Rebuttal

Inr J Radwrron Oncology Bml Phyr , Vol. Printed in the U.S.A All rights reserved.

IO.

pp.

439-441 Copyright

f

036&3016/84 13.00 + .W 1984 Pcrgamon Press Ltd.

@ Correspondence Letters to the Editor will be pubMwd if tkey are suitable and if space

melanoma. Cancer 38: 2258-2262, 1976.

permits. The Letter &wouldke typewritten (double spaced) and must not exceed It/z pages including references; submit in triplicate. l%e Letter may ke edited and shortened in our Editorial office. A letter regarding I recent Joumal article should be received within six weeks of the article’x publication date.

7. Hanvood, A.R. Cummings, B.J.: Radiotherapy for mucosal melanomas. Int. J. R&or. Oncol. Biol. Phys. 8: 1121-1126, 1982.

8. Homsey. S.: The relationship between total dose, number of fractions and fraction size in the resonance of malignant melanoma in patients. Br. J. Radiol. 51: 905909, 1978. 9. Lobo, P.A., Liebner, E.J., Chao, J.J., Kanji, A.M.: Radiotherapy in the management of malignant melanoma. Int. J. Radiut. Oncol. Biol. Phys. 7: 21-26, 1981. 10. Overgaard, J.: Radiation treatment of malignant melanoma. Inl. J. Radiar. Oncol. Biol. Phys. 6: 41-44, 1980. 11. Scaly, R., Hockly, J., Shepstone, B.: The treatment of malignant melanoma with cobalt and hyperbaric oxygen. C/in. Radial. 25: 211-215, 1974. 12. Smith, I.E., Courtenay, V.D., Mills, J., Peckham, M.J.: In uirro radiation response of cells from four human tumours propagated in immume suppressed mice. Cancer Res. 38: 390-392, 1978. 13. Strauss, A., Dritschild, A., Nathanson, L., Piro, A.J.: Radiation therapy of malignant melanomas: an evaluation of clinically used fractionation schemes. Cancer 4’1: 1262-1266, 1981. 14. Trott, K.R., Von Lieven, H., Kummermehr, J., Skopal, D., Lukacs, S., Braun-Falco, O., Kellerer, A.M.: The radiosensitivity of malignant melanomas. Part II: clinical studies. Inr. J. Rod&. Oncol. Biol. Phys. 7: 15-20, 1981. 15. Weininger, J., Guichard, M.. Joly, A.M., Malaise, E.P., Lachet, B.: Radiosensitivity and growth parameters in vitro of three human melanoma strains. Int. J. Rad. Biol. 34: 285-290, 1978. 16. Wheldon, T.E.: Optimal fractionation for the radiotherapy of tumour cells possessing wide-shouldered survival curves. Br. J.

RADIORESPONSIVENESS OF MALIGNANT MELANOMA TO FRACTIONATED IRRADIATION To the Ediror: I am writing to ensure that any publications of clinical results on this subject should include all three of the usual parameters, total dose, overall time, and size (or number) of fractions. Shorthand versions, such as NSD or CRE, are not adequate without the three parameters actually used. The two papers published in the July issue”’ exhibited contrasting examples in this respect. In one paper’ it was not possible to deduce overall time, so that no check could be made on whether this correlated with tumour response as well as fraction size did. It was therefore not possible to test any hypothesis other than that assumed by the authors. Be-cause large shoulders were found on some of the earliest survival curves of malignant melonoma cells measured in oirro2~’ it was predicted that a few large fractions might be the best radiation treatment for malignant melanoma8.i6 and this treatment has become the fashion. There is certainly some supporting e~dence’“.6.7.‘0.“,‘3but these non-randomized series cannot constitute proof if they are only using the one approach. There is some opposing evidence, both of modest shoulders in cell survival curves in virro5.‘z*‘5and of good local control without the use of large doses per fraction9.i’ The fashion may be correct but we must not accept it too uncritically. In the study by Trott er uf. I4 local control was reported to depend more on overall time than on fraction size. Overall time is a plausible factor to consider in some treatments, depending on the proliferation rate of the clonogenic cells in the tumour, and it is possible that a correlation exists between large fractions and short overall times. If so, it will not be easy to distinguish, from the evidence so far analyzsed, whether it is the larger fraction size or the shorter overall time which is the dominant factor. It is important therefore not to “cut comers” in the description of clinical treatment schedules. It is of course desirable to keep an open mind about any optimum treatment schedules for malignant melanomas until definitive, prospectively randomized clinical trials are done, as suggested by Adam ef al.’

Radio/. 52: 417-418,

REBUTTAL To the Edifor: Thank you for allowing us to respond to Dr. Fowler’s comments.’ The hypothesis that complete response rate in melanoma is increased significantly by the use of higher individual fractions is confirmed by our series. The analysis of our data shows the coefficient for the fraction to be significantly different from zero; the coefficients for time and dose are not. We enclose for publication our table of responses showing overall time of treatment, total dose, and fraction size (Table I, overleaf). Using a logistic regression procedure with the dependent variable being response, we found the following (Table 2):

J.F. Fowtna D.Sc., PH.D. Gray Laboratory Mount Vernon Hospital Northwood Middlesex HA6 2RN England

Table 2. Variable Time Fraction size Total dose

1. Adam, J.S., Habeshaw,

2.

3. 4. 5. 6.

1979.

T., Kirk, J.: Response rate of malignant melanoma to large fraction irradiation. Br. J. R&of. 55: 605-607, 1982. Barranco, S.C., Romsdahl, M.M., Humphrey, R.M.: The radiation response of human malignant melanoma cells grown in virro. Cuncer Res. 31: 830-833, 1971. Dewey, D.L.: The radiosensitivity of melanoma cells in culture. Br. J. Radio/. 44: 816-817, 1971. Doss, L.L., Memula, N.: The radioresponsiveness of melanoma. In!. J. Rod. Oncol. Biol. Phys. 8: 1131-1134, 1982. Guichard, M., Goose, C., Malaise, E.P.: Survival curve of human melanoma cells in nude mice. J. N&l. Cancer Insr. 58~ 1665-1669, 1977. Halbermalz, H.J., Fischer, J.J.: Radiation therapy of malignant

Chi-square

P

1.58 6.25 0.01

0.2992 0.0124 0.9188

L.L. Doss, M.D. B.J.SKIPPER, PH.D. N. !bfEMULA,M.D.

The University of New Mexico Cancer Center Albuquerque, NM 87131

Fowler, J.F.: Radioresponsiveness of malignant melanoma to fractionated irradiation. Int. J. Radiat. Oncol. Biol. Phys. 10: 439, 1984. 439

440

Radiation Oncology ??Biology ??Physics

March 1984, Volume 10, Number 3

Table 1.

Case No.

Response No Yes

Overall time Days

Number of fractions IO 10

la lb

X X

15 12 33

11 I5 10

2at

X

2b 3a 3b 4

X

st

X

19

w

X

52

6b 7

X X

8

10 2 6 17 5

I

1

X X X

8t 9at 9b 10 lla Ilb 12 13 14 1Sa 15b 16 17a 17b 18 19a 19b 20a 20b 2Oc 21 22

X

I 17

I

X

17

X

2 16 24

X

X

X

X

:: 18 14 I 22 11 14 14 41 14 II 17 17 17 11 16

X

21

:: X X X X

X

X X

X X X :: X

w 24a 24b 24c

13 1

13 8 17

:: X

25t

X

21

26 2la 27b

X X X

25 36 36

I I IO

2

Fraction size

Total dose

400

4ooo

300 250 400 400 12500 800 300 320 500 400 238 270 500 600

I 5 5 2 10 14 10 18 18 10 7 IO 10 10 IO 30 10 IO IO 14 17 10 13 5 IO 10 6 14 10 8 8 II II

3 300 500 400 300 300 160 241 460 400 300 :E!l 250 250 400 400 400 270 250 400 400 500 300 400 400 350 300 188 500 400 400

3000 8750 4000 1250 800 3000 4200 6446 1350 500 2000 3500 1000 4000 4200 3000 2880 4338 4600 2800 3000 :Ez 2500 4ooo 4ooo 4ooo

3780 4250 4000 5200 5500 4000 2400 4900 4504 4400

4400

tcombinations. LETTER TO THE EDITOR To the Editor:I thoroughly agree with what Dr. Moss’ wrote and particularly with the following statements: “the health and life of our continuing practice of radiation therapy concerns our teaching of medical students”; “we cannot expezt significant or intelligent referral of patients from physicians who have never been properly informed of the indications or usefulness of radiation therapy” and “our difficulty in recruiting enthusiastic, aggressive, articulate students for residents”. 1 also agree with Moss’s remarks on the university teaching of radio-therapy in the U.S.A., but I must add that the American situation is still better than the Italian: even if-or perhaps just because-an examination in “Radiology” is compulsory in Italian universities. I feel that a description of the Italian situation, however brief and incomplete, may enlighten my American colleagues on the reasons for my pessimism. All the Italian medical faculties. nearly 30, have a “professore ordinario” of Radiology; some have two and one, at least, has three. In two faculties there is a “professore ordinario” of Radiotherapy; there are not “professori ordinari” of Radiobiology.

Recently another category, professori associati, was established and the first appointments are now being made. For radiological sciences, the number of professori associati will be about 60 for the next academic year. Over 20 of them will work in “Radiology”; another score will work in different areas but all referable to radiodiagnostics: radiological anatomy, experimental radiology (sic), neuroradiology, cardioradiology and pediatric radiology. One or two will work in interventional radiology and not more than five or six will work in radiotherapy. Finally about 10 professori associati will bear the title-simply for convenience, in my opinion-of radiobiology; however, they are nearly all doctors involved in clinical activities. The more widely used textbooks, written by Italians for university teaching, are entitled “radiology” and 70 to WA of the subject matter is radio-diagnostics, oRen at a good level; the rest is devoted to radioprotection, radiobiology and radiotherapy. Obviously the presence of one professore ordinario of radiotherapy in only two Italian medical faculties is not sufficient. Today I do not know of any professore ordinario in radiology who has made an