- Email: [email protected]
Radiation therapy of malignant melanoma
Dermatol Clin 20 (2002) 713 – 716
Radiation therapy of malignant melanoma Jay S. Cooper, MD Radiation Oncology, New York University Medical Center, 560 First Avenue, New York, NY 10016, USA
For many years, malignant melanomas were considered unresponsive to radiation therapy. Although modern data clearly show this not to be true, irradiated melanomas often regress more slowly than do other types of tumors, leading to an incorrect assessment of the effects of radiation if measured too soon.
Palliative therapy of macroscopic disease The benefit of radiation therapy for malignant melanoma is most easily observed in the palliative management of metastatic lesions, both because relatively little shrinkage of the tumor is needed to provide symptomatic relief (and is relatively easy to detect) and because such treatment is the most common use of radiation therapy for malignant melanoma. Approximately one in four treated patients experience excellent relief (complete response); approximately one in three experience partial relief; and the rest do not benefit clinically (little or no relief). Placed in the perspective of other uses of radiation therapy, the subjective response of irradiated malignant melanomas that have metastasized, for example, to the brain or bone is virtually identical to the response observed following treatment of other types of disseminated neoplasms that are generally regarded as radiosensitive [1 – 3]. Precisely why some tumors respond well, whereas others do not, has intrigued many scientists and has led to considerable debate about the existence of a biologic factor that potentially could be exploited to increase the likelihood of response. The degree of damage caused by radiation is a complex function of the way that radiation is deliv-
E-mail address: [email protected]
ered; it is not merely a reflection of the total dose, but is influenced by the amount in each fraction and the time interval between fractions. Moreover, different tissues, both normal and malignant, have their varying inherent responses to differences in patterns of dose delivery. Approximately 25 years ago, investigators observed that some animal and human melanomas grown in vitro could withstand (better than other types of tumors), and subsequently repair (if given sufficient time), the amount of damage produced by one typical (conventional) single fraction of radiation therapy [4,5]. Consequently, some hypothesized that repackaged radiation therapy, delivering a particularly high-dose-per-fraction, might overcome the inherent repair capacity of melanomas and lead to their control. Three independent clinical series [6 – 8] seemed to confirm this hypothesis. These series reported a direct correlation of response with the size of the dose delivered in each fraction of treatment and, in contrast to the effect typically observed with other types of tumors, no correlation with the total dose delivered. Other investigators [9 – 11], however, repported that conventionally irradiated malignant melanomas responded equally well or that highdose-per-fraction techniques were superior to conventional techniques for the production of short-term tumor responses, but inferior to conventional techniques for the production of long-term local control. Between 1983 and 1988, the Radiation Therapy Oncology Group designed and conducted a prospective randomized trial [12] comparing 800 cGy delivered four times at weekly intervals (high-doseper-fraction therapy) with 250 cGy daily for 20 fractions over 26 to 28 days (conventional-doseper-fraction therapy) for malignant melanoma. A mathematic model [13] predicts that these two very different-appearing radiation therapy regimens produce approximately equivalent damage in normal
0733-8635/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 7 3 3 - 8 6 3 5 ( 0 2 ) 0 0 0 2 9 - 3
714
J.S. Cooper / Dermatol Clin 20 (2002) 713–716
tissues. The results showed no difference in response rates between tumors treated with high-dose-per-fraction techniques and those treated with conventional techniques. There was a 24.2% complete response rate (plus a 35.5% partial response rate) for lesions treated with high-dose-per-fraction radiation versus a 23.4% complete response (plus a 34.4% partial response rate) following conventional radiation. Although this trial failed to confirm the hypothesis that justified it, this trial provides irrefutable evidence that malignant melanomas do respond to radiation therapy and clearly demonstrates that complete response can be expected approximately 25% of the time.
Potentially curative radiation therapy of macroscopic disease Having established that malignant melanomas are not radioresistant, it is appropriate to ask if there are any that radiation therapy can eradicate. At least in theory, the thinnest tumors (which likely contain the fewest number of malignant cells), the noninvasive lentigo malignas, should be the best candidates to demonstrate the potential of curative-intent radiation therapy. Several physicians have reported 95% to 100% control of lentigo malignas by using extremely large doses of relatively nonpenetrating radiation [14 – 16]. Such cure may be obtained by indiscriminate desquamation, however, rather than by selective killing of the tumor cells. More convincing evidence comes from Harwood and Cummings [17] who treated both lentigo malignas and lentigo maligna melanomas with x-ray beams ranging from 100 to 280 kV (approximately the voltage used for diagnostic-quality radiographs and slightly higher) and doses ranging from 3250 cGy in five fractions over 1 week (for lesions less than 2 cm in diameter) to 4500 cGy in 10 fractions over 2 weeks (for lesions 2 to 5 cm in diameter). With follow-up ranging from 1.5 to 13 years, 15 of 17 lentigo malignas and 21 of 23 lentigo maligna melanomas were controlled by a single course of radiation therapy. Others have reported similar results. Christie and Tiver [18] treated seven lentigo malignas with 100-kV therapy and relatively conventional doses (4400 to 5750 cGy in 11 to 23 fractions over 15 to 34 days) and observed local control in all patients with follow-up ranging from 8 to 37 months. Panizzon [19] treated 104 lentigo malignas with superficial radiation therapy and reported a 100% cure rate after 7.5 years of follow-up; similarly, 18 lentigo maligna melanomas exhibited an 89% cure rate. Tsang et al [20] observed a 5-year actuarial tumor control rate of 86% in 36
elderly patients treated for lentigo malignas that were characterized as ‘‘larger lesions located in the head and neck area.’’ Such therapy, however, has not gained wide acceptance and questions remain about the potentially curative role of radiation therapy in the setting of small, visibly detectable disease.
Potentially curative treatment of microscopic disease Moving down one order of magnitude, radiation therapy has somewhat more clearly been shown to have beneficial effects when applied to microscopicsize disease. It has long been accepted that surgical resection of all gross evidence of one or more intracerebral metastases typically leaves behind small amounts of tumor that are subclinical (ie, too small to be detected by current clinical means). For such patients, radiation therapy clearly has been shown to kill at least some of the remaining tumor cells. Skibber et al [21] reported 34 patients who had clinically solitary, intracerebral, metastatic malignant melanomas that were macroscopically completely excised. Twelve were treated by surgery alone and 22 were treated by surgery and elective postoperative irradiation. Intracerebral recurrence decreased from 75% (9 of 12) in patients who did not receive radiation therapy to 23% (5 of 22) in patients who did. This, in turn, influenced survival; median survival was tripled in the group receiving radiation therapy from 6 months to 18 months ( P = .002). Similarly, Hagen et al [22] reported the outcome following resection alone of clinically single intracerebral metastatic malignant melanomas (16 patients) or in combination with postoperative radiation therapy (19 patients). The median time to recurrence of central nervous system disease was extended from 6 months following surgery alone to 27 months by the addition of radiation therapy, and 85% of patients treated by surgery alone died because of their central nervous system disease versus only 24% of patients who also received radiation therapy. Most recently, elective irradiation has been considered in other situations wherein a high-risk for recurrence remains (eg, following resection of aggressive primary tumors, resection of locally recurrent disease, or resection of metastases in regional lymph nodes) despite expertly done surgery. For example, O’Brien et al [23] reported a 24% local recurrence rate following surgery of cutaneous melanomas 4-mm or more thick and a 34% recurrence rate following a therapeutic neck dissection [24]. Byers [25] reported a 46% regional failure rate following modified cervical
J.S. Cooper / Dermatol Clin 20 (2002) 713–716
neck dissection. If only a solitary node less than 3 cm was involved the local recurrence rate was 22%. If there were either multiple involved nodes or extracapsular extension present, however, the local-regional recurrence rate was 50%. Lee et al [26] reported that resection of histologically involved lymph nodes resulted in a 30% nodal basin recurrence rate. Furthermore, some factors were associated with particularly high risks of recurrence: extracapsular extension of disease (63%); multiple nodes invaded by tumor (46% for 4 to 10 nodes and 63% for more than 10 nodes); and cervical lymph node involvement (43%). It is now becoming clear that the risk of recurrence in such situations can be reduced substantially by radiation therapy. The largest series of patients treated electively because of high-risk malignant melanomas comes from the MD Anderson Cancer Center in Houston, Texas [27,28]. Their definition of high risk included malignant melanomas at least 1.5 mm thick (79 patients); clinically detectable regional nodal disease (32 patients); and recurrent previously resected disease (63 patients). Treatment was designed to deliver 6 Gy per fraction for a total of five fractions over 2.5 weeks. Although this high-dose-per-fraction technique was designed to exploit the inherent radiobiologic behavior of some melanomas (as discussed previously), it has the additional convenience of relatively few treatments that some patients who are ambivalent about taking an elective therapy find appealing. After a median follow-up of 35 months only 6 patients experienced isolated local-regional recurrence, 9 patients experienced both local-regional and distant recurrence, and 58 patients developed solely distant metastatic disease. Overall, the 5-year actuarial local-regional control rate was 88%, which far exceeded the historic experience at the same institution. As additional evidence of this principle, O’Brien et al [29] reported a nonrandomized comparison of patients who had high-risk malignant melanomas that were treated with or without elective radiation therapy in Sidney, Australia. Forty-five high-risk patients (65% having at least two involved lymph nodes and 48% having extracapsular extension of disease) received six fractions of 5.5 Gy each. Local-regional failure occurred in only 6.5% and all failures were evident within 1 year of treatment. Unfortunately, only 40% survived for at least 5 years. In comparison, 107 other patients (40% having two or more involved nodes and 19% having extracapsular extension [ie, a relatively more favorable group]) received no radiation therapy and experienced an 18.7% local-regional failure rate. This group had a 35% 5-year survival rate. Corry et al [30] reported the outcome of 42 patients who received more conventionally fractionated
715
elective radiation therapy for high-risk malignant melanomas in Melbourne, Australia, most often 50 to 60 Gy delivered in 2-Gy-per-day fractions. With 5 years of follow-up, the first site of treatment failure was nodal recurrence in 20% and an additional 2% experienced simultaneous nodal and distant recurrence of disease. Sadly, the overall 5-year survival rate was only 33% because 52% of these high-risk patients developed distant metastases, despite remaining free of local-regional disease. The author recently reported [31] his experience in using high-dose-per-fraction elective radiation therapy for high-risk malignant melanomas. Despite the aggressive nature of the tumors treated (multiple involved lymph nodes [21 patients]; close or microscopically involved surgical margins [9 patients]; extracapsular extension [6 patients]; previously resected, recurrent disease [3 patients]; or primary tumors more than 4 mm thick [4 patients]) the patients were provided with an 84% local-regional control rate at 5 years. Unfortunately, the patients (like those of Ang et al [27,28], O’Brien et al [23,24,29], and Corry et al [30]) failed to have a commensurate improvement in survival, only 39% living 5 years, suggesting that distant metastases are shed from the high-risk sites before they are irradiated. Perhaps most remarkable is the similarity in outcome in these four worldwide reports. The localregional recurrence rates, the distant metastasis rates, and the 5-year survival rates fall within a 10% range in all reports, firmly suggesting that the reported observations are universally applicable. When the results of elective radiation therapy are grouped with the results of the randomized Radiation Therapy Oncology Group study, it becomes evident that (1) malignant melanomas are not impervious to radiation therapy, and that (2) radiation therapy can be beneficial, particularly when only small volumes of disease need to be treated. Clearly, more effective systemic agents are needed to improve overall survival rates. It is likely that when systemic therapy improves, however, the importance of local-regional control may increase and the value of elective radiation therapy will become more evident. Until then, radiation therapy has a relatively small, but potentially important, role to play in the management of aggressive malignant melanomas.
References [1] Carella RJ, Gelber R, Hendrickson F, et al. Value of radiation therapy in the management of patient with cerebral metastases from malignant melanoma;
716
[2]
[3]
[4]
[5] [6] [7]
[8] [9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
J.S. Cooper / Dermatol Clin 20 (2002) 713–716 R.T.O.G. Brain Metastases Study I & II. Cancer 1980; 45:679 – 83. Hilaris BS, Raben M, Calabrese AS, et al. Value of radiation therapy for distant metastases from malignant melanoma. Cancer 1963;16:765 – 73. Katz HR. The results of different fractionation schemes in the palliative irradiation of metastatic melanoma. Int J Radiat Oncol Biol Phys 1981;7:907 – 11. Barranco SC, Romsdahl MM, Humphrey RM. The radiation response of human malignant melanoma cells grown in vitro. Cancer Res 1971;31:830 – 3. Dewey DL. The radiosensitivity of melanoma cells in culture. Br J Radiol 1971;44:816 – 7. Habermalz HJ, Fischer JJ. Radiation therapy of malignant melanoma. Cancer 1976;38:2258 – 62. Hornsey S. The relationship between total dose, number of fractions and fraction size in the response of malignant melanoma in patients. Br J Radiol 1978; 51:905 – 9. Overgaard J. Radiation treatment of malignant melanoma. Int J Radiat Oncol Biol Phys 1980;6:41 – 4. Lobo PA, Liebner EJ, Chao JJ, et al. Radiotherapy in the management of malignant melanoma. Int J Radiat Oncol Biol Phys 1981;7:21 – 6. Rounsaville MC, Cantril ST, Fontanesi J, et al. Radiotherapy in the management of cutaneous melanoma: effect of time, dose and fractionation. Front Radiat Ther Oncol 1998;22:62 – 78. Trott KR, von Lieden H, Kummermehr J, et al. The radiosentivity of malignant melanomas. Part 2: Clinical studies. Int J Radiat Oncol Biol Phys 1981;7: 15 – 20. Sause WT, Cooper JS, Rush S, et al. Fraction size in external beam radiation therapy in the treatment of melanoma. Int J Radiat Oncol Biol Phys 1991;20:429 – 32. Orton CG, Ellis F. A simplification in the use of the NSD concept in practical radiotherapy. Br J Radiol 1973;46:529 – 37. Arma-Szlachcic M, Ott F, Storck H. Zur strahlentherapie der melanotischen pra¨-cancerosen. Hautartz 1970; 21:505 – 8. Braun-Falco O, Lukacs S, Schoefinius HH. Zur behandlung der melanosis circumscripta praecancerosa Dubreuilh. Hautartz 1975;26:207 – 10. De Groot WP. Provisional results of treatment of the melanose pre´cance´reuse circonscrite Dubreuilh by Bucky-rays. Dermatologica 1968;136:429 – 31. Harwood AR, Cummings BJ. Radiotherapy for malignant melanoma: a re-appraisal. Cancer Treat Rev 1981;8:271 – 82.
[18] Christie DRH, Tiver KW. Radiotherapy for melanotic freckles. Australas Radiol 1996;40:331 – 3. [19] Panizzon RG. Die roentgenweichstrahlentherapie als alternative bei alteren patienten. In: Burg G, Hartmann AA, Konz B, editors. Onkologische dermatologie: fortschritte der dermatologischen und onkologischen dermatologie, BAND 7. Heidelberg: Springer-Verlag; 1992. p. 263 – 7. [20] Tsang RW, Liu F-F, Wells W, et al. Lentigo maligna of the head and neck: results of treatment by radiotherapy. Arch Dermatol 1994;130:1008 – 12. [21] Skibber JM, Soong S, Austin L, et al. Cranial irradiation after surgical excision of brain metastases in melanoma patients. Ann Surg Oncol 1996;3:118 – 23. [22] Hagen NA, Cirrincione C, Thaler HT, et al. The role of radiation therapy following resection of single brain metastases from melanoma. Neurology 1990; 40:158 – 60. [23] O’Brien CJ, Coates AS, Petersen-Schaefer K, et al. Experience with 998 cutaneous melanomas of the head and neck over 30 years. Am J Surg 1991;162:310 – 4. [24] O’Brien CJ, Gianoutsos MP, Morgan MJ. Neck dissection for cutaneous malignant melanoma. World J Surg 1992;16:222 – 6. [25] Byers RM. The role of modified neck dissection in the treatment of cutaneous melanoma of the head and neck. Arch Surg 1986;121:1338 – 41. [26] Lee RJ, Gibbs JF, Proulx GM, et al. Nodal basin recurrence following lymph node dissection for melanoma: implications for adjuvant radiotherapy. Int J Radiat Oncol Biol Phys 2000;46:467 – 74. [27] Ang KK, Byers RM, Peters LJ, et al. Regional radiotherapy as adjuvant treatment for head and neck malignant melanoma: preliminary results. Arch Otolaryngol Head Neck Surg 1990;116:169 – 72. [28] Ang KK, Peters LJ, Weber RS, et al. Postoperative radiotherapy for cutaneous melanoma of the head and neck region. Int J Radiat Oncol Biol Phys 1994; 30:795 – 8. [29] O’Brien CJ, Petersen-Schaefer K, Stevens GN, et al. Adjuvant radiotherapy following neck dissection and parotidectomy for metastatic malignant melanoma. Head Neck 1997;19:589 – 94. [30] Corry J, Smith JG, Bishop M, et al. Nodal radiation therapy for metastatic melanoma. Int J Radiat Oncol Biol Phys 1999;44:1065 – 9. [31] Cooper JS, Chang WS, Oratz R, et al. Elective radiation therapy for high-risk malignant melanomas. Cancer J 2001;7:498 – 502.
Radiation therapy of malignant melanoma Jay S. Cooper, MD Radiation Oncology, New York University Medical Center, 560 First Avenue, New York, NY 10016, USA
For many years, malignant melanomas were considered unresponsive to radiation therapy. Although modern data clearly show this not to be true, irradiated melanomas often regress more slowly than do other types of tumors, leading to an incorrect assessment of the effects of radiation if measured too soon.
Palliative therapy of macroscopic disease The benefit of radiation therapy for malignant melanoma is most easily observed in the palliative management of metastatic lesions, both because relatively little shrinkage of the tumor is needed to provide symptomatic relief (and is relatively easy to detect) and because such treatment is the most common use of radiation therapy for malignant melanoma. Approximately one in four treated patients experience excellent relief (complete response); approximately one in three experience partial relief; and the rest do not benefit clinically (little or no relief). Placed in the perspective of other uses of radiation therapy, the subjective response of irradiated malignant melanomas that have metastasized, for example, to the brain or bone is virtually identical to the response observed following treatment of other types of disseminated neoplasms that are generally regarded as radiosensitive [1 – 3]. Precisely why some tumors respond well, whereas others do not, has intrigued many scientists and has led to considerable debate about the existence of a biologic factor that potentially could be exploited to increase the likelihood of response. The degree of damage caused by radiation is a complex function of the way that radiation is deliv-
E-mail address: [email protected]
ered; it is not merely a reflection of the total dose, but is influenced by the amount in each fraction and the time interval between fractions. Moreover, different tissues, both normal and malignant, have their varying inherent responses to differences in patterns of dose delivery. Approximately 25 years ago, investigators observed that some animal and human melanomas grown in vitro could withstand (better than other types of tumors), and subsequently repair (if given sufficient time), the amount of damage produced by one typical (conventional) single fraction of radiation therapy [4,5]. Consequently, some hypothesized that repackaged radiation therapy, delivering a particularly high-dose-per-fraction, might overcome the inherent repair capacity of melanomas and lead to their control. Three independent clinical series [6 – 8] seemed to confirm this hypothesis. These series reported a direct correlation of response with the size of the dose delivered in each fraction of treatment and, in contrast to the effect typically observed with other types of tumors, no correlation with the total dose delivered. Other investigators [9 – 11], however, repported that conventionally irradiated malignant melanomas responded equally well or that highdose-per-fraction techniques were superior to conventional techniques for the production of short-term tumor responses, but inferior to conventional techniques for the production of long-term local control. Between 1983 and 1988, the Radiation Therapy Oncology Group designed and conducted a prospective randomized trial [12] comparing 800 cGy delivered four times at weekly intervals (high-doseper-fraction therapy) with 250 cGy daily for 20 fractions over 26 to 28 days (conventional-doseper-fraction therapy) for malignant melanoma. A mathematic model [13] predicts that these two very different-appearing radiation therapy regimens produce approximately equivalent damage in normal
0733-8635/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 7 3 3 - 8 6 3 5 ( 0 2 ) 0 0 0 2 9 - 3
714
J.S. Cooper / Dermatol Clin 20 (2002) 713–716
tissues. The results showed no difference in response rates between tumors treated with high-dose-per-fraction techniques and those treated with conventional techniques. There was a 24.2% complete response rate (plus a 35.5% partial response rate) for lesions treated with high-dose-per-fraction radiation versus a 23.4% complete response (plus a 34.4% partial response rate) following conventional radiation. Although this trial failed to confirm the hypothesis that justified it, this trial provides irrefutable evidence that malignant melanomas do respond to radiation therapy and clearly demonstrates that complete response can be expected approximately 25% of the time.
Potentially curative radiation therapy of macroscopic disease Having established that malignant melanomas are not radioresistant, it is appropriate to ask if there are any that radiation therapy can eradicate. At least in theory, the thinnest tumors (which likely contain the fewest number of malignant cells), the noninvasive lentigo malignas, should be the best candidates to demonstrate the potential of curative-intent radiation therapy. Several physicians have reported 95% to 100% control of lentigo malignas by using extremely large doses of relatively nonpenetrating radiation [14 – 16]. Such cure may be obtained by indiscriminate desquamation, however, rather than by selective killing of the tumor cells. More convincing evidence comes from Harwood and Cummings [17] who treated both lentigo malignas and lentigo maligna melanomas with x-ray beams ranging from 100 to 280 kV (approximately the voltage used for diagnostic-quality radiographs and slightly higher) and doses ranging from 3250 cGy in five fractions over 1 week (for lesions less than 2 cm in diameter) to 4500 cGy in 10 fractions over 2 weeks (for lesions 2 to 5 cm in diameter). With follow-up ranging from 1.5 to 13 years, 15 of 17 lentigo malignas and 21 of 23 lentigo maligna melanomas were controlled by a single course of radiation therapy. Others have reported similar results. Christie and Tiver [18] treated seven lentigo malignas with 100-kV therapy and relatively conventional doses (4400 to 5750 cGy in 11 to 23 fractions over 15 to 34 days) and observed local control in all patients with follow-up ranging from 8 to 37 months. Panizzon [19] treated 104 lentigo malignas with superficial radiation therapy and reported a 100% cure rate after 7.5 years of follow-up; similarly, 18 lentigo maligna melanomas exhibited an 89% cure rate. Tsang et al [20] observed a 5-year actuarial tumor control rate of 86% in 36
elderly patients treated for lentigo malignas that were characterized as ‘‘larger lesions located in the head and neck area.’’ Such therapy, however, has not gained wide acceptance and questions remain about the potentially curative role of radiation therapy in the setting of small, visibly detectable disease.
Potentially curative treatment of microscopic disease Moving down one order of magnitude, radiation therapy has somewhat more clearly been shown to have beneficial effects when applied to microscopicsize disease. It has long been accepted that surgical resection of all gross evidence of one or more intracerebral metastases typically leaves behind small amounts of tumor that are subclinical (ie, too small to be detected by current clinical means). For such patients, radiation therapy clearly has been shown to kill at least some of the remaining tumor cells. Skibber et al [21] reported 34 patients who had clinically solitary, intracerebral, metastatic malignant melanomas that were macroscopically completely excised. Twelve were treated by surgery alone and 22 were treated by surgery and elective postoperative irradiation. Intracerebral recurrence decreased from 75% (9 of 12) in patients who did not receive radiation therapy to 23% (5 of 22) in patients who did. This, in turn, influenced survival; median survival was tripled in the group receiving radiation therapy from 6 months to 18 months ( P = .002). Similarly, Hagen et al [22] reported the outcome following resection alone of clinically single intracerebral metastatic malignant melanomas (16 patients) or in combination with postoperative radiation therapy (19 patients). The median time to recurrence of central nervous system disease was extended from 6 months following surgery alone to 27 months by the addition of radiation therapy, and 85% of patients treated by surgery alone died because of their central nervous system disease versus only 24% of patients who also received radiation therapy. Most recently, elective irradiation has been considered in other situations wherein a high-risk for recurrence remains (eg, following resection of aggressive primary tumors, resection of locally recurrent disease, or resection of metastases in regional lymph nodes) despite expertly done surgery. For example, O’Brien et al [23] reported a 24% local recurrence rate following surgery of cutaneous melanomas 4-mm or more thick and a 34% recurrence rate following a therapeutic neck dissection [24]. Byers [25] reported a 46% regional failure rate following modified cervical
J.S. Cooper / Dermatol Clin 20 (2002) 713–716
neck dissection. If only a solitary node less than 3 cm was involved the local recurrence rate was 22%. If there were either multiple involved nodes or extracapsular extension present, however, the local-regional recurrence rate was 50%. Lee et al [26] reported that resection of histologically involved lymph nodes resulted in a 30% nodal basin recurrence rate. Furthermore, some factors were associated with particularly high risks of recurrence: extracapsular extension of disease (63%); multiple nodes invaded by tumor (46% for 4 to 10 nodes and 63% for more than 10 nodes); and cervical lymph node involvement (43%). It is now becoming clear that the risk of recurrence in such situations can be reduced substantially by radiation therapy. The largest series of patients treated electively because of high-risk malignant melanomas comes from the MD Anderson Cancer Center in Houston, Texas [27,28]. Their definition of high risk included malignant melanomas at least 1.5 mm thick (79 patients); clinically detectable regional nodal disease (32 patients); and recurrent previously resected disease (63 patients). Treatment was designed to deliver 6 Gy per fraction for a total of five fractions over 2.5 weeks. Although this high-dose-per-fraction technique was designed to exploit the inherent radiobiologic behavior of some melanomas (as discussed previously), it has the additional convenience of relatively few treatments that some patients who are ambivalent about taking an elective therapy find appealing. After a median follow-up of 35 months only 6 patients experienced isolated local-regional recurrence, 9 patients experienced both local-regional and distant recurrence, and 58 patients developed solely distant metastatic disease. Overall, the 5-year actuarial local-regional control rate was 88%, which far exceeded the historic experience at the same institution. As additional evidence of this principle, O’Brien et al [29] reported a nonrandomized comparison of patients who had high-risk malignant melanomas that were treated with or without elective radiation therapy in Sidney, Australia. Forty-five high-risk patients (65% having at least two involved lymph nodes and 48% having extracapsular extension of disease) received six fractions of 5.5 Gy each. Local-regional failure occurred in only 6.5% and all failures were evident within 1 year of treatment. Unfortunately, only 40% survived for at least 5 years. In comparison, 107 other patients (40% having two or more involved nodes and 19% having extracapsular extension [ie, a relatively more favorable group]) received no radiation therapy and experienced an 18.7% local-regional failure rate. This group had a 35% 5-year survival rate. Corry et al [30] reported the outcome of 42 patients who received more conventionally fractionated
715
elective radiation therapy for high-risk malignant melanomas in Melbourne, Australia, most often 50 to 60 Gy delivered in 2-Gy-per-day fractions. With 5 years of follow-up, the first site of treatment failure was nodal recurrence in 20% and an additional 2% experienced simultaneous nodal and distant recurrence of disease. Sadly, the overall 5-year survival rate was only 33% because 52% of these high-risk patients developed distant metastases, despite remaining free of local-regional disease. The author recently reported [31] his experience in using high-dose-per-fraction elective radiation therapy for high-risk malignant melanomas. Despite the aggressive nature of the tumors treated (multiple involved lymph nodes [21 patients]; close or microscopically involved surgical margins [9 patients]; extracapsular extension [6 patients]; previously resected, recurrent disease [3 patients]; or primary tumors more than 4 mm thick [4 patients]) the patients were provided with an 84% local-regional control rate at 5 years. Unfortunately, the patients (like those of Ang et al [27,28], O’Brien et al [23,24,29], and Corry et al [30]) failed to have a commensurate improvement in survival, only 39% living 5 years, suggesting that distant metastases are shed from the high-risk sites before they are irradiated. Perhaps most remarkable is the similarity in outcome in these four worldwide reports. The localregional recurrence rates, the distant metastasis rates, and the 5-year survival rates fall within a 10% range in all reports, firmly suggesting that the reported observations are universally applicable. When the results of elective radiation therapy are grouped with the results of the randomized Radiation Therapy Oncology Group study, it becomes evident that (1) malignant melanomas are not impervious to radiation therapy, and that (2) radiation therapy can be beneficial, particularly when only small volumes of disease need to be treated. Clearly, more effective systemic agents are needed to improve overall survival rates. It is likely that when systemic therapy improves, however, the importance of local-regional control may increase and the value of elective radiation therapy will become more evident. Until then, radiation therapy has a relatively small, but potentially important, role to play in the management of aggressive malignant melanomas.
References [1] Carella RJ, Gelber R, Hendrickson F, et al. Value of radiation therapy in the management of patient with cerebral metastases from malignant melanoma;
716
[2]
[3]
[4]
[5] [6] [7]
[8] [9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
J.S. Cooper / Dermatol Clin 20 (2002) 713–716 R.T.O.G. Brain Metastases Study I & II. Cancer 1980; 45:679 – 83. Hilaris BS, Raben M, Calabrese AS, et al. Value of radiation therapy for distant metastases from malignant melanoma. Cancer 1963;16:765 – 73. Katz HR. The results of different fractionation schemes in the palliative irradiation of metastatic melanoma. Int J Radiat Oncol Biol Phys 1981;7:907 – 11. Barranco SC, Romsdahl MM, Humphrey RM. The radiation response of human malignant melanoma cells grown in vitro. Cancer Res 1971;31:830 – 3. Dewey DL. The radiosensitivity of melanoma cells in culture. Br J Radiol 1971;44:816 – 7. Habermalz HJ, Fischer JJ. Radiation therapy of malignant melanoma. Cancer 1976;38:2258 – 62. Hornsey S. The relationship between total dose, number of fractions and fraction size in the response of malignant melanoma in patients. Br J Radiol 1978; 51:905 – 9. Overgaard J. Radiation treatment of malignant melanoma. Int J Radiat Oncol Biol Phys 1980;6:41 – 4. Lobo PA, Liebner EJ, Chao JJ, et al. Radiotherapy in the management of malignant melanoma. Int J Radiat Oncol Biol Phys 1981;7:21 – 6. Rounsaville MC, Cantril ST, Fontanesi J, et al. Radiotherapy in the management of cutaneous melanoma: effect of time, dose and fractionation. Front Radiat Ther Oncol 1998;22:62 – 78. Trott KR, von Lieden H, Kummermehr J, et al. The radiosentivity of malignant melanomas. Part 2: Clinical studies. Int J Radiat Oncol Biol Phys 1981;7: 15 – 20. Sause WT, Cooper JS, Rush S, et al. Fraction size in external beam radiation therapy in the treatment of melanoma. Int J Radiat Oncol Biol Phys 1991;20:429 – 32. Orton CG, Ellis F. A simplification in the use of the NSD concept in practical radiotherapy. Br J Radiol 1973;46:529 – 37. Arma-Szlachcic M, Ott F, Storck H. Zur strahlentherapie der melanotischen pra¨-cancerosen. Hautartz 1970; 21:505 – 8. Braun-Falco O, Lukacs S, Schoefinius HH. Zur behandlung der melanosis circumscripta praecancerosa Dubreuilh. Hautartz 1975;26:207 – 10. De Groot WP. Provisional results of treatment of the melanose pre´cance´reuse circonscrite Dubreuilh by Bucky-rays. Dermatologica 1968;136:429 – 31. Harwood AR, Cummings BJ. Radiotherapy for malignant melanoma: a re-appraisal. Cancer Treat Rev 1981;8:271 – 82.
[18] Christie DRH, Tiver KW. Radiotherapy for melanotic freckles. Australas Radiol 1996;40:331 – 3. [19] Panizzon RG. Die roentgenweichstrahlentherapie als alternative bei alteren patienten. In: Burg G, Hartmann AA, Konz B, editors. Onkologische dermatologie: fortschritte der dermatologischen und onkologischen dermatologie, BAND 7. Heidelberg: Springer-Verlag; 1992. p. 263 – 7. [20] Tsang RW, Liu F-F, Wells W, et al. Lentigo maligna of the head and neck: results of treatment by radiotherapy. Arch Dermatol 1994;130:1008 – 12. [21] Skibber JM, Soong S, Austin L, et al. Cranial irradiation after surgical excision of brain metastases in melanoma patients. Ann Surg Oncol 1996;3:118 – 23. [22] Hagen NA, Cirrincione C, Thaler HT, et al. The role of radiation therapy following resection of single brain metastases from melanoma. Neurology 1990; 40:158 – 60. [23] O’Brien CJ, Coates AS, Petersen-Schaefer K, et al. Experience with 998 cutaneous melanomas of the head and neck over 30 years. Am J Surg 1991;162:310 – 4. [24] O’Brien CJ, Gianoutsos MP, Morgan MJ. Neck dissection for cutaneous malignant melanoma. World J Surg 1992;16:222 – 6. [25] Byers RM. The role of modified neck dissection in the treatment of cutaneous melanoma of the head and neck. Arch Surg 1986;121:1338 – 41. [26] Lee RJ, Gibbs JF, Proulx GM, et al. Nodal basin recurrence following lymph node dissection for melanoma: implications for adjuvant radiotherapy. Int J Radiat Oncol Biol Phys 2000;46:467 – 74. [27] Ang KK, Byers RM, Peters LJ, et al. Regional radiotherapy as adjuvant treatment for head and neck malignant melanoma: preliminary results. Arch Otolaryngol Head Neck Surg 1990;116:169 – 72. [28] Ang KK, Peters LJ, Weber RS, et al. Postoperative radiotherapy for cutaneous melanoma of the head and neck region. Int J Radiat Oncol Biol Phys 1994; 30:795 – 8. [29] O’Brien CJ, Petersen-Schaefer K, Stevens GN, et al. Adjuvant radiotherapy following neck dissection and parotidectomy for metastatic malignant melanoma. Head Neck 1997;19:589 – 94. [30] Corry J, Smith JG, Bishop M, et al. Nodal radiation therapy for metastatic melanoma. Int J Radiat Oncol Biol Phys 1999;44:1065 – 9. [31] Cooper JS, Chang WS, Oratz R, et al. Elective radiation therapy for high-risk malignant melanomas. Cancer J 2001;7:498 – 502.