Journal of Cancer Research and Therapeutics Medknow Publications on behalf of the Association of Radiation Oncologists of India (AROI) ISSN: 0973-1482 EISSN: 1998-4138 Vol. 1, Num. 2, 2005, pp. 75-78

Journal of Cancer Research and Therapeutics, Vol. 1, No. 2, April-June, 2005, pp. 75-78

Original Article

AK-2123 (Sanazol) as a radiation sensitizer in the treatment of stage iii cancer cervix: Initial results of an IAEA multicentre randomized trial

Werner Dobrowsky¹ , Nagraj G. Huigol², Ranapala S. Jayatilake³, Noor-I- Alam Kizilbash⁴, Sait Okkan⁵, Tsutomu V. Kagiya⁶, Hideo Tatsuzaki⁷

¹Northern Centre for Cancer Treatment, Newcastle General Hospital, Newcastle upon Tyne, NE4,6BE, UK
²Division of Radiation Oncology, Dr. Nanavati Hospital & MRC, Bombay 400 056, India
³38 Nelson Place, Colombo, Sri Lanka
⁴Nuclear Medicine, Oncology and Radiotherapy Institute, Islamabad, Pakistan
⁵Radiation Oncology Department, Cerraphasa Medical School, Istanbul 34303, Turkey
⁶Health Research Foundation, Kyoto 606, Japan
⁷Section of Applied Radiation Biology and Radiotherapy, International Atomic Energy Agency, Vienna, Austria
For correspondence: ¹Northern Centre for Cancer Treatment, Newcastle General Hospital, Newcastle upon Tyne, NE4 6BE,UK, E-mail: werner.dobrowsky@nuth.nhs.uk.

Code Number: cr05016

Abstract

PURPOSE : AK-2123, a nitrotriazole hypoxic cell sensitizer has reportedly improved results in head and neck cancers, uterine cervical cancers and other solid tumours when added to radical radiotherapy. A prospectively randomised trial was initiated by the International Atomic Energy Agency (IAEA) evaluating AK-2123 and radiotherapy in treatment of uterine cervical cancer stage IIIA and IIIB.
MATERIALS AND METHODS : A total of 333 patients were randomised between May1995 and December1998. Patients were randomised to either standard radical treatment (radiation therapy alone, RT) or standard radical radiotherapy and additional administration of AK-2123 (RT+AK-2123). The total dose of 45-50.8 Gy was delivered in 20 to 28 fractions over 4 to 5 1/2 weeks. The dose to the central disease was escalated to a radiobiologically equivalent dose of 70 Gy by external beam or brachytherapy, in accordance with each centres individual practice. In the study arm, patients received 0.6 g/sqm AK-2123 by intravenous administration before external beam radiotherapy, treating with AK-2123 on alternate days (e.g. Monday-Wednesday-Friday) during the entire course of external beam therapy .
RESULTS: After a median follow up of 57 months (range 30-73 months) the rate of local tumour control was significantly higher in the group who received radiotherapy and additional administration of AK-2123. Local tumour control at the last follow up was 61% after combined radiotherapy and AK-2123 and 46% after radiotherapy alone (p = 0.005). AK-2123 neither increased gastro-intestinal toxicity nor gave any haematological toxicity. A mild peripheral neuropathy (Grade 1:11% and Grade 2:3%) was seen infrequently after AK-2123 administration and was usually completely reversible. Crude survival rates were 41% after radical treatment compared to 57% after combined therapy (p = 0.007)
CONCLUSION : We conclude that the addition of AK-2123 to radical radiotherapy significantly increases response rates and local tumour control in advanced squamous cell cancer of the uterine cervix without any increase in major toxicity. Further analysis and follow up are needed to evaluate if this benefit will translate into prolonged survival. We strongly suggest that our initially very promising study should lead other centres to further studies of AK-2123 in randomised clinical trials.

Keywords: Radiotherapy, Hypoxic radiosensitizer, Cervical cancer

Introduction

It is estimated that more than 450.000 cases of cancer of the uterine cervix were diagnosed in 2000. Early disease can be treated curatively either by surgery or irradiation but patients with locally advanced cervical cancer have a poor prognosis mainly due to failure to control the local disease with radiotherapy even though technique and methods of treatment have improved over the last decade. Women with advanced stage (Stage IIIB and IV) disease have a high rate of pelvic relapse of more than 50% and a poor prognosis. In spite of the various efforts to enhance the efficacy of irradiation, local failure is still the main cause of death in these cases. One of the reasons for radiation failing to achieve a better survival is the presence of a less radiosensitive hypoxic cell population.[1] Hyperbaric oxygen trials and blood transfusion studies have suggested that hypoxia is a major problem for tumour control in carcinoma of the cervix.[2],[3] Trials to overcome the radioresistance with radiosensitizers have generally not shown a significant clinical benefit. The reason for this may be attributed to limitation on the dose of sensitizer given because of neurotoxicity caused by the drug. Experimental data and preliminary clinical studies in the literature suggest that, a nitratriazole derivative, AK-2123, a hypoxic cell sensitizer with lower neurotoxicity than most nitroimidazols has been beneficial.[4] Early studies testing AK-2123 as a radiosensitizer with irradiation in various tumours showed encouraging results.[5], [6]

A phase III randomized trial was designed in order to evaluate the sensitizing effect of the drug.

This multi centric randomised study was conducted under the auspicous by IAEA with participating centres from India, Sri Lanka, Pakistan and Turkey.

Materials and Methods

In a randomised multicentre trial a total of 333 patients were randomised between May1995 and December1998. Patients were randomised to either standard radical treatment (radiation therapy alone, RT) or standard radical radiotherapy and additional administration of AK-2123 (RT+AK-2123), a hypoxic cell radiation sensitizer. All patients were diagnosed with stage IIIA or IIIB squamous cell carcinoma of the uterine cervix. Inclusion criteria were patients up to 75 years at diagnosis, absence of distant metastases and no prior therapy for cancer (except skin cancer). The mean (= median) age of the patients at time of randomisation was 52 years. Prior to therapy all patients were informed about the randomisation and had given written informed consent to participate in the study. All centres participating in the trial did this after approval of their local Ethical Committee. Patients were stratified for therapy centre. The characteristics of the patients in the two randomization groups is seen in [Table - 1].

The distribution of the patients prior to therapy regarding stage, age, presence of hydronephrosis or bilateral disease and their haemoglobin level and performance status shows an equal distribution in the two groups. The dose delivered by external beam radiotherapy and brachytherapy was equal in the two treatment arms.

Pharmakokinetics
AK-2123(N-(2-methlyoxyethyl)-3-(3"-nitro-1"triazoyl) acetamide) is a water soluble compound. It has an octanol to water coefficient of 0.15, which ensures decreased distribution of the drug in neural tissues including brain. The drug can be administered orally or intravenously. The drug is well absorbed following oral administration but takes time to achieve peak plasma level.[7] Intra venous administration of the drug results in an rapid peak plasma level.[7] The pharmacokinetics of AK-2123 follows a two compartment model. The elimination of the drug from plasma follows a bi-exponential decay with an elimination half time of 5.18 hours. Thus most of the drug is eliminated in 24 hours and, cumulative toxicity of the drug is negligible. It is predominantly excreted in urine in unchanged form. Few 3- aminoderavatives have been isolated as metabolites of AK-2123 in urine.

Treatment
External radiation treatment was performed with Co-60 machines or by linear accelerator. Dose prescription was performed according to ICRU 38. The treatment volume comprised the primary tumour and pelvic lymph nodes. The upper field border was at L4/L5 or L5/S1, the lower border the obturator foramen, or at least one cm beyond palpable disease. The lateral borders were outside of the bony pelvis by at least 1-2 cm. Treatment was given by parallel opposed fields or a four-field arrangement ("box technique"). In the case of four field technique, the upper and lower borders were identical as above, the anterior field border was the symphysis and the posterior border parallel to the anterior part of S2/S3. The fraction sizes were range between 1.8 and 2.25 Gy as measured in the mid-plane. The total dose of 45-50.8 Gy was delivered in 20 to 28 fractions in an overall time of 4 to 5 1/2 weeks. This range of dose and fractionation was due to the prevailing standard therapy used by individual participating institutions and was maintained throughout the study and was the same in the two randomization groups. Brachytherapy was performed either by HDR or LDR (Soures: Ir, Co, Cs) aiming to increase the dose in point A to at least 70.0 Gy by application of 1 to 3 fractions. If brachytherapy was not performed, the dose of external beam was increased to ensure that the total dose in point A was at least 70 Gy. The identical radical radiotherapy was used in the experimental study arm with the addition of AK-2123.

In the study arm, patients received 0.6 g/sqm AK-2123 by intravenous administration 20-30 minutes before external beam radiotherapy, treating with AK-2123 on alternate days (e.g. Monday-Wednesday-Friday) during the entire course of external beam therapy.

Follow-up examinations were performed at the end of radiotherapy, one-month after radiotherapy, at regular intervals, every 4 months during the first two years and thereafter 6-monthly during the next 2 years and yearly thereafter.

Statistical analysis
Patients were randomised to either radical radiotherapy treatment (RT) or radical radiotherapy treatment with administration of AK-2123. Patients were stratified by centre.

Response rate and overall survival were chosen as end points for the study. Analysis of patient characteristics was performed using all randomised patients. For this analysis, 6 patients were excluded since they never appeared for treatment and were lost to follow up. Thus, a total of 327 patients were analyzed, on an intention to treat basis. The Chi-square test was used to assess factors influencing tumour control between the treatment groups. Assessment of the results was performed in 2001.

Results

Tolerance of therapy

Acute toxicity
Local, gastro-intestinal toxicity did not differ significantly in the two treatment groups (utilising WHO criteria). There was no haematological toxicity following administration of AK-2123. There was a significant proportion of patients in the AK-2123 arm who experienced peripheral neuropathy. Seventeen patients developed grade 1 and three patients developed grade 2 peripheral neurotoxicity compared to none in the radiotherapy-only arm (p < 0.0001). In most cases these symptoms had returned to normal within 6 months. One patient has been recorded with mild, permanent peripheral neuropathy. A summary of acute toxicity is shown in [Table - 2].

Late toxicity
Patients on follow up for more than 2 months from randomisation were analysed for late toxicity to the bladder and rectum. There was no significant increase in the late toxicity in the AK-2123 treated patients. Bladder grade 1 toxicity was seen in 2 cases after radiotherapy alone and in 4 cases after AK-2123 treatment, in one case a grade 2 toxicity was recorded after AK-2123 treatment. Rectal late toxicity grade 2 was recorded in 4 patients after AK-2123 treatment compared to 3 after radiotherapy alone. One patient experienced a grade 3 toxicity after radiotherapy alone.

Initial treatment response [Table - 3]
The initial rate of complete response as determined at the end of radiotherapy or at the first follow up examination (within 4-6 weeks after completion of therapy) showed a statistical advantage for those patients treated with radiotherapy combined with AK-2123 compared to radiotherapy alone (64% vs. 49%, p = 0.01).

The Patients who had brachytherapy to escalate the dose to the central axis did better with regard to achieving complete response (73% vs 47%).

Distant metastases
A total of 24 patients have developed distant metastases. They were seen in both groups of patients. Sixteen patients in the RT group and 8 in the AK-2123 group have developed distant metastases with bone and lung being most frequent (p < 0.05).

Local tumour control
The rate of local tumour control was significantly higher in the group after radiotherapy and additional administration of AK-2123. Including patients who did not attend follow up examinations the rate of local tumour control at the last follow up visit was 61% after AK-2123 and 46% after radiotherapy alone (p = 0.005).

Discussion

Results of radiotherapy in treatment of advanced uterine cervical cancer remains poor. Methods to increase the efficacy of radiotherapy have included combinations with chemotherapy and the use of radiosensitisers. Until recently, these combinations were not considered to be of general benefit for patients and did not have any major effect with regard to altering treatment standards. In 1999 three published trials demonstrated an increase in local control and survival with regimens including cisplatin.[8], [9], [10] More recent data have suggested no significant benefit for chemo-radiotherapy with cisplatin compared to radiotherapy alone.[11], [12] Morbidity is significantly increased when chemotherapeutic drugs are administered concurrently with radiotherapy, this has not only implications for the intensified care of patients but also rising costs for treatment of leucopenic septicaemia and hospitalisation of patients.[13] The present study shows promising results with a significant improvement similar to the initial positive reports on cisplatin and radiotherapy. Our results are comparable to meta-analyses in treatment of cervical cancer.[14] The advantage of using AK-2123 is not only the improvement compared to radiotherapy alone, but also its relatively low toxicity, without any potentially life threatening haematological toxicity. Unlike nitroimidazol sensitizers, neurotoxicity was mild and generally transient. In clinical trials AK-2123 has been found to be well tolerated when administered with concomitant conventional fractionated radiotherapy, using doses of up to 1 g/sqm thrice weekly.[7],[15] AK-2123 has also been used to sensitise accelerated fractionation radiotherapy in head and neck cancer and the results reported are significantly in favour of AK-2123.[6]

Our results emphasises the improvement of outcome in patients who had brachytherapy to increase the central dose, reflected in an improvement of rate of complete response from 47% after external beam alone to 73% after external beam and brachytherapy.

We found no increase in severe late toxicity after additional administration of AK-2123. The plasma half-life of 51/2 hours, with most of the drug being eliminated within 24 hours, means that it is useful for fractionated administration throughout a course of radiotherapy, without the fear of drug accumulation and increased toxicity.

This study is larger than most studies using radiosensitisers in treatment of cervical cancers. Previous studies using sensitizers have either shown no effect,[16], [17], [18], [19], [20] adverse effect[21] or advantage[22] with regard to local tumour control.

We conclude that the addition of AK-2123 to radical radiotherapy significantly increases local tumour control from 45% to 62% (p = 0.006) and survival from 41% to 57% (p = 0.007) in advanced squamous cell cancer of the uterine cervix. AK-2123 neither increasd local toxicity nor did it give haematological toxicity. A mild peripheral toxicity, usually completely reversible was infrequently seen after AK-2123 administration.

References

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