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Misonidazole and radiotherapy in lung cancer: A randomized double-blind trial
0360 30l6/82/l0l71942$03.00/0 CopyrIght 0 1982 Pergamon Press Lrd
Inr J Radiarwn Oncology 8101 Phys Vol 8. pp. 17 I9- I720 Prmted in the U S A All rights reserved
??Original Contribution MISONIDAZOLE AND RADIOTHERAPY IN LUNG CANCER: A RANDOMIZED DOUBLE-BLIND TRIAL
M.J.M;~NTYL& M.D.',E.M. NORDMAN, M.D.',P.J.RUOTSALAINEN, M.D., M.Sc.' AND T.T.KYLMAMAA, M.Sc.' ‘Department of Radiotherapy, Middle Finland Central Hospital, SF-40620 Jyviskylj: 62, Finland; ‘Department of Radiotherapy, Turku University Central Hospital, Turku. Finland; jDepartment of Clinical Research, Hoffmann-La Roche Ltd., Espoo. Finland
Forty-six patients with inoperable bronchial cancer have been treated by a fractionated course of radiotherapy with misonidazole or placebo. The main purpose of the administration of the drug to these patients was to determine tumor response and safe dosage in clinical squamous cell cancer by misonidazole. Misonidazole,
Fractionation,
radiotherapy.
Hypoxic-cell
It seems possible to enhance the radiosensitivity
radiosensitizer,
INTRODUCTION
The purposes of this randomized study were: (l)To establish whether misonidazole has any efficacy as an adjuvant to radiotherapy in the treatment of patients with inoperable bronchial cancer; and (2)To assess the tolerance to misonidazole. AND MATERIALS
All consecutive patients with inoperable bronchial cancer giving informed consent were included in the study. The following criteria had to be fulfilled: a) Karnofsky index 2 60; b) tumor classified according to TNM (classification of malignant tumors, UICC 1978)’ as Tl-T3, NO-N2, MO; c) histologically or cytologically confirmed diagnosis of epidermoidal (squamous cell) or adenomatous bronchial cancer; d) no earlier treatment for bronchial cancer with chemotherapy, radiotherapy or surgery. Forty-six patients with inoperable bronchial cancer entered the study. The patients were randomly allocated into two groups receiving either misonidazole or placebo. The age of the patients was 63.2 * 5.8 (mean i SD) years in the misonidazole group and 67.6 -+ 7.2 years in the placebo group (Table I). The weight of the patients was 7 1.6 +- 12.9 kg in the misonidazole group and 68.6 2 12.6
Reprint requests to: M.J. MgntylZ,
Bronchial cancer.
kg in the placebo group. All patients were ambulatory. All patients in the misonidazole group were males; in the placebo group there were 21 males and two females. Every patient had inoperable squamous cell bronchial cancer without distant metastases. Radiotherapy was delivered with megavoltage equipment to a total dose of 5500 rad divided into 25 fractions (220 rad/a fraction) in eight weeks. After 3300 rad there was a three week interval. Misonidazole or placebo capsules were given four hours before each fraction of radiotherapy. The dose of misonidazole was 0.6 g/day; the total dose was I5 g. The etTect of the treatment was evaluated as a decrease in the volume of the tumor. Tumor volume before, in the middle and at the end of radiotherapy was calculated with t b)/8. Dimensions a and the formula: V = 4/3.*+a.b(a b are perpendicular dimensions of the tumor measured from roentgenograms.
Bronchial cancer is the most common cancer in Finnish males. The majority of these patients have an inoperable tumor. The overall 5-year survival rate of these patients is under 10%. It is therefore of particular interest that misonidazole can increase the effect of ionizing radiation.l.?.h
METHODS
of human
RESULTS
AND DISCUSSION
The mean tumor volume before radiotherapy was 46 T 7 ml in the misonidazole group and 50 + IO ml in the Table
I. Characteristic\ Visonida~lc
Age (ycar5) Weight (kg)
63.7 71.6
of patients
group
. 5.x* ’ 12 9
Placebo group
hl.6 + l.? * I I.6
6X. 6
Sex Male
23
71
Female
0
2
*Mean + SD.
M.D.
Accepted 1719
for publication
7 June 1982.
I720
Radiation
Oncology
??Biology 0 Physics
October 1982. Volume 8. Number IO
Table 2. Tumor response in the middle of therapy and at the end of therap) Misonidazole patients
Response Complete remission Partial remission
Y0 100 99-76 75-5 I 50-26 25-o
Middle of therapy
End of therapy
I
3 11 4 I I
Progressive disease
7 6 4 I I
Not measurable
3
Stationary
disease
of the treatment the tumor volume in the misonidazole group and 45.3 f 7. I % in the placebo group (Figure 1). At the end of the treatment the values were 20.2 t 5.6% and 29.1 + 5.8%. respectively. Objective response rates in the tumors are shown in Table 2. It seems that the effect of misonidazole is more favorable during the first period of irradiation than during the second. The differences between misonidazole and placebo groups, however, are not statistically significant. The treatment was well-tolerated in both groups. No patient had signs or symptoms of peripheral neuropathy. Three patients had mild dysphagia during radiotherapy in the misonidazole group and two patients in the placebo group. Our results are preliminary and the study is continuing. It seems that it is possible to enhance the radiosensitivity of human squamous cell cancer by using misonidazole. This is in accordance to the results obtained in animal experiments 2,6and in clinical tria1s.3,4 The follow-up in our work is too short to evaluate the final recurrence freedom and survival of the patients. placebo group.
volume
Placebo patients Middle of therapy
End 01 therapy ___.-
6 6 4 2 2 3
8 6 4
I
3
4
In the middle
was 35.9 + 6.7% from the initial
MISONIDAZOLE
n=
Fig. I.
IN
THE
OF
TREATMENT
MIDDLE
AT
THE
OF
TREATMENT
END
PLACEBO
EXAMINATION
TIME
Tumor volume during misonidazole and radiotherapy.
REFERENCES Adams, G.E., Dische, S., Fowler, J.F., Thomlinson, R.H.: Hypoxic sensitisers in radiotherapy. Lancet. 186-l 88, 1976. Dische, S., Fowler, J.F., Saunders, M.I., Stratford, M.R.L., Anderson, P., Minchinton, A.I., Lee, M.E.: A drug for improved radiosensitization in radiotherapy. Br. J. Cancer
42: 153-155,
1980.
Dische, S., Saunders, M.I.: Clinical experience with misonidazole. Br. J. Cancer37 (Suppl. Ill): 31 l-313, 1978. Fowler, J.F., Sheldon, P.W., Denekamp, J., Field, S.B.:
Optimum fractionation of the C3H mouse mammary carcinoma using X-rays, the hypoxic-cell radiosensitizer Ro 070582, or fast neutrons. Int. J. Radiat. Oncol. Biol. Phys. 1: 579-592, 1976. 5. International Union Against Cancer (UICC): TNM Clnssijication of Malignant Tumors. Geneva, 1978. 6. Stone, H.B., Withers, H.R.: Enhancement of the radioresponse of a murine tumour by a nitroimidazole. Br. J.
Radiol. 48: 41 l-415, 1975.
Inr J Radiarwn Oncology 8101 Phys Vol 8. pp. 17 I9- I720 Prmted in the U S A All rights reserved
??Original Contribution MISONIDAZOLE AND RADIOTHERAPY IN LUNG CANCER: A RANDOMIZED DOUBLE-BLIND TRIAL
M.J.M;~NTYL& M.D.',E.M. NORDMAN, M.D.',P.J.RUOTSALAINEN, M.D., M.Sc.' AND T.T.KYLMAMAA, M.Sc.' ‘Department of Radiotherapy, Middle Finland Central Hospital, SF-40620 Jyviskylj: 62, Finland; ‘Department of Radiotherapy, Turku University Central Hospital, Turku. Finland; jDepartment of Clinical Research, Hoffmann-La Roche Ltd., Espoo. Finland
Forty-six patients with inoperable bronchial cancer have been treated by a fractionated course of radiotherapy with misonidazole or placebo. The main purpose of the administration of the drug to these patients was to determine tumor response and safe dosage in clinical squamous cell cancer by misonidazole. Misonidazole,
Fractionation,
radiotherapy.
Hypoxic-cell
It seems possible to enhance the radiosensitivity
radiosensitizer,
INTRODUCTION
The purposes of this randomized study were: (l)To establish whether misonidazole has any efficacy as an adjuvant to radiotherapy in the treatment of patients with inoperable bronchial cancer; and (2)To assess the tolerance to misonidazole. AND MATERIALS
All consecutive patients with inoperable bronchial cancer giving informed consent were included in the study. The following criteria had to be fulfilled: a) Karnofsky index 2 60; b) tumor classified according to TNM (classification of malignant tumors, UICC 1978)’ as Tl-T3, NO-N2, MO; c) histologically or cytologically confirmed diagnosis of epidermoidal (squamous cell) or adenomatous bronchial cancer; d) no earlier treatment for bronchial cancer with chemotherapy, radiotherapy or surgery. Forty-six patients with inoperable bronchial cancer entered the study. The patients were randomly allocated into two groups receiving either misonidazole or placebo. The age of the patients was 63.2 * 5.8 (mean i SD) years in the misonidazole group and 67.6 -+ 7.2 years in the placebo group (Table I). The weight of the patients was 7 1.6 +- 12.9 kg in the misonidazole group and 68.6 2 12.6
Reprint requests to: M.J. MgntylZ,
Bronchial cancer.
kg in the placebo group. All patients were ambulatory. All patients in the misonidazole group were males; in the placebo group there were 21 males and two females. Every patient had inoperable squamous cell bronchial cancer without distant metastases. Radiotherapy was delivered with megavoltage equipment to a total dose of 5500 rad divided into 25 fractions (220 rad/a fraction) in eight weeks. After 3300 rad there was a three week interval. Misonidazole or placebo capsules were given four hours before each fraction of radiotherapy. The dose of misonidazole was 0.6 g/day; the total dose was I5 g. The etTect of the treatment was evaluated as a decrease in the volume of the tumor. Tumor volume before, in the middle and at the end of radiotherapy was calculated with t b)/8. Dimensions a and the formula: V = 4/3.*+a.b(a b are perpendicular dimensions of the tumor measured from roentgenograms.
Bronchial cancer is the most common cancer in Finnish males. The majority of these patients have an inoperable tumor. The overall 5-year survival rate of these patients is under 10%. It is therefore of particular interest that misonidazole can increase the effect of ionizing radiation.l.?.h
METHODS
of human
RESULTS
AND DISCUSSION
The mean tumor volume before radiotherapy was 46 T 7 ml in the misonidazole group and 50 + IO ml in the Table
I. Characteristic\ Visonida~lc
Age (ycar5) Weight (kg)
63.7 71.6
of patients
group
. 5.x* ’ 12 9
Placebo group
hl.6 + l.? * I I.6
6X. 6
Sex Male
23
71
Female
0
2
*Mean + SD.
M.D.
Accepted 1719
for publication
7 June 1982.
I720
Radiation
Oncology
??Biology 0 Physics
October 1982. Volume 8. Number IO
Table 2. Tumor response in the middle of therapy and at the end of therap) Misonidazole patients
Response Complete remission Partial remission
Y0 100 99-76 75-5 I 50-26 25-o
Middle of therapy
End of therapy
I
3 11 4 I I
Progressive disease
7 6 4 I I
Not measurable
3
Stationary
disease
of the treatment the tumor volume in the misonidazole group and 45.3 f 7. I % in the placebo group (Figure 1). At the end of the treatment the values were 20.2 t 5.6% and 29.1 + 5.8%. respectively. Objective response rates in the tumors are shown in Table 2. It seems that the effect of misonidazole is more favorable during the first period of irradiation than during the second. The differences between misonidazole and placebo groups, however, are not statistically significant. The treatment was well-tolerated in both groups. No patient had signs or symptoms of peripheral neuropathy. Three patients had mild dysphagia during radiotherapy in the misonidazole group and two patients in the placebo group. Our results are preliminary and the study is continuing. It seems that it is possible to enhance the radiosensitivity of human squamous cell cancer by using misonidazole. This is in accordance to the results obtained in animal experiments 2,6and in clinical tria1s.3,4 The follow-up in our work is too short to evaluate the final recurrence freedom and survival of the patients. placebo group.
volume
Placebo patients Middle of therapy
End 01 therapy ___.-
6 6 4 2 2 3
8 6 4
I
3
4
In the middle
was 35.9 + 6.7% from the initial
MISONIDAZOLE
n=
Fig. I.
IN
THE
OF
TREATMENT
MIDDLE
AT
THE
OF
TREATMENT
END
PLACEBO
EXAMINATION
TIME
Tumor volume during misonidazole and radiotherapy.
REFERENCES Adams, G.E., Dische, S., Fowler, J.F., Thomlinson, R.H.: Hypoxic sensitisers in radiotherapy. Lancet. 186-l 88, 1976. Dische, S., Fowler, J.F., Saunders, M.I., Stratford, M.R.L., Anderson, P., Minchinton, A.I., Lee, M.E.: A drug for improved radiosensitization in radiotherapy. Br. J. Cancer
42: 153-155,
1980.
Dische, S., Saunders, M.I.: Clinical experience with misonidazole. Br. J. Cancer37 (Suppl. Ill): 31 l-313, 1978. Fowler, J.F., Sheldon, P.W., Denekamp, J., Field, S.B.:
Optimum fractionation of the C3H mouse mammary carcinoma using X-rays, the hypoxic-cell radiosensitizer Ro 070582, or fast neutrons. Int. J. Radiat. Oncol. Biol. Phys. 1: 579-592, 1976. 5. International Union Against Cancer (UICC): TNM Clnssijication of Malignant Tumors. Geneva, 1978. 6. Stone, H.B., Withers, H.R.: Enhancement of the radioresponse of a murine tumour by a nitroimidazole. Br. J.
Radiol. 48: 41 l-415, 1975.