Radiotherapy and Oncology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Original article
IAEA-HypoX. A randomized multicenter study of the hypoxic radiosensitizer nimorazole concomitant with accelerated radiotherapy in head and neck squamous cell carcinoma Mohamed A. Hassan Metwally a,⇑, Rubina Ali b, Maire Kuddu c, Tarek Shouman d, Primoz Strojan e, Kashif Iqbal b, Rajiv Prasad f, Cai Grau g, Jens Overgaard a a Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark; b Oncology Department, Nuclear Medicine, Oncology & Radiotherapy Institute, Islamabad, Pakistan; c Radiation Oncology Center, North Estonia Medical Center, Tallinn, Estonia; d Radiation Oncology Department, National Cancer Institute, Cairo, Egypt; e Department of Radiation Oncology, Institute of Oncology, Ljubljana, Slovenia; f Applied Radiation Biology and Radiotherapy Section, International Atomic Energy Agency, Vienna, Austria; g Department of Oncology, Aarhus University Hospital, Denmark
a r t i c l e
i n f o
Article history: Received 8 January 2015 Received in revised form 10 April 2015 Accepted 10 April 2015 Available online xxxx Keywords: Clinical trials Accelerated radiotherapy Hypoxic radiosensitization HNSCC Hypoxia Nimorazole
a b s t r a c t Purpose: To test the hypothesis that radiotherapy (RT) of head and neck squamous cell carcinoma (HNSCC) can be improved by hypoxic modification using nimorazole (NIM) in association with accelerated fractionation. Materials and methods: The protocol was activated in March 2012 as an international multicenter randomized trial in patients with HNSCC. Tumors were treated to a dose of 66–70 Gy, 33–35 fractions, 6 fractions per week. NIM was administered in a dose of 1.2 g per m2, 90 min before the first daily RT fraction. The primary endpoint was loco-regional failure. The trial was closed prematurely by June 2014 due to poor recruitment. An associated quality assurance program was performed to ensure the consistency of RT with the protocol guidelines. Results: The trial was dimensioned to include 600 patients in 3 years, but only 104 patients were randomized between March 2012 and May 2014 due to the inability to involve three major centers and the insufficient recruitment rate from the other participating centers. Twenty patients from two centers had to be excluded from the analysis due to the unavailability of the follow-up data. Among the remaining 84 patients, 82 patients were evaluable (39 and 43 patients in the RT + NIM and the RT-alone arms, respectively). The treatment compliance was good with only six patients not completing the full planned RT course, and 31 patients (79%) out of 39 allocated for NIM, achieving at least 90% of the prescribed drug dose. At the time of evaluation, 40 patients had failed to achieve persistent loco-regional tumor control, and a total of 45 patients had died. The use of NIM improved the loco-regional tumor control with an 18 month post-randomization cumulative failure rate of 33% versus 51% in the control arm, yielding a risk difference of 18% (CI 3% to 39%; P = 0.10). The corresponding values for overall death was 43% versus 62%, yielding a risk difference of 19% (CI 3% to 42%; P = 0.10). Sixteen patients, out of 55 patients analyzed for hypoxic gene expression, were classified as having more hypoxic tumors. Such patients, if treated with RT alone, had a higher loco-regional tumor failure rate as compared to the rest of the patients with known hypoxic status (P = 0.05). Conclusion: Although the trial was incomplete and suffered from a small number of patients, the results suggested an improvement in loco-regional tumor control and overall survival in patients with advanced HNSCC given the hypoxic modifier NIM in addition to accelerated fractionation RT. However, the trial also revealed that conducting multicenter and multinational study combining drug and RT in developing countries may suffer from uncontrolled and unsolvable problems. Ó 2015 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2015) xxx–xxx
Advanced head and neck squamous cell carcinoma (HNSCC) is a loco-regional disease that is frequently treated with radiotherapy ⇑ Corresponding author at: Department of Experimental Clinical Oncology, Aarhus University Hospital, Nørrebrogade 44, Building 5, 8000 Aarhus C, Denmark. E-mail address: [email protected] (M.A. Hassan Metwally).
(RT). Enhancing the effect of radiation treatment, using different treatment strategies, is an area of extensive research. One of these strategies considered the reduction of the overall treatment time of the RT course by a so called "accelerated fractionation" schedule. The aim of acceleration is to overcome the effect of
http://dx.doi.org/10.1016/j.radonc.2015.04.005 0167-8140/Ó 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Hassan Metwally MA et al. IAEA-HypoX. A randomized multicenter study of the hypoxic radiosensitizer nimorazole concomitant with accelerated radiotherapy in head and neck squamous cell carcinoma. Radiother Oncol (2015), http://dx.doi.org/10.1016/ j.radonc.2015.04.005
2
IAEA-HypoX trial of HNSCC
radiation-induced repopulation of tumor cells during treatment [1]. Accelerated fractionation has demonstrated an improvement in the loco-regional tumor control and disease specific survival in patients with HNSCC in some clinical trials, as well as in metaanalysis, using different strategies to reduce the overall treatment time [2–4]. One of these trials was the IAEA-ACC trial, where acceleration of RT was performed by adding an extra fraction in each week of treatment (going from 5 fractions/week to 6 fractions/week), thus allowing the delivery of the same dose in a shorter overall treatment time. The accelerated fractionation schedule in this trial improved the 5-year actuarial rate of locoregional tumor control by 12% relative to the conventional fractionation arm [4]. Another factor that plays an important role in the tumor response to radiation, particularly in patients with HNSCC, is the absence of oxygen (hypoxia) in tumor tissue [5,6]. Different methods have been used to improve the radiation treatment effect through the modification of hypoxia, resulting in a significantly better loco-regional tumor control, disease-specific and overall survival in different randomized trials [7–10] as well as demonstrated in meta-analyses [6,11,12]. One of the modifications was the concomitant administration of hypoxic radiosensitizers with the radiation treatment [11–13]. Among these, nimorazole (NIM) has demonstrated a significant improvement in loco-regional control in HNSCC [8], and since it has neither serious nor long-lasting side effects, it has been adopted for routine clinical use in some places [8,14,15]. Repopulation and hypoxia are two independent factors, and it is thus to be expected that combining accelerated fractionation and hypoxic modification will result in an improvement in the treatment effect without overlapping toxicity. Such a principle has been adopted by the DAHANCA group [3,14,16], but the true benefit (in the form of tumor control and morbidity) has not been evaluated in a controlled clinical trial. Furthermore, this treatment principle does not require additional RT resources, and is therefore applicable in a resource limited environment. Therefore, the aim of the present study was to determine the possible therapeutic gain of using NIM as a hypoxic radiosensitizer in conjunction with accelerated fractionated RT for invasive HNSCC, and evaluate the tolerance, compliance and toxicity of using the drug, in a randomized trial. So far, treatment with hypoxic modification have mostly been performed in Western Europe and North America, and it is unclear to which extent such treatment principle can be generalized to RT practice in the developing world, where the therapeutic resources are less and the patients have often a more heavy tumor burden. Therefore, the current study was attempted to test the applicability of such treatment strategy in a global setting. The study is therefore in line with the strategy developed by the IAEA aimed at improving RT of HNSCC through an optimization of the radiobiological properties [4,13,17]. A recent study has identified a gene profile, consisting of 15 genes, that was able to distinguish between more-hypoxic and less-hypoxic tumors in vivo, based on gene expression [18]. The gene-profile was also able to predict which patients will benefit from the hypoxic modification using NIM [19]. Tumors categorized as more-hypoxic based on this gene profile were associated with a significantly poorer clinical outcome than less-hypoxic tumors. A prospective study by EORTC has been activated to investigate the benefit of adding NIM to accelerated concomitant chemoradiation in patients with HNSCC [20], where the indication of NIM in the patients is evaluated based on the status of the hypoxic geneprofile. The classification of tumors in more or less hypoxic according to the 15-gene profile is expected to offer a good prediction for treatment individualization, where NIM is only given if hypoxic radiosensitization is warranted, thus avoiding unnecessary side effects [15].
The present report has been performed according to the CONSORT guidelines for reporting clinical trials [21]. Patients and methods The IAEA-HypoX study protocol was activated in March 2012 as a multicenter randomized double arm trial. The trial was activated in six centers situated in four different countries. The study design was a stratified, balanced, and randomized phase III study in patients with HNSCC. The criteria for eligibility were invasive squamous cell carcinoma of the larynx (stage I–IV, except stage I–II glottis cancer), pharynx (stage I–IV, except nasopharynx), or oral cavity (stage I–IV) according to the TNM classification of malignant tumors, 7th ed. [22]. Patients had to be P18 years old, with performance status 0–2 according to WHO criteria, normal liver and kidney functions and without neurological disorders as assessed by clinical examination. Patients had not to be planned for surgical excision (except biopsy) before inclusion in the trial (including elective neck dissection). Patients had not to be pregnant or with distant metastases at the time of inclusion in the trial. The trial was designed according to the Helsinki declaration and was approved by the relevant ethics committees and health authorities. The trial was registered under the ClinicalTrials.gov with the following identifier: NCT01507467. The full trial protocol is provided as a Supplementary material. Prior to randomization, patients were stratified according to primary tumor and nodal stage, primary tumor localization (pharynx, larynx, and oral cavity), performance status, and center. Patients were randomized centrally to accelerated fractionated RT with or without NIM. Patients were treated with external beam RT based on Co-60 or linear accelerator machines. The treatment principles and dose specifications were prescribed according to the guidelines given in the ICRU-50 and ICRU-83 reports. Treatment was planned with either a conventional 2D technique on a simulator or CT-based 3D conformal RT (3D-CRT) or Intensity Modulated Radiation Therapy (IMRT) techniques; however, the chosen technique had to be used for the entire course of treatment. The treatment was given in 6 fractions per week, to a centrally absorbed target dose of 2 Gy per fraction. The macroscopic tumor was treated to a dose of 66–70 Gy in 33–35 fractions in both arms. Treatment had to be given with 1 fraction per day through the first five weekdays; the sixth fraction was given on either a weekend day or as an extra fraction on one of the first five weekdays, but always allowing at least 6 h interval between fractions. Patients treated with IMRT are allowed to receive the sixth fraction as simultaneously integrated boost (SIB) technique. Concomitant boost using separate IMRT plans was not allowed. With IMRT treatment, the primary tumor and involved nodes (PTV1) were prescribed a total dose 66–70 Gy (2 Gy/fraction), high-risk sub-clinical disease sites (PTV2) had to receive at least 60 Gy (1.7–1.8 Gy/fraction), and lower-risk targets (PTV3) were prescribed at least 50 Gy (1.4–1.5 Gy/fraction). NIM was supplied by Azanta A/S, Denmark, in the form of 500 mg oral tablets. The drug was administered in doses of approximately 1.2 g per m2 body surface area (BSA), 90 min before each first daily radiation treatment as follows: 1.5 g (3 tablets) for patients with BSA 61.6 m2, 2 g (4 tablets) for patients with BSA >1.6 to 61.9 m2, and 2.5 g (5 tablets) for patients with BSA >1.9 m2. Total dose over the entire radiation period (33–35 fractions) should be approximately 36 g/m2 and must not exceed 40 g/m2 or a total of 75 g. A RT quality assurance (RTQA) program was associated with the trial from its beginning. The participating centers were asked to send the details of the RT planning for the first five recruited patients with the documentation of the received doses according to the ICRU-50 and ICRU-83 guidelines. The plans, reported doses
Please cite this article in press as: Hassan Metwally MA et al. IAEA-HypoX. A randomized multicenter study of the hypoxic radiosensitizer nimorazole concomitant with accelerated radiotherapy in head and neck squamous cell carcinoma. Radiother Oncol (2015), http://dx.doi.org/10.1016/ j.radonc.2015.04.005
M.A. Hassan Metwally et al. / Radiotherapy and Oncology xxx (2015) xxx–xxx
for different volumes, and the overall treatment times were independently checked by the quality coordinator for any deviations from the protocol guidelines. A list of the reported deviations according to predefined criteria was sent to the centers immediately afterward. Patients were evaluated weekly during treatment. The common radiation-related adverse events (dysphagia, mucosal edema, mucositis, and skin reaction) were graded and documented. NIM related adverse events (nausea, vomiting, flushing, and skin rash) were also graded according to the CTCAE v3.0 [23]. Patients were seen two months after the end of treatment to record persistent acute toxicity and early tumor response. Afterward, the patients were seen every three months. The study design, stratification, randomization, treatment and follow up, are detailed in the trial protocol. The trial was designed to include 600 patients. This number was expected to be recruited over a 3-year period. Assuming a true improvement of the loco-regional tumor control rate of 12% in the RT + NIM arm; then the probability that such an event would be detected at a significant level of P = 0.05 was greater than 90%. The primary endpoint was time to loco-regional tumor failure (locoregional tumor control). The definition of this end-point was complete and persistent disappearance of the disease in the primary site (T-site) and regional lymph nodes (N-site) after RT. Failure was recorded in the event of a recurrent tumor, or if the primary tumor and/or nodal disease never completely disappeared. In the latter situation the tumor was then assumed to have failed at the time of the end of RT course. All time estimates were done using the date of randomization as the initial value. The primary end-point does not include the effect of a successful procedure with salvage surgery. The Kaplan–Meier method was used to estimate time-to-event curves. Patterns of first failure were analyzed using a "competingrisks" analysis for the loco-regional failure. The treatment groups were compared with respect to the time to loco-regional failure, and overall survival using the Cox proportional hazards model. The trial was closed prematurely after 27 months by June 2014 due to the poor recruitment rate. The total recruitment was 104 patients compared to an expected recruitment of more than 400 patients at the same time point. Only 6 out of 9 centers have succeeded to obtain the required approvals for conducting the trial in their countries. The present analysis was performed for the randomized patients on an intention to treat basis, and patients were included in their randomization group irrespective of whether or not they had completed the planned treatment. Frequency tables with counts and percentages were used to describe the patients and their distribution in the two treatment arms. Patients were followed up in all centers until the time of evaluation on March 30, 2015. An associated protocol for translational research was included in this trial. The aim was to identify biomarkers that can predict which patients will benefit from the use of NIM. The biological analysis was performed retrospectively. Biological materials were collected from the participating centers as formalin fixed and paraffin embedded samples. Hypoxia status was determined through gene expression analysis of hypoxia-induced 15-gene profile on RNA extracted from the samples. Gene expression was determined by quantitative PCR analysis. Immunohistochemical staining for the HPV-associated p16 expression was performed on 49 tumor samples and tumors were classified as being HPV positive or negative according to a standardized DAHANCA protocol [24]. The results of the HPV status determination for further four patients from one of the centers were included in the analysis.
3
of communication from the local investigators. These centers have randomized a total of 20 patients (9 patients were in the RT-alone arm, and 11 patients were in the RT + NIM arm). Among the remaining 84 eligible patients, two patients (one in each treatment arm) did not start the allocated treatment after randomization. One patient was lost to follow up immediately after randomization due to unknown reasons and the other patient was diagnosed with claustrophobia during preparation procedures for RT. The remaining 82 patients were evaluable (39 and 43 patients in the RT + NIM and the RT-alone arms, respectively). The trial flow chart is shown in (Fig. 1). There were 30 females and 52 males with a median age at randomization of 56 years (range 28–75 years). Most of patients (78%) presented with well/moderate differentiated tumors, 9% had poor/ undifferentiated tumors, and 13% had unknown differentiation with equal distribution between both treatment arms. Only 5 patients, out of 53 patients with known HPV/p16 status, were HPV/p16 positive (3 and 2 patients in RT-alone and RT + NIM arms, respectively). The patient- and treatment-related characteristics in both randomization arms are shown in (Table 1). The majority of patients have received radiation treatment using the 2D planning technique (56 patients). Most of patients received 66 Gy in 33 fractions to the gross tumor volume, and the vast majority completed the full prescribed radiation dose (66–70 Gy). Only 6 patients could not complete the full RT course: four were due to severe treatment-related toxicity; one was due to non-compliance, and one died during treatment due to complications of jejunostomy. As a whole, 31 (79%) patients received at least 90% of the prescribed NIM dose and 19 (49%) patients completed the full prescribed dose (Table 1). The cause of failure to fulfill the planned treatment was mainly due to the treatment-related acute toxicity, with the majority of patients complaining of mild to moderate nausea and vomiting. A few patients suffered from flushing and skin rash (Table 2). At the time of evaluation, 40 patients had failed to achieve persistent loco-regional tumor control, and a total of 45 patients had died. The median follow-up time of patients who were still alive at the time of evaluation was 19 months (range 1–34 months), and the median follow-up time of patients who died was 7 months (range 1–29 months). From a total of 40 patients with loco-regional
Results From March 2012 to May 2014, 104 patients were included. However, all included patients from two centers were excluded from the final analysis due to major deficiency of data and the lack
Fig. 1. Trial profile and outcome.
Please cite this article in press as: Hassan Metwally MA et al. IAEA-HypoX. A randomized multicenter study of the hypoxic radiosensitizer nimorazole concomitant with accelerated radiotherapy in head and neck squamous cell carcinoma. Radiother Oncol (2015), http://dx.doi.org/10.1016/ j.radonc.2015.04.005
4
IAEA-HypoX trial of HNSCC
Table 1 Patient and treatment characteristics as a function of the randomization arm.§
Age (years) Median (range) Gender Female Male Performance status 0–1 2–3 Tumor site Larynx Pharynx Oral cavity T-classification T1–2 T3–4 N-classification N0 N1–3 Stage I–II III–IV HPV/p16 status HPV/p16 +ve HPV/p16 ve Unknown Hypoxic status More hypoxic Less hypoxic Unknown RT technique 2D 3DCRT IMRT RT Dose
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Original article
IAEA-HypoX. A randomized multicenter study of the hypoxic radiosensitizer nimorazole concomitant with accelerated radiotherapy in head and neck squamous cell carcinoma Mohamed A. Hassan Metwally a,⇑, Rubina Ali b, Maire Kuddu c, Tarek Shouman d, Primoz Strojan e, Kashif Iqbal b, Rajiv Prasad f, Cai Grau g, Jens Overgaard a a Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark; b Oncology Department, Nuclear Medicine, Oncology & Radiotherapy Institute, Islamabad, Pakistan; c Radiation Oncology Center, North Estonia Medical Center, Tallinn, Estonia; d Radiation Oncology Department, National Cancer Institute, Cairo, Egypt; e Department of Radiation Oncology, Institute of Oncology, Ljubljana, Slovenia; f Applied Radiation Biology and Radiotherapy Section, International Atomic Energy Agency, Vienna, Austria; g Department of Oncology, Aarhus University Hospital, Denmark
a r t i c l e
i n f o
Article history: Received 8 January 2015 Received in revised form 10 April 2015 Accepted 10 April 2015 Available online xxxx Keywords: Clinical trials Accelerated radiotherapy Hypoxic radiosensitization HNSCC Hypoxia Nimorazole
a b s t r a c t Purpose: To test the hypothesis that radiotherapy (RT) of head and neck squamous cell carcinoma (HNSCC) can be improved by hypoxic modification using nimorazole (NIM) in association with accelerated fractionation. Materials and methods: The protocol was activated in March 2012 as an international multicenter randomized trial in patients with HNSCC. Tumors were treated to a dose of 66–70 Gy, 33–35 fractions, 6 fractions per week. NIM was administered in a dose of 1.2 g per m2, 90 min before the first daily RT fraction. The primary endpoint was loco-regional failure. The trial was closed prematurely by June 2014 due to poor recruitment. An associated quality assurance program was performed to ensure the consistency of RT with the protocol guidelines. Results: The trial was dimensioned to include 600 patients in 3 years, but only 104 patients were randomized between March 2012 and May 2014 due to the inability to involve three major centers and the insufficient recruitment rate from the other participating centers. Twenty patients from two centers had to be excluded from the analysis due to the unavailability of the follow-up data. Among the remaining 84 patients, 82 patients were evaluable (39 and 43 patients in the RT + NIM and the RT-alone arms, respectively). The treatment compliance was good with only six patients not completing the full planned RT course, and 31 patients (79%) out of 39 allocated for NIM, achieving at least 90% of the prescribed drug dose. At the time of evaluation, 40 patients had failed to achieve persistent loco-regional tumor control, and a total of 45 patients had died. The use of NIM improved the loco-regional tumor control with an 18 month post-randomization cumulative failure rate of 33% versus 51% in the control arm, yielding a risk difference of 18% (CI 3% to 39%; P = 0.10). The corresponding values for overall death was 43% versus 62%, yielding a risk difference of 19% (CI 3% to 42%; P = 0.10). Sixteen patients, out of 55 patients analyzed for hypoxic gene expression, were classified as having more hypoxic tumors. Such patients, if treated with RT alone, had a higher loco-regional tumor failure rate as compared to the rest of the patients with known hypoxic status (P = 0.05). Conclusion: Although the trial was incomplete and suffered from a small number of patients, the results suggested an improvement in loco-regional tumor control and overall survival in patients with advanced HNSCC given the hypoxic modifier NIM in addition to accelerated fractionation RT. However, the trial also revealed that conducting multicenter and multinational study combining drug and RT in developing countries may suffer from uncontrolled and unsolvable problems. Ó 2015 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2015) xxx–xxx
Advanced head and neck squamous cell carcinoma (HNSCC) is a loco-regional disease that is frequently treated with radiotherapy ⇑ Corresponding author at: Department of Experimental Clinical Oncology, Aarhus University Hospital, Nørrebrogade 44, Building 5, 8000 Aarhus C, Denmark. E-mail address: [email protected] (M.A. Hassan Metwally).
(RT). Enhancing the effect of radiation treatment, using different treatment strategies, is an area of extensive research. One of these strategies considered the reduction of the overall treatment time of the RT course by a so called "accelerated fractionation" schedule. The aim of acceleration is to overcome the effect of
http://dx.doi.org/10.1016/j.radonc.2015.04.005 0167-8140/Ó 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Hassan Metwally MA et al. IAEA-HypoX. A randomized multicenter study of the hypoxic radiosensitizer nimorazole concomitant with accelerated radiotherapy in head and neck squamous cell carcinoma. Radiother Oncol (2015), http://dx.doi.org/10.1016/ j.radonc.2015.04.005
2
IAEA-HypoX trial of HNSCC
radiation-induced repopulation of tumor cells during treatment [1]. Accelerated fractionation has demonstrated an improvement in the loco-regional tumor control and disease specific survival in patients with HNSCC in some clinical trials, as well as in metaanalysis, using different strategies to reduce the overall treatment time [2–4]. One of these trials was the IAEA-ACC trial, where acceleration of RT was performed by adding an extra fraction in each week of treatment (going from 5 fractions/week to 6 fractions/week), thus allowing the delivery of the same dose in a shorter overall treatment time. The accelerated fractionation schedule in this trial improved the 5-year actuarial rate of locoregional tumor control by 12% relative to the conventional fractionation arm [4]. Another factor that plays an important role in the tumor response to radiation, particularly in patients with HNSCC, is the absence of oxygen (hypoxia) in tumor tissue [5,6]. Different methods have been used to improve the radiation treatment effect through the modification of hypoxia, resulting in a significantly better loco-regional tumor control, disease-specific and overall survival in different randomized trials [7–10] as well as demonstrated in meta-analyses [6,11,12]. One of the modifications was the concomitant administration of hypoxic radiosensitizers with the radiation treatment [11–13]. Among these, nimorazole (NIM) has demonstrated a significant improvement in loco-regional control in HNSCC [8], and since it has neither serious nor long-lasting side effects, it has been adopted for routine clinical use in some places [8,14,15]. Repopulation and hypoxia are two independent factors, and it is thus to be expected that combining accelerated fractionation and hypoxic modification will result in an improvement in the treatment effect without overlapping toxicity. Such a principle has been adopted by the DAHANCA group [3,14,16], but the true benefit (in the form of tumor control and morbidity) has not been evaluated in a controlled clinical trial. Furthermore, this treatment principle does not require additional RT resources, and is therefore applicable in a resource limited environment. Therefore, the aim of the present study was to determine the possible therapeutic gain of using NIM as a hypoxic radiosensitizer in conjunction with accelerated fractionated RT for invasive HNSCC, and evaluate the tolerance, compliance and toxicity of using the drug, in a randomized trial. So far, treatment with hypoxic modification have mostly been performed in Western Europe and North America, and it is unclear to which extent such treatment principle can be generalized to RT practice in the developing world, where the therapeutic resources are less and the patients have often a more heavy tumor burden. Therefore, the current study was attempted to test the applicability of such treatment strategy in a global setting. The study is therefore in line with the strategy developed by the IAEA aimed at improving RT of HNSCC through an optimization of the radiobiological properties [4,13,17]. A recent study has identified a gene profile, consisting of 15 genes, that was able to distinguish between more-hypoxic and less-hypoxic tumors in vivo, based on gene expression [18]. The gene-profile was also able to predict which patients will benefit from the hypoxic modification using NIM [19]. Tumors categorized as more-hypoxic based on this gene profile were associated with a significantly poorer clinical outcome than less-hypoxic tumors. A prospective study by EORTC has been activated to investigate the benefit of adding NIM to accelerated concomitant chemoradiation in patients with HNSCC [20], where the indication of NIM in the patients is evaluated based on the status of the hypoxic geneprofile. The classification of tumors in more or less hypoxic according to the 15-gene profile is expected to offer a good prediction for treatment individualization, where NIM is only given if hypoxic radiosensitization is warranted, thus avoiding unnecessary side effects [15].
The present report has been performed according to the CONSORT guidelines for reporting clinical trials [21]. Patients and methods The IAEA-HypoX study protocol was activated in March 2012 as a multicenter randomized double arm trial. The trial was activated in six centers situated in four different countries. The study design was a stratified, balanced, and randomized phase III study in patients with HNSCC. The criteria for eligibility were invasive squamous cell carcinoma of the larynx (stage I–IV, except stage I–II glottis cancer), pharynx (stage I–IV, except nasopharynx), or oral cavity (stage I–IV) according to the TNM classification of malignant tumors, 7th ed. [22]. Patients had to be P18 years old, with performance status 0–2 according to WHO criteria, normal liver and kidney functions and without neurological disorders as assessed by clinical examination. Patients had not to be planned for surgical excision (except biopsy) before inclusion in the trial (including elective neck dissection). Patients had not to be pregnant or with distant metastases at the time of inclusion in the trial. The trial was designed according to the Helsinki declaration and was approved by the relevant ethics committees and health authorities. The trial was registered under the ClinicalTrials.gov with the following identifier: NCT01507467. The full trial protocol is provided as a Supplementary material. Prior to randomization, patients were stratified according to primary tumor and nodal stage, primary tumor localization (pharynx, larynx, and oral cavity), performance status, and center. Patients were randomized centrally to accelerated fractionated RT with or without NIM. Patients were treated with external beam RT based on Co-60 or linear accelerator machines. The treatment principles and dose specifications were prescribed according to the guidelines given in the ICRU-50 and ICRU-83 reports. Treatment was planned with either a conventional 2D technique on a simulator or CT-based 3D conformal RT (3D-CRT) or Intensity Modulated Radiation Therapy (IMRT) techniques; however, the chosen technique had to be used for the entire course of treatment. The treatment was given in 6 fractions per week, to a centrally absorbed target dose of 2 Gy per fraction. The macroscopic tumor was treated to a dose of 66–70 Gy in 33–35 fractions in both arms. Treatment had to be given with 1 fraction per day through the first five weekdays; the sixth fraction was given on either a weekend day or as an extra fraction on one of the first five weekdays, but always allowing at least 6 h interval between fractions. Patients treated with IMRT are allowed to receive the sixth fraction as simultaneously integrated boost (SIB) technique. Concomitant boost using separate IMRT plans was not allowed. With IMRT treatment, the primary tumor and involved nodes (PTV1) were prescribed a total dose 66–70 Gy (2 Gy/fraction), high-risk sub-clinical disease sites (PTV2) had to receive at least 60 Gy (1.7–1.8 Gy/fraction), and lower-risk targets (PTV3) were prescribed at least 50 Gy (1.4–1.5 Gy/fraction). NIM was supplied by Azanta A/S, Denmark, in the form of 500 mg oral tablets. The drug was administered in doses of approximately 1.2 g per m2 body surface area (BSA), 90 min before each first daily radiation treatment as follows: 1.5 g (3 tablets) for patients with BSA 61.6 m2, 2 g (4 tablets) for patients with BSA >1.6 to 61.9 m2, and 2.5 g (5 tablets) for patients with BSA >1.9 m2. Total dose over the entire radiation period (33–35 fractions) should be approximately 36 g/m2 and must not exceed 40 g/m2 or a total of 75 g. A RT quality assurance (RTQA) program was associated with the trial from its beginning. The participating centers were asked to send the details of the RT planning for the first five recruited patients with the documentation of the received doses according to the ICRU-50 and ICRU-83 guidelines. The plans, reported doses
Please cite this article in press as: Hassan Metwally MA et al. IAEA-HypoX. A randomized multicenter study of the hypoxic radiosensitizer nimorazole concomitant with accelerated radiotherapy in head and neck squamous cell carcinoma. Radiother Oncol (2015), http://dx.doi.org/10.1016/ j.radonc.2015.04.005
M.A. Hassan Metwally et al. / Radiotherapy and Oncology xxx (2015) xxx–xxx
for different volumes, and the overall treatment times were independently checked by the quality coordinator for any deviations from the protocol guidelines. A list of the reported deviations according to predefined criteria was sent to the centers immediately afterward. Patients were evaluated weekly during treatment. The common radiation-related adverse events (dysphagia, mucosal edema, mucositis, and skin reaction) were graded and documented. NIM related adverse events (nausea, vomiting, flushing, and skin rash) were also graded according to the CTCAE v3.0 [23]. Patients were seen two months after the end of treatment to record persistent acute toxicity and early tumor response. Afterward, the patients were seen every three months. The study design, stratification, randomization, treatment and follow up, are detailed in the trial protocol. The trial was designed to include 600 patients. This number was expected to be recruited over a 3-year period. Assuming a true improvement of the loco-regional tumor control rate of 12% in the RT + NIM arm; then the probability that such an event would be detected at a significant level of P = 0.05 was greater than 90%. The primary endpoint was time to loco-regional tumor failure (locoregional tumor control). The definition of this end-point was complete and persistent disappearance of the disease in the primary site (T-site) and regional lymph nodes (N-site) after RT. Failure was recorded in the event of a recurrent tumor, or if the primary tumor and/or nodal disease never completely disappeared. In the latter situation the tumor was then assumed to have failed at the time of the end of RT course. All time estimates were done using the date of randomization as the initial value. The primary end-point does not include the effect of a successful procedure with salvage surgery. The Kaplan–Meier method was used to estimate time-to-event curves. Patterns of first failure were analyzed using a "competingrisks" analysis for the loco-regional failure. The treatment groups were compared with respect to the time to loco-regional failure, and overall survival using the Cox proportional hazards model. The trial was closed prematurely after 27 months by June 2014 due to the poor recruitment rate. The total recruitment was 104 patients compared to an expected recruitment of more than 400 patients at the same time point. Only 6 out of 9 centers have succeeded to obtain the required approvals for conducting the trial in their countries. The present analysis was performed for the randomized patients on an intention to treat basis, and patients were included in their randomization group irrespective of whether or not they had completed the planned treatment. Frequency tables with counts and percentages were used to describe the patients and their distribution in the two treatment arms. Patients were followed up in all centers until the time of evaluation on March 30, 2015. An associated protocol for translational research was included in this trial. The aim was to identify biomarkers that can predict which patients will benefit from the use of NIM. The biological analysis was performed retrospectively. Biological materials were collected from the participating centers as formalin fixed and paraffin embedded samples. Hypoxia status was determined through gene expression analysis of hypoxia-induced 15-gene profile on RNA extracted from the samples. Gene expression was determined by quantitative PCR analysis. Immunohistochemical staining for the HPV-associated p16 expression was performed on 49 tumor samples and tumors were classified as being HPV positive or negative according to a standardized DAHANCA protocol [24]. The results of the HPV status determination for further four patients from one of the centers were included in the analysis.
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of communication from the local investigators. These centers have randomized a total of 20 patients (9 patients were in the RT-alone arm, and 11 patients were in the RT + NIM arm). Among the remaining 84 eligible patients, two patients (one in each treatment arm) did not start the allocated treatment after randomization. One patient was lost to follow up immediately after randomization due to unknown reasons and the other patient was diagnosed with claustrophobia during preparation procedures for RT. The remaining 82 patients were evaluable (39 and 43 patients in the RT + NIM and the RT-alone arms, respectively). The trial flow chart is shown in (Fig. 1). There were 30 females and 52 males with a median age at randomization of 56 years (range 28–75 years). Most of patients (78%) presented with well/moderate differentiated tumors, 9% had poor/ undifferentiated tumors, and 13% had unknown differentiation with equal distribution between both treatment arms. Only 5 patients, out of 53 patients with known HPV/p16 status, were HPV/p16 positive (3 and 2 patients in RT-alone and RT + NIM arms, respectively). The patient- and treatment-related characteristics in both randomization arms are shown in (Table 1). The majority of patients have received radiation treatment using the 2D planning technique (56 patients). Most of patients received 66 Gy in 33 fractions to the gross tumor volume, and the vast majority completed the full prescribed radiation dose (66–70 Gy). Only 6 patients could not complete the full RT course: four were due to severe treatment-related toxicity; one was due to non-compliance, and one died during treatment due to complications of jejunostomy. As a whole, 31 (79%) patients received at least 90% of the prescribed NIM dose and 19 (49%) patients completed the full prescribed dose (Table 1). The cause of failure to fulfill the planned treatment was mainly due to the treatment-related acute toxicity, with the majority of patients complaining of mild to moderate nausea and vomiting. A few patients suffered from flushing and skin rash (Table 2). At the time of evaluation, 40 patients had failed to achieve persistent loco-regional tumor control, and a total of 45 patients had died. The median follow-up time of patients who were still alive at the time of evaluation was 19 months (range 1–34 months), and the median follow-up time of patients who died was 7 months (range 1–29 months). From a total of 40 patients with loco-regional
Results From March 2012 to May 2014, 104 patients were included. However, all included patients from two centers were excluded from the final analysis due to major deficiency of data and the lack
Fig. 1. Trial profile and outcome.
Please cite this article in press as: Hassan Metwally MA et al. IAEA-HypoX. A randomized multicenter study of the hypoxic radiosensitizer nimorazole concomitant with accelerated radiotherapy in head and neck squamous cell carcinoma. Radiother Oncol (2015), http://dx.doi.org/10.1016/ j.radonc.2015.04.005
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IAEA-HypoX trial of HNSCC
Table 1 Patient and treatment characteristics as a function of the randomization arm.§
Age (years) Median (range) Gender Female Male Performance status 0–1 2–3 Tumor site Larynx Pharynx Oral cavity T-classification T1–2 T3–4 N-classification N0 N1–3 Stage I–II III–IV HPV/p16 status HPV/p16 +ve HPV/p16 ve Unknown Hypoxic status More hypoxic Less hypoxic Unknown RT technique 2D 3DCRT IMRT RT Dose
