy number variations of the FGFR1 gene occur in a subset of OTSCC with approximately 10% of cases showing amplification of the gene. FGFR1 amplification may represent a therapeutic target in OTSCC.

The efficacy of erlotinib (Tarceva, Roche Products, Dee Why, Australia) has been demonstrated in patients with advanced non-small-cell lung cancer (NSCLC). Tarceva lung cancer survival treatment (TRUST) is an open-label, single-arm, phase IV global trial which investigated erlotinib in advanced NSCLC patients who had failed prior therapy or were unsuitable for chemo/radiotherapy. The aim of this analysis was to report the safety and efficacy of erlotinib in the Australian patient subpopulation.Patients with stage IIIB/IV NSCLC progressing after standard systemic chemotherapy or unsuitable to receive chemo/radiotherapy were eligible for the study. The patients were treated with erlotinib at 150 mg/day orally, until disease progression or unacceptable toxicity.In Australia, 460 patients were recruited. Erlotinib was given as first-line (16%), second-line (49%) or third-line (35%) treatment. In the intent-to-treat population (N = 460), the median progression-free survival was 2.7 months (95% CI 2.3-3.4), 1-year survival was 35% (95% CI 30-39%) and median overall survival was 6.9 months (95% CI 5.7-8.0). Tumor response rates were available for 363 patients, with a disease control rate of 58%. Of the 460 patients included in the safety analysis, 24% had one or more erlotinib-related adverse event (AE). Rash was reported in 77% of patients, most commonly grade 1/2 (63%). Treatment-related serious AE were reported in 7% of patients; most commonly diarrhea (2%). Dose modifications were required in 18% of patients.Outcomes for Australian patients confirmed the efficacy and tolerability of erlotinib for the treatment of advanced NSCLC in routine clinical practice.