Inr J Rodrorion Oncok~~v Bioi t’h?\ Vol. 20. pp 905-907 Printed in the U S.A. All nghts reserved.
Copyright
0360.3016191 $3.00 + .OO 0 199 I Pergamon Press plc
0 Editorial THE OPTIMAL RADIATION DOSE PER FRACTION FOR THE TREATMENT OF MALIGNANT MELANOMAS KLAUS-RUDIGER Department
TROTT,
PROF.,
M.D.
of Radiation Biology, St Bartholomew’s Medical College, Charterhouse Square, London ECl, United Kingdom published. In an unpublished M.D. thesis written in Munich (Haider and Hummermehr, unpublished data, 1987) cu/p ratios of the Harding Passey and the B- 16 melanomas in vivo were determined using the TCD-50 assay and the regrowth delay assay after fractionated irradiation with fractional doses ranging from 2 Gy to 12 Gy. The derived ol/fl ratios varied between experiments, assays and melanoma types; the lowest value was 6 Gy, the highest value was 18 Gy, the mean of 5 separate experiments was 12 Gy. Neither the mean nor the variation of the IX/P ratios of these melanomas are different from those of other tumor types from the same laboratory. In conclusion, the argument that high doses per fraction have a better therapeutic effect on malignant melanomas is not supported by radiobiological data in vitro or in rodent melanomas in viva. It rests entirely on the retrospective analysis of clinical experience in palliative radiotherapy of metastatic melanoma. Some special features of these studies have to be considered before discussing the validity of these investigations. As, until recently, melanomas were regarded extremely radioresistant tumors, radiotherapists only saw very advanced cases often with multiple metastases in different sites requiring palliative radiotherapy, which usually was prescribed on a very individualized basis. In practically all reports patient numbers were small, size and site of metastases were varied, and they received treatment schedules which differed in overall time, dose per fraction and total dose, and follow-up was short due to the short overall survival of these advanced cases. This makes any stringent analysis of the results virtually impossible. The first retrospective studies to emphasize the importance of the dose per fraction were by Habermalz and Fisher (5), Hornsey (7), and Overgaard (11). Ten years ago, in an editorial in this journal, Habermalz (4) summarized their findings. There was an overall 38% (85/ 22 1) complete response rate of cutaneous, subcutaneous and lymph node melanoma metastases. Total dose was not a good predictor of response, but dose per fraction
The long-held belief that malignant melanomas are a particularly radioresistant type of cancer has been profoundly shattered by a large number of clinical reports published over the last 10 years. There is general agreement, now, that radiation doses commonly used in curative treatment, say of squamous cell carcinomas, lead to complete remission and even permanent local control in a large proportion of melanoma patients. However, there has been considerable disagreement on the optimal radiation dose per fraction for the treatment of malignant melanomas. In viva studies of the radiosensitivity of various melanoma cell lines of murine (3) hamster (1 S), and human origin ( 1, 10) (and many others) commonly yielded survival curves with particularly wide shoulders, suggesting that the perceived radioresistance of malignant melanomas might be due to the large amount of wasted dose in the shoulder region of the dose response curve which could be associated with a low cy/p ratio indicating a high fractionation sensitivity (6). This led to the recommendation to treat melanomas with few large fractional doses each well beyond the shoulder region of the survival curve. Yet, as more melanoma cell lines were studied in vitro, it became obvious that the large shoulder is not necessarily a characteristic feature of melanoma cells. Rofstad (13) reviewed cell survival curves of some 40 human melanoma cell lines and found an extrapolation number of 10 or more in only 14143 and an cu/fl ratio of 5 Gy or less in only 17/40. The extensive experimental research on the cellular radiobiology of malignant melanomas in vitro provided evidence for wide heterogeneity of cellular response characteristics which may, indeed, be wider than for some other types of cancer. The mean values of those cell survival curve parameters, however, which have been related to clinical response like Do, n, Q/P, SF2 are not systematically different between malignant melanomas and the vast majority of other cancers commonly treated by radiotherapy. No in vivo data on the fractionation sensitivity of malignant melanomas in experimental animals have been
Reprint requests to K. R. Trott, M.D.
Accepted for publication 905
3 January 199 1
906
I. J. Radiation
Oncology 0 Biology 0 Physics
looked better: the complete response rate was 35/ 1 10 only if the dose per fraction was less than 4 Gy/f but it was 50/l 11 with dose per fraction of 4 Gy or more (p < 0.05). The difference became bigger if partial responses were included: overall response rates were 54% with less than 4 Gy/f to rise to 85% with fractional doses over 4 Gy. These results were taken as evidence that malignant melanomas were special in that they respond better to large fractional doses than to conventional dose fractionation. Yet each ofthese and subsequent studies are flawed with a very heterogeneous distribution of tumor sizes (large tumors were more often treated with lower doses per fraction) and of total doses (most tumors were clearly underdosed with conventional fractionation, the maximum usually was 20 X 2.5 Gy), with short follow-up and small numbers of comparable cases. The largest retrospective study was performed by Overof 17 1 cases of gaard et a/. (12) on radiation treatment malignant melanomas metastatic to skin or lymph nodes. From their data, which span doses per fraction between 2 Gy and 9 Gy, they estimated a very low LY/~ratio of 2.5 Gy. However, close examination of their response data, which are presented in a scattergram of inverse total dose vs dose per fraction (their Fig. 2) reveals some typical problems. With low doses per fraction. the majority of patients received doses that would be regarded as too low for the control of any carcinoma: 12/23 patients received less than 50 Gy (with 2.5 Gy/f), and all those failed. But of the 9 patients who received 55-60 Gy (2.5 Gy/f). 5 achieved a complete response. The majority of patients (61 altogether) were treated with 5 Gy per fraction, yet no dose response could be established in this group: the complete response rate was 2/5 at about 25 Gy. 13/ 18 at about 40 Gy and 3/6 at about 60 Gy. There is another group of 32 patients treated with 3 doses of 9 Gy leading to 20 complete responses. Bentzen et a/. (2) reanalyzed an expanded sample of these melanomas and demonstrated that the absence of a dose response relationship in the biggest group of 85 patients treated with 5 Gy fractions was due to large heterogeneity of tumor size. By correcting for tumor size, a smooth S-shaped dose response curve described the response ofthe 85 melanomas well with a TCD5” of seven times 5 Gy. Submitting all 239 cases to a single direct analysis, Bentzen et al. (2) caiculated an a/p ratio of 0.57 Gy (with 95% confidence limits of - 1 Gy and +2.5 Gy). Whereas this study as well as some other, smaller studies stressed that due to extraordinary fractionation sensitivity (low cy/p ratio) melanomas should be treated with few high fractional doses. other studies demonstrated that with total doses of 55-60 Gy given in 2-2.5 Gy fractions, similar response rates can be achieved (9, 16). This controversy called for a randomized prospective clinical trial to resolve the issue. In the trial (RTOG 83-05) reported in this issue by Sause et al., the tumor response rates were identical for both schedules, whereas late normal skin damage was
April
I99
I.
Volume
20. Number
4
more severe in the high fraction size arm. The distribution of cases appears to be comparable between both arms of the trial, although stratification with regard to tumor size was crude. The real problem with this trial lies in the choice of doses that were compared. Whereas the one arm with 20 times 2.5 Gy gives a commonly used conventional treatment of proven effectiveness which yields response rates of about 50%. the high fractional dose schedule of4 times 8 Gy is consistent with an intermediate level of fractionation sensitivity. i.e., an cw/p ratio of 7 Gy. This is higher than proposed by Overgaard et a/. (I 2) or Bentzen ~1 a/. (2) but lower than for most other human cancers (14). If an cu//3 ratio of 2.5 Gy were correct, the isoeffective dose should have been 4 times 6.8 Gy; if, however. the cu/b ratio were 15 Gy. the isoeffective dose should have been four times 9 Gy. Given the shallow slope of the dose response curve for malignant melanomas (e.g., ref 2. figure 5b) with a change in the complete response rate of 1OYclifthe dose changes by 20% an increase or decrease of the given intermediate dose of 4 times 8 Gy by 12- 16% would go unrecognised in any trial. Therefore, an cy/p ratio for melanomas of 7 Gy or considerably less cannot be ruled out by the results of this study-nor can there be an (Y/P ratio of 15 Gy as has been estimated for squamous cell carcinomas. Yet it may look rather unlikely that 4 times 5.9 Gy (one quarter less, which would be isoeffective to twenty times 2.5 Gy with an (u/B ratio of 0.6 Gy) could be expected to produce the same response rates. In the dose response curves of Bentzen cf al. (2), the size corrected response rates should differ significantly between 4 times 8 Gy (as given and shown isoeffective with 20 times 2.5 Gy) and 4 times 6 Gy. Thus the trial opens up some interesting speculations. But the trial confers one solid tncssagc very clearly: that the risk of late complications increases ifthe dose per fraction is increased without decreasing total dose in line with an (u/p ratio of less than 5 Gy. For the clinical radiotherapist. the trial demonstrates that 20 times 2.5 Gy is a safe and effective treatment for malignant melanoma. It remains to be shown whether or not higher response rates can be achieved by further escalating the total dose with conventional fractionation. No improvement of results can, however, be expected by increasing the dose per fraction unless one accepts a considerably increased risk of late complications. The radiobiologist. on the other hand, has to realize that the question of the fractionation sensitivity of human malignant melanomas cannot be resolved in clinical trials; the clinical material simply is too heterogeneous. Yet if one assumes that the fractionation sensitivity of a tumor is a characteristic feature of its cells, appropriate fractionation studies in human melanoma xenografts similar to those performed on squamous cell carcinoma xenografts by Lindenberger et a/. (8) should provide us with a sound answer and might also display the degree of heterogeneity of fractionation sensitivity suggested by the in vitro single dose oc//3 ratios (13). Unless human xenograft investiga-
Optimal
radiation
tions of this kind provided firm evidence that the majority of human malignant melanomas have an inherent unusually low ar/p ratio, I would be very cautious and, in
dose 0 K.-R. TROTT
907
those cases where morbidity from late normal tissue injury might become a problem, I would not recommend treating malignant melanomas with large fraction sizes.
REFERENCES 1. Barranco,
2.
3. 4.
5.
6. 7.
8.
9.
S. C.; Rohmedahl, M. M.; Humphrey, R. M. The radiation response of human malignant melanoma cells grown in vitro. Cancer Res. 3 I :830-833; 197 1. Bentzen, S. M.; Overgaard, J.; Thames, H. D.; Overgaard, M.; Vejby Hansen, P.; von der Maase, H.; Meder, J. Clinical radiobiology of malignant melanoma. Radiother. Oncol. 16: 169-182; 1989. Dewey, D. L. The radiosensitivity of melanoma cells in culture. Br. J. Radiol. 44:816-817; 1971. Habermalz, H. J. Irradiation of malignant melanoma: experience in the past and present. Int. J. Radiat. Oncol. Biol. Phys. 7:131-133; 1981. Habermalz, H. J.; Fisher, J. J. Radiation therapy of malignant melanoma. Experience with high individual treatment doses. Cancer 38:2258-2262; 1976. Hornsey, S. The radiosensitivity of melanoma cells in culture. Br. J. Radiol. 45:158; 1972. Hornsey, S. The relationship between total dose, number of fractions and fraction size in the response of malignant melanoma in patients. Br. J. Radiol. 5 1:905-909; 1978. Lindenberger, J.; Hermeking, H.; Kummermehr, J.; Denekamp, J. Response of human xenografts to fractionated X-irradiation. Radiother. Oncol. 6: 15-27; 1986. Lobo, P. A.; Liebner, E. J.; Chao, J. J. H.; Kanji, A. M. Radiotherapy in the management of malignant melanoma. Int. J. Radiat. Oncol. Biol. Phys. 7:21-26; 1981.
10.
11.
12.
13. 14.
Malaise, E. P.; Weininger, J.; Joly, A. M.; Guichard, M. Measurements in vitro with three cell lines derived from melanomas. In: T. Alper Ed. Cell survival after low doses of radiation. London: Wiley & Sons; 1975:223-225. Overgaard, J. Radiation treatment of malignant melanoma. Int. J. Radiat. Oncol. Biol. Phys. 6:41-44; 1980. Overgaard, J.; Overgaard, M.; Vejby Hansen, P.; von der Maase, H. Some factors of importance in the radiation treatment of malignant melanoma. Radiother. Oncol. 5: 183-192; 1986. Rofstad, E. K. Radiation biology of malignant melanoma. Review article. Acta Radiol. Oncol. 25:1-10; 1986. Thames, H. D.; Bentzen, S. M.; Turesson, I.; Overgaard, M.; van den Bogaert, W. Fractionation parameters for human tissues and tumors. In: G. Steel Ed. The Radiobiology of Human Cells and Tissues. London: Taylor and Francis; 1989:701-710.
15. Trott, K. R.; von Lieven, H.; Kummermehr, J.; Skopal, D.; Lukacs, S.; Braun-Falco, 0. The radiosensitivity of malignant melanomas part I: experimental studies. Int. J. Radiat. Oncol. Biol. Phys. 7:9-13; 1981. 16. Trott, K. R.; von Lieven, H.; Kummermehr, J.; Skopal, D.; Lukacs, S.; Braun-Falco, 0.; Kellerer, A. M. The radiosensitivity of malignant melanomas part II: clinical studies. Int. J. Radiat. Oncol. Biol. Phys. 7: 15-20; 198 I.
Copyright
0360.3016191 $3.00 + .OO 0 199 I Pergamon Press plc
0 Editorial THE OPTIMAL RADIATION DOSE PER FRACTION FOR THE TREATMENT OF MALIGNANT MELANOMAS KLAUS-RUDIGER Department
TROTT,
PROF.,
M.D.
of Radiation Biology, St Bartholomew’s Medical College, Charterhouse Square, London ECl, United Kingdom published. In an unpublished M.D. thesis written in Munich (Haider and Hummermehr, unpublished data, 1987) cu/p ratios of the Harding Passey and the B- 16 melanomas in vivo were determined using the TCD-50 assay and the regrowth delay assay after fractionated irradiation with fractional doses ranging from 2 Gy to 12 Gy. The derived ol/fl ratios varied between experiments, assays and melanoma types; the lowest value was 6 Gy, the highest value was 18 Gy, the mean of 5 separate experiments was 12 Gy. Neither the mean nor the variation of the IX/P ratios of these melanomas are different from those of other tumor types from the same laboratory. In conclusion, the argument that high doses per fraction have a better therapeutic effect on malignant melanomas is not supported by radiobiological data in vitro or in rodent melanomas in viva. It rests entirely on the retrospective analysis of clinical experience in palliative radiotherapy of metastatic melanoma. Some special features of these studies have to be considered before discussing the validity of these investigations. As, until recently, melanomas were regarded extremely radioresistant tumors, radiotherapists only saw very advanced cases often with multiple metastases in different sites requiring palliative radiotherapy, which usually was prescribed on a very individualized basis. In practically all reports patient numbers were small, size and site of metastases were varied, and they received treatment schedules which differed in overall time, dose per fraction and total dose, and follow-up was short due to the short overall survival of these advanced cases. This makes any stringent analysis of the results virtually impossible. The first retrospective studies to emphasize the importance of the dose per fraction were by Habermalz and Fisher (5), Hornsey (7), and Overgaard (11). Ten years ago, in an editorial in this journal, Habermalz (4) summarized their findings. There was an overall 38% (85/ 22 1) complete response rate of cutaneous, subcutaneous and lymph node melanoma metastases. Total dose was not a good predictor of response, but dose per fraction
The long-held belief that malignant melanomas are a particularly radioresistant type of cancer has been profoundly shattered by a large number of clinical reports published over the last 10 years. There is general agreement, now, that radiation doses commonly used in curative treatment, say of squamous cell carcinomas, lead to complete remission and even permanent local control in a large proportion of melanoma patients. However, there has been considerable disagreement on the optimal radiation dose per fraction for the treatment of malignant melanomas. In viva studies of the radiosensitivity of various melanoma cell lines of murine (3) hamster (1 S), and human origin ( 1, 10) (and many others) commonly yielded survival curves with particularly wide shoulders, suggesting that the perceived radioresistance of malignant melanomas might be due to the large amount of wasted dose in the shoulder region of the dose response curve which could be associated with a low cy/p ratio indicating a high fractionation sensitivity (6). This led to the recommendation to treat melanomas with few large fractional doses each well beyond the shoulder region of the survival curve. Yet, as more melanoma cell lines were studied in vitro, it became obvious that the large shoulder is not necessarily a characteristic feature of melanoma cells. Rofstad (13) reviewed cell survival curves of some 40 human melanoma cell lines and found an extrapolation number of 10 or more in only 14143 and an cu/fl ratio of 5 Gy or less in only 17/40. The extensive experimental research on the cellular radiobiology of malignant melanomas in vitro provided evidence for wide heterogeneity of cellular response characteristics which may, indeed, be wider than for some other types of cancer. The mean values of those cell survival curve parameters, however, which have been related to clinical response like Do, n, Q/P, SF2 are not systematically different between malignant melanomas and the vast majority of other cancers commonly treated by radiotherapy. No in vivo data on the fractionation sensitivity of malignant melanomas in experimental animals have been
Reprint requests to K. R. Trott, M.D.
Accepted for publication 905
3 January 199 1
906
I. J. Radiation
Oncology 0 Biology 0 Physics
looked better: the complete response rate was 35/ 1 10 only if the dose per fraction was less than 4 Gy/f but it was 50/l 11 with dose per fraction of 4 Gy or more (p < 0.05). The difference became bigger if partial responses were included: overall response rates were 54% with less than 4 Gy/f to rise to 85% with fractional doses over 4 Gy. These results were taken as evidence that malignant melanomas were special in that they respond better to large fractional doses than to conventional dose fractionation. Yet each ofthese and subsequent studies are flawed with a very heterogeneous distribution of tumor sizes (large tumors were more often treated with lower doses per fraction) and of total doses (most tumors were clearly underdosed with conventional fractionation, the maximum usually was 20 X 2.5 Gy), with short follow-up and small numbers of comparable cases. The largest retrospective study was performed by Overof 17 1 cases of gaard et a/. (12) on radiation treatment malignant melanomas metastatic to skin or lymph nodes. From their data, which span doses per fraction between 2 Gy and 9 Gy, they estimated a very low LY/~ratio of 2.5 Gy. However, close examination of their response data, which are presented in a scattergram of inverse total dose vs dose per fraction (their Fig. 2) reveals some typical problems. With low doses per fraction. the majority of patients received doses that would be regarded as too low for the control of any carcinoma: 12/23 patients received less than 50 Gy (with 2.5 Gy/f), and all those failed. But of the 9 patients who received 55-60 Gy (2.5 Gy/f). 5 achieved a complete response. The majority of patients (61 altogether) were treated with 5 Gy per fraction, yet no dose response could be established in this group: the complete response rate was 2/5 at about 25 Gy. 13/ 18 at about 40 Gy and 3/6 at about 60 Gy. There is another group of 32 patients treated with 3 doses of 9 Gy leading to 20 complete responses. Bentzen et a/. (2) reanalyzed an expanded sample of these melanomas and demonstrated that the absence of a dose response relationship in the biggest group of 85 patients treated with 5 Gy fractions was due to large heterogeneity of tumor size. By correcting for tumor size, a smooth S-shaped dose response curve described the response ofthe 85 melanomas well with a TCD5” of seven times 5 Gy. Submitting all 239 cases to a single direct analysis, Bentzen et al. (2) caiculated an a/p ratio of 0.57 Gy (with 95% confidence limits of - 1 Gy and +2.5 Gy). Whereas this study as well as some other, smaller studies stressed that due to extraordinary fractionation sensitivity (low cy/p ratio) melanomas should be treated with few high fractional doses. other studies demonstrated that with total doses of 55-60 Gy given in 2-2.5 Gy fractions, similar response rates can be achieved (9, 16). This controversy called for a randomized prospective clinical trial to resolve the issue. In the trial (RTOG 83-05) reported in this issue by Sause et al., the tumor response rates were identical for both schedules, whereas late normal skin damage was
April
I99
I.
Volume
20. Number
4
more severe in the high fraction size arm. The distribution of cases appears to be comparable between both arms of the trial, although stratification with regard to tumor size was crude. The real problem with this trial lies in the choice of doses that were compared. Whereas the one arm with 20 times 2.5 Gy gives a commonly used conventional treatment of proven effectiveness which yields response rates of about 50%. the high fractional dose schedule of4 times 8 Gy is consistent with an intermediate level of fractionation sensitivity. i.e., an cw/p ratio of 7 Gy. This is higher than proposed by Overgaard et a/. (I 2) or Bentzen ~1 a/. (2) but lower than for most other human cancers (14). If an cu//3 ratio of 2.5 Gy were correct, the isoeffective dose should have been 4 times 6.8 Gy; if, however. the cu/b ratio were 15 Gy. the isoeffective dose should have been four times 9 Gy. Given the shallow slope of the dose response curve for malignant melanomas (e.g., ref 2. figure 5b) with a change in the complete response rate of 1OYclifthe dose changes by 20% an increase or decrease of the given intermediate dose of 4 times 8 Gy by 12- 16% would go unrecognised in any trial. Therefore, an cy/p ratio for melanomas of 7 Gy or considerably less cannot be ruled out by the results of this study-nor can there be an (Y/P ratio of 15 Gy as has been estimated for squamous cell carcinomas. Yet it may look rather unlikely that 4 times 5.9 Gy (one quarter less, which would be isoeffective to twenty times 2.5 Gy with an (u/B ratio of 0.6 Gy) could be expected to produce the same response rates. In the dose response curves of Bentzen cf al. (2), the size corrected response rates should differ significantly between 4 times 8 Gy (as given and shown isoeffective with 20 times 2.5 Gy) and 4 times 6 Gy. Thus the trial opens up some interesting speculations. But the trial confers one solid tncssagc very clearly: that the risk of late complications increases ifthe dose per fraction is increased without decreasing total dose in line with an (u/p ratio of less than 5 Gy. For the clinical radiotherapist. the trial demonstrates that 20 times 2.5 Gy is a safe and effective treatment for malignant melanoma. It remains to be shown whether or not higher response rates can be achieved by further escalating the total dose with conventional fractionation. No improvement of results can, however, be expected by increasing the dose per fraction unless one accepts a considerably increased risk of late complications. The radiobiologist. on the other hand, has to realize that the question of the fractionation sensitivity of human malignant melanomas cannot be resolved in clinical trials; the clinical material simply is too heterogeneous. Yet if one assumes that the fractionation sensitivity of a tumor is a characteristic feature of its cells, appropriate fractionation studies in human melanoma xenografts similar to those performed on squamous cell carcinoma xenografts by Lindenberger et a/. (8) should provide us with a sound answer and might also display the degree of heterogeneity of fractionation sensitivity suggested by the in vitro single dose oc//3 ratios (13). Unless human xenograft investiga-
Optimal
radiation
tions of this kind provided firm evidence that the majority of human malignant melanomas have an inherent unusually low ar/p ratio, I would be very cautious and, in
dose 0 K.-R. TROTT
907
those cases where morbidity from late normal tissue injury might become a problem, I would not recommend treating malignant melanomas with large fraction sizes.
REFERENCES 1. Barranco,
2.
3. 4.
5.
6. 7.
8.
9.
S. C.; Rohmedahl, M. M.; Humphrey, R. M. The radiation response of human malignant melanoma cells grown in vitro. Cancer Res. 3 I :830-833; 197 1. Bentzen, S. M.; Overgaard, J.; Thames, H. D.; Overgaard, M.; Vejby Hansen, P.; von der Maase, H.; Meder, J. Clinical radiobiology of malignant melanoma. Radiother. Oncol. 16: 169-182; 1989. Dewey, D. L. The radiosensitivity of melanoma cells in culture. Br. J. Radiol. 44:816-817; 1971. Habermalz, H. J. Irradiation of malignant melanoma: experience in the past and present. Int. J. Radiat. Oncol. Biol. Phys. 7:131-133; 1981. Habermalz, H. J.; Fisher, J. J. Radiation therapy of malignant melanoma. Experience with high individual treatment doses. Cancer 38:2258-2262; 1976. Hornsey, S. The radiosensitivity of melanoma cells in culture. Br. J. Radiol. 45:158; 1972. Hornsey, S. The relationship between total dose, number of fractions and fraction size in the response of malignant melanoma in patients. Br. J. Radiol. 5 1:905-909; 1978. Lindenberger, J.; Hermeking, H.; Kummermehr, J.; Denekamp, J. Response of human xenografts to fractionated X-irradiation. Radiother. Oncol. 6: 15-27; 1986. Lobo, P. A.; Liebner, E. J.; Chao, J. J. H.; Kanji, A. M. Radiotherapy in the management of malignant melanoma. Int. J. Radiat. Oncol. Biol. Phys. 7:21-26; 1981.
10.
11.
12.
13. 14.
Malaise, E. P.; Weininger, J.; Joly, A. M.; Guichard, M. Measurements in vitro with three cell lines derived from melanomas. In: T. Alper Ed. Cell survival after low doses of radiation. London: Wiley & Sons; 1975:223-225. Overgaard, J. Radiation treatment of malignant melanoma. Int. J. Radiat. Oncol. Biol. Phys. 6:41-44; 1980. Overgaard, J.; Overgaard, M.; Vejby Hansen, P.; von der Maase, H. Some factors of importance in the radiation treatment of malignant melanoma. Radiother. Oncol. 5: 183-192; 1986. Rofstad, E. K. Radiation biology of malignant melanoma. Review article. Acta Radiol. Oncol. 25:1-10; 1986. Thames, H. D.; Bentzen, S. M.; Turesson, I.; Overgaard, M.; van den Bogaert, W. Fractionation parameters for human tissues and tumors. In: G. Steel Ed. The Radiobiology of Human Cells and Tissues. London: Taylor and Francis; 1989:701-710.
15. Trott, K. R.; von Lieven, H.; Kummermehr, J.; Skopal, D.; Lukacs, S.; Braun-Falco, 0. The radiosensitivity of malignant melanomas part I: experimental studies. Int. J. Radiat. Oncol. Biol. Phys. 7:9-13; 1981. 16. Trott, K. R.; von Lieven, H.; Kummermehr, J.; Skopal, D.; Lukacs, S.; Braun-Falco, 0.; Kellerer, A. M. The radiosensitivity of malignant melanomas part II: clinical studies. Int. J. Radiat. Oncol. Biol. Phys. 7: 15-20; 198 I.
