Clinical Radiology (1988) 39, 182-185

Interstitial Misonidazole" Clinical Experience in Advanced Mouth Cancer R. SEALY*, S. C R I D L A N D ? , G. B L E K K E N H O R S T * , L. BA RRY * and T. R O M B O U T S $

Departments of *Radiotherapy, ?Pharmacology, and SMedical Physics, Groote Schuur Hospital and University of Cape Town, South Africa

In an attempt to obtain full radiosensitisation and avoid dose-limiting neurotoxicity, a needle has been specially developed for the injection of misonidazole pellets into tumours. The methods of production and insertion of the pellets are described. Thirteen advanced, untreated squamous carcinomas of the mouth were injected and then irradiated to tolerance. Twelve out of 13 implanted lesions had completely regressed at the end of treatment but only six remained healed after 1 year.

A new approach to the interstitial application of a radia- tion sensitiser, in this instance misonidazole, has been previously reported (Sealy et al., 1984) in patients with recurrent malignant disease. The rationale for this approach is that the action of this agent is concentration- dependent and there is a systemic dose-limiting neuro- toxicity. This agent is a radiation sensitiser, is cytotoxic to hypoxic cells, and can be expected in high concentra- tion to cause some re-distribution of molecular oxygen within the tumour (Sealy et al., 1984).

We now describe a pilot study on previously untreated patients, using the technique of interstitial implantation of the drug with a new and specially developed needle.

MATERIALS AND METHODS

Needle Design

It was felt necessary to deposit as large a concentra- tion as possible of misonidazole in the tumour and sur- rounding areas. Because of low solubility of the drug and probable rapid clearance through the bloodstream, it was considered that this would be best achieved by implantation in a solid rather than a liquid form which with conventional injection can readily leak from necro- tic friable tumours. A needle was therefore designed to insert solid pellets containing misonidazole.

The needle (Fig. 1) consisted of a split tube of 2 mm internal diameter in a holder (B). The implant material was contained between the two halves of the tube (A, C) which were held together by means of a screw clamp (D).

The needle was loaded by inserting the push-rod (E) into the holder (B) to allow for the desired length of misonidazole pellet (F). The push-rod holder screw (G) was then tightened, after which the misonidazole pellet was loaded into the half tube (A). The opposing half tube (C) was then inserted into the holder. The screw clamp (D) was closed in such a position that the misonidazole could be inserted to the desired depth. The movable bobbin (H) was held against the skin dur- ing insertion to keep the two halves of the needle in opposition.

Pellet Manufacture

A mixture of misonidazole, glucose and glycerol (20:3:1 by weight) was ground in a mortar, then transfer- red to a glass tube and heated to a melt at 105 ° to 110°F. The liquid was drawn up into polytetrafluoroethylene (PTFE) tubing of 1.8 mm internal diameter and allowed to solidify. The tubing was split longitudinally to release the pellets. They were found to contain either 24 or 34 mg misonidazole/cm. In an experiment in vitro, it was found that the pellets dissolved completely in 1% agar in 8 h at 37°C, regardless of batch.

Method of Implantation

Skin punctures were made with a scalpel at the desired sites of implant. With the bobbin against the skin the needle was inserted to the desired depth until the screw clamp touched the bobbin. The screw clamp and the push-rod holding the screw were then loosened. With the handle of the push-rod maintained in a fixed posi- tion, the needle holder was withdrawn until it touched the push-rod handle. The needle and its elements were then free of the skin and the misonidazole pellet was left in the tumour.

Patient Selection

Patients with locally advanced, histologically con- firmed, squamous carcinoma of the mouth were offered this treatment. All were inoperable and had Cape Town Stage t 3 (4 to 6 cm) or t 4 (greater than 6 cm) disease except one patient with Cape Town t 2 disease (2 to 4 cm) invading the root of the tongue. Those with large nodes infiltrating neck structures were excluded because of possible hazards of implantation into the great vessels.

Prior Ethical Review Commit tee approval was sought and informed consent to the experimental nature of the procedure was obtained from all patients.

Treatment Method

Implant

Prior to implantation, patients were planned for stan- dard radiotherapy, with individually made immobilisa- tion and beam directional casts, plans, and Ellis-type tissue compensators. In addition, a separate cast was used to record the centre and axes of two parallel oppos- ing fields which were used for a single t reatment of 6 Gy 4 h after the misonidazole implant. This was necessary because of the oedema which followed the implant and lasted for about 36 h.

The implant was performed under general anaesthesia. The tumour was assessed, the limits marked out and a grid consisting of 1.5 c m × l . 5 cm

INTERSTITIAL MISONIDAZOLE 183

G

13

c

A F D

? H

C i-

G

B

4 3 2

B A D H H

Fig. 1 - Diagram of needle for interstitial misonidazole insertion (see text).

squares marked out on the skin or mucosa of the area to be implanted. The length of individual implants depended on the structure to be implanted. Where it was anatomically possible, attempts were made to extend the implant about 1.5 cm beyond the tumour mass. The procedure typically lasted about 50 minutes. At the end of treatment, powdered misonidazole was packed on to the ulcerated tumour and held in place by an individually made plastic carrier similar to a denture which was sutured into the mouth. The anaesthetic was then discontinued and the patient returned to the ward. Patient data are shown in Table 1.

Irradiation

Four hours after the implant, the patient was given a single dose of 6 Gy (6°Co) through parallel opposing fields with tissue equivalent bolus. Forty-eight hours later conventional irradiation was started. With the exception of the first patient, who received daily frac- tions, treatment Was given three times per week (3 Gy tumour dose/fraction). Except in cases where it was anatomically impossible (four) or where the patient Was intolerant (one), powdered misonidazole was packed on to the tumour and kept in place with a carrier for 2 h immediately before subsequent treatments.

In all, 13 patients received 15 implants. In two patients the procedure was repeated because persisting disease in the implantation site was suspected.

R E S U L T S

Clinical Effects and React ions

All patients experienced slight oozing from the punc- ture sites and moderate swelling of the implanted area. With One exception, none of these were of significance.

One patient experienced moderate local bleeding from the puncture sites for about 12 h and another patient experienced a large haematoma of the tongue and floor of mouth which took nearly three weeks to resolve. Two patients had minor peripheral sensory neuropathy and one of these had numbness of the tongue. At least nine patients had a history of alcoholic abuse. Early radiation reactions (erythema and membrane formation) were scored and did not appear to differ from those normally seen (Sealy etal., 1982). One patient had moderate post- radiation oedema and one necrosis of the mandibular arch. The latter patient, however, had extensive bone involvement before treatment. There were no major complications.

Pharmacokinet ics

It was not possible to study the pharmacokinetics of the drugs in the local tissues in man. Implantation of pellets with a core of steel Mre into pig'muscle, followed by fluoroscopy, showed that the pellets did not remain in the positions expected when the implanting needle ,was withdrawn, so it was not possible to know where to take biopsies in vivo for analysis without risking inclusion of pellet debris.

Three patients wer e implanted with misonidazole pel- lets as described above and, in addition, small (aboUf0.5

14 cm long) pellets containing C-misonidazole were implanted in the apparent geometrical centre of their tumours. Blood plasma samples were analysed separately for total and radioactive misonidazoie, The half-life of absorption and elimination were calculated for each form of~he drug. On the assumption that radio- labelled misonidazole was implanted into the centre of the tumour, it might b e expected that radioactive misonidazole would be released.more slowly-into the blood than the unlabelled drug; this was observed in two

184

Table 1 - Misonidazole implants with split needle

CLINICAL RADIOLOGY

Patient Tumour site t n no. stage stage Size (cm)

Tumour Node

Misonidazole (g) No. Aver- Radi- at implant needle age ation

Inter- Topical punc- mg dose stitial tures M I S O / (Gy)

cm ~ tissue

No. doses (lg) topical MISO with subse- quent radi- ation

Results (months)

Commen t

1 Tongue 4 0 5x3x3 - 2 Floor of mouth 3 0 5x2x3 - 3 Floor of mouth 3 0 6x3x2.5 -

4 Tongue 3 2

5 Mandible 4 0

6 Buccal mucosa 4 1 7 Floor of mouth 4 0 8 Floor of mouth/ 3 0

tongue 9 Floor of mouth/ 3 0

tongue I0 Jaw 4 2

11 Floor of mouth 3 1

12 Floor of mouth 2 0

13 Lip 4 0 7×7x3

2.3 3.0 24 51 6 & 5 6 0.966 1.0 14 24 6 & 4 5 5 2.07 1.0 15 59 6 & 4 8 12

5x4x3 2x2x2 1.6 0.75 14 36 6 & 5 5 1 x l x 1

8x3x2 - 1.618 0.5 20 33 6 & 45

5x6x3 1 x l x 1 2.312 0.5 9 21 5×3×2 - 2.448 1.0 11 81 5x3x2.5 - 2.653 2.0 26 24

5x2x3 - 3.3 2.0 22 100

6.5x3x2 2 × l x t 1.2 1.0 14 32 l x l × l

5×2.5×3 2×2 4.454 2.0 29 82 6 & 54 17

3×3x3 - (2.142 2.0 16 85 6 & 4 8 15 / 61 days ~0.75 1.0 8 53 6 & 3 1

0.5×0.5(2.7 1.0 7 150 6 & 12 { 21 days 1.1.428 7 40 6 & 24

LR 9/12 LR5/12 D- 11/12

LR 4/12

LR 7/12

6 & 45 13 A- 15/12 6 & 45 12 A- 18/12 6 & 54 No

response 6 & 51 15 LR 5/12

6 & 52 16 A- 12/12

LR 5/12

A- 16/12

Respiratory failure

Local bleeding 12 h after implant

Necrotic bone present o}iginally suggested recurrence

Marked haematoma after implant

Moderate late oedema

Local sensory neuropathy

A- 12/12 Mass outside treated area at 13 months

A-=Alive without malignant disease; D-=Died without malignant disease; LR=Local recurrence. MISO=Misonidazole.

lOO[ 80

70

60

=L 50

40

30

20

10

0 ; 10 1 ; 2'0 25 30 35 40 5'0 Time elapsed (h) after median t ime of implantation

Fig. 2 - The peripheral concentration of misonidazole against time (h) after interstitial implant, in four patients.

p a t i e n t s . T h e ha l f - l i ves o f a b s o r p t i o n f r o m t u m o u r in to b l o o d of r a d i o a c t i v e m i s o n i d a z o l e v a r i e d f r o m 2.5 to 8 h a n d o f u n l a b e l l e d d r u g f r o m i to 5 h, w h i c h c o n f i r m s t h a t t u m o u r s d i f f e r g r e a t l y and a re n o t h o m o g e n e o u s . T h e b l o o d c o n c e n t r a t i o n o f m i s o n i d a z o l e aga ins t t i m e is s h o w n in Fig . 2.

T u m o u r C o n t r o l

T w e l v e o f t h e 13 t u m o u r s u n d e r w e n t c o m p l e t e c l in ica l r e g r e s s i o n a f t e r t r e a t m e n t bu t six r e c u r r e d in t h e t r e a t e d a r e a a n d o n e r e c u r r e d i m m e d i a t e l y o u t s i d e t h e i m p l a n t e d a r ea . O n e t u m o u r s h o w e d no r e s p o n s e at all to t r e a t m e n t . I n c l u d i n g t h e p a t i e n t w h o d i e d o f r e sp i r a - t o r y f a i l u re at 50 w e e k s w i t h no e v i d e n c e o f t u m o u r , six o f 13 p a t i e n t s w e r e f r e e o f d i s ea se in t h e t r e a t e d s i te 1 y e a r a f t e r t r e a t m e n t . T h e re su l t s o f t r e a t m e n t in p a t i e n t s e v e n is s h o w n in F i g u r e s 3 and 4. T h e r e was no o b v i o u s c o r r e l a t i o n b e t w e e n t h e p r e s u m e d t i s sue c o n c e n t r a t i o n o f m i s o n i d a z o l e a n d f r e e d o m f r o m d i s ea se at 1 yea r , n o r was t h e r e any o b v i o u s c o r r e l a t i o n w i t h s i te and s t age o f d i s e a s e

D I S C U S S I O N

T h i s m e t h o d o f t r e a t m e n t has b e e n s h o w n to b e p r a c - t i cab l e a n d safe . T h e d o s e o f m i s o n i d a z o l e and r a d i a t i o n

INTERSTITIAL MISONIDAZOLE 185

Fig. 3 - Patient 7 before treatment. An extensive tumour of the mouth floor and tongue can be seen.

al., 1984), which may be acting as a cytotoxic agent as well as a radiat ion sensitiser. The disappoint ing result, despite a theoret ical concent ra t ion th roughout the tumours of about 100 raM, may be due to an uneven distribution of the drug in the tumour , as was demonst r - ated in the pig muscle exper iment . This had led us to believe that in spite of the known good tissue diffusion of misonidazole, there will still be areas of hypoxic cells in the t umour which will no t be comple te ly radiosensitised. One such surviving microscopic hypoxic area would be enough to ensure recurrence. Two pat ients experienced local recurrence on the edge of, and one outside the implanted area. This would suggest that peripheral microscopic hypoxic foci are present which were not el iminated by this t rea tment . It also suggests that if a local form of sensitisation is to be used, it should be capable of being del ivered to a larger volume. This is probably not technically or clinically possible with solid agents used in this way.

Others have repor ted u p o n the local inject ion of misonidazole solution into tumours ( H o n g et al., 1984). They, however , used a lower concen t ra t ion of drug and had, in a diverse group of tumours , only eight comple te responses in 17 patients. This may be dose-re la ted since our experiences with higher doses apparent ly demon- strated a bet ter response rate in larger lesions.

We are investigating o ther me thods of interstitial application of radiat ion sensitisers which might achieve a more even distribution of the drug.

Fig. 4 - Patient 7 1 year after treatment. Complete healing with some fibrosis and mucosal atrophy is evident.

Acknowledgements. Thanks are due to the Medical Superintendent, Dr J. Kane-Berman, for permission to publish this work, to Roche Products, Welwyn Garden City, United Kingdom, for the supply of misonidazole, 14C-misonidazole and support, and to Dr I. Lenox- Smith for his unfailing courtesy and help.

The manuscript was typed by Mrs D. G0dley and the diagrams drawn by Miss Jenny Bosman.

repor ted here might reasonably have been expected to cause a total t umour cell kill of at least 10 -1 with the first t rea tment and thus allow extensive reoxygenat ion of the tumour . This view is suppor ted in that the 3-month tumour c learance rate (12 out of 13) compared favoura- bly with that of a series of similar patients who received a tumour dose of 63 Gy in 30 daily fractions, in w h o m only 37 of 64 (58%) were free of disease at 3 months (X2=5.5), but this apparen t advantage is lost at a year (5 out of 13 (38%) compared with 15 out of 56 (27%) determinate patients. This suggests an improved but still inadequate cell kill by the added misonidazole (Sealy et

REFERENCES

Hong, SS, Abe, Y, Kaneta, K & Matsuzawa, T (1984). Combined treatment of radiation and local injections of misonidazole. Inter- national Journal of Radiation Oncology, Biology, Physics, 10, 2369 2373.

Sealy, R, Williams, A, Cridland, S, Stratford, M, Minchinton, A & Hallet, C (1982). A report on misonidazole in a randomized trial in locally advanced head and neck cancer. International Journal of Radiation Oncology, Biology, Physics, 8, 339-342.

Sealy, R, Korrubel, J, Cridland, S & Blekkenhorst G (1984). Intersti- tial misonidazole: A preliminary report on a new perspective in clinical radiation sensitization and hypoxic cell chemotherapy. Cancer, 54, 1535-1540.