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Radiotherapy in the management of malignant melanoma
O36cr3Olb/Sl/OloO2lWMz.oo/O Copynghr 8 I98 I Pcr~amon Press Ltd.
??Original Contribution RADIOTHERAPY PHILIP
IN THE MANAGEMENT A. LOBO, M.D.*
AND
OF MALIGNANT
EDWIN
MELANOMA
J. LIEBNER, M.D.?
Universityof Illinois Hospital. Chicago, Illinois JOHN JEN-HUNG
CHAO, M.D.*
AND ABDULHAMID M. KANJI, M.D.**
Mercy Hospital and Medical Center, Chicago, Illinois We performed a retrospective analysis of 45 patients with malignant mekoroa who were treated with radiition therapy at tbe University of Illinois and Mercy Hospitals, Chicago, between I%2 and 1978. Thirty-nine patients received 69 courses of radiation tberapy for metastatic disease, six patients received radiotherapy with curative intent for kocalietd lesii We uulyzed some of tbe factors governingtbe response to radiation tberapy. Although mt of tbe patier& were treated with cooventional daily fractions, tbeir response seemed comparable to that reported by otber investigators using large fractions. Until the issoe of optimum fractioa size is settled by a indicates that conventionalfractionation may be equally effective. comparative tri4 ourexperience Maliint
melanoma, Radiotberapy, Factors goveming radio response.
INTRODUCTION Many consider malignant melanomas to be radio-resistant and incurable by radiotherapy. However, in 1963, Hilaris et aL3 reported a satisfactory response in 73 patients with metastatic melanoma who were treated with radiation therapy. Habermalz and Fischer,’ Hornsey’ and recently 0vergaard6 have published data on patients with malignant melanoma. When they analyzed response in relation to fraction size they observed a better response when fraction sizes were greater than 400 rad. This paper evaluates our experience in the radiotherapeutic management of patients with malignant melanoma who were treated at the University of Illinois Hospital and Mercy Hospital between 1962 and 1978.
mean (49 years) and median (50 years) for males. The youngest patient was 8-years-old and the oldest was 78. Thirty-nine of the 45 patients received 69 courses of radiation therapy with palliative intent; the remaining six received radiotherapy with curative intent. The distribution of metastatic sites appear in Table 1. Megavoltage therapy alone was used in 84% of the treatments. Orthovoltage therapy was used in 6.7% a combination of megavoltage and superficial therapy was used in another 5.3%; megavoltage in combination with brachytherapy comprised the remaining 4% of treatment courses. Techniques of treatment consisted of simple set-ups with one or two opposed fields. The standard treatment of brain metastases consisted of whole brain irradiation to a mid-plane dose of 3000 rad in two weeks through opposed lateral fields. Bone lesions were treated with 300 rad fractions for 9-10 treatments. Individual fractions of 180-250 rad were used in the remainder of courses. We employed fractions greater than 600 rad in only 2 courses of treatment.
METHODS AND MATERIALS Between 1962 and 1978, 65 patients with biopsy proven malignant melanoma were referred to the Radiation Therapy Department of the University of Illinois and Mercy Hospitals Medical Center. Twenty patients were not evaluable because of lack of follow-up. The group that we evaluated included 24 males and 21 females. The male to female ratio was 1.2:1. For females, the mean (40 years) and median (41 years) ages were lower than the
RESULTS Reduction of the tumor to half its original size or its total disappearance constituted a response in visible
*Department of Therapeutic Radiology. TDirector, Department of Therapeutic Radiology and Professor of Radiology. .
peutic Radiology, University of Illinois Medical Center, 840 S. Wood St., Chicago, IL 60608. Acknowledgments-Ms. Christine Moore, Ms. Mary Ann Shaw and the Tumor Registry of the University of Illinois Hospital helped in the preparation of this manuscript. Accepted for publication 27 August 1980.
*Director, Department of Therapeutic Radiology and Associate Clinical Professor of Radiology. **Resident Physician. Reprint requests to: P.A. Lobe, M.D., Department of Thera21
Radiation Oncology ??Biology 0 Physics
22
Table
%
Bone Brain
22 18
31.9 26.1
Skin Lymph nodes
13 8 3
18.8
Lung Liver Other Total
Il.5
4.4
3 2 69
Table 2. Dose range distribution
4.4 2.9 100
Total
Brain Bone Skin Nodes Lung Liver
18 22 13 8 3 3 2 69
Non-responders
0 5 18 8 16 47
1 3 10 5 3 22
lesions located in skin and lymph nodes. Fourteen of the 21 visible lesions responded: of these 11 disappeared totally while 3 were reduced to half their original size. In sites such as brain, bone, liver and lung where .the tumor size could not be measured, substantial relief of symptoms for more than four months constituted a response. There were 33 such responses in 48 sites. Table 2 shows the distribution of total tumor dose in relation to response to radiation therapy. Table 3 shows the results according to the sites that were treated. Lesions in bone, brain, skin and lymph nodes responded favorably; responses varied between 60-80s. Metastatic lesions in lung and liver responded poorly, although in
Table 4. Malignant
15 15 9 5
I 0 2 47
*
3 I 4 3 2 3 0 22
Previous treatment
melanoma: Analysis of patients
Dose & treatment (rad/fraction)
Total dose
Sex
Nasopharynx
60
M
None
200
Orbital
56
M
Enucleation exentenation
200
6000 (nasopharynx) 8050
Nasal cavity
45
F
Wide local excision on two occasions
200
6200
Maxillary
40
M
None
200
6000
Cutaneous
32
F
Excision biopsy
270
8000
Cutaneous
63
M
Surgical excision
200
6000
antrum
No improvement
one patient with lung metastases. hemoptysis was controlled for eight months. Complete local control was achieved in three of the six patients who were treated with curative intent (Table 4); two of the three survived for 48 and 56 months. One of these patients, a 60 year old male, presented with nasal obstruction, epistaxis and hearing loss on the left side. On examination he was found to have a lesion in the nasopharynx involving the left eustachian tube. A biopsy of the lesion confirmed it histologically to be a malignant melanoma. The patient was referred for radiotherapy; external cobalt radiotherapy was delivered through opposing lateral fields. 9 x IO cm. A direct anterior field, 10 x 12 cm, was used prophylactically to treat the neck which was clinically negative. The patient was treated with 200 rad fractions given daily (five times a week). The primary tumor in the nasopharynx was treated with 6000 rad in 30 fractions given over 43 days. The neck was treated with 5000 rad given in 25 fractions over 35 days. At the completion of treatment there was complete regression of the lesion. The other patient, a 32-year-old female, presented with a 4 x 3 cm pigmented lesion on the calf of the right
Age
cavity
improvement
by site
according to response
Responders
4000 Total (69)
1
Volume 7. Number
Site
Other Total
Dose range (rad)
I,
Table 3. Results of radiotherapy (Metastatic melanoma)
No. of patients
site
I98
I. Distribution of metastatic sites
Site
Primary
January
(rad)
Treatment source
Response
Cobalt
Complete
4 yrs. died of CVA.
Cobalt 137 cs Mould Cobalt
Complete
8.2 months cause of death unknown.
None
20 MeV electron I1 MeV electron beam Cobalt I I MeV
Partial
Had recurrence within a year of radiotherapy and further excision was performed. 6 months cause of death unknown. 55.7 months then lost to follow-up.
Complete
None
Follow-up
2.4 months died of disseminated melanoma.
Radiotherapeutic
management
of malignant
melanoma 0 P. A. LOBOer al
Fig. 1A. Seventy-one year old male who had extensive metastatic melanoma of right neck following previous surgical procedures. Note various stages of development of the lesions.
Fig. 1B. Same patient, 5 months after first radiation treatment. He received 200 rad doses, 16 fractions over 23 days for a total of 3200 rad. Patient died 11 months after first radiation treatment of disseminated melanoma.
23
Radiation Oncology ?? Biology 0 Physics
January 198 1, Volume 7, Number 1
Fig. 2A. Fifty-six year old female with extensive metastatic melanoma of the anterior abdominal wall following surgicai excision of primary on the back 14 months earlier.
Fig. 2B. Same patient, 36 days after first radiation treatment. She received 200-300 rad doses, 12 fractions over 17 days. Patient died approximately four months later of disseminated melanoma.
Radiotherapeutic
management
of malignant
Fig. 3A. Eighteen year old female with advanced amelanotic melanoma of right upper cervical region.
leg. The pre-operative diagnosis was hemangioma; when the lesion was excised, pathological examination revealed it to be a malignant melanoma, with margins positive for tumor. The patient was referred for radiotherapy because she refused further surgery. She was treated with an 11 MeV electron beam. A 6 x 10 cm straight on field was used and a total of 8000 rad in 30 fractions was delivered in 43 days. At the completion of therapy a brisk erythema of the skin with intense pigmentation was noted. At the time of last follow-up, 56 months after treatment a mild telangiectasia was seen with no evidence of tumor locally or in the lymph nodes of the groin. This patient was subsequently lost to follow-up. DISCUSSION Sixty-eight percent of our patients who were treated with palliative intent responded to radiation therapy and had significant palliation. In 1976 Habermalz and Fischer,’ in 1978 Hornsey’ and recently in 1980 Overgaard6 reported success with large individual fractions (greater than 600, 400 and 800 rad respectively) particularly in cutaneous lesions; they failed to note any response* when relatively small fractions were used. Their clinical trials were prompted by reports of the existence of a large shoulder on the radiation survival curve of cultured mouse and human malignant melanoma cells. However,
melanoma 0 P. A.
LOBOer al.
25
Fig. 3B. Same patient, five months after her first radiation treatment. She received 200 rad doses,23 fractions over 33 days for a total of 5600 rad. Patient died 11 months later from metastatic liver and lung disease.
of our responders were treated with conventional fractions. See Figures 1,2, 3. This finding is at variance with the observations made by Habermalz and Fischer* who did not observe any response in 11 lesions that were treated with fractions less than 600 rad. However, Homsey’ observed responses in 17 of 28 lesions that were treated with fractions less than 400 rad. The experimental work of Malaise et al.’ showed that some of the malignant melanoma cells grown in vitro did not show large shoulders on their radiation survival curves; this may explain the above mentioned findings in part. It does help to explain the spectrum of responses that are observed when malignant melanomas are treated with radiation. Like Habermalz and Fischer,* Hornsey’ and Overgaard6 we were unable to show a relationship between response and total dose although we had greater success with higher doses.’ In our patients, metastatic lesions that involved lymph nodes, bones, brain and skin responded favorably to radiation therapy although, liver and lung metastasis seemed to respond poorly. Similar success in treating metastatic lesions from malignant melanoma were reported by Hilaris et al.’ and Buschke and Parker.’
most
26
RadiationOncology0
Biology 0 Physics
A majority of our responders received a total dose of 3000 rad in 2 weeks. None of our patients who were treated with curative intent received less than a total
January
1981, Volume 7. Number
I
tumor dose of 6000 rad. We noted complete local control of the disease in three of the six patients in this group: two of these patients survived more than four years.
REFERENCES I. Buschke, F.. Parker, R.G.: Radiation Therapy in Cancer Management. New York, Grune and Stratton. 1972, p. 72. 2. Habermalz, H.J.. Fischer, J.J.: Radiation therapy of maiig-
nant melanoma-Experiences with high individual treatment doses. Cancer 38: 2258-2262, 1976. 3. Hilaris, B.S., Raben, M., Calabrese. AS., Phillips, R.F., Henscke, U.K.: Value of radiation therapy for distant metastases from malignant melanoma. Cancer 16: 765-773, 1963. 4. Hornsey. S.: The relationship between total dose, number of
fractions and fraction size in the response of malignant melanoma in patients. Br. J. Radiol.. 51: 905-909, 1978. 5. Malaise, E.P.. Weininger, J., Joiy, A.M., Guichard, M.: Measurements in vitro with three cell lines derived from melanoma. In Cell Survival After Low Doses of Radiation. Theoretical and Clinical Implications. T. Alp (Ed.). London, Institute for Physics and John Wiley. 1975, pp. 223-225. 6. Overgaard. J.: Radiation treatment of malignant melanoma. Int. J. Radiat. Oncol. Biol. fhys.. 6: 41-44. 1980.
??Original Contribution RADIOTHERAPY PHILIP
IN THE MANAGEMENT A. LOBO, M.D.*
AND
OF MALIGNANT
EDWIN
MELANOMA
J. LIEBNER, M.D.?
Universityof Illinois Hospital. Chicago, Illinois JOHN JEN-HUNG
CHAO, M.D.*
AND ABDULHAMID M. KANJI, M.D.**
Mercy Hospital and Medical Center, Chicago, Illinois We performed a retrospective analysis of 45 patients with malignant mekoroa who were treated with radiition therapy at tbe University of Illinois and Mercy Hospitals, Chicago, between I%2 and 1978. Thirty-nine patients received 69 courses of radiation tberapy for metastatic disease, six patients received radiotherapy with curative intent for kocalietd lesii We uulyzed some of tbe factors governingtbe response to radiation tberapy. Although mt of tbe patier& were treated with cooventional daily fractions, tbeir response seemed comparable to that reported by otber investigators using large fractions. Until the issoe of optimum fractioa size is settled by a indicates that conventionalfractionation may be equally effective. comparative tri4 ourexperience Maliint
melanoma, Radiotberapy, Factors goveming radio response.
INTRODUCTION Many consider malignant melanomas to be radio-resistant and incurable by radiotherapy. However, in 1963, Hilaris et aL3 reported a satisfactory response in 73 patients with metastatic melanoma who were treated with radiation therapy. Habermalz and Fischer,’ Hornsey’ and recently 0vergaard6 have published data on patients with malignant melanoma. When they analyzed response in relation to fraction size they observed a better response when fraction sizes were greater than 400 rad. This paper evaluates our experience in the radiotherapeutic management of patients with malignant melanoma who were treated at the University of Illinois Hospital and Mercy Hospital between 1962 and 1978.
mean (49 years) and median (50 years) for males. The youngest patient was 8-years-old and the oldest was 78. Thirty-nine of the 45 patients received 69 courses of radiation therapy with palliative intent; the remaining six received radiotherapy with curative intent. The distribution of metastatic sites appear in Table 1. Megavoltage therapy alone was used in 84% of the treatments. Orthovoltage therapy was used in 6.7% a combination of megavoltage and superficial therapy was used in another 5.3%; megavoltage in combination with brachytherapy comprised the remaining 4% of treatment courses. Techniques of treatment consisted of simple set-ups with one or two opposed fields. The standard treatment of brain metastases consisted of whole brain irradiation to a mid-plane dose of 3000 rad in two weeks through opposed lateral fields. Bone lesions were treated with 300 rad fractions for 9-10 treatments. Individual fractions of 180-250 rad were used in the remainder of courses. We employed fractions greater than 600 rad in only 2 courses of treatment.
METHODS AND MATERIALS Between 1962 and 1978, 65 patients with biopsy proven malignant melanoma were referred to the Radiation Therapy Department of the University of Illinois and Mercy Hospitals Medical Center. Twenty patients were not evaluable because of lack of follow-up. The group that we evaluated included 24 males and 21 females. The male to female ratio was 1.2:1. For females, the mean (40 years) and median (41 years) ages were lower than the
RESULTS Reduction of the tumor to half its original size or its total disappearance constituted a response in visible
*Department of Therapeutic Radiology. TDirector, Department of Therapeutic Radiology and Professor of Radiology. .
peutic Radiology, University of Illinois Medical Center, 840 S. Wood St., Chicago, IL 60608. Acknowledgments-Ms. Christine Moore, Ms. Mary Ann Shaw and the Tumor Registry of the University of Illinois Hospital helped in the preparation of this manuscript. Accepted for publication 27 August 1980.
*Director, Department of Therapeutic Radiology and Associate Clinical Professor of Radiology. **Resident Physician. Reprint requests to: P.A. Lobe, M.D., Department of Thera21
Radiation Oncology ??Biology 0 Physics
22
Table
%
Bone Brain
22 18
31.9 26.1
Skin Lymph nodes
13 8 3
18.8
Lung Liver Other Total
Il.5
4.4
3 2 69
Table 2. Dose range distribution
4.4 2.9 100
Total
Brain Bone Skin Nodes Lung Liver
18 22 13 8 3 3 2 69
Non-responders
0 5 18 8 16 47
1 3 10 5 3 22
lesions located in skin and lymph nodes. Fourteen of the 21 visible lesions responded: of these 11 disappeared totally while 3 were reduced to half their original size. In sites such as brain, bone, liver and lung where .the tumor size could not be measured, substantial relief of symptoms for more than four months constituted a response. There were 33 such responses in 48 sites. Table 2 shows the distribution of total tumor dose in relation to response to radiation therapy. Table 3 shows the results according to the sites that were treated. Lesions in bone, brain, skin and lymph nodes responded favorably; responses varied between 60-80s. Metastatic lesions in lung and liver responded poorly, although in
Table 4. Malignant
15 15 9 5
I 0 2 47
*
3 I 4 3 2 3 0 22
Previous treatment
melanoma: Analysis of patients
Dose & treatment (rad/fraction)
Total dose
Sex
Nasopharynx
60
M
None
200
Orbital
56
M
Enucleation exentenation
200
6000 (nasopharynx) 8050
Nasal cavity
45
F
Wide local excision on two occasions
200
6200
Maxillary
40
M
None
200
6000
Cutaneous
32
F
Excision biopsy
270
8000
Cutaneous
63
M
Surgical excision
200
6000
antrum
No improvement
one patient with lung metastases. hemoptysis was controlled for eight months. Complete local control was achieved in three of the six patients who were treated with curative intent (Table 4); two of the three survived for 48 and 56 months. One of these patients, a 60 year old male, presented with nasal obstruction, epistaxis and hearing loss on the left side. On examination he was found to have a lesion in the nasopharynx involving the left eustachian tube. A biopsy of the lesion confirmed it histologically to be a malignant melanoma. The patient was referred for radiotherapy; external cobalt radiotherapy was delivered through opposing lateral fields. 9 x IO cm. A direct anterior field, 10 x 12 cm, was used prophylactically to treat the neck which was clinically negative. The patient was treated with 200 rad fractions given daily (five times a week). The primary tumor in the nasopharynx was treated with 6000 rad in 30 fractions given over 43 days. The neck was treated with 5000 rad given in 25 fractions over 35 days. At the completion of treatment there was complete regression of the lesion. The other patient, a 32-year-old female, presented with a 4 x 3 cm pigmented lesion on the calf of the right
Age
cavity
improvement
by site
according to response
Responders
1
Volume 7. Number
Site
Other Total
Dose range (rad)
I,
Table 3. Results of radiotherapy (Metastatic melanoma)
No. of patients
site
I98
I. Distribution of metastatic sites
Site
Primary
January
(rad)
Treatment source
Response
Cobalt
Complete
4 yrs. died of CVA.
Cobalt 137 cs Mould Cobalt
Complete
8.2 months cause of death unknown.
None
20 MeV electron I1 MeV electron beam Cobalt I I MeV
Partial
Had recurrence within a year of radiotherapy and further excision was performed. 6 months cause of death unknown. 55.7 months then lost to follow-up.
Complete
None
Follow-up
2.4 months died of disseminated melanoma.
Radiotherapeutic
management
of malignant
melanoma 0 P. A. LOBOer al
Fig. 1A. Seventy-one year old male who had extensive metastatic melanoma of right neck following previous surgical procedures. Note various stages of development of the lesions.
Fig. 1B. Same patient, 5 months after first radiation treatment. He received 200 rad doses, 16 fractions over 23 days for a total of 3200 rad. Patient died 11 months after first radiation treatment of disseminated melanoma.
23
Radiation Oncology ?? Biology 0 Physics
January 198 1, Volume 7, Number 1
Fig. 2A. Fifty-six year old female with extensive metastatic melanoma of the anterior abdominal wall following surgicai excision of primary on the back 14 months earlier.
Fig. 2B. Same patient, 36 days after first radiation treatment. She received 200-300 rad doses, 12 fractions over 17 days. Patient died approximately four months later of disseminated melanoma.
Radiotherapeutic
management
of malignant
Fig. 3A. Eighteen year old female with advanced amelanotic melanoma of right upper cervical region.
leg. The pre-operative diagnosis was hemangioma; when the lesion was excised, pathological examination revealed it to be a malignant melanoma, with margins positive for tumor. The patient was referred for radiotherapy because she refused further surgery. She was treated with an 11 MeV electron beam. A 6 x 10 cm straight on field was used and a total of 8000 rad in 30 fractions was delivered in 43 days. At the completion of therapy a brisk erythema of the skin with intense pigmentation was noted. At the time of last follow-up, 56 months after treatment a mild telangiectasia was seen with no evidence of tumor locally or in the lymph nodes of the groin. This patient was subsequently lost to follow-up. DISCUSSION Sixty-eight percent of our patients who were treated with palliative intent responded to radiation therapy and had significant palliation. In 1976 Habermalz and Fischer,’ in 1978 Hornsey’ and recently in 1980 Overgaard6 reported success with large individual fractions (greater than 600, 400 and 800 rad respectively) particularly in cutaneous lesions; they failed to note any response* when relatively small fractions were used. Their clinical trials were prompted by reports of the existence of a large shoulder on the radiation survival curve of cultured mouse and human malignant melanoma cells. However,
melanoma 0 P. A.
LOBOer al.
25
Fig. 3B. Same patient, five months after her first radiation treatment. She received 200 rad doses,23 fractions over 33 days for a total of 5600 rad. Patient died 11 months later from metastatic liver and lung disease.
of our responders were treated with conventional fractions. See Figures 1,2, 3. This finding is at variance with the observations made by Habermalz and Fischer* who did not observe any response in 11 lesions that were treated with fractions less than 600 rad. However, Homsey’ observed responses in 17 of 28 lesions that were treated with fractions less than 400 rad. The experimental work of Malaise et al.’ showed that some of the malignant melanoma cells grown in vitro did not show large shoulders on their radiation survival curves; this may explain the above mentioned findings in part. It does help to explain the spectrum of responses that are observed when malignant melanomas are treated with radiation. Like Habermalz and Fischer,* Hornsey’ and Overgaard6 we were unable to show a relationship between response and total dose although we had greater success with higher doses.’ In our patients, metastatic lesions that involved lymph nodes, bones, brain and skin responded favorably to radiation therapy although, liver and lung metastasis seemed to respond poorly. Similar success in treating metastatic lesions from malignant melanoma were reported by Hilaris et al.’ and Buschke and Parker.’
most
26
RadiationOncology0
Biology 0 Physics
A majority of our responders received a total dose of 3000 rad in 2 weeks. None of our patients who were treated with curative intent received less than a total
January
1981, Volume 7. Number
I
tumor dose of 6000 rad. We noted complete local control of the disease in three of the six patients in this group: two of these patients survived more than four years.
REFERENCES I. Buschke, F.. Parker, R.G.: Radiation Therapy in Cancer Management. New York, Grune and Stratton. 1972, p. 72. 2. Habermalz, H.J.. Fischer, J.J.: Radiation therapy of maiig-
nant melanoma-Experiences with high individual treatment doses. Cancer 38: 2258-2262, 1976. 3. Hilaris, B.S., Raben, M., Calabrese. AS., Phillips, R.F., Henscke, U.K.: Value of radiation therapy for distant metastases from malignant melanoma. Cancer 16: 765-773, 1963. 4. Hornsey. S.: The relationship between total dose, number of
fractions and fraction size in the response of malignant melanoma in patients. Br. J. Radiol.. 51: 905-909, 1978. 5. Malaise, E.P.. Weininger, J., Joiy, A.M., Guichard, M.: Measurements in vitro with three cell lines derived from melanoma. In Cell Survival After Low Doses of Radiation. Theoretical and Clinical Implications. T. Alp (Ed.). London, Institute for Physics and John Wiley. 1975, pp. 223-225. 6. Overgaard. J.: Radiation treatment of malignant melanoma. Int. J. Radiat. Oncol. Biol. fhys.. 6: 41-44. 1980.