• chemotherapy;
  • head and neck cancers;
  • hypoxia;
  • radiotherapy;
  • tirapazamine


  1. Top of page
  2. Abstract
  6. Acknowledgements


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 treatement 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. Cancer 2006. © 2006 American Cancer Society.

Hypoxia, or the condition of low oxygen level, is a common occurrence in solid tumors and is recognized as a major factor that contributes to radioresistance and, potentially, to chemoresistance.1, 2 Several studies have shown a strong correlation between pretreatment tumor oxygen pressure (pO2), as measured by the Eppendorf microelectrode (Eppendorf, Hamburg, Germany), and locoregional control (LRC) and survival in patients who receive radiotherapy (RT) for head and neck squamous cell carcinomas (HNSCC).3–5 Tirapazamine (3-amino-1, 4-benzotriazine-1-N-oxide; also known as TPZ, SR 4233, WIN 59074, or Tirazone™ [Sanofi-Synthelabo. New York, NY]) is a benzotriazine with selective cytotoxicity for hypoxic cells. Under hypoxic conditions, it undergoes a 1-electron reduction to form a cytotoxic free radical that poisons topoisomerase II and causes DNA breaks, chromosomal aberrations, and cell death.6, 7 In the presence of oxygen, the TPZ radical is back oxidized to the nontoxic parent compound. In vitro studies have demonstrated selective cytotoxicity in hypoxic cells for TPZ.8 In preclinical testing, TPZ selectively kills hypoxic cells in vitro, is an effective sensitizer of fractionated RT,8 and enhances the tumor cell-killing effect of several cytotoxic agents, particularly cisplatin.9, 10 It has shown promising results in Phase I and II clinical trials when combined with RT alone or with chemoradiotherapy (CRT)11–13 in patients with locally advanced HNSCC. Based on these encouraging results, we performed an institutional Phase II randomized study to assess the toxicity and efficacy of combining TPZ with aggressive CRT in patients with locally advanced HNSCC under the auspices of the National Cancer Institute (NCI).

We previously performed a Phase II efficacy study using a regimen that consist of 2 cycles of induction cisplatin and 5-fluorouracil (5-FU) chemotherapy followed by simultaneous cisplatin, 5-FU, and RT in patients with resectable, TNM Stage III and IV HNSCC.14 That regimen yielded a promising organ-preservation rate of 78% and a 3-year survival rate of 60%. Therefore, we employed the same regimen as our standard approach and randomized patients with pathologically proven, lymph node-positive, Stage IV HNSCC to receive either the above-described regimen alone or the same regimen with TPZ. Because all patients undergo pO2 measurements in the involved cervical lymph nodes, the primary endpoint of this study was to evaluate the effect of TPZ on the complete lymph node response rate in these patients. Other endpoints were to assess the rates of treatment-related toxicity, complete response (CR) at the primary site, LRC, freedom from recurrence (FFR), cause-specific survival (CCS), and overall survival (OS). This is a report on the mature results from this Phase II randomized study.


  1. Top of page
  2. Abstract
  6. Acknowledgements

Patient Eligibility

Patients with resectable Stage IV HNSCC with metastasis to cervical lymph nodes were invited to enroll in the protocol. Cervical lymph node metastasis was proven by fine-needle aspiration prior to enrollment. Eligibility criteria included the following: 1) age 17 years or older; 2) an Eastern Cooperative Oncology Group performance status from 0 to 2; 3) no prior RT or chemotherapy; 4) adequate bone marrow, hepatic, and renal function; 5) no concurrent malignancy and no prior malignancy within 5 years; and 6) signed informed consent approved by the Institutional Review Board. Patients with unknown primary cancers who had metastatic cervical lymph nodes also were candidates for the protocol, because the main study endpoint was the lymph node CR rate. Pretreatment evaluation included a complete history and physical examination, complete blood counts and comprehensive chemistry panel, 24-hour creatinine clearance, magnetic resonance imaging (MRI) or computed tomography (CT) studies of the head and neck sites, chest X-ray, and baseline audiogram.

Assessment of Tumor Hypoxia

Two different assays were used to measure tumor hypoxia in the involved lymph nodes: 1) pO2 measurement with the Eppendorf microelectrode (pO2 histograph) and 2) assessment of single-stranded DNA breaks measured by the comet assay before and 1 minute after 5 Grays (Gy) of irradiation. Both methods have been described previously.15–19

Study Design

The primary endpoint of the current study was to evaluate the effect of TPZ on lymph node response. Stratification factors included lymph node status (N1 vs. N2 or N3); pO2, as measured by the Eppendorf electrode (median pO2≤12 mm Hg vs. >12 mm Hg); and the primary tumor site (oral cavity vs. pharynx vs. larynx vs. other sites). Assuming a complete lymph node response rate of 50% in the control arm, we estimated that 60 patients would yield 80% power to detect a 32% improvement rate with TPZ with a 2-sided level of significance = .05. Patients were randomized according to permuted block procedure. According to the study design, we analyzed toxicity data every 6 months. The investigators met weekly to discuss patient care issues and scientific data in relation to the pO2 measurements and the comet assay. The Data Management Committee met yearly to review toxicity data.


Figure 1 summarizes the treatment regimen. Patients received 2 cycles of induction chemotherapy with cisplatin at a dose of 100 mg/m2 per day on Days 1 and 22, and continuous infusion (CI) 5-FU at a dose of 1000 mg/m2 per day for 120 hours per cycle starting on Days 1 and 22. Clinical and radiographic evaluations with head and neck CT or MRI studies were used to assess treatment response to induction chemotherapy approximately 1 week prior to starting RT. Simultaneous CRT consisted of cisplatin at a dose of 20 mg/m2 given 3 times per week (Monday, Wednesday, and Friday) and CI 5-FU at a dose of 600 mg/m2 per day for 96 hours per cycle in Weeks 1 and 5 of RT.

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Figure 1. Treatment schema. HNSCC: head and neck squamous cell carcinoma; PT: cisplatin; 5-FU: 5-fluorouracil; NM Stage: lymph node and metastasis status; pO2: oxygen tension; TPZ: tirapazamine.

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TPZ was administered on Days 1 and 22 prior to the administration of neoadjuvant cisplatin and on Days 43, 45, 47, 71, 73, and 75 within 1 or 2 hours prior to each simultaneous cisplatin dose. The first 4 patients received TPZ at a doses of 300 mg/m2 during the induction phase and 160 mg/m2 during the simultaneous phase (Level 1). It was observed that these doses were tolerated well, with Grade 3 mucositis (2 of 4 patients) and Grade 3 weight loss (3 of 4 patients) found to be the most frequent severe toxicity. The majority of the weight loss occurred after the completion of RT for all 3 patients. After reports indicated that tolerated TPZ doses were >300 mg/m2 when combined with cisplatin alone20 and >160 mg/m2 when combined with RT,21 we decided to be more aggressive with nutritional support and to escalate the TPZ doses to 330 mg/m2 for the induction phase and 260 mg/m2 for the simultaneous phase (Level 2). Four patients received these escalated doses. With aggressive nutrition intervention and oral care, the incidence of Grade 3 weight loss during and after CRT in these patients decreased to 25% (1 of 4 patients). However, 2 of 4 patients developed Grade 4 granulocytopenia during the induction chemotherapy phase, and 1 of 4 patients had similar and prolonged toxicity during the simultaneous CRT phase, which required significant treatment delay and met the definition for dose-limiting toxicity. This necessitated TPZ dose reductions to 300 mg/m2 for the induction phase and to 220 mg/m2 for the simultaneous phase (Level 3), and those doses were delivered to the remaining TPZ-treated patients (n = 25 patients).

RT was administered within 3 hours of the end of the TPZ infusion. Conventional RT techniques with parallel opposed fields to cover the prechemotherapy tumor volume and both aspects of the upper neck were used in the majority of these patients. An anteroposterior supraclavicular field also was used to treat the lower neck lymph nodes. The dose for the parallel-opposed fields at the central axis was 2 Gy per fraction per day given 5 days per week up to a total dose of 66 to 70 Gy to the areas of macroscopic tumor. The dose to the supraclavicular region was 50 Gy prescribed at a depth of 3 cm and delivered in 25 fractions. Supervoltage photons (≥4 megavolts) were used to treat the primary tumor and the regional lymph nodes. Electrons were used to boost the posterior neck and the involved lymph nodes.

After 50 Gy were delivered to the primary site and regional lymph nodes, all sites were reassessed for clinical response by physical examination, direct fiber optic evaluation, and radiographic imaging (CT or MRI). Patients who achieved a CR at the primary site and in the neck completed RT treatment to a total dose ≥66 Gy to the primary site and the involved lymph node(s). Patients who achieved a CR at the primary site but a partial response (PR) at the neck completed RT treatment to the primary site followed by a neck dissection. Patients who achieved a PR at the primary site stopped radiation at 50 Gy and underwent surgery to both the primary site and the neck. Surgery consisted of the originally planned procedure outlined at the time of the tumor board evaluation. These policies, although they are not used widely, have been employed in our 3 consecutive organ-preservation studies.

Toxicity Evaluation

All patients had weekly evaluations for toxicity. Chemotherapy was required to be given at the full dose and on time whenever possible. If patients had an absolute neutrophil count <1500/dL or a platelet count <100,000/dL, then chemotherapy was delayed, and blood counts were obtained weekly. The treatment was given at the full dose once the counts recovered. Dose modification using the standard criteria also was used. Dose reductions of all agents were observed for Grade 4 neutropenia that lasted > 5 days, for Grade 4 thrombocytopenia, or any for other Grade 3 or 4 toxicity. Dose reduction of cisplatin alone was observed for Grade ≥ 3 ototoxicity, Grade ≥ 2 neurotoxicity, or creatinine clearance < 60 cc/minute; and dose reduction of 5-FU alone was observed for Grade 4 mucositis or Grade 3 and 4 diarrhea.

RT was delayed or interrupted for the following toxicities: 1) a platelet count <50,000/dL, (2) leukocyte count <1000/dL, 3) hospitalization for infection, and 4) Grade 4 mucositis or dermatitis according to the Radiation Therapy Oncology Group (RTOG) criteria. It was resumed when improvements above those levels occurred. Most acute toxicities were defined according to the NCI Common Toxicity Criteria (version 2.0).22 The RTOG scoring system was used to determine radiation-induced mucositis and dermatitis.21 All toxicities that occurred within 3 months after the completion of all treatments were considered acute toxicities.

Only significant late toxicities were reported. Significant complications were defined as chronic percutaneous gastrostomy tube dependence for greater than 1 year, osteoradionecrosis or mandibular bone exposure, or any other toxicity that required surgical intervention, hospitalization, or chronic-medical intervention.

Follow-Up Evaluation

Follow-up evaluations were performed monthly for the first year, every 2 months for the second year, every 3 months for the third year, every 6 months until Year 5, and yearly thereafter. Imaging studies of the head and neck region were obtained at 2 weeks after the completion of RT, then at 6 months, 1 year, and as indicated clinically. Chest X-rays were obtained every 6 months for 2 years and yearly thereafter. Follow-up audiograms were obtained at 1 month after the last chemotherapy cycle and then as indicated clinically.

Statistical Analysis

Statistical analyses were performed with Statview statistical software (SAS Institute Inc., Cary, NC). For qualitative and quantitative outcomes, respectively, the chi-square test and 2-sample Student t tests were use to identify significance differences in any pretreatment or treatment parameters between the 2 treatment arms. Survival rates were calculated using the Kaplan–Meier product-limit method.24, 25 Significance levels for curves were determined using the log-rank test on univariate analysis. All sites of recurrence were coded as failures for FFR; and all deaths, regardless of cause, were recorded for OS. Only head and neck cancer-related deaths were included for the calculation of cause-specific survival.


  1. Top of page
  2. Abstract
  6. Acknowledgements

Patient Characteristics

Between July 1996 and June 2001, 63 patients were accrued to the study, and 1 patient withdrew consent prior to treatment for personal reasons. The median follow-up for living patients was 61 months (range, 16-96 months). Table 1 shows the characteristics of these patients by treatment arm. The most common primary tumor site was the oropharynx, predominantly the base of the tongue, followed by the hypopharynx. One patient had 2 primary tumors, including 1 tumor in the floor of mouth and 1 tumor in the pyriform sinus. The others included 2 patients with involved cervical lymph nodes from unknown primary sites and 1 patient with a T3N3 maxillary sinus cancer. Patients in the TPZ arm were slightly younger than patients in the non-TPZ arm, although the difference was not statistically significant.

Table 1. Patient and Tumor Characteristics by Treatment
CharacteristicNon-TPZ Group (n = 29)TPZ Group (n = 33)P value
  • TPZ: tirapazamine; pO2: oxygen tension.

  • *

    One patient had 2 primary tumor sites (oral cavity and larynx). “Others” included 1 maxillary sinus site and 2 unknown primary tumor sites (1 in the nontirapazamine group and 1 in the tirapazamine group).

Median age in y (range)59 (47–81)56 (39–75).19
Male:female ratio27:227:6.19
Primary tumor site*   
 Oral cavity13 
Median tumor pO2   
 ≤ 12 mm Hg1714 
 > 12 mm Hg1219.20

Table 2 shows the patient distribution by tumor (T) and lymph node (N) classification. There were more patients with T3 and T4 tumors in the non-TPZ arm, and the difference between the 2 arms was found to be statistically significant (P = .03). In contrast, there were more patients with N3 lymph nodes in the TPZ arm, although the difference was not statistically significant (P = .35).

Table 2. Tumor Stage and Lymph Node Status Distribution of by Treatment Arm
Tumor StageLymph Node StatusTotal
  • TPZ: tirapazamine.

  • *

    Only included the stage for the oral cavity tumor in the patient with 2 primary sites.

Non-TPZ group    
TPZ group    

Treatment Compliance

Table 3 shows treatment compliance by treatment arm. More patients in the non-TPZ arm than in the TPZ arm completed all 4 cycles of chemotherapy, and the difference nearly reached significance (P = .09). The most common reason for not completing all 4 cycles of chemotherapy was hematologic toxicity, followed by patient refusal and incomplete responses. In addition, significantly more patients in the TPZ arm than in the non-TPZ arm required dose reductions (P = .01). These imbalances were because of the dose escalation attempted in the TPZ arm.

Table 3. Treatment Compliance by Treatment Group
TreatmentPercent of PatientsP value
Non-TPZ Group (n = 29)TPZ Group (n = 33)
  1. TPZ: tirapazamine; RT: radiotherapy.

No. of chemotherapy cycles completed   
Percent of patients with chemotherapy dose reduction736.01
Percent of patients with chemotherapy dose delay7661.20
Median overall RT time in d (range)56.5 (38–74)53 (32–76) 
Percent of patients with total RT treatment break ≥10 d3421.27

The median RT overall treatment time, range, and significant RT treatment delays (defined as total treatment interruption ≥ 10 days) are shown in Table 3. Most of the treatment interruptions were because of Grade ≥ 3 skin reaction or mucositis. There were slightly more patients with significant treatment delays in the non-TPZ arm, indicating that TPZ did not affect RT delivery adversely.

Acute Treatment-Related Toxicity

The incidences of Grade 3 and 4 acute toxicities by treatment group are shown in Table 4. Neutropenia, dermatitis, mucositis, and esophagitis were the most common adverse effects. There were significantly more incidences of granulocytopenia (P = .02) and thrombocytopenia (P = .05) in the TPZ arm compared with the control arm. There also were more patients with Grade ≥ 3 hypomagnesemia and hepatic toxicity in the TPZ arm, but the difference was not statistically significant. It is noteworthy that both patients who had transaminase elevations on TPZ tested positive for hepatitis B or C pretreatment. We did not observe any increase in Grade 3 or 4 nausea or muscle cramps with TPZ, although 4 patients had Grade 1 or 2 muscle cramps. The adverse side effects commonly associated with RT, such as dermatitis, esophagitis, and mucositis, did not increase with TPZ. There was 1 treatment-related death in the TPZ arm because of an overdose of cisplatin. Autopsy confirmed pancytopenia and renal failure from cisplatin toxicity without evidence of residual cancer.

Table 4. Incidence Acute Treatment-Related Toxicity by Treatment Arm
Toxicity*No. of patientsP value
Non-TPZ Group (n = 29)TPZ Group (n = 33)
Grade 3Grade 4Grade 5Grade 3Grade 4Grade 5
  • TPZ: tirapazamine; 5-FU: 5-fluorouracil, NA: not available.

  • * The majority of acute toxicities were defined according to the National Cancer Institute Common Toxicity Criteria (version 2.0). The Radiation Therapy Oncology Group scoring system was used to determine radiation-induced mucositis and dermatitis

  • *, †

    Four patients with Grade 1–2 muscle cramps in the TPZ group.

5-FU stomatitis110010.91
Radiation mucositis19001910.89
Weight loss400500.83
Muscle cramp000000.16

Treatment Response

The treatment response rates after induction chemotherapy and simultaneous CRT, as assessed at the 50-Gy evaluation, are shown in Table 5. There was a higher CR rate in the neck at the 50-Gy evaluation for the non-TPZ arm, but the difference was not statistically significant. Eight patients in the non-TPZ arm and 14 patients in the TPZ arm underwent neck dissection (P = .29). A pathologic CR in the neck dissection specimen was achieved in 6 of 8 patients in the non-TPZ arm and in 6 of 14 patients in the TPZ arm (P = .20). Therefore, the overall lymph node CR rate (clinical and pathologic) was 90% in the non-TPZ arm and 74% in the TPZ arm (P = .08; 2 sided). There was no difference in the CR rate at the primary tumor site between the 2 arms.

Table 5. Tumor Response by Treatment Arm in Evaluable Patients
Treatment Response*No. of Patients (%)
Lymph Node StatusPrimary Tumor Status
Non-TPZ Group (n = 29)TPZ Group (n = 31)P ValueNon-TPZ Group (n = 28)TPZ Group (N = 30)P Value
  • TPZ: tirapazamine; CR: complete response; CRT: chemoradiotherapy; ND: neck dissection; NA: not available.

  • *

    In the non-TPZ arm, 1 patient was inevaluable at the primary site for an unknown primary tumor. In the TPZ arm, 1 patient was inevaluable at the primary site for an unknown primary tumor and 2 patients were inevaluable at both the primary sites and the lymph node sites for treatment-related death in 1 patient and for early treatment termination in 1 patient.

  • One patient died of progressive tumor after induction chemotherapy.

After induction chemotherapy      
CR8 (28)8 (26)0.8914 (50)15 (50).79
Less than CR21 (72)23 (74) 145 (50)15 (50) 
After CRT      
CR20 (69)17 (55).3123 (82)23 (77).53
Less than CR9 (31)14 (45) 5 (18)7 (23) 
No. of patients with ND814.29NANA 
No. of patients without ND2017    
Pathologic response      
Less than CR28 33 
Overall (clinical and pathologic)      
CR26 (90)23 (74).0825 (89)27 (90).71
Less than CR3(10)8 (26) 3 (11)3 (10) 

With regard to lymph node response based on TPZ dose levels, the lymph node CR rate was 75% (3 of 4 patients) at Level 1, 50% (2 of 2 patients) at Level 2, and 78% (18 of 23 patients) at Level 3. The difference was not statistically significant, presumably because of the small numbers of patients at each TPZ dose level. The lower response rate associated with Level 2 may have been related to chemotherapy dose reductions because of increased the hematologic toxicity noted for this level.

Outcome Analysis

At a median follow-up of 61 months, 19 patients develop recurrent disease, including 9 recurrences above the clavicle only, 3 recurrences both above and below the clavicle, and 7 distant recurrences. The median time to recurrence in patients who failed was 13 month (range, 1.5-61.0 months). Table 6 shows the 5-year survival estimates for the entire group and for the 2 treatment arms. There were no differences in the rates of LRC (P = .86), freedom from distant metastasis (P = .77), FFR (P = .90) (Fig. 2A), or cause-specific survival (P = .59) (Fig. 2B) between the 2 treatment arms.

Table 6. 5-Year Survival Outcomes by Treatment Group
Parameter5-Year Survival (%)P Value
AllNon-TPZ GroupTPZ Group
  1. TPZ: tirapazamine.

Locoregional control777974.86
Freedom from distant metastasis818476.77
Freedom from recurrence697265.90
Cause-specific survival687364.59
Overall survival596554.47
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Figure 2. (A) Freedom from disease recurrence. (B) Cause-specific survival by treatment arm. TPZ: tirapazamine.

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At the time of last follow-up, 25 patients had died, including 18 deaths from HNSCC recurrence or progression; 1 death from acute treatment-related toxicity, as described earlier; 2 deaths from lung cancer; 3 deaths from aspiration pneumonia and sepsis that were related to either pharyngeal dysfunction or esophageal strictures; and 1 death from a presumed myocardial infarction as the cause of sudden death. The 5-year OS rate was 59%, and there was no significant difference noted in survival between the 2 treatment arms (Fig. 3).

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Figure 3. Overall survival by treatment arm. TPZ: tirapazamine.

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Late Toxicity

The incidence and types of significant late treatment-related toxicity are shown in Table 7. Some patients had multiple toxicities. The most common complications were hypothyroidism, mandibular bone exposure or osteoradionecrosis (usually after dental manipulation or extraction), and cisplatin-related hearing loss. Another common significant toxicity was esophageal stricture or pharyngeal dysfunction that resulted in chronic gastrostomy tube dependence or repeated aspiration pneumonia, which was a cause of intercurrent death in 3 patients. Overall, the incidence and types of late complications were similar between the 2 treatment arms, with the exception of myocardial infarction, which was observed only in the TPZ group.

Table 7. Late Treatment-Related Toxicity by Treatment Arm
ToxicityNo. of Incidents
Non-TPZ Group (n = 29)TPZ Group (n = 31)
  • TPZ: tirapazamine; PEG: percutaneous endoscopic gastrostomy tube.

  • *

    Aspiration pneumonia was the cause of intercurrent death in 3 patients, and myocardial infarction was the presumed cause of intercurrent death in 1 patient.

Mandibular bone exposure with or without osteoradionecrosis34
Aspiration pneumonia01*
Esophageal stricture, chronic PEG dependency3*1
Carotid stenosis requiring end-arterectomy01
Hearing loss requiring hearing aids31
Fixed true vocal cord (unilateral)10
Renal failure requiring dialysis10
Myocardial infarction02*
Delayed wound healing > 6 m after neck dissection01


  1. Top of page
  2. Abstract
  6. Acknowledgements

Since the pioneering work of Gray et al.,26 who showed that tissue sensitivity to radiation damage depended on the presence of oxygen at the time of irradiation, tumor hypoxia has been studied extensively as a mechanism for radioresistance in HNSCC, and targeting this hypoxia has become a major focus in cancer therapy. Past studies using the nitroimidazoles as hypoxic cell radiosensitizers have yielded disappointing results.27–30 TPZ represents a new class of agents with selective cytotoxicity for hypoxic cells. Preliminary results in both preclinical and clinical settings in which TPZ was combined with either RT alone or CRT have been encouraging,8, 9, 11, 12 thereby prompting us to conduct the current Phase II randomized trial.

Similar to Rischin et al.,12, 13 we noted increased hematologic toxicity, specifically granulocytopenia and thrombocytopenia, in the TPZ group. Most of these toxicities were noted when TPZ doses were escalated from 300 mg/m2 to 330 mg/m2 for the induction phase and from 160 mg/m2 to 260 mg/m2 for the simultaneous phase after it was found to be well tolerated at lower doses. With this dose increase, we noted more hematologic toxicity and 1 acute Grade 3 hearing loss. The TPZ dose subsequently was reduced to 300 mg/m2 for the induction phase and to 220 mg/m2 for the concomitant phase, and no increased toxicity was observed. With regard to RT toxicity, we noted no increased incidence of mucositis or dermatitis with TPZ, an observation similar to that reported by Lee et al.11

To our knowledge to date, there has been no difference in the response, tumor recurrence, or survival rates between the 2 treatment arms. Several possibilities may account for these findings: First, this was a rather small study, with only 30 patients in each treatment arm, and it was powered only to detect a substantial improvement (32%) in the experimental arm based on a historic lymph node CR rate of 50%. However, our lymph node CR rate with CRT alone in the current study was considerably better than that observed previously (80% after CRT and 90% overall), which made the study underpowered to detect any difference in the 2 arms. Second, despite our attempts to stratify patients by lymph node status and tumor pO2, there was an imbalance in the treatment arms, with more N3 disease and a trend toward more oxygenated tumors in the TPZ arm. It is unclear how these imbalances influence the observed results. Third, the potential benefit of adding TPZ well may have been negated by the lower compliance for chemotherapy in terms of both dose reduction rates and completion rates in the TPZ arm. This is corroborated by the lower lymph node CR rate for patients who were treated in the second TPZ level, in which more patients required chemotherapy dose reductions because of hematologic toxicity. Fourth, because of the intensity of the chemotherapy regimen, we were able to deliver TPZ only 6 times during the RT course. Therefore, it is not possible to generalize our results to a protocol in which TPZ is given more often during the course of concomitant CRT. Finally, we cannot rule out the possibility that aggressive chemotherapy can overcome the effect of tumor hypoxia in these patients.

The results of the current study differ from those reported from a randomized Phase II study by the Trans-Tasman Radiation Oncology Group (TROG)13. In the TROG study, 122 patients with locally advanced HNSCC were randomized to receive either simultaneous CRT with cisplatin and TPZ according to the authors' previously reported regimen12 or cisplatin and 5-FU delivered in the last 2 weeks of RT as a chemoboost approach. There was a near statistically significant trend toward improved LRC and failure-free survival in favor of the TPZ arm. The difference between our results and those from the TROG trial may be explained by the schedule of CRT use (induction and simultaneous CRT in the current trial vs. simultaneous CRT alone in the TROG trial), the number of TPZ doses administered during simultaneous CRT (6 in our trial vs. 9 in the TROG trial), and the type of patients enrolled (patients with resectable disease in our trial vs. patients with resectable and unresectable disease in the TROG trial). Two on-going, large consortium Phase III trials randomizing patients with locally advanced HNSCC to receive simultaneous cisplatin and RT versus the same regimen plus TPZ will shed new light on the role of TPZ in the management of HNSCC.

Although the tumor control and survival rates are favorable in this group of patients with Stage IV HNSCC, long-term toxicity with aggressive CRT are substantial and may be permanent for many patients. Efforts should be made to avoid these late toxicities. The use of intensity-modulated RT, which allows for precise targeting of the tumor while sparing critical normal structures, has shown early promise in reducing xerostomia and related complications.30, 31 Certain pharmacologic agents, such as amifostine, also have demonstrated similar xerostomia reductions.32 These approaches and novel agents should be evaluated in the management of patients with locally advanced HNSCC to minimize their risk of long-term treatment complications.

The addition of TPZ, as administered using our approach with induction and concomitant chemotherapy, did not improve treatment outcomes in patients with Stage IV HNSCC compared with the same regimen without TPZ. However, the current study was underpowered to detect a difference in lymph node responses between the 2 treatment arms. Based on the observed complete lymph node response rates, at least 91 patients per arm (182 patients in total) are required to provide 80% power with 95% confidence to detect a difference between the 2 treatment arms. Aggressive CRT with induction and simultaneous treatment yielded excellent survival in this group of patients with advanced-staged disease but at a cost of late toxicity. There is clearly a need for novel treatment approaches in the management of these patients to improve outcomes while minimizing late toxicity.


  1. Top of page
  2. Abstract
  6. Acknowledgements

The authors thank Neeta Nair for her administrative assistance in the preparation and submission of the article.


  1. Top of page
  2. Abstract
  6. Acknowledgements
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  • 12
    Rischin D, Peters L, Hicks R, et al. Phase I trial of concurrent tirapazamine, cisplatin, and radiotherapy in patients with advanced head and neck cancer. J Clin Oncol. 2001; 19: 535542.
  • 13
    Rischin D, Peters L, Fisher R, et al. Tirapazamine, cisplatin, and radiation versus fluorouracil, cisplatin, and radiation in patients with locally advanced head and neck cancer: a randomized Phase II trial of the Trans-Tasman Radiation Oncology Group (TROG 98.02). J Clin Oncol. 2005; 23: 7987.
  • 14
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