tirapazamine and Head-and-Neck-Neoplasms

Topics: Carcinoma, Squamous Cell; Cell Hypoxia; Cisplatin; Clinical Trials as Topic; Head and Neck Neoplasms; Humans; Positron-Emission Tomography; Prognosis; Radiation-Sensitizing Agents; Tirapazamine; Triazines

Radiotherapy and concurrent chemotherapy (CRT) is superior to radiotherapy alone for the treatment of locally advanced, nonmetastatic squamous carcinoma of the head and neck (HNC). Three issues affect the use of CRT as primary treatment for advanced HNC. The first issue is the definition of advanced stage and the initial therapeutic choice of surgery or CRT and the role of post-CRT neck dissection. Function preservation considerations should guide the choice between surgery and CRT for patients with resectable disease. Fluorodeoxyglucose-positron emission tomography scanning may identify patients who require adjuvant neck dissection. The second issue is optimization of radiotherapy and chemotherapy schedules. Ideally, concurrent chemotherapy should be incorporated into radiotherapy (RT) regimens that would constitute optimal therapy were RT to be administered as single-modality treatment. Modified fractionation schemes constitute optimal single-modality RT. Platinum schedules other than bolus dosing every 3 to 4 weeks are effective and may be less toxic. The third issue is integration of biologically targeted therapy into CRT treatment programs. Epidermal growth factor receptor blockade enhances the effectiveness of RT alone. Its role and that of angiogenic blockade in CRT are under investigation.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma, Squamous Cell; Cetuximab; Cisplatin; Combined Modality Therapy; Consensus; Dose Fractionation, Radiation; Drug Administration Schedule; Head and Neck Neoplasms; Humans; Neck Dissection; Neoplasm Invasiveness; Neoplasm Staging; Patient Selection; Positron-Emission Tomography; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Tirapazamine; Triazines

Eppendorf electrode measurements of tumor oxygenation have defined an adverse effect of tumor hypoxia on prognosis after radiotherapy and other treatment modalities, in particular in head and neck and cervix carcinomas as well as soft tissue sarcomas. Recently, the immunohistochemical detection of proteins involved in the "hypoxic response" of tumor cells has been discussed as a method to estimate hypoxia in clinical tumor specimens.. This review focuses on clinical and experimental data, regarding prognostic impact and comparability with other methods of hypoxia detection, for three proteins suggested as endogenous markers of tumor hypoxia: hypoxia-inducible factor-1alpha(HIF-1alpha), carbonic anhydrase 9 (CA 9), and glucose transporter 1 (GLUT1).. None of the three potential hypoxia markers is exclusively hypoxia-specific, and in each case protein can be detected under normoxic conditions in vitro. HIF-1alpha responds rapidly to hypoxia but also to reoxygenation, making this marker quite unstable in the context of clinical sample collection. The perinecrotic labeling pattern typical of chronic hypoxia and a reasonable agreement with injectable hypoxia markers such as pimonidazole have most consistently been described for CA 9. All three markers showed correlation with Eppendorf electrode measurements of tumor oxygenation in carcinoma of the cervix. In nine of 13 reports, among them all three that refer to curative radiotherapy for head and neck cancer, HIF-1alpha overexpression was associated with poor outcome. CA 9 was an adverse prognostic factor in cervix, head and neck and lung cancer, but not in two other head and neck cancer reports. GLUT1 predicted for poor survival in colorectal, cervix and lung cancer.. Endogenous markers have the potential to indicate therapeutically relevant levels of hypoxia within tumors. Clinical trials assessing a marker's ability to predict a benefit from specific hypoxia-directed treatment (e. g., tirapazamine, "ARCON" concept) are necessary to define the potential of individual markers.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Carbonic Anhydrases; Cell Hypoxia; Cell Line, Tumor; Female; Forecasting; Glucose Transporter Type 1; Head and Neck Neoplasms; HeLa Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Lung Neoplasms; Male; Monosaccharide Transport Proteins; Neoplasms; Oxygen; Prognosis; Radiation Tolerance; Radiation-Sensitizing Agents; Tirapazamine; Transcription Factors; Treatment Outcome; Triazines; Uterine Cervical Neoplasms

The idea of 'targeting' hypoxia stems from recognition of the fact that oxygen (or its lack) is central to the practice of radiation oncology. Targeting embraces the alternative goals of trying to overcome hypoxia on the one hand and trying to exploit it on the other. This presentation briefly reviews these two approaches with major emphasis on the latter.

Topics: Cell Survival; Combined Modality Therapy; Head and Neck Neoplasms; Humans; Hypoxia; Radiation Oncology; Radiation-Sensitizing Agents; Regional Blood Flow; Tirapazamine; Triazines

Tumour hypoxia is well recognised as a major factor contributing to radioresistance. This article examines the role of hypoxia in influencing the treatment outcome following radiotherapy (RT), and reviews the rationale and results of clinical trials that utilise hypoxic sensitizers or cytotoxins in the treatment of head and neck carcinoma. Histologic evidence for tumour hypoxia in human neoplasms was first reported in 1955. Since then, direct measurement by microelectrodes has revealed heterogeneity in intratumoural oxygen concentrations, and low oxygen concentrations are associated with poor local-regional control by RT. These findings coupled with the result of nuclear imaging studies employing radiolabelled imidazoles, provide strong evidence for the existence of tumour hypoxia which influences RT treatment outcome. Hyperbaric oxygen (HBO) trials for head and neck cancer, conducted in the early 1970s, demonstrated that HBO improved local control and survival rates in patients with head and neck cancer receiving radiotherapy (RT). Since the mid-1970s, clinical research in overcoming tumour hypoxia was mainly centred on the use of nitro-imidazoles as hypoxic cell sensitizers. However, the results from several major clinical trials remain inconclusive. Specifically, the Radiation Therapy Oncology Group (RTOG) misonidazole head and neck trial (298 patients) showed no benefit. The Danish misonidazole trial (626 patients) showed no overall benefit, however positive results were observed in a subgroup (304 pharyngeal cancer patients). Although the European Organisation for Research and Teaching of Cancer (EORTC) misonidazole trial with hyperfractionated RT showed no benefit, the Danish nimorazole trial demonstrated an overall benefit in survival as well as local control. The European etanidazole (ETA) trial (374 patients) showed no advantage of adding the drug to RT. The RTOG ETA trial (504 patients) showed no global benefit. However, positive results were observed in a subset of patients with early nodal disease (197 patients). In addition, a recent meta-analysis by Overgaard, utilising pooled results in the literature demonstrated that modification of tumour hypoxia significantly improved local-regional control in head and neck cancers with an odds ratio of 1.23 (95% confidence limits 1.09 to 1.37). Hypoxic cytotoxins, such as tirapazamine, represent a novel approach in overcoming radioresistant hypoxic cells. Tirapazamine is a bioreductive agent which, by

Topics: Animals; Antineoplastic Agents; Carcinoma; Cell Hypoxia; Clinical Trials as Topic; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Etanidazole; Head and Neck Neoplasms; Humans; Hyperbaric Oxygenation; Mice; Microelectrodes; Misonidazole; Oxygen Consumption; Radiation Tolerance; Radiation-Sensitizing Agents; Survival Rate; Tirapazamine; Treatment Outcome; Triazines

High plasma osteopontin (OPN) levels have been reported to be an adverse prognostic factor in head and neck squamous cell carcinomas (HNSCC), correlate with tumor hypoxia, and be predictive of benefit from hypoxia-targeted therapy. We sought to confirm the prognostic and predictive significance of OPN in patients treated on a large international trial.. Patients with stage III/IV HNSCC were randomized to receive definitive radiotherapy concurrently with cisplatin or cisplatin plus the hypoxic cell cytotoxin, tirapazamine (TPZ). Eligibility criteria for this prospective substudy included plasma sample availability for OPN assay by ELISA and absence of major radiation therapy deviations (N = 578). OPN concentrations were analyzed for overall survival (OS) and time to locoregional failure (TTLRF), adjusting for known prognostic factors. Additional analysis was carried out in patients with available tumor p16(INK4A) staining status.. The median OPN level was 544 ng/mL (range: 7-2,640). High OPN levels were not associated with worse OS (relative HR, 1.03 for highest tertile) or TTLRF (relative HR 0.91 for highest tertile). There was no interaction between OPN and treatment arm for OS or TTLRF (P = 0.93 for OS; P = 0.87 for TTLRF). For the highest tertile the 2-year OS was 66% on control arm and 67% on TPZ arm (HR = 1.11, P = 0.67). Similarly for p16(INK4A) negative patients in the highest tertile, the 2-year OS was 61% on control arm and 63% on TPZ arm (HR = 1.05, P = 0.86).. We found no evidence that high plasma OPN levels were associated with an adverse prognosis in HNSCC, or were predictive of benefit with hypoxia targeting therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cisplatin; Cyclin-Dependent Kinase Inhibitor p16; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Head and Neck Neoplasms; Humans; Immunoenzyme Techniques; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Osteopontin; Prospective Studies; Survival Rate; Tirapazamine; Treatment Outcome; Triazines

Hepatocyte growth factor (HGF) is a hypoxia-induced secreted protein that binds to cMet and regulates interleukin (IL)-8 expression. We evaluated the role of circulating HGF and IL-8 as prognostic and predictive factors for efficacy of tirapazamine (TPZ), a hypoxic cell cytotoxin.. Patients with stages III to IV head and neck cancer were randomized to receive radiotherapy with cisplatin (CIS) or CIS plus TPZ (TPZ/CIS). Eligibility for the substudy included plasma sample availability for HGF and IL-8 assay by ELISA and no major radiation deviations (N = 498). Analyses included adjustment for major prognostic factors. p16(INK4A) staining (human papillomavirus surrogate) was carried out on available tumors. Thirty-nine patients had hypoxia imaging with (18)F-fluoroazomycin arabinoside ((18)FAZA)-positron emission tomography.. Elevated IL-8 level was associated with worse overall survival (OS) irrespective of treatment. There was an interaction between HGF and treatment arm (P = 0.053); elevated HGF was associated with worse OS in the control but not in the TPZ/CIS arm. Similar trends were observed in analyses restricted to p16(INK4A)-negative patients. Four subgroups defined by high and low HGF/IL-8 levels were examined for TPZ effect; the test for interaction with arm was P = 0.099. TPZ/CIS seemed to be beneficial for patients with high HGF and IL-8 but adverse for low HGF and high IL-8. Only HGF correlated with (18)FAZA tumor standard uptake value.. IL-8 is an independent prognostic factor irrespective of treatment. There is an interaction between HGF and treatment arm. Certain subgroups based on IL-8/HGF levels seemed to do better with TPZ/CIS while others did worse, highlighting the complexity of hypoxia targeting in unselected patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Squamous Cell; Chemoradiotherapy; Female; Head and Neck Neoplasms; Hepatocyte Growth Factor; Humans; Interleukin-8; Male; Middle Aged; Positron-Emission Tomography; Tirapazamine; Triazines

Promising results in a randomized phase II trial with the hypoxic cytotoxin tirapazamine (TPZ) combined with cisplatin (CIS) and radiation led to this phase III trial.. Patients with previously untreated stage III or IV (excluding T1-2N1 and M1) squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx were randomly assigned to receive definitive radiotherapy (70 Gy in 7 weeks) concurrently with either CIS (100 mg/m(2)) on day 1 of weeks 1, 4, and 7 or CIS (75 mg/m(2)) plus TPZ (290 mg/m(2)/d) on day 1 of weeks 1, 4, and 7 and TPZ alone (160 mg/m(2)/d) on days 1, 3, and 5 of weeks 2 and 3 (TPZ/CIS). The primary end point was overall survival (OS). The planned sample size was 850, estimated to result in 334 deaths, which would provide 90% power to detect a difference in 2-year survival rates of 60% v 70% for CIS versus TPZ/CIS, respectively (hazard ratio = 0.69).. Eight hundred sixty-one patients were accrued from 89 sites in 16 countries. In an intent-to-treat analysis, the 2-year OS rates were 65.7% for CIS and 66.2% for TPZ/CIS (TPZ/CIS--CIS: 95% CI, -5.9% to 6.9%). There were no significant differences in failure-free survival, time to locoregional failure, or quality of life as measured by Functional Assessment of Cancer Therapy-Head and Neck.. We found no evidence that the addition of TPZ to chemoradiotherapy, in patients with advanced head and neck cancer not selected for the presence of hypoxia, improves OS.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Female; Follow-Up Studies; Head and Neck Neoplasms; Humans; International Agencies; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Quality of Life; Radiotherapy Dosage; Survival Rate; Tirapazamine; Treatment Outcome; Triazines

Reirradiation (re-RT) with concurrent chemotherapy offers a therapeutic option in patients who have locoregional recurrence of head and neck cancer (HNC). The hypoxic cell sensitizer, tirapazamine (TPZ), has demonstrated promising results in first-line therapy for HNC. This phase I trial was designed to test the feasibility of giving TPZ in the re-RT setting.. Patients with recurrent HNC who received prior radiotherapy (RT) were enrolled and received TPZ (260 mg/m2) and cisplatin (50 mg/m2) Weeks 1, 3, and 5 concurrently with RT (72 Gy, 42 fractions over 6 weeks). TPZ (160 mg/m2) alone was added on Days 1, 3, and 5 of Week 2 (cohort 1) or Weeks 2 and 4 (cohort 2).. Twenty-five subjects were enrolled, 7 and 18 on cohorts 1 and 2, respectively. Significant toxicities included Grade 3 dermatitis (20%) and Grade 3 mucositis (40%). Dose-limiting toxicity was observed on cohort 2 (1 patient with aspiration pneumonia). Four deaths occurred during treatment. Two fatalities occurred after completing therapy as a result of carotid artery rupture. With a minimum and median follow-up of 14 and 24 months, respectively, median overall survival was 14 months with actuarial 1-year and 2-year survival of 56% and 27%, respectively.. Reirradiation with concomitant chemotherapy including TPZ in patients with unresectable recurrent HNC is feasible and results in long-term survival in a significant proportion of patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Confidence Intervals; Feasibility Studies; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Radiation-Sensitizing Agents; Radiotherapy Dosage; Retreatment; Tirapazamine; Triazines

The objective of this article was to report the results from a randomized trial that evaluated the efficacy and toxicity of adding tirapazamine (TPZ) to chemoradiotherapy in the treatment of patients with head and neck squamous cell carcinomas (HNSCC).. Sixty-two patients with lymph node-positive, resectable, TNM Stage IV HNSCC were randomized to receive either 2 cycles of induction chemotherapy (TPZ, cisplatin, and 5-fluorouracil [5-FU]) followed by simultaneous chemoradiotherapy (TPZ, cisplatin, and 5-FU) or to receive the same regimen without TPZ. Patients who did not achieve a complete response at 50 Grays underwent surgical treatment. Stratification factors for randomization included tumor site, TNM stage, and median tumor oxygen tension. The primary endpoint was complete lymph node response.. The addition of TPZ resulted in increased hematologic toxicity. There was 1 treatment-related death from induction chemotherapy. The complete clinical and pathologic response rate in the lymph nodes was 90% and 74% for the standard treatment arm and the TPZ arm, respectively (P = .08) and 89% and 90% at the primary site in the respective treatment arms (P = .71). The 5-year overall survival rate was 59%, the cause-specific survival rate was 68%, the rate of freedom from recurrence was 69%, and the locoregional control rate was 77% for the entire group. There was no difference with regard to any of the outcome parameters between the 2 treatment arms. The significant long-term toxicity rate also was found to be similar between the 2 arms.. The addition of TPZ increased hematologic toxicity but did not improve outcomes in patients with resectable, Stage IV HNSCC using the protocol administered this small randomized study. The combination of induction and simultaneous chemoradiotherapy resulted in excellent survival in these patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Male; Middle Aged; Patient Compliance; Survival Rate; Tirapazamine; Treatment Outcome; Triazines

To determine the association between tumor hypoxia, treatment regimen, and locoregional failure (LRF) in patients with stage III or IV squamous cell carcinoma of the head and neck randomly assigned to radiotherapy (70 Gy in 35 fractions over 7 weeks) plus either tirapazamine and cisplatin in weeks 1, 4, and 7 and tirapazamine alone in weeks 2 and 3 (TPZ/CIS) or cisplatin and infusional fluorouracil during weeks 6 and 7 (chemoboost).. Forty-five patients were enrolled onto a hypoxic imaging substudy of a larger randomized trial. Pretreatment and midtreatment [18F]-fluoromisonidazole positron emission tomography scans (FMISO-PET) were performed 2 hours after tracer administration, with qualitative scoring of uptake in both primary tumors and nodes.. Thirty-two patients (71%) had detectable hypoxia in either or both primary and nodal disease. In patients who received chemoboost, one of 10 patients without hypoxia had LRF compared with eight of 13 patients with hypoxia; the risk of LRF was significantly higher in hypoxic patients (exact log-rank, P = .038; hazard ratio [HR] = 7.1). By contrast, in patients who received the TPZ/CIS regimen, only one of 19 patients with hypoxic tumors had LRF; risk of LRF was significantly higher in chemoboost patients (P = .001; HR = 15). Similarly, looking at the primary site alone, in patients with hypoxic primaries, zero of eight patients treated with TPZ/CIS experienced failure locally compared with six of nine patients treated with chemoboost (P = .011; HR = 0).. Hypoxia on FMISO-PET imaging, in patients receiving a nontirapazamine-containing chemoradiotherapy regimen, is associated with a high risk of LRF. Our data provide the first clinical evidence to support the experimental observation that tirapazamine acts by specifically targeting hypoxic tumor cells.

Topics: Cell Hypoxia; Combined Modality Therapy; Female; Fluorodeoxyglucose F18; Head and Neck Neoplasms; Humans; Male; Middle Aged; Misonidazole; Positron-Emission Tomography; Prognosis; Tirapazamine; Treatment Failure; Triazines

To select one of two chemoradiotherapy regimens for locally advanced squamous cell carcinoma (SCC) of the head and neck as the experimental arm for the next Trans-Tasman Radiation Oncology Group phase III trial.. One hundred twenty-two previously untreated patients with stage III/IV SCC of the head and neck were randomized to receive definitive radiotherapy (70 Gy in 7 weeks) concurrently with either cisplatin (75 mg/m(2)) plus tirapazamine (290 mg/m(2)/d) on day 2 of weeks 1, 4, and 7, and tirapazamine alone (160 mg/m(2)/d) on days 1, 3, and 5 of weeks 2 and 3 (TPZ/CIS), or cisplatin (50 mg/m(2)) on day 1 and infusional fluorouracil (360 mg/m(2)/d) on days 1 through 5 of weeks 6 and 7 (chemoboost).. Three-year failure-free survival rates were 55% with TPZ/CIS (95% CI, 39% to 70%) and 44% with chemoboost (95% CI, 30% to 60%; log-rank P = .16). Three-year locoregional failure-free rates were 84% in the TPZ/CIS arm (95% CI, 71% to 92%) and 66% in the chemoboost arm (95% CI, 51% to 79%; P = .069). More febrile neutropenia and grade 3 or 4 late mucous membrane toxicity were observed with TPZ/CIS, while acute skin radiation reaction was more severe and prolonged with chemoboost. Compliance with protocol treatment was satisfactory on both arms.. Both regimens are feasible and are associated with significant but acceptable toxicity profiles in the cooperative group setting. Based on the promising efficacy seen in this trial, TPZ/CIS is being evaluated in a large phase III trial.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Male; Middle Aged; Patient Compliance; Radiotherapy; Survival Rate; Tirapazamine; Triazines

The purpose of the study was to evaluate [(18)F]fluoromisonidazole (FMISO) PET in advanced head and neck cancer during hypoxia-targeting therapy.. Fifteen of 16 patients in a phase I trial of chemoradiation plus tirapazamine (specific cytotoxin for hypoxic cells) in advanced (T3/4 and/or N2/3) head and neck cancer underwent serial [(18)F]fluorodeoxyglucose (FDG) and FMISO PET. We have previously reported excellent early clinical outcome of these patients and now review FMISO PET results in the context of longer follow-up of this patient cohort.. Based on blinded qualitative scoring by two readers, FMISO PET was positive in 13/15 patients at baseline: 12/15 of primary sites and 8/13 neck nodes were scored as positive. All sites of corresponding FDG and FMISO abnormality at baseline showed marked qualitative reduction of uptake within 4 weeks of commencing therapy, consistent with effective hypoxia-targeted therapy. With a median follow-up of 6.9 years, there have been only four locoregional failures, while three other patients have died of metachronous lung cancer. The 5-year overall survival was 50% (95% CI 27-73%), the 5-year failure-free survival was 44% (95% CI 22-68%) and the 5-year freedom from locoregional failure was 68% (95% CI 38-88%).. The high prevalence of hypoxia demonstrated on FMISO PET imaging is consistent with the advanced disease stage of these patients and would be expected to predict an adverse prognosis. Evidence of the early resolution of FMISO abnormality during treatment, associated with excellent locoregional control in this patient cohort, supports further investigation of hypoxia-targeting agents in advanced head and neck cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzylamines; Carcinoma, Squamous Cell; Cell Hypoxia; Chemotherapy, Adjuvant; Cisplatin; Cohort Studies; Drug Delivery Systems; Female; Follow-Up Studies; Head and Neck Neoplasms; Humans; Male; Middle Aged; Positron-Emission Tomography; Prognosis; Radiation-Sensitizing Agents; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity; Single-Blind Method; Tirapazamine; Treatment Outcome; Triazines

To compare the Eppendorf PO2 histograph and the alkaline comet assay as methods of measuring tumor hypoxia in patients with head-and-neck squamous cell carcinomas.. As part of a larger clinical trial, 65 patients with head-and-neck squamous cell carcinoma nodal metastasis underwent tumor oxygenation measurements with Eppendorf PO2 histographs and comet assays, performed on fine-needle aspirates at 1 and 2 min after 5 Gy. Fifty-four patients had sufficient tumor cells for comet analysis at 1 min and 26 at both 1 and 2 min. Individual cells were examined for DNA single-strand breaks by alkaline gel electrophoresis, and the distribution of values was quantified using median tail moment (MTM). Nonirradiated tumor cells from pretreatment fine-needle aspirates received 5 Gy in vitro to establish the oxygenated response.. There was a significant correlation between the 1- and 2-min MTM (slope = 0.77 +/- 0.03). There was no relationship between DNA damage in tumor cells irradiated in vitro and in vivo. No correlation was found between Eppendorf PO2 measurements and comet MTM. There was a statistically significant correlation between the treatment response in the node studied and comet MTMs, whereas no correlation was observed between treatment response and Eppendorf measurements.. Comet assays are reproducible, as shown by biopsies at 1 and 2 min. Intertumor variation in the MTM is not a result of intrinsic radiosensitivity but of tumor hypoxia. There was no correlation between Eppendorf PO2 measurements and comet MTM. Comet assays were better than Eppendorf in predicting treatment response as an end point for short-term outcome. Longer follow-up is needed to determine the role of the comet assay as a predictor for locoregional tumor control and survivals.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cell Hypoxia; Cisplatin; Comet Assay; DNA Damage; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Male; Microelectrodes; Middle Aged; Oxygen; Radiation-Sensitizing Agents; Tirapazamine; Triazines

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.. 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.. 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%).. 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.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cell Hypoxia; Cisplatin; Combined Modality Therapy; Dose Fractionation, Radiation; Drug Administration Schedule; Fluorodeoxyglucose F18; Head and Neck Neoplasms; Humans; Middle Aged; Misonidazole; Radiation-Sensitizing Agents; Radiopharmaceuticals; Survival Analysis; Tirapazamine; Tomography, Emission-Computed; Triazines

Tirapazamine (TPZ) [3-amino-1,2,4-benzotriazine 1,4-dioxide, SR4233, WIN 59075, and Tirazone] is a novel anticancer drug that is selectively activated by the low oxygen environment in solid tumors. By killing the radioresistant hypoxic cells, TPZ potentiates the antitumor efficacy of fractionated irradiation of transplanted tumors in mice. As this cell kill is closely correlated with TPZ-induced DNA damage, we investigated whether human head and neck cancers would show DNA damage similar to that seen in mouse tumors following TPZ administration. TPZ-induced DNA damage in both transplanted tumors in mice and in neck nodes of 13 patients with head and neck cancer was assessed using the alkaline comet assay on cells obtained from fine-needle aspirates. The oxygen levels of the patients' tumors were also measured using a polarographic oxygen electrode. Cells from the patients' tumors showed DNA damage immediately following TPZ administration that was comparable to, or greater than, that seen with transplanted mouse tumors. The heterogeneity of DNA damage in the patients' tumors was greater than that of individual mouse tumors and correlated with tumor hypoxia. The similarity of TPZ-induced DNA damage in human and rodent tumors suggests that tirapazamine should be effective when added to radiotherapy or to cisplatin-based chemotherapy in head and neck cancers.

Topics: Animals; Antineoplastic Agents; Comet Assay; DNA Damage; Dose-Response Relationship, Drug; Head and Neck Neoplasms; Humans; Mice; Mice, Inbred C3H; Mice, SCID; Neoplasm Transplantation; Oxygen; Time Factors; Tirapazamine; Triazines; Tumor Cells, Cultured

For patients with squamous cell carcinoma of the head and neck (HNSCC), persistence of cervical adenopathy following organ-preservation therapy is a strong predictor of locoregional failure. Squamous cell granulomas of the neck may represent a regressed state of metastatic HNSCC; however, relevant clinicopathologic features of this lesion including its morphologic characteristics, association with therapy, and relationship to disease progression are not well defined.. We reviewed 866 consecutive neck dissections performed at The Johns Hopkins Hospital from 1984 to 1996. A total of eight cases showing a foreign-body giant-cell reaction to keratin in the absence of viable tumor formed the basis of this study.. All eight cases were from patients with stage III or IV HNSCC with concurrent neck masses. Patients were initially treated by chemotherapy (n = 1), radiotherapy (n = 1), or chemotherapy plus radiotherapy (n = 6); and all patients subsequently underwent neck dissection for persistence of their neck masses. Histologically, the neck lesions were characterized by a foreign-body giant-cell reaction to keratin and extensive scarring. None (0%) of the patients developed recurrent regional disease in the treated neck. Two (25%) of the patients had tumor recurrence at the primary site. Two (25%) of the patients developed widely metastatic disease.. These observations suggest that squamous cell granulomas represent histologic regression of metastatic squamous cell carcinoma in patients with HNSCC treated by chemotherapy and/or radiotherapy. Although persistent cervical adenopathy is an established risk factor for locoregional failure in this group of patients, squamous cell granulomas of the neck paradoxically may reflect enhanced regional tumor sensitivity to cytotoxic agents.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Cisplatin; Culture Techniques; Diagnosis, Differential; Female; Fibrosis; Fluorouracil; Granuloma, Foreign-Body; Head and Neck Neoplasms; Humans; Immunohistochemistry; Lymphatic Metastasis; Male; Middle Aged; Neck; Neck Dissection; Neoplasm Staging; Paclitaxel; Radiotherapy, Adjuvant; Registries; Remission Induction; Tirapazamine; Triazines

To evaluate the efficacy and toxicity of tirapazamine, a hypoxic cytotoxin, combined with conventional radiotherapy (RT) for advanced head and neck carcinomas.. From Oct. 1994 to Nov. 1996, 40 patients with stage III or IV carcinomas of the head and neck were enrolled in a Phase II trial to receive conventional RT (70 Gy in 7 weeks) with concurrent tirapazamine (159 mg/m2 intravenously, 3 times per week for 12 doses). One patient subsequently withdrew from the protocol treatment, and was excluded from analyses. Among the 39 cases, the primary sites were located in the oropharynx (n = 28), supraglottic larynx (n = 6), or hypopharynx (n = 5). Twenty-seven patients had T3 or T4, and 27 had N2 or N3 disease.. Thirty-two (82%) patients received full 12 drug doses. Thirty-two patients (82%) received full 70 Gy of RT. The most frequent drug toxicities were muscle cramps (77%) and nausea/vomiting (62%), usually grade 1 or 2. Overall, 13 patients (33%) experienced grade 3 or 4 drug-related toxicities. No excessive RT-associated acute normal tissue reactions were observed. With a median follow-up of 13 months, the 1-year and 2-year local control rate was 64% and 59% respectively.. The tirapazamine regimen was well tolerated with a compliance rate of 82%. The toxicity of RT with concurrent tirapazamine was acceptable in treating advanced head and neck carcinomas. The disease control trend was encouraging. Further clinical studies are warranted.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Combined Modality Therapy; Female; Follow-Up Studies; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neoplasm Staging; Radiation-Sensitizing Agents; Radiotherapy Dosage; Tirapazamine; Triazines

Hypoxia is a prevalent feature of many tumors contributing to disease progression and treatment resistance, and therefore constitutes an attractive therapeutic target. Several hypoxia-activated prodrugs (HAP) have been developed, including the phase III candidate TH-302 (evofosfamide) and the preclinical agent SN30000, which is an optimized analogue of the well-studied HAP tirapazamine. Experience with this therapeutic class highlights an urgent need to identify biomarkers of HAP sensitivity, including enzymes responsible for prodrug activation during hypoxia. Using genome-scale shRNA screens and a high-representation library enriched for oxidoreductases, we identified the flavoprotein P450 (cytochrome) oxidoreductase (POR) as the predominant determinant of sensitivity to SN30000 in three different genetic backgrounds. No other genes consistently modified SN30000 sensitivity, even within a POR-negative background. Knockdown or genetic knockout of POR reduced SN30000 reductive metabolism and clonogenic cell death and similarly reduced sensitivity to TH-302 under hypoxia. A retrospective evaluation of head and neck squamous cell carcinomas showed heterogeneous POR expression and suggested a possible relationship between human papillomavirus status and HAP sensitivity. Taken together, our study identifies POR as a potential predictive biomarker of HAP sensitivity that should be explored during the clinical development of SN30000, TH-302, and other hypoxia-directed agents.

Topics: Activation, Metabolic; Antineoplastic Agents; Biomarkers; Carcinoma, Squamous Cell; Cell Hypoxia; Cell Line, Tumor; Chemoradiotherapy; Cyclic N-Oxides; Cytochrome P-450 Enzyme System; Head and Neck Neoplasms; High-Throughput Screening Assays; Humans; Neoplasm Proteins; Nitroimidazoles; Papillomaviridae; Papillomavirus Infections; Phosphoramide Mustards; Prodrugs; Retrospective Studies; RNA Interference; RNA, Messenger; RNA, Small Interfering; Tirapazamine; Triazines; Tumor Microenvironment; Tumor Stem Cell Assay

To assess the role of a planned neck dissection (PND) after sequential chemoradiotherapy for patients with head-and-neck cancer with N2-N3 nodal disease.. We reviewed 90 patients with N2-N3 head-and-neck squamous cell carcinoma treated between 1991 and 2001 on two sequential chemoradiotherapy protocols. All patients received induction and concurrent chemotherapy with cisplatin and 5-fluorocuracil, with or without tirapazamine. Patients with less than a clinical complete response (cCR) in the neck proceeded to a PND after chemoradiation. The primary endpoint was nodal response. Clinical outcomes and patterns of failure were analyzed.. The median follow-up durations for living and all patients were 8.3 years (range, 1.5-16.3 year) and 5.4 years (range, 0.6-16.3 years), respectively. Of the 48 patients with nodal cCR whose necks were observed, 5 patients had neck failures as a component of their recurrence [neck and primary (n = 2); neck, primary, and distant (n = 1); neck only (n = 1); neck and distant (n = 1)]. Therefore, PND may have benefited only 2 patients (4%) [neck only failure (n = 1); neck and distant failure (n = 1)]. The pathologic complete response (pCR) rate for those with a clinical partial response (cPR) undergoing PND (n = 30) was 53%. The 5-year neck control rates after cCR, cPR→pCR, and cPR→pPR were 90%, 93%, and 78%, respectively (p = 0.36). The 5-year disease-free survival rates for the cCR, cPR→pCR, and cPR→pPR groups were 53%, 75%, and 42%, respectively (p = 0.04).. In our series, patients with N2-N3 neck disease achieving a cCR in the neck, PND would have benefited only 4% and, therefore, is not recommended. Patients with a cPR should be treated with PND. Residual tumor in the PND specimens was associated with poor outcomes; therefore, aggressive therapy is recommended. Studies using novel imaging modalities are needed to better assess treatment response.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemoradiotherapy; Cisplatin; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neck Dissection; Neoplasm Recurrence, Local; Neoplasm, Residual; Organ Sparing Treatments; Prospective Studies; Survival Rate; Tirapazamine; Treatment Outcome; Triazines

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cetuximab; Head and Neck Neoplasms; Humans; Porphyrins; Radiation-Sensitizing Agents; Radiation, Ionizing; Survival Rate; Tirapazamine; Triazines; Uroporphyrinogen Decarboxylase

To report the impact of radiotherapy quality on outcome in a large international phase III trial evaluating radiotherapy with concurrent cisplatin plus tirapazamine for advanced head and neck cancer.. The protocol required interventional review of radiotherapy plans by the Quality Assurance Review Center (QARC). All plans and radiotherapy documentation underwent post-treatment review by the Trial Management Committee (TMC) for protocol compliance. Secondary review of noncompliant plans for predicted impact on tumor control was performed. Factors associated with poor protocol compliance were studied, and outcome data were analyzed in relation to protocol compliance and radiotherapy quality.. At TMC review, 25.4% of the patients had noncompliant plans but none in which QARC-recommended changes had been made. At secondary review, 47% of noncompliant plans (12% overall) had deficiencies with a predicted major adverse impact on tumor control. Major deficiencies were unrelated to tumor subsite or to T or N stage (if N+), but were highly correlated with number of patients enrolled at the treatment center (< five patients, 29.8%; > or = 20 patients, 5.4%; P < .001). In patients who received at least 60 Gy, those with major deficiencies in their treatment plans (n = 87) had a markedly inferior outcome compared with those whose treatment was initially protocol compliant (n = 502): -2 years overall survival, 50% v 70%; hazard ratio (HR), 1.99; P < .001; and 2 years freedom from locoregional failure, 54% v 78%; HR, 2.37; P < .001, respectively.. These results demonstrate the critical importance of radiotherapy quality on outcome of chemoradiotherapy in head and neck cancer. Centers treating only a few patients are the major source of quality problems.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Clinical Trials as Topic; Combined Modality Therapy; Follow-Up Studies; Guideline Adherence; Head and Neck Neoplasms; Humans; International Agencies; Neoplasm Recurrence, Local; Neoplasm Staging; Quality Assurance, Health Care; Radiotherapy Dosage; Survival Rate; Tirapazamine; Treatment Outcome; Triazines

Well-differentiated hypoxic regions in head and neck squamous cell carcinoma like in A253 xenografts are avascular and, therefore, hinder drug delivery leading to drug resistance and tumor regrowth. Methylselenocysteine (MSC, 0.2 mg/mouse per day per oral for 35 days starting 7 days before the first irinotecan (CPT-11)) has been found to increase efficacy of a wide variety of chemotherapeutic agents including CPT-11 (100 mg/kg per week x 4 intravenously). Whereas CPT-11 leads to a 10% complete response (CR) in A253 xenografts, the combination of MSC and CPT-11 increased the CR to 70%. Surviving tumors were found to consist largely of avascular hypoxic regions. Here, we investigated the combination of tirapazamine (TPZ, 70 mg/kg per week intraperitoneal x 4 administered 3 or 72 hours before CPT-11), a bioreductive drug in clinical trial with selective toxicity for hypoxic cells, with MSC and CPT-11 in further enhancing the cure rates. Tumor response, change in tumor hypoxic regions, and DNA damage were monitored in vivo. Tirapazamine administered 3 hours before CPT-11 in combination with MSC + CPT-11 led to a lower tumor burden. Tirapazamine did not increase cure rate beyond that of MSC + CPT-11 combination and was instead found to decrease cures with no evidence of an increased DNA damage or a significant reduction in avascular hypoxic tumor regions. CD31 immunostaining in A253 demonstrated disruption of tumor vessels by TPZ that could lower cytotoxic drug delivery to carbonic anhydrase IX-positive hypoxic tumor cells and may explain at least partially these unexpected results.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Squamous Cell; Cell Differentiation; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Cysteine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Forkhead Transcription Factors; Head and Neck Neoplasms; Humans; Irinotecan; Maximum Tolerated Dose; Mice; Mice, Nude; Neoplasm Transplantation; Organoselenium Compounds; Selenocysteine; Tirapazamine; Triazines; Xenograft Model Antitumor Assays

Topics: Animals; Antineoplastic Agents; Cell Hypoxia; Fluorine Radioisotopes; Head and Neck Neoplasms; Humans; Mammary Neoplasms, Experimental; Nitroimidazoles; Positron-Emission Tomography; Radiation-Sensitizing Agents; Tirapazamine; Triazines

Topics: Antigens, Neoplasm; Biomarkers; Carbonic Anhydrase IX; Carbonic Anhydrases; Carcinoma, Squamous Cell; Cell Hypoxia; Electrodes; Etanidazole; Head and Neck Neoplasms; Humans; Hydrocarbons, Fluorinated; Intracellular Signaling Peptides and Proteins; Mitochondrial Proteins; Neoplasm Proteins; Nitroimidazoles; Osteopontin; Oxygen; Partial Pressure; Radiation-Sensitizing Agents; Tirapazamine; Triazines

Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/mp53) or with neo vector as a control (SAS/neo) were inoculated subcutaneously into both the hind legs of Balb/cA nude mice. Mice bearing the tumors received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all proliferating (P) cells in the tumors. The mice then received a hypoxic cytotoxin, tirapazamine (TPZ) or TX-402, with or without a vascular targeting agent (VTA), ZD6126. Another group of mice given ZD6126 received a series of test doses of gamma-rays while alive or after tumor clamping to obtain hypoxic fractions (HFs) in the tumors. After each treatment, the tumor cells were isolated and incubated with a cytokinesis blocker (cytochalasin-B), and the micronucleus (MN) frequency in cells without BrdU labeling [quiescent (Q) cells] was determined using immunofluorescence staining for BrdU. The MN frequency in total (P+Q) tumor cells was determined from the tumors that were not pretreated with BrdU. Both hypoxic cytotoxins showed significantly greater toxicity toward SAS/mp53 and Q than SAS/neo and total tumor cells, respectively. The sensitivity to TX-402 was significantly higher than that to TPZ in both total and Q tumor cells of both tumors. The significant enhancive effect by ZD6126 combined with each hypoxic cytotoxin was similar irrespective of p53 status, and slightly greater for total than Q cells probably because of a more marked increase in the size of the HFs in total than Q cells on the use of ZD6126 in both tumors, resulting in a reduction of the difference in the sensitivity to the hypoxic cytotoxin between total and Q cells. In the treatment of conventional cancer therapy-resistant Q tumor cells or p53-mutated tumor cells, the use of hypoxic cytotoxin was very promising either alone or when VTA was co-administered. TX-402 might be more promising than TPZ, although further study of the toxicity to normal tissue is needed.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Cell Survival; Combined Modality Therapy; Cyclic N-Oxides; Gamma Rays; Head and Neck Neoplasms; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Micronucleus Tests; Mutation; Organophosphorus Compounds; Quinoxalines; Radiotherapy; Tirapazamine; Triazines; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/mp53) or with neo vector as a control (SAS/neo) were inoculated subcutaneously into both hind legs of Balb/cA nude mice. Mice bearing the tumors received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all proliferating (P) cells in the tumors. The mice then received tirapazamine (TPZ) with or without mild temperature hyperthermia (40 degrees C, 60 min) (MTH), gamma-ray irradiation with or without MTH and/or TPZ, cisplatin (CDDP) with or without MTH and/or TPZ, or paclitaxel (TXL) with or without MTH and/or TPZ. After each treatment, the tumors were excised, minced and trypsinized. The tumor cell suspensions thus obtained were incubated with a cytokinesis blocker (cytochalasin-B), and the micronucleus (MN) frequency in cells without BrdU labeling (i.e., quiescent (Q) cells) was determined by using immunofluorescence staining for BrdU. Meanwhile, 6 h after gamma-ray irradiation or 24 h after other cytotoxic treatments, tumor cell suspensions obtained in the same manner were used for determining the frequency of apoptosis in Q cells. The MN frequency and apoptosis frequency in total (P+Q) tumor cells were determined from the tumors that were not pretreated with BrdU. On the whole, gamma-ray irradiation and CDDP injection induced a higher frequency of apoptosis and lower frequency of MN in SAS/neo cells than SAS/mp53 cells. There were no apparent differences in the induced frequency of apoptosis and MN between SAS/neo and SAS/mp53 cells after TPZ or TXL treatment. MTH sensitized cells to TPZ-inducing cytotoxicity more markedly in SAS/mp53 and Q cells than in SAS/neo cells and total cells, respectively. In gamma-ray irradiation and CDDP treatment, the enhancement in combination with MTH and/or TPZ was more remarkable in SAS/mp53 cells and Q cells than in SAS/neo and total tumor cells, respectively. Also in the case of TXL treatment, the combination with MTH and/or TPZ induced a slightly greater enhancement effect in SAS/mp53 cells and Q cells. In view of the difficulty in controlling mutated p53 status tumors and intratumor Q cells, combination treatment with MTH and/or TPZ as a cooperative modality in cancer therapy is considered to have potential for controlling solid tumors as a whole.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bromodeoxyuridine; Carcinoma, Squamous Cell; Cell Hypoxia; Cisplatin; Combined Modality Therapy; DNA Damage; Gamma Rays; Genes, p53; Head and Neck Neoplasms; Humans; Hyperthermia, Induced; Mice; Mice, Inbred BALB C; Mice, Nude; Micronucleus Tests; Neoplasm Proteins; Paclitaxel; Radiation-Sensitizing Agents; Tirapazamine; Triazines; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Enormous progress has been made in the past 5 years in our understanding of the gene products governing the response of mammalian cells to ionizing radiation. Many of these are potential targets for enhancing the effectiveness of radiotherapy. However, a major barrier to such efforts is the requirement for a preferential effect on tumor vs. normal cells. Such a requirement can only come about by exploiting a known difference between tumor and normal cells.. This review highlights three differences between tumor and normal cells that are being exploited with fractionated radiotherapy.. The three strategies to enhance preferentially tumor response to radiotherapy are inhibition of ras activity using farnesyltransferase inhibitors (FTIs), inhibition of epidermal growth factor receptors (EGFRs), and the use of drugs that preferentially kill hypoxic cells. Each of these strategies exploits a known difference between at least some tumors and their surrounding normal tissues, and each has shown encouraging results when combined with fractionated radiation in preclinical studies.. For each of the three strategies to enhance preferentially the sensitivity of cancers, the preclinical and early clinical data are promising for their successful application in radiotherapy.

Topics: Alkyl and Aryl Transferases; Antibodies, Monoclonal; Antineoplastic Agents; Cell Division; Cell Hypoxia; Dose Fractionation, Radiation; Enzyme Inhibitors; ErbB Receptors; Farnesyltranstransferase; Genes, ras; Head and Neck Neoplasms; Humans; Methionine; Neoplasms; Radiation Tolerance; Radiation-Sensitizing Agents; Signal Transduction; Tirapazamine; Triazines; Tumor Cells, Cultured