The radioresponsiveness of melanoma

0360 3016/S2/07ll3l-04$0300/O Copyright 0 1982 Pergamon Press Ltd

??Original Contribution THE RADIORESPONSIVENESS LARRY

OF MELANOMA

L. Doss, M.D.* AND NARAYANAGOUD MEMULA, M.D.?

Ellis Fischel State Cancer

Hospital

and the Cancer Research

Center, Columbia,

Missouri

The variability of malignant melanoma in its response to irradiation is well documented. Recent radiobiological studies suggest that high individual dose and low total fraction regimens will enhance the responsiveness of this tumor to irradiation. The experience of the Ellis Fischel State Cancer Hospital and the Cancer Research Center, Columbia, Missouri was reviewed with particular attention to such radiotherapeutic regimens. Of 41 lesions in 27 patients, the overall response rate to irradiation was 37 % . When regimens using more than 400 cCy per fraction were analyzed, a 67 % response rate was noted. Complete response and small volume of tumor correlated significantly (p = 0.008) with long-term survival. Melanoma, Malignant, Radioresponsiveness,

Radiation therapy, Radiotherapy, Metastasis.

INTRODUCTION

als as shown in Figure 1. Fifteen (15) complete responses occurred among 13 patients. Six of these patients lived ten months or longer after completion of irradiation. Increasing the total dose given during the radiotherapy regimen does not consistently influence the tumor response rate until doses above 4500 cGy are reached (Table 3). This was true with both low and high individual fractionation regimens. In this series, osseous and cerebral metastases predominate, in contrast to the reports of Habermalz and Fischer,’ Hornsey,s and Overgaard’ where lymph node and primary lesions are represented most frequently. This reflects an institutional pattern wherein patients with melanoma were referred for radiotherapeutic management only when surgery was not feasible or when chemotherapy had failed to halt or control distant metastases. Nevertheless, the overall complete response rate was 15 of 41 lesions (37%). A complete response was defined as the entire disappearance of measurable lesions in the case of the primary tumors. Metastatic lesions were not coded for complete response unless all symptoms referable to such lesions ceased within two months after X ray therapy and, in the case of osseous lesions, 75% or more of the lytic regions were reconstructed to a normal pattern within six months of the irradiation. Using such criteria, the complete response rate for osseous metastases was disappointingly low: three of 14 lesions (21%). Although the majority of patients with osseous metastases had relief of pain (79%), significant reconstruction of the normal bony

The variability in response of malignant melanoma, both primary and metastatic, has been the subject of three recent reviews. Each has advanced the proposition that high individual fraction size, rather than total dose, is the critical factor in achieving control of these lesions by means of radiation. A review of our institutional experience is presented which supports this hypothesis. METHODS

AND MATERIALS

Between 1964 and 1979, 27 patients with 41 melanomatous lesions were referred to our radiotherapy department. There were 14 women and 13 men. One patient presented with two primary lesions, two patients had postoperative recurrences after orbital exenterations, and 24 patients presented with 37 metastatic lesions. Of these, three patients received radiotherapy exclusively, while the remainder had surgery or chemotheapy or both prior to referral. Their ages ranged from 16 to 82, with an average of 5 1 years. The distribution of lesions is shown in Table I. RESULTS The relationship of tumor response to individual fraction size (dose) is shown in Table 2. The complete response rate is increased significantly with the use of higher individual fractions. Such increases in complete response are translated into long-term surviv-

Reprint requests to: Larry L. Doss, M.D., Radiation Oncology, UNM Cancer Center, 900 Camino de Salud N.E., Albuquerque, New Mexico 87 I3 1. Accepted for publication 22 February 1982.

*Acting Director, Dept. of Radiation Therapy and Assistant Scientist, Cancer Research Center. tStaff Radiation Therapist, Dept. of Radiation Therapy. This investigation was supported in part by grant no. CA 22486 from the National Cancer Institute, National Institutes of Health, DHHS. 1131

Radiation Oncology 0 Biology 0 Physics

1132

Table 1. Distribution

of lesions No. of lesions

Lesion sites Primary

1 1 2 3 2 1 5 3 2 2 4 11 3 1 41

Vagina Periurethral tissue Orbit Femur Tibia Pelvis Vertebrae Ribs Mediastinal nodes Bronchus Extradural space Brain Lymph node Parotid Total

Recurrence Metastasis

July 1982, Volume 8, Number 7

did not always accompany symptomatic relief. Of the 11 patients with cerebral metastases, four (36%) had a complete response, i.e., return of all neurologic functions to normal and a stable or decreasing lesion on isotopic brain scan. Despite their response, in this group the complete responders fared little better than noncomplete responders in terms of survival; median survival was four months for complete response (CR), two months for all others. Although, in part, this was a result of the presence of other metastatic lesions, it is interesting that the only long-term survival (13 months) occurred in a

Fig. 1. The survival curve of melanoma patients treated with radiotherapy. Complete response correlates directly with longterm survivaL2.”

architecture

Table 2. Response

of lesions by maximum treatment dose

individual

No. of responses/ no. lesions

Individual treatment dose (cGy) 100 - 200 201 - 300 301 - 400

O/l 4113 4114

401 - 500 800 1250 Combinations

214 l/l J/J

188 + 300 238 + 400 2501400 300 + 400 300 + 500 320 + 500 600 + 800

l/l O/J O/l O/l l/l O/l ‘/l

Combined tumor responses: Low individual fraction to high individual fraction CR NR CCY 200 - 400 400 - 800

CR = complete

9 6

response;

23 3 Total NR = noncomplete

man who presented with a solitary cerebral metastasis and no other evidence of disease. Patients with small volume lesions and no metastases fared best in this series (Table 4). Two primary lesions and two post-enucleation recurrences were treated with high individual fraction therapy with the results found in Table 4. In the case of patient 1, the vaginal lesion became pigmented at 1200 cCy tumor dose; biopsies at that time revealed melanin deposition occurring in what had originally been called an amelanotic melanoma. At 1600 cGy tumor dose, the entire tumor had disappeared, leaving only a pigmented region which was biopsy-negative for melanoma. The periurethral melanoma also developed deep melanin pigmentation and then entirely sloughed during the last few days of therapy. Patient 2 had the largest tumor. It was demonstrable on brain scan. The tumor involved the posterior orbital wall in an osteolytic process. Although this recurrence was controlled by radiotherapy, the patient developed liver metastases at 19 months post-therapy and pulmonary metastases at 32 months, resulting in her death. Patient 3 had a flat, 2 x 2 cm, , orbital recurrence 15 months after enucleation of the left eye. The recurrent lesion responded completely, and the patient was able to

Table 3. Response compared

32 9 41 response.

Total dose (CCY) 500 1401 2501 3501

~ -

1400 2500 3500 4500

over 4500 Total

as a function of total dose

Total no. of lesions

Complete response/ no. of lesions

5 4 10 15

215 214 2/10 4115

7 41

517 15/41

1133

Radioresponsiveness of Melanoma 0 L. L. DOSS Table 4. High individual

3

CR = complete

400

11

4x4cm

500 300

5 IO

2x

250

30

Left orbit

3cm

2cm

ICD = intercurrent

melanoma

No. of fractions

1 x2cm

Periurethral tissue Right orbit

Response CR@ 1600 cGy Cr@ 4400 cGy CR@ 2500 cGy

CR@ 7500 cGy

Status Alive NED at 13 mos Alive NED at 13 mos Died of pulmonary metastasis at 33 mos Died of ICD at 1I years

disease; NED = no evidence of disease.

an ocular prosthesis thereafter. The patient died 11 years later of cardiac disease. Sequelae from high individual dose regimens were not significantly different than those of standard radiation courses. Of nine patients treated with 400 cGy or more per fraction, one patient had a moist desquamation of the perineum which took five weeks to heal, and one patient had persistent, mild, pitting edema of the upper extremity, following axillary lymph node irradiation. Such minimal side effects were obtained by careful consideration of the tumor volume and its margin and subsequent use of the smallest volume acceptable for treatment. This technique is especially important when the tumor lies near or over a critically radiosensitive structure such as the spinal cord, kidney, or lens.

DISCUSSION The relationship of fraction size in melanoma is as yet a poorly understood determinant of response. The following principles can be obtained from consideration of our results: (a) In patients who have small primary lesions, small recurrences, or solitary metastasis, radiation therapy can produce a complete response. The volume of tumor may have as great an effect on response as fraction size. (b) Complete responses correlate significantly with

Table 5. Combined

and primary

11

2x

wear

_

in recurrent

400

Vaginal apex

response;

therapy

Dose per fraction (~GY)

Lesion size

Lesion site

Patient

fraction

long-term survival, especially when patients have solitary lesions and no evidence of distant metastases. Patients with multiple lesions must have a complete response at each site for such survival benefit to occur. Patients with a mixed response, e.g., CR plus NR, had short-term survival similar to those who were nonresponders. (c) Complete responses can be obtained by the use of high individual fraction radiation regimens. The incidence of complete response is directly related to the fraction size with a threshold around 400 cGy. CR is obtained also when a combination regimen is used, where standard and high individual fractions are given sequentially or in a mixed fashion. Other authors have described the correlation between high individual dose and response in melanoma, but their case material has been primarily skin lesions and lymph node metastases.435.8~‘0 Their results are combined in Table 5 for comparison with our results. These authors have postulated that the effectiveness of high individual dose therapy is due to its ability to overwhelm the mechanisms by which sublethal radiation damage is repaired. The evidence for such reparative mechanisms is derived from in vitro cell survival curves which demonstrate a “wide shoulder” or D, for malignant melanoma (Figure 2).’ The D, or “shoulder” represents

Squamous = Malignant

cell carcinoma melanoma

data: Present series + published series Dose (cGy)

Author HornseyS Habermalz & Fisher’ Overgaard’ Present series

NR

CR

%CR

NR

CR

%CR

35 9 17 23

22 0

39 0 6 39

17 35 21 3

20 29 II 6

54 45 34 67

1 9

-___--+

400 - 800

200 ~ 400

Note: Partial responses are grouped with nonresponses purposes of this comparison.

for the

Dqa

\\

I Increasing Dose

-----w

Fig. 2. The demonstration of quasi-threshold (D,) in in vitro cell systems. Melanoma cells have a wide shoulder (I),) necessitating higher individual radiation doses.

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Radiation

Oncology

0 Biology 0 Physics

dosage wasted before actual cell killing begins.4 There is radiobiological evidence that superoxide dismutase, which occurs at high levels in melanin granules, scavenges and neutralizes the free radicals produced by ionizing radiations6” With such an enzyme present in melanoma lesions, massive single doses have to be given to counter the loss of free radicals to the reparative actions of the enzyme. Undoubtedly, this radiobiological aspect in melanoma does play a decisive factor in the outcome of radiation as primary therapy. However, for treatment to prolong the patient’s life, the natural history of melanoma must be considered.’ Large lesions, whether primary or secondary, may not be responsive to high total dose or high individual dose therapy because of hypoxic and

July 1982, Volume 8, Number

7

resistant cell compartments which may be relatively large.8 In such cases, the addition of radiosensitizers such as misonidazole and metronidazole, or radiosensitizing chemotherapeutic agents, for example, adriamycin or actinomycin-D, concurrently with high individual fraction radiation may result in a response. Small lesions will benefit from high individual dose therapy and, if distant metastases are lacking, long-term survival can occur. In patients with distant metastases, complete response may not be as much of a goal as palliation of symptoms. Using high individual dose therapy will accomplish the same end in a shorter interval. Therefore, early intervention, high individual dose therapy offers great potential for a future role in the management of malignant melanoma.

REFERENCES 1. Barranco, S.C., Romsdahl, M.M., Humphrey,

2. 3.

4.

5.

R.M.: The radiation response of human malignant melanoma cells grown in vitro. Cancer Res. 31: 830-833, 1971. Breslow N.: Covariance analysis of censored survival data. Biometrics 30: 89-99, 1974. Habermalz, H.F., Fischer, J.J.: Radiation therapy of malignant melanoma. Experience with high individual doses. Cancer 38: 2258-2262,1976. Hornsey, S.: Letter to the editor. The radiation response of human malignant melanoma cells in vitro and in vivo. Cancer Res. 32: 65&651, 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. 51: 905-909, 1978.

6. MC Cord, J.M., Fridovich, I.: The biology and pathology of oxygen radicals. Ann. Intern. Med. 89: 122-l 27, 1978. 7. Oberley, L.W., Buettner, G.R.: Role of superoxide dismutase in cancer: A review. Cancer Res. 39: 1141-l 149, 1979. 8. Overgaard, J.: Radiation treatment of malignant melanoma. Int. J. Radiat. Oncol. Biol. Phys. 6: 41-44, 1980. 9. Patel, J.K., Didolkar, MS., Pickren, J.W., Moore, R.H.: Metastatic pattern of malignant melanoma. A study of 216 autopsy cases. Am. J. Surg. 135: 807-810, 1978. 10. Weitzel, G.: Die Strahlenbehandlung des melanoms. Schweiz. Med. Wschr. 100: 982-987, 1970. 11. Wilcox, D.R.: Regression models and life tables. J. R. Statis. Sot. B. 34: 187-220, 1972.