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Total skin electron irradiation for mycosis fungoides: Failure analysis and prognostic factors
0360~3016/X3/09127949$03.00/0 Copyright 0 1983 Pergamon Press Ltd
Inl. J. Rodiarion Onrologv Biol Phyc.. Vol. 9. pp. 1219-1287 Printed in the U.S A All rights reserved
?? Original
Contribution
TOTAL SKIN ELECTRON IRRADIATION FOR MYCOSIS FUNGOIDES: FAILURE ANALYSIS AND PROGNOSTIC FACTORS A. A. M. TADROS, M.B., DMRT, FFR, B.Sc.,* D.
W. M. HRYNIUK,
M.D.,
F.R.C.P.
F.R.C.P.
(C),’ B. S. TEPPERMAN, M.D.,
(C),’ V. G. PETERS,
B.SC.,~
M.D., F.R.C.P. (C),’ J. T. ROBERTS, M.B., CH.B., MRC PATH., F.R.C.P. (C)” AND A. T. FIGUEREDO, M.D., F.R.C.P. (C)’
ROSENTHAL,
The Ontario
Cancer
Foundation
and the Faculty of Medicine,
McMaster
University,
Hamilton.
Ontario,
Canada
From 1970 to 1980, 106 patients with mycosis fungoides received total skin electron irradiation to full tolerance. The majority received 30 Gy of 3 MeV electrons in 12 treatments over three weeks. Eighty-eight patients had received prior therapy. Fifty patients had cutaneous plaques only (T,_2N,,)rand 56 had more advanced disease. At five years, actuarial survival is 66.7% and disease-free survival 21.4%. The median time to relapse is 12 months; prolonged survival is seen only with complete response. Compared with more advanced stages, T,_,N, patients have more frequent complete response (96% vs 71%) and better relapse-free survival at five years (32 vs 7% ). Of 14 patients with T, disease in continuous complete remission for from 45-l 13 months, only one has relapsed. This suggests that cure is possible in up to 26% of patients with T2 disease who achieve complete response. In advanced stages, complete response is more likely with doses over 25 Gy (80 vs 50 % ). First recurrences were predominently in sites of previous involvement. Death resulted mainly from extracutaneous dissemination or failure to induce remission. Electron beam, Lymphoma, cutaneous, Lymphoma, Non-Hodgkin, therapy, Skin malignancies, Whole skin irradiation.
INTRODUCTION
Lymphoma, T-cell, Mycosis fungoides, Radio-
skin surface to a specified depth. The pioneering experience at Stanford University suggests that, in limited cutaneous MF, radical TSEI may offer durable remission without maintenance therapy.“.16 Because of the rarity of the disease, only four series of over 100 patients treated by TSEI have been reported,‘s~‘6.20.2’.24.37~40 We report herewith our results of I I years’ experience with TSEI in 106 patients.
Mycosis fungoides (MF) is a lymphoproliferative malignancy that evolves from localized cutaneous infiltrates of neoplastic helper T-cells.‘.‘4,2” Early lesions frequently simulate a chronic dermatosis. with non-diagnostic pathologic findings.’ The natural history of MF is prolonged: the plaques generalize, evolve to ulcerating tumors or generalized erythroderma, and then disseminate to viscera. Recent studies indicate that dissemination is more common than previously believed.3,35,43 Progression beyond the plaque phase limits the prognosis to months.’ Cutaneous MF responds to various local or systemic therapies, but responses are usually transient.“.“17.20.21.23.24.31.37.40.42.44.4S In total skin electron irradiation (TSEI) high-intensity electron sources treat the entire
METHODS
AND MATERIALS
From January I, 1970, to December 31, 1980, I I6 patients with MF were referred to the Ontario Cancer Foundation, Hamilton Regional Center for TSEI. All were assessed at an interdisciplinary Mycosis Fungoides clinic attended by specialists in dermatology, pathology,
‘Radiation Oncologist. ‘Fellow. Radiation Oncology. ‘Medical Oncologist; Director, Ontario Cancer Foundation, Hamilton Regional Center. 4Medical Physicist. ‘Coordinator, Dermatology Program, McMaster University. ‘Pathologist. ‘Medical Oncologist. Presented in part at the 24th Annual Meeting, American Society of Therapeutic Radiologists, Orlando, Florida, October 28, 1982. Reprint requests to: Dr. A. Tadros, Hamilton Clinic, Ontario Cancer Foundation, 711 Concession Street, Hamilton, Ontario, Canada L8V 1C3.
Acknowledgements-We acknowledge the assistance of the many physicians who referred their patients to us for electronbeam therapy and co-operated in their management. Physicists John Saunders and Robert Price have been invaluable in the initial development and continued maintenance of the electronbeam program in Hamilton. The constructive criticisms of Drs. B. Wilson (Head, Medical Physics) and W. Muirhead, (Head, Radiation Oncology) and the skills of Sue Loft, Sharon Morrow, Gloria Kimber and the Audio-visual Department of the Hamilton Civic Hospitals are gratefully acknowledged. Accepted for publication 19 April 1983.
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Radiation Oncology 0 Biology 0 Physics
treated patients were involved, our conclusions are not altered. The failure analysis is limited to 66 stage T,., patients treated to over 25 Gy. to control for dose response and for sampling heterogeneities introduced by the smallest stage groups. Patient characteristics in this subset are similar to the full series. Unless otherwise noted, time is measured from the first TSEI treatment. Endpoints are complete clinical remission of disease (confirmed by biopsy in doubtful cases), remission duration, onset of systemic dissemination, and death. Age and disease duration were compared by student’s t-test.” Contingency table analysis used either Yates’ corrected chi-square statistic or Fisher’s exact test according to sample size.39 Relapse rates were tested by Byar’s method.” Survival and disease-free survival curves were calculated by the Kaplan-Meier actuarial method” and compared by the log-rank chi-square statistic.16 All probabilities quoted are two-sided values. Patient characteristics are summarized in Table 1. Referral patterns were stable during the period under review. Eighty-eight patients were referred after other therapies. Advanced stage patients (T,N+-T,_,) had more frequent prior exposure to systemic chemotherapy (p = .04) or irradiation (p = .0002). Female patients are clustered in stage T, (p = .009). There was a shorter delay from pathologic diagnosis to TSEI in T,N, (p = 3 x IO- ‘). Follow-up was shorter in stages T,N, (p = .004) and in advanced stages (p = .0009). No patient had visceral metastases at referral.
medical oncology, and radiation oncology. Staging investigations included clinical examination, photographs, review of pathology specimens, complete hemogram, serum liver function studies and protein electrophoresis, chest X ray, and 99mTc liver-spleen scintigram. Retroperitoneal lymph nodes were assessed variously by inferior vena cavography, intravenous pyelography, bipedal lymphangiography, ultrasonography, or computed tomography. Buffy coat analysis for Sezary cells and routine electron microscopy have been performed only since 1978, and are excluded from this analysis. Skin lesions, suspicious lymph nodes, and bone marrow were routinely rebiopsied, and all tissue specimens were interpreted independently by two pathologists. Patients were accepted for TSEI only if both the dermatologist and the pathologist agreed with the diagnosis. Stage at referral is summarized by a modification of the classification of the Mycosis Fungoides Co-operative Group.4 We have retained their T-stages for cutaneous lesions (T, - cutaneous plaques, < 105%body surface; T, plaques, > 10% body surface; T, - tumorous lesions; T, generalized erythroderma). However, we have classified lymph node involvement according to the absence (N,) or or lymphomatous infilpresence (N f ) of dermopathic trates.3h Ten patients did not receive TSEI and are excluded from this analysis because of incorrect diagnosis (two patients), simultaneous presence of another lymphoma (one patient), or patient or physician preference for other therapies (eight patients). Follow-up ranges from four to 143 months (median 30 months) to December 31, 1981. No cases were lost to follow-up. Following TSEI, 12 patients received adjuvant therapies at other centers (IO topical nitrogen mustard, one each systemic chemotherapy and total nodal irradiation). In nine patients, the adjuvant therapy was given during the final year of this review. The impact of these adjuvants cannot yet be assessed, but since only recently
TREATMENT
TECHNIQUE
Our approach to TSEI is to treat the entire skin surface to full tolerance. Two complementary fields each received 2-2.5 Gy daily for four days per week over three weeks. The treatment dose is defined at D,,, (3mm for the 3 MeV electron beam) at normal incidence to a calibration point between the patient’s legs, 50 cm above the floor in
Table I. Patient characteristics Plaque
Number Sex: Male/female Mean age at diagnosis Prior therapy Systemic chemotherapy Topical chemotherapy PUVA Radiotherapy None Mean duration before TSEI (months) From clinical onset From pathologic diagnosis Median follow-up after TSEI (months)
Advanced
T,No
T2No
T,N+
T,No
T,N<
T‘l
Total
I
43 217116 51
20 1416 56
14 13/l 56
12 II/l 65
IO 713 66
106 78/28 59
611 66 0
11
2
4
30 7 IO 5
5 11 1 4 6
6 6 0 6 1
I 9 3 6 0
6 I 0 1 2
35 65 I2 21 I8
79 2 I2
125 23 53
151 22 22
66 26 28
80 38 9
68 15 24
113 23 30
0
Note: Some patients had received multiple previous therapies. PUVA = Psoralen-ultraviolet photochemotherapy; TSEI = Total skin electron irradiation
TSEI for MF 0 A. A. M. TADROS et al.
the treatment plane. In 1970-7 1 (12 patients) only anterior and posterior fields were treated, to a total dose of 20 Gy. In 1972, we adopted a six-field technique (anterior, posterior, right and left anterior and posterior oblique fields) for all patients able to cooperate.2s,4’ Fields are moved daily to minimize edge effects. Skin dose, specified as the sum of three of the six fields, was increased to 30 Gy from 1973379, and to 35 Gy for the last year of this review. This three-week schedule is a more rapid fractionation than used elsewhere.15 ‘7~‘o~2’~23~24~37~40.45 Seventy-nine patients (75%) received over 25 Gy. A linear accelerator* delivers a single horizontal electron beam to the erect patient at a source-surface distance of 7 meters. Electron scatter in air at this distance produces a beam uniform within + 10% without the use of scattering foils or beam flatteners (Figure 1). Beam energy is selected by tuning the accelerator rather than through the use of energy degraders. Maintaining an air path free of beam modifiers between the window of the accelerator wave-guide and the patient reduces X ray contamination to less than 0.3% of the electron dose delivered to D,,,.” This X ray contribution is monitored continuously during treatment by a lead-shielded chamber.? The beam energy generally used during this period was 3.0 MeV, as measured by electron range in the treatment plane.” Energies up to 5.7 MeV were used in individuals with thicker plaques or tumors. The 3.0 MeV beam at normal incidence to unit density medium delivers a maximum dose at 3 mm depth (D,,,), falling to 80%) at 6 mm and 10% at 10.8 mm. Oblique incidence at the skin surface in some areas decreases the effective treatment depth, which varies with body contour and positioning.4’ Dose is measured at the calibration point by a 0.6 cm.3 thimble ionization chamber in a polystyrene phantom. The electrometer$ is interlocked with the accelerator to terminate exposure at a preset dose. A dose rate of approximately 4 Gy per minute limits the treatment time to under one minute per field. Patient dose is routinely verified by thermoluminescence. When the accelerator is operated at lower energies, changes of 0.5 MeV or more could occur during treatment. A diode detector system monitors the beam energy continuously to allow appropriate correction of the radio frequency during treatment.33 Dose uniformity is maintained within i 20% of the recorded dose for most of the skin surface. Limbs are positioned to avoid self-shielding. Self-shielded areas such as inner thighs and skin folds receive supplementary booster fields. The soles of the feet are treated separately with 6 MeV electrons. Shoulders, scalp, digits, and other areas at glancing incidence for all six treatment positions receive a high surface dose and lower depth dose. We therefore shield the hands and feet and treat anterior and posterior fields only beyond 22.5 Gy. *Varian Clinic-6, Palo Alto, CA. Wondenser chamber, Model 70, Victoreen
OH. SNuclear
Enterprises
lonex 2500/3.
Inc., Cleveland.
1281
;160 8
5.7
?120 Y
0 $
80
t
f
CentralAxis / I /’il
: Cylibrat~ Poinini
50
60 70 RELATIVE
80 90 DOSE (O/o)
100
\ -I
k+
I 600 20 DISTANCE
\\
\
I I I 40 60 80 100 FRO$l~ENTRALAXlS
Fig. I. Uniformity of the electron beam in the (a) vertical and (b) transverse planes.
Uninvolved or previously treated areas, or sites of extreme reactions are shielded with l-2 mm of lead. External eye shields are shaped from lead clay to avoid air gaps over the eyelids. If the peri-orbital skin or eyelids are involved, internal eye shields of stainless steel are used. These reduce the dose to the eyelid from electron backscatter compared to internal lead shields, while transmitting less than 1% of the incident 3.0 MeV electron beam.3’ A lead skull cap or helmet was used in 40 patients (38%) without gross scalp involvement who refused to accept epilation. Since 1973, the scalp has been routinely treated in advanced stages.
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Radiation Oncology 0 Biology ??Physics
September
Table 2. Correlates
of therapeutic
Stratification
Subgroup
Stage
Complete
1983, Volume 9, Number
9
response
remission
P=
(‘70)
T, zNo
48150
(96)
T,N+ - T,N,
29134
(85)
0.18 0.00003 0.005 T,N.
-- T,
I l/22
(50)
32140 8116
(80) (50)
Dose
(T2N. - T,,only) Note: Factors correlating
>25 Gy 125 Gy
0.02
with response to TSEI.
RESULTS TSEI produced complete remission in 88 of 106 (83%) patients. As shown in Table 2, the incidence of remission was related to stage and, in advanced stages, to dose. Figure 2 summarizes total survival (excluding deaths from other causes) by stage. The five year survival was 66.7% for all patients with the greatest attrition during the first three yr. Both survival and disease-free survival (Figure 3) are significantly related to stage. At five years, only 21.4% of all patients remain free of disease after initial TSEI, and median disease-free survival overall is 12 months. Survival is also significantly related to completeness of response to TSEI (Figure 4). While no general dose-response relationship was evident in stage
T2N,, with TSEI doses under 30 Gy remission duration was shorter for patients who had elective scalp shielding (median six months, all relapsed by 44 months) than for those who had no such shielding (of whom 80% are disease-free at 5 years; p = .007). The relapse rate of Stage Tz patients who achieve complete remission decreases progressively with time (Figure 5). During the first 18 months, there was a 3.4% relapse per month. Subsequently, the monthly risk of relapse decreases to 0.28% (p = lo-*‘). Only one of 14 patients in continuous complete remission from 45 to 1 13 months following TSEI has relapsed in 340 patientmonths at risk. We could not retrospectively distinguish the I4 T,N, patients in continuous remission for over 36 months from those who relapsed early. Two T2N+ 100 90 80
70 60
10
’
0
’
-20
’
’
40
’
’
60
’
’
’
*
80 loo MONTHS
’
*
120
’
’
’
1
*
140
Fig. 2. Survival (corrected for intercurrent deaths) for full series, stratified by stage (T,_*NO-50 patients; T2N+ - T,, 56 patients).
0
20
40
60
80
loo
120
140
MONTHS
Fig. 3. Disease-free survival for full series, stratified (T,_,N, - 50 patients; T,N+ - T,, - 56 patients).
by stage.
1283
TSEI for MFO A. A. M. TADROSet al.
1
Complete
80-
,
7060-
p = 8x10
-10
1
$ Partial N%?
20
40
60
MONTHS Fig. 4. Survival (corrected for intercurrent deaths) stratified by response. (Complete -~ 88 patients; Partial or none -18 patients).
patients
for over 36 months had received total nodal irradiation or topical nitrogen
in remission
either adjuvant mustard. Sixty of 66 patients (91%) with T,_, disease treated to over 25 Gy achieved complete remission. Of these, 43 (72%) have relapsed. As summarized in Table 3, relapse sites were not related to stage. Thirty-nine patients (9 1%) failed first in skin. In 36 of these, the site of cutaneous failure could be evaluated from initial clinical photographs or diagrams. In 29 (9l%), relapse was at sites involved before treatment. Shielded skin was an initial site of relapse only in the scalp in one-third of patients after elective shielding (p = .Ol). Relapse was limited to skin in 26 patients (60%). In 17 cases, both skin and extracutaneous sites became involved. In the latter group, the median time between relapse in skin and spread to nodes and viscera was three months. Following complete remission, two subgroups were at high risk for dissemination: advanced stage patients over age 55, and stage T,N, patients who received low doses and first relapsed in shielded skin (Table 4). Of the entire group, 27 patients have died of MF, and only four of other causes. Of the 27 deaths due to MF, 25 occurred in patients with incomplete remission (Figure 4) or extracutaneous failure (Figure 6). After relapse, 37 of 40 (93%) TZ-3 patients given over
80
100
120
140
MONTHS
Fig. 5. Disease-free survical in 59 stage T, patients achieving complete remission.
25 Gy were retreated by other modalities. Second complete remissions were achieved in I2 (32%) of these patients, exclusively in those who had received no prcvious systemic chemotherapy (41%; p = .03). In Stage TzN’ and T, second remissions were more likely when the initial time to relapse was over 12 months (100% vs. 12.5%, p = ,003). The median duration of second remission was 21 months. No patient achieving second remission has died of MF, with a median follow-up after relapse of 19 (range 22102) months. When retreatment is unsuccessful, median survival after extracutaneous relapse is only four months (p = .02).
Table 3. Site of first relapse in T,_, patients achieving complete remission after 225 Gy Advanced First site of relapse Skin only Original Shielded Original and shielded New Original and new Unspecified Node: (+ skin +_node) Viscera: (f skin + node)
T,N, (n = 31)
8 3 I 3 2 2 0 0
(T,N+ - T,) (n = 29)
13 I I 0 4 I 2 2
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Radiation Oncology 0 Biology Q Physics Table 4. Factors correlating
with extracutaneous relapse after initial complete Correlates of extracutaneous failure
Stratification
T,N+ - T, T,N, t30 Gy, shielded area all others >55 years 555 years
TOXICITY
11
4
D= .owo2
V
cutaneous
1OL 0
V
20
40
80
MONTHS
1
Ot30
(Evaluable
13/20 (65) l/l9 (5) 2/2 (100) O/21 (0) IO/l1 (91) 3/9 (33)
relapse site only):
P=
.00002 ,004
.Ol
DISCUSSION
The acute side-effects of TSEI are seen uniformly in our patients. These include generalized erythema, localized edema, apparent exacerbation of preexisting lesions, transient loss of treated skin adnexae, including nails and hair, and blistering of the digits and other areas of high local dose, culminating in generalized exfoliation with moist desquamation in intertriginous areas.‘7~27.28.40Most patients required hospitalization for support, but only five patients (5%) were unable to complete planned therapy. Acute or late hematologic toxicity, as indicated by changes in peripheral blood counts, were never observed. Late cutaneous sequelae were persistent thickening of extremities and residual pigmentation.
Extl
remission
Extracutaneous failure (%)
Subgroup
Stage(>25 GY) Dose and first relapse site (all T&) Age (T,N+ - TJ, >25 GY)
I
September 1983, Volume 9, Number 9
’
’
!
loo
AFTER
’
’
120
’
’
’
140
RELAPSE
Fig. 6. Survival following first relapse, stratified by relapse site. (Cutaneous - 26 patients; extracutaneous - 17 patients).
Thirty years’ experience confirms the usefulness of TSEI in effecting sustained control of cutaneous MF. ‘s.‘7,23~37 Because of small patient numbers and short follow-up in many series, and the large number of prognostic factors, and the potential for cure after TSEI remains undefined.‘6.20.2’.24 Four other centers have documented the outcome after TSEI in series of more than 100 patients. ‘5~‘6~20~2’~24~37~40 Because of differences in endpoints, eligibility, and technique, it is difficult to compare results from these series. The Lahey Clinic group considers that TSEI alone is unlikely to be curative.20.2’.37 Their patients are given low doses of TSEI (usually under I5 Gy) so that retreatment is possible when relapse occurs. Only 7% of their patients have prolonged remissions. At three years, 54% survive, but deaths continue subsequently.*‘.*’ Patients are treated at the Memorial Hospital with weekly fractions of TSEI to high doses. Ninety percent of the patients are in advanced stages. Yet, using stringent criteria, a high complete response rate is achieved. If remission lasts I2 months, 46% remain disease-free for a median of 26 months. No further information is available on remission durability or survival.24 Reports from St. John’s Hospital in London show an average remission duration of IS months, but details regarding stage distribution, other prognostic factors, or overall remission rate and durability are not available.40 The group at Stanford has adopted an aggressive approach on the assumption that it can offer the possibility of cure in plaque-phase disease and the best palliation of advanced disease.15,16 We concur, and results from both centers tend to support this stance. In the Stanford series, there were no relapses following three years’ continuous complete remission in patients given 30 Gy or more, yielding a stable disease-free survival of 39%. This has been given as evidence of cure of MF by TSEI.” Thirtyone percent of our 59 patients with generalized plaques (Stage T2) achieving complete remission, remain continuously disease-free for five years after TSEI. The relapse rate decreases markedly after 18 months, again suggesting the possibility of long-term control (Figure 5). In advanced stage (T2N+ - T,_,), our patients achieved a median survival of 49 months and a five-year survival rate of 43%, whereas the median survival has
TSEI for MF 0 A. A. M.
historically been under 30 months without treatment.’ Although such comparisons are risky, we believe that aggressive TSEI yields sustained palliation for disseminated disease, and a better quality of remaining life at an acceptable cost in toxicity. An overall male predominance in MF has been preThe women in this series have a viously reported.” favorable course but are clustered in early stages. Within each stage, women fare no better than men. In advanced stages, age over 55 augurs ill. Because TSEI was not routinely available elsewhere in Canada during the period of this study, our series may be biased toward patients fit to travel long distances for treatment, or toward patients with progressive or advanced disease or extensive prior therapy. Such variations among centers in referral patterns and differences in techniques of giving TSEI, mean that questions regarding prior therapy, dose-response, and optimum treatment technique are unresolved. Prior treatment with other modalities could select for cell lines also resistant to TSE1.45 No such effect was seen in the Memorial Hospital experience,24 but we have been unable to induce second remissions in patients who relapse after both prior systemic chemotherapy and TSEI. The Stanford series documents a dose-response relationship in cutaneous plaque disease. Neither we nor the Lahey Clinic group have been able to detect this in our data.‘%‘7.*’ In patients with more advanced stages, we have seen an increased remission rate with higher doses, corroborating the Stanford experience. In the series from the Lahey Clinic, there was increased response with increased dose in erythroderma (T4), but an inverse relationship in cutaneous tumors (TX).*’ These discrepancies may result from different samples of patients, TSEI techniques, or fractionation schemes. Neither the present analysis nor the Memorial series show significant prolongation of remission with increased dose.24 Dose homogeneity is superior with plans using six or with simpler eight fields or rotation.4’ The experience techniques at Memorial shows that failures are more likely to occur in sites of relative underdose. This is consistent with our observation that the relapse patterns is affected by shielding. In radical TSEI, the entire skin surface is treated to maximum acute tolerance. Higher doses would not improve results without a disproportionate increase in morbidity. Patients who fail to respond completely to TSEI have a uniformly dismal prognosis. As no other therapy offers the possibility of cure, salvage in this group will demand new approaches. Complete responders fail most commonly as an isolated
TADROS et al.
1285
event in skin. This may be a purely local phenomenon related to underdose, tumor deposits below the penetration of the electron beam, or relative radioresistance. The group at Stanford has documented subcutaneous relapses that may result from inadequate electron beam penetration.30 The adverse effect of elective scalp shielding indicates that untreated occult disease within the skin surface may be a source of relapse. Recent changes in our treatment policies include increases of total dose to 35 Gy, electron beam energy of 4 MeV, and elimination of elective shielding to address these possibilities. However, with systemic failure, the time lag from cutaneous relapse to dissemination is minimal, suggesting that both sites may be seeded by circulating epidermotropic malignant T-cells from deep occult sites.8.35 There is considerable risk of death in advanced stages of MF, especially in those over age 55. Effective systemic therapies should be sought and applied to reduce the risk of extracutaneous failure for patients in this subgroup who respond to TSEI.‘2,23.29 The major alternative therapy for long-term control of MF is topical nitrogen mustard. Topical chemotherapy is easy to use and accessible to patients in communities where TSEI is not available.42,44 Vonderheid et a1.44report remissions in 70% of 140 patients with pre-tumorous infiltrative MF. However, disease-free survival at three years is only 13% and topical chemotherapy as currently used is not curative. Five of 16 patients, who discontinuing treatment after three years’ continuous complete remission, relapsed shortly thereafter. Permanent maintenance therapy has been recommended.44 Frequent cutaneous hypersensitivity limits the usefulness of this treatment when patients cannot be successfully desensitized.42 A randomized clinical trial is necessary to settle the outstanding questions of optimal techniques and timedose parameters in TSEl for MF. Because of the rarity of the disease, the cooperation of several centers will be necessary. Our results suggest several possibilities where adjuvants to TSEI should be tested. Patients given TSEI for plaque disease (T,_,N,) rarely die from MF, and the majority relapse in skin. A systemic adjuvant is unnecessary in this group, and inclusion of this low-risk group in a trial of systemic adjuvants could obscure any benefit accruing to high-risk subgroups. A non-cross-resistant local adjuvant might decrease the failures in skin and prolong freedom from symptoms. Adjuvant topical nitrogen mustard does not significantly prolong disease-free survival.2.29 Since both alkylators and ionizing radiation have a common mode of cellular action, this failure is not surprising.’ Photochemotherapy with methoxsalen (PUVA) or with hematoporphyrin derivative may be worth testing as local adjuvants to TSE1.7.‘0,23.3’
REFERENCES 1. Broder, S., Uchiyama, T., Waldmann, T.A.: Current con2. Bunn, P.A., Jr., Fischmann, A.B., Schechter, G.P., Kjmar, cepts in immunoregulatory T-cell neoplasms. Cancer Treat. P.P., Ihde, D.C., Cohen, M.H., Fossieck, B.E., Gazdar, Rep. 63: 607-612, 1979. A.F., Matthews, M.J.; Eddy, J.L., Minna, J.D.: Combined-
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20.
Radiation Oncology 0 Biology ??Physics
modality therapy with electron-beam irradiation and systemic chemotherapy for cutaneous T-cell lymphoma. Cancer Treat. Rep. 63: I 13-I 17, 1979. Bunn, P.A., Jr., Huberman, M.S., Whang-Peng J., Schechter, G.P., Guccion, J.G., Matthews, M.J., Gazdar, A.F., Dunnick, N.R.. Fischmann, A.B., Ihde, D.C., Cohen, M.H., Fossieck, B., Minna, J.D.: Prospective staging evaluation of patients with cutaneous T-cell lymphomas. Ann. Int. Med. 93: 223-230, 1980. Bunn, P.A., Jr., Lamberg. S.I.: Report of the committee on staging and classification of cutaneous T-cell lymphomas. Cancer Treat. Rep. 63: 725-129, 1919. Chabner, B.A., Myers, C.E.: Clinical pharmacology of cancer chemotherapy. In Cancer: Principles and Practice of Oncology. DeVita, V.T., Jr., Hellman, S., Rosenberg, S.A. (Eds.). Philadelphia, J.B. Lippincott. 1982, pp. 156-197. Clendenning, W.E., Rappaport, H.W.: Report of the committee on pathology of cutaneous T-cell lymphomas. Cancer Treat Rep. 63: I 19-724, 1979. Dougherty, T.J., Weishaupt, K.R., Boyle, D.G.: Photosensitizers. In Cancer: Principles and Practice of Oncology. DeVita, V.T., Jr., Hellman, S., Rosenberg, S.A., (eds.). Philadelphia, J.B. Lippincott, 1982. pp. 1836-1844. Edelson, R.L.: Cutaneous T-cell lymphoma; mycosis fungoides, Sezary syndrome, and other variants. J. Am. Acad. Dermatol. 2: 89-l 06, 1980. Epstein, E.A., Jr, Levin, D.L., Croft, J.D., Jr., Lutzner, M.A.: Mycosis fungoides: survival, prognostic factors, response to therapy, and autopsy findings. Medicine 51: 61-72, 1972. Gilchrist, B.A.: Methoxsalen photochemotherapy for mycosis fungoides. Cancer Treat. Rep. 63: 663-667, 1979. Greene, M.H., Dalager, N.A., Lamberg, S.I., Argyropoulos, C.E., Fraumeni. J.F., Jr.: Mycosis fungoides: EpiderCancer Treat. Rep. 63: 597-606, miologic observations. 1979. Griem, M.L., Tokars, R.P., Petras, V., Variakojis, D., Baron, J.M., Griem, S.F.: Combined therapy for patients with mycosis fungoides. Cancer Treat. Rep. 63: 655-657, 1979. Grollman, J.M., Jr., Bierman, S.M., Morgan, J.E., Ottoman, R.E.: X-ray contamination in total-skin electron therapy of lymphoma cutis and exfoliative dermatitis. Radiology 85: 356-360, 1965. Haynes, B.F., Metzgar, R.F., Minna J.D., Bunn, P.A.: Phenotypic characterization of cutaneous T-cell lymphoma. N. Engl. J. Med. 304: 13 19-l 323, I98 I. Hoppe, R.T., Cox, R.S., Fuks, Z., Price, N.M., Bagshaw, M.A., Farber, E.M.: Electron-beam therapy for mycosis Cancer fungoides: The Stanford University experience. Treat. Rep. 63: 691-700, 1979. Hoppe, R.T., Fuks, Z., Bagshaw, M.A.: The rationale for curative radiotherapy in mycosis fungoides. Int. J. Radiat. Oncol. Biol. Phys. 2: 843-851, 1971. Hoppe, R.T., Fuks, Z., Bagshaw, M.A.: Radiation therapy in the management of cutaneous T-cell lymphomas. Cancer Treat. Rep. 63: 625-632, 1979. International Commission on Radiation Units and Measurements: Radiation dosimetry: Electrons with initial energies between I and 50 MeV. ICRU Report 21. Washington, ICRU, 1972. Kaplan, E.L., Meier, P.: Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53: 547-58 I, 1958. Lo, T.C.M., Salzman, F.A., Moschella, S.L., Tolman, E.L., Wright, K.A.: Whole body surface electron irradiation in
September
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22.
23.
24.
25.
26.
27. 28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38. 39. 40. 41.
1983, Volume 9, Number
9
the treatment of mycosis fungoides. Radiology 130: 453457, 1979. Lo, T.C.M., Salzman, F.A., Wright, K.A.: Dose considerations in total skin electron irradiation for mycosis fungoides. Am J. Roentgenol. 132: 26 l-263, 1979. Lutzner. M., Edelson, R., Schein, P., Green, I., Kirkpatrick, C., Ahmed, A.: Cutaneous T-cell lymphoma: the Sezary syndrome, mycosis fungoides, and related disorders. Ann Int. Med. 83: 534-552, 1915. Minna, J.D., Roenigk, H.H., Jr., Glatstein, E.: Report of the committee on therapy for mycosis fungoides and Sezary syndrome. Cancer Treat. Rep. 63: 729-736, 1979. Nisce, L.Z., Safai, B., Kim, J.H.: Effectiveness of once weekly total skin electron beam therapy in mycosis fungoides and Sezary syndrome. Cancer 47: 870-876, I98 I. Page, V., Gardner, A., Karzmark, C.J.: Patient dosimetry in the electron treatment of large superficial lesions. Radiology 94: 635-64 I, 1970. Peto, R., Pike, M.C.: Conservation of the approximation z(O-E)2/E in the logrank test for survival data or tumour incidence data. Biometrics 29: 579-584, 1973. Price, N.M.: Radiation dermatitis following electron beam therapy. Arch. Dermatol. 144: 63-66, 1978. Price, N.M.: Electron beam therapy: its effect on eccrine gland function in mycosis fungoides patients. Arch. Dermatel. 115: 1068-1070, 1.979. Price, N.M., Hoppe, R.T.. Constantine, V.S., Fuks, Z.Y., Farber, E.M.: The treatment of mycosis fungoides: Adjuvant topical mechlorethamine after electron beam therapy. Cancer 40: 2851-2853, 1977. Proctor, MS., Price, N.M., Cox, A.J., Hoppe, R.T.: Subcutaneous mycosis fungoides. Arch. Dermatol. 114: l3261328, 1978. Roenigk, H.H., Jr.: Photochemotherapy for mycosis fungoides: long-term follow-up study. Cancer Treat. Rep. 63: 669-673, 1979. Rothman, K.J., Boice, J.D., Jr.: Epidemiologic Analysis With a Programmable Calculator. Washington, National Institute of Health. 1979, p. 29. Saunders, J.E.: The application of the logarithmic response of silicon diodes to monitoring beam symmetry and electron energy. Phys. Med. Biol. 19: 373-378, 1914. Saunders, J.E., Peters, V.G.: Back scattering from metals in superficial therapy with high energy electrons. Brit. J. Radiol. 47: 461-470, 1914. Schechter, G.P., Bunn, P.A., Fischman, B., Matthews, M.J., Guccion, J., Soehnlen, F., Monson, D., Minna, J.D.: Blood and lymph node T lymphocytes in cutaneous T-cell lymphoma: evaluation by light microscopy. Cancer Treat. Rep. 63: 571-574, 1979. Scheffer. E., Meijer, C.J.L.M., Van Vloten, W.A.: Dermatopathic lymphadenopathy and lymph node involvement in mycosis fungoides. Cancer 45: 137-l 48, 1980. Smedal, M.I., Johnson, D.O., Salzman, F.A., Trump, J.G., Wright, K.A.: Ten year experience with low megavolt electron therapy. Am. J. Roentgenol. 88: 215-228, 1962. Sokal, R.R., Rohlf, F.J.: Biometry. San Francisco, W.H. Freeman, 1969, pp. 2 16-226. Sokal, R.R., Rohlf. F.J.: Biometry. San Francisco, W.H. Freeman, 1969, pp. 585-601. Spittle, M.F.: Electron-beam therapy in England. Cancer Treat. Rep. 63: 639-641, 1979. Tetenes, P.J., Goodwin, P.V.: Comparative study of superficial whole-body radiotherapeutic technique using a 4-MeV nonangulated electron beam. Radiology 122: 219-226, 1977.
TSEI for MF 0 A. A. M. TADROSet al.
42. Van Scott, E.J., Kalmanson, J.D.: Complete remission of mycosis fungoides lymphoma induced by topical nitrogen mustard (HN,). Cancer 32: 18-30, 1973. 43. Variakojis, D., Rosas-Uribe, A., Rappaport, H.: Mycosis fungoides: pathologic findings in staging laporotomies. Cancer 33: 1589-l 600, 1974. 44. Vonderheid, E.C., Van Scott, E.J., Wallner, P.E., Johnson,
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W.C.: A IO-year experience with topical mechlorethamine for mycosis fungoides. Cancer Treat. Rep. 63: 681--689. 1979. 45. Wallner, P.E., Vonderheid. E.C., Brady, L.W., Van Scott, E.J., Asbell, SO.: Evaluation and recommendations for therapy of advanced-mycosis fungoides lymphoma. Inr. J. Radial. Oncol. Biol. Phys. 5: 23-27. 1979.
Inl. J. Rodiarion Onrologv Biol Phyc.. Vol. 9. pp. 1219-1287 Printed in the U.S A All rights reserved
?? Original
Contribution
TOTAL SKIN ELECTRON IRRADIATION FOR MYCOSIS FUNGOIDES: FAILURE ANALYSIS AND PROGNOSTIC FACTORS A. A. M. TADROS, M.B., DMRT, FFR, B.Sc.,* D.
W. M. HRYNIUK,
M.D.,
F.R.C.P.
F.R.C.P.
(C),’ B. S. TEPPERMAN, M.D.,
(C),’ V. G. PETERS,
B.SC.,~
M.D., F.R.C.P. (C),’ J. T. ROBERTS, M.B., CH.B., MRC PATH., F.R.C.P. (C)” AND A. T. FIGUEREDO, M.D., F.R.C.P. (C)’
ROSENTHAL,
The Ontario
Cancer
Foundation
and the Faculty of Medicine,
McMaster
University,
Hamilton.
Ontario,
Canada
From 1970 to 1980, 106 patients with mycosis fungoides received total skin electron irradiation to full tolerance. The majority received 30 Gy of 3 MeV electrons in 12 treatments over three weeks. Eighty-eight patients had received prior therapy. Fifty patients had cutaneous plaques only (T,_2N,,)rand 56 had more advanced disease. At five years, actuarial survival is 66.7% and disease-free survival 21.4%. The median time to relapse is 12 months; prolonged survival is seen only with complete response. Compared with more advanced stages, T,_,N, patients have more frequent complete response (96% vs 71%) and better relapse-free survival at five years (32 vs 7% ). Of 14 patients with T, disease in continuous complete remission for from 45-l 13 months, only one has relapsed. This suggests that cure is possible in up to 26% of patients with T2 disease who achieve complete response. In advanced stages, complete response is more likely with doses over 25 Gy (80 vs 50 % ). First recurrences were predominently in sites of previous involvement. Death resulted mainly from extracutaneous dissemination or failure to induce remission. Electron beam, Lymphoma, cutaneous, Lymphoma, Non-Hodgkin, therapy, Skin malignancies, Whole skin irradiation.
INTRODUCTION
Lymphoma, T-cell, Mycosis fungoides, Radio-
skin surface to a specified depth. The pioneering experience at Stanford University suggests that, in limited cutaneous MF, radical TSEI may offer durable remission without maintenance therapy.“.16 Because of the rarity of the disease, only four series of over 100 patients treated by TSEI have been reported,‘s~‘6.20.2’.24.37~40 We report herewith our results of I I years’ experience with TSEI in 106 patients.
Mycosis fungoides (MF) is a lymphoproliferative malignancy that evolves from localized cutaneous infiltrates of neoplastic helper T-cells.‘.‘4,2” Early lesions frequently simulate a chronic dermatosis. with non-diagnostic pathologic findings.’ The natural history of MF is prolonged: the plaques generalize, evolve to ulcerating tumors or generalized erythroderma, and then disseminate to viscera. Recent studies indicate that dissemination is more common than previously believed.3,35,43 Progression beyond the plaque phase limits the prognosis to months.’ Cutaneous MF responds to various local or systemic therapies, but responses are usually transient.“.“17.20.21.23.24.31.37.40.42.44.4S In total skin electron irradiation (TSEI) high-intensity electron sources treat the entire
METHODS
AND MATERIALS
From January I, 1970, to December 31, 1980, I I6 patients with MF were referred to the Ontario Cancer Foundation, Hamilton Regional Center for TSEI. All were assessed at an interdisciplinary Mycosis Fungoides clinic attended by specialists in dermatology, pathology,
‘Radiation Oncologist. ‘Fellow. Radiation Oncology. ‘Medical Oncologist; Director, Ontario Cancer Foundation, Hamilton Regional Center. 4Medical Physicist. ‘Coordinator, Dermatology Program, McMaster University. ‘Pathologist. ‘Medical Oncologist. Presented in part at the 24th Annual Meeting, American Society of Therapeutic Radiologists, Orlando, Florida, October 28, 1982. Reprint requests to: Dr. A. Tadros, Hamilton Clinic, Ontario Cancer Foundation, 711 Concession Street, Hamilton, Ontario, Canada L8V 1C3.
Acknowledgements-We acknowledge the assistance of the many physicians who referred their patients to us for electronbeam therapy and co-operated in their management. Physicists John Saunders and Robert Price have been invaluable in the initial development and continued maintenance of the electronbeam program in Hamilton. The constructive criticisms of Drs. B. Wilson (Head, Medical Physics) and W. Muirhead, (Head, Radiation Oncology) and the skills of Sue Loft, Sharon Morrow, Gloria Kimber and the Audio-visual Department of the Hamilton Civic Hospitals are gratefully acknowledged. Accepted for publication 19 April 1983.
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September 1983, Volume 9, Number 9
Radiation Oncology 0 Biology 0 Physics
treated patients were involved, our conclusions are not altered. The failure analysis is limited to 66 stage T,., patients treated to over 25 Gy. to control for dose response and for sampling heterogeneities introduced by the smallest stage groups. Patient characteristics in this subset are similar to the full series. Unless otherwise noted, time is measured from the first TSEI treatment. Endpoints are complete clinical remission of disease (confirmed by biopsy in doubtful cases), remission duration, onset of systemic dissemination, and death. Age and disease duration were compared by student’s t-test.” Contingency table analysis used either Yates’ corrected chi-square statistic or Fisher’s exact test according to sample size.39 Relapse rates were tested by Byar’s method.” Survival and disease-free survival curves were calculated by the Kaplan-Meier actuarial method” and compared by the log-rank chi-square statistic.16 All probabilities quoted are two-sided values. Patient characteristics are summarized in Table 1. Referral patterns were stable during the period under review. Eighty-eight patients were referred after other therapies. Advanced stage patients (T,N+-T,_,) had more frequent prior exposure to systemic chemotherapy (p = .04) or irradiation (p = .0002). Female patients are clustered in stage T, (p = .009). There was a shorter delay from pathologic diagnosis to TSEI in T,N, (p = 3 x IO- ‘). Follow-up was shorter in stages T,N, (p = .004) and in advanced stages (p = .0009). No patient had visceral metastases at referral.
medical oncology, and radiation oncology. Staging investigations included clinical examination, photographs, review of pathology specimens, complete hemogram, serum liver function studies and protein electrophoresis, chest X ray, and 99mTc liver-spleen scintigram. Retroperitoneal lymph nodes were assessed variously by inferior vena cavography, intravenous pyelography, bipedal lymphangiography, ultrasonography, or computed tomography. Buffy coat analysis for Sezary cells and routine electron microscopy have been performed only since 1978, and are excluded from this analysis. Skin lesions, suspicious lymph nodes, and bone marrow were routinely rebiopsied, and all tissue specimens were interpreted independently by two pathologists. Patients were accepted for TSEI only if both the dermatologist and the pathologist agreed with the diagnosis. Stage at referral is summarized by a modification of the classification of the Mycosis Fungoides Co-operative Group.4 We have retained their T-stages for cutaneous lesions (T, - cutaneous plaques, < 105%body surface; T, plaques, > 10% body surface; T, - tumorous lesions; T, generalized erythroderma). However, we have classified lymph node involvement according to the absence (N,) or or lymphomatous infilpresence (N f ) of dermopathic trates.3h Ten patients did not receive TSEI and are excluded from this analysis because of incorrect diagnosis (two patients), simultaneous presence of another lymphoma (one patient), or patient or physician preference for other therapies (eight patients). Follow-up ranges from four to 143 months (median 30 months) to December 31, 1981. No cases were lost to follow-up. Following TSEI, 12 patients received adjuvant therapies at other centers (IO topical nitrogen mustard, one each systemic chemotherapy and total nodal irradiation). In nine patients, the adjuvant therapy was given during the final year of this review. The impact of these adjuvants cannot yet be assessed, but since only recently
TREATMENT
TECHNIQUE
Our approach to TSEI is to treat the entire skin surface to full tolerance. Two complementary fields each received 2-2.5 Gy daily for four days per week over three weeks. The treatment dose is defined at D,,, (3mm for the 3 MeV electron beam) at normal incidence to a calibration point between the patient’s legs, 50 cm above the floor in
Table I. Patient characteristics Plaque
Number Sex: Male/female Mean age at diagnosis Prior therapy Systemic chemotherapy Topical chemotherapy PUVA Radiotherapy None Mean duration before TSEI (months) From clinical onset From pathologic diagnosis Median follow-up after TSEI (months)
Advanced
T,No
T2No
T,N+
T,No
T,N<
T‘l
Total
I
43 217116 51
20 1416 56
14 13/l 56
12 II/l 65
IO 713 66
106 78/28 59
611 66 0
11
2
4
30 7 IO 5
5 11 1 4 6
6 6 0 6 1
I 9 3 6 0
6 I 0 1 2
35 65 I2 21 I8
79 2 I2
125 23 53
151 22 22
66 26 28
80 38 9
68 15 24
113 23 30
0
Note: Some patients had received multiple previous therapies. PUVA = Psoralen-ultraviolet photochemotherapy; TSEI = Total skin electron irradiation
TSEI for MF 0 A. A. M. TADROS et al.
the treatment plane. In 1970-7 1 (12 patients) only anterior and posterior fields were treated, to a total dose of 20 Gy. In 1972, we adopted a six-field technique (anterior, posterior, right and left anterior and posterior oblique fields) for all patients able to cooperate.2s,4’ Fields are moved daily to minimize edge effects. Skin dose, specified as the sum of three of the six fields, was increased to 30 Gy from 1973379, and to 35 Gy for the last year of this review. This three-week schedule is a more rapid fractionation than used elsewhere.15 ‘7~‘o~2’~23~24~37~40.45 Seventy-nine patients (75%) received over 25 Gy. A linear accelerator* delivers a single horizontal electron beam to the erect patient at a source-surface distance of 7 meters. Electron scatter in air at this distance produces a beam uniform within + 10% without the use of scattering foils or beam flatteners (Figure 1). Beam energy is selected by tuning the accelerator rather than through the use of energy degraders. Maintaining an air path free of beam modifiers between the window of the accelerator wave-guide and the patient reduces X ray contamination to less than 0.3% of the electron dose delivered to D,,,.” This X ray contribution is monitored continuously during treatment by a lead-shielded chamber.? The beam energy generally used during this period was 3.0 MeV, as measured by electron range in the treatment plane.” Energies up to 5.7 MeV were used in individuals with thicker plaques or tumors. The 3.0 MeV beam at normal incidence to unit density medium delivers a maximum dose at 3 mm depth (D,,,), falling to 80%) at 6 mm and 10% at 10.8 mm. Oblique incidence at the skin surface in some areas decreases the effective treatment depth, which varies with body contour and positioning.4’ Dose is measured at the calibration point by a 0.6 cm.3 thimble ionization chamber in a polystyrene phantom. The electrometer$ is interlocked with the accelerator to terminate exposure at a preset dose. A dose rate of approximately 4 Gy per minute limits the treatment time to under one minute per field. Patient dose is routinely verified by thermoluminescence. When the accelerator is operated at lower energies, changes of 0.5 MeV or more could occur during treatment. A diode detector system monitors the beam energy continuously to allow appropriate correction of the radio frequency during treatment.33 Dose uniformity is maintained within i 20% of the recorded dose for most of the skin surface. Limbs are positioned to avoid self-shielding. Self-shielded areas such as inner thighs and skin folds receive supplementary booster fields. The soles of the feet are treated separately with 6 MeV electrons. Shoulders, scalp, digits, and other areas at glancing incidence for all six treatment positions receive a high surface dose and lower depth dose. We therefore shield the hands and feet and treat anterior and posterior fields only beyond 22.5 Gy. *Varian Clinic-6, Palo Alto, CA. Wondenser chamber, Model 70, Victoreen
OH. SNuclear
Enterprises
lonex 2500/3.
Inc., Cleveland.
1281
;160 8
5.7
?120 Y
0 $
80
t
f
CentralAxis / I /’il
: Cylibrat~ Poinini
50
60 70 RELATIVE
80 90 DOSE (O/o)
100
\ -I
k+
I 600 20 DISTANCE
\\
\
I I I 40 60 80 100 FRO$l~ENTRALAXlS
Fig. I. Uniformity of the electron beam in the (a) vertical and (b) transverse planes.
Uninvolved or previously treated areas, or sites of extreme reactions are shielded with l-2 mm of lead. External eye shields are shaped from lead clay to avoid air gaps over the eyelids. If the peri-orbital skin or eyelids are involved, internal eye shields of stainless steel are used. These reduce the dose to the eyelid from electron backscatter compared to internal lead shields, while transmitting less than 1% of the incident 3.0 MeV electron beam.3’ A lead skull cap or helmet was used in 40 patients (38%) without gross scalp involvement who refused to accept epilation. Since 1973, the scalp has been routinely treated in advanced stages.
1282
Radiation Oncology 0 Biology ??Physics
September
Table 2. Correlates
of therapeutic
Stratification
Subgroup
Stage
Complete
1983, Volume 9, Number
9
response
remission
P=
(‘70)
T, zNo
48150
(96)
T,N+ - T,N,
29134
(85)
0.18 0.00003 0.005 T,N.
-- T,
I l/22
(50)
32140 8116
(80) (50)
Dose
(T2N. - T,,only) Note: Factors correlating
>25 Gy 125 Gy
0.02
with response to TSEI.
RESULTS TSEI produced complete remission in 88 of 106 (83%) patients. As shown in Table 2, the incidence of remission was related to stage and, in advanced stages, to dose. Figure 2 summarizes total survival (excluding deaths from other causes) by stage. The five year survival was 66.7% for all patients with the greatest attrition during the first three yr. Both survival and disease-free survival (Figure 3) are significantly related to stage. At five years, only 21.4% of all patients remain free of disease after initial TSEI, and median disease-free survival overall is 12 months. Survival is also significantly related to completeness of response to TSEI (Figure 4). While no general dose-response relationship was evident in stage
T2N,, with TSEI doses under 30 Gy remission duration was shorter for patients who had elective scalp shielding (median six months, all relapsed by 44 months) than for those who had no such shielding (of whom 80% are disease-free at 5 years; p = .007). The relapse rate of Stage Tz patients who achieve complete remission decreases progressively with time (Figure 5). During the first 18 months, there was a 3.4% relapse per month. Subsequently, the monthly risk of relapse decreases to 0.28% (p = lo-*‘). Only one of 14 patients in continuous complete remission from 45 to 1 13 months following TSEI has relapsed in 340 patientmonths at risk. We could not retrospectively distinguish the I4 T,N, patients in continuous remission for over 36 months from those who relapsed early. Two T2N+ 100 90 80
70 60
10
’
0
’
-20
’
’
40
’
’
60
’
’
’
*
80 loo MONTHS
’
*
120
’
’
’
1
*
140
Fig. 2. Survival (corrected for intercurrent deaths) for full series, stratified by stage (T,_*NO-50 patients; T2N+ - T,, 56 patients).
0
20
40
60
80
loo
120
140
MONTHS
Fig. 3. Disease-free survival for full series, stratified (T,_,N, - 50 patients; T,N+ - T,, - 56 patients).
by stage.
1283
TSEI for MFO A. A. M. TADROSet al.
1
Complete
80-
,
7060-
p = 8x10
-10
1
$ Partial N%?
20
40
60
MONTHS Fig. 4. Survival (corrected for intercurrent deaths) stratified by response. (Complete -~ 88 patients; Partial or none -18 patients).
patients
for over 36 months had received total nodal irradiation or topical nitrogen
in remission
either adjuvant mustard. Sixty of 66 patients (91%) with T,_, disease treated to over 25 Gy achieved complete remission. Of these, 43 (72%) have relapsed. As summarized in Table 3, relapse sites were not related to stage. Thirty-nine patients (9 1%) failed first in skin. In 36 of these, the site of cutaneous failure could be evaluated from initial clinical photographs or diagrams. In 29 (9l%), relapse was at sites involved before treatment. Shielded skin was an initial site of relapse only in the scalp in one-third of patients after elective shielding (p = .Ol). Relapse was limited to skin in 26 patients (60%). In 17 cases, both skin and extracutaneous sites became involved. In the latter group, the median time between relapse in skin and spread to nodes and viscera was three months. Following complete remission, two subgroups were at high risk for dissemination: advanced stage patients over age 55, and stage T,N, patients who received low doses and first relapsed in shielded skin (Table 4). Of the entire group, 27 patients have died of MF, and only four of other causes. Of the 27 deaths due to MF, 25 occurred in patients with incomplete remission (Figure 4) or extracutaneous failure (Figure 6). After relapse, 37 of 40 (93%) TZ-3 patients given over
80
100
120
140
MONTHS
Fig. 5. Disease-free survical in 59 stage T, patients achieving complete remission.
25 Gy were retreated by other modalities. Second complete remissions were achieved in I2 (32%) of these patients, exclusively in those who had received no prcvious systemic chemotherapy (41%; p = .03). In Stage TzN’ and T, second remissions were more likely when the initial time to relapse was over 12 months (100% vs. 12.5%, p = ,003). The median duration of second remission was 21 months. No patient achieving second remission has died of MF, with a median follow-up after relapse of 19 (range 22102) months. When retreatment is unsuccessful, median survival after extracutaneous relapse is only four months (p = .02).
Table 3. Site of first relapse in T,_, patients achieving complete remission after 225 Gy Advanced First site of relapse Skin only Original Shielded Original and shielded New Original and new Unspecified Node: (+ skin +_node) Viscera: (f skin + node)
T,N, (n = 31)
8 3 I 3 2 2 0 0
(T,N+ - T,) (n = 29)
13 I I 0 4 I 2 2
1284
Radiation Oncology 0 Biology Q Physics Table 4. Factors correlating
with extracutaneous relapse after initial complete Correlates of extracutaneous failure
Stratification
T,N+ - T, T,N, t30 Gy, shielded area all others >55 years 555 years
TOXICITY
11
4
D= .owo2
V
cutaneous
1OL 0
V
20
40
80
MONTHS
1
Ot30
(Evaluable
13/20 (65) l/l9 (5) 2/2 (100) O/21 (0) IO/l1 (91) 3/9 (33)
relapse site only):
P=
.00002 ,004
.Ol
DISCUSSION
The acute side-effects of TSEI are seen uniformly in our patients. These include generalized erythema, localized edema, apparent exacerbation of preexisting lesions, transient loss of treated skin adnexae, including nails and hair, and blistering of the digits and other areas of high local dose, culminating in generalized exfoliation with moist desquamation in intertriginous areas.‘7~27.28.40Most patients required hospitalization for support, but only five patients (5%) were unable to complete planned therapy. Acute or late hematologic toxicity, as indicated by changes in peripheral blood counts, were never observed. Late cutaneous sequelae were persistent thickening of extremities and residual pigmentation.
Extl
remission
Extracutaneous failure (%)
Subgroup
Stage(>25 GY) Dose and first relapse site (all T&) Age (T,N+ - TJ, >25 GY)
I
September 1983, Volume 9, Number 9
’
’
!
loo
AFTER
’
’
120
’
’
’
140
RELAPSE
Fig. 6. Survival following first relapse, stratified by relapse site. (Cutaneous - 26 patients; extracutaneous - 17 patients).
Thirty years’ experience confirms the usefulness of TSEI in effecting sustained control of cutaneous MF. ‘s.‘7,23~37 Because of small patient numbers and short follow-up in many series, and the large number of prognostic factors, and the potential for cure after TSEI remains undefined.‘6.20.2’.24 Four other centers have documented the outcome after TSEI in series of more than 100 patients. ‘5~‘6~20~2’~24~37~40 Because of differences in endpoints, eligibility, and technique, it is difficult to compare results from these series. The Lahey Clinic group considers that TSEI alone is unlikely to be curative.20.2’.37 Their patients are given low doses of TSEI (usually under I5 Gy) so that retreatment is possible when relapse occurs. Only 7% of their patients have prolonged remissions. At three years, 54% survive, but deaths continue subsequently.*‘.*’ Patients are treated at the Memorial Hospital with weekly fractions of TSEI to high doses. Ninety percent of the patients are in advanced stages. Yet, using stringent criteria, a high complete response rate is achieved. If remission lasts I2 months, 46% remain disease-free for a median of 26 months. No further information is available on remission durability or survival.24 Reports from St. John’s Hospital in London show an average remission duration of IS months, but details regarding stage distribution, other prognostic factors, or overall remission rate and durability are not available.40 The group at Stanford has adopted an aggressive approach on the assumption that it can offer the possibility of cure in plaque-phase disease and the best palliation of advanced disease.15,16 We concur, and results from both centers tend to support this stance. In the Stanford series, there were no relapses following three years’ continuous complete remission in patients given 30 Gy or more, yielding a stable disease-free survival of 39%. This has been given as evidence of cure of MF by TSEI.” Thirtyone percent of our 59 patients with generalized plaques (Stage T2) achieving complete remission, remain continuously disease-free for five years after TSEI. The relapse rate decreases markedly after 18 months, again suggesting the possibility of long-term control (Figure 5). In advanced stage (T2N+ - T,_,), our patients achieved a median survival of 49 months and a five-year survival rate of 43%, whereas the median survival has
TSEI for MF 0 A. A. M.
historically been under 30 months without treatment.’ Although such comparisons are risky, we believe that aggressive TSEI yields sustained palliation for disseminated disease, and a better quality of remaining life at an acceptable cost in toxicity. An overall male predominance in MF has been preThe women in this series have a viously reported.” favorable course but are clustered in early stages. Within each stage, women fare no better than men. In advanced stages, age over 55 augurs ill. Because TSEI was not routinely available elsewhere in Canada during the period of this study, our series may be biased toward patients fit to travel long distances for treatment, or toward patients with progressive or advanced disease or extensive prior therapy. Such variations among centers in referral patterns and differences in techniques of giving TSEI, mean that questions regarding prior therapy, dose-response, and optimum treatment technique are unresolved. Prior treatment with other modalities could select for cell lines also resistant to TSE1.45 No such effect was seen in the Memorial Hospital experience,24 but we have been unable to induce second remissions in patients who relapse after both prior systemic chemotherapy and TSEI. The Stanford series documents a dose-response relationship in cutaneous plaque disease. Neither we nor the Lahey Clinic group have been able to detect this in our data.‘%‘7.*’ In patients with more advanced stages, we have seen an increased remission rate with higher doses, corroborating the Stanford experience. In the series from the Lahey Clinic, there was increased response with increased dose in erythroderma (T4), but an inverse relationship in cutaneous tumors (TX).*’ These discrepancies may result from different samples of patients, TSEI techniques, or fractionation schemes. Neither the present analysis nor the Memorial series show significant prolongation of remission with increased dose.24 Dose homogeneity is superior with plans using six or with simpler eight fields or rotation.4’ The experience techniques at Memorial shows that failures are more likely to occur in sites of relative underdose. This is consistent with our observation that the relapse patterns is affected by shielding. In radical TSEI, the entire skin surface is treated to maximum acute tolerance. Higher doses would not improve results without a disproportionate increase in morbidity. Patients who fail to respond completely to TSEI have a uniformly dismal prognosis. As no other therapy offers the possibility of cure, salvage in this group will demand new approaches. Complete responders fail most commonly as an isolated
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event in skin. This may be a purely local phenomenon related to underdose, tumor deposits below the penetration of the electron beam, or relative radioresistance. The group at Stanford has documented subcutaneous relapses that may result from inadequate electron beam penetration.30 The adverse effect of elective scalp shielding indicates that untreated occult disease within the skin surface may be a source of relapse. Recent changes in our treatment policies include increases of total dose to 35 Gy, electron beam energy of 4 MeV, and elimination of elective shielding to address these possibilities. However, with systemic failure, the time lag from cutaneous relapse to dissemination is minimal, suggesting that both sites may be seeded by circulating epidermotropic malignant T-cells from deep occult sites.8.35 There is considerable risk of death in advanced stages of MF, especially in those over age 55. Effective systemic therapies should be sought and applied to reduce the risk of extracutaneous failure for patients in this subgroup who respond to TSEI.‘2,23.29 The major alternative therapy for long-term control of MF is topical nitrogen mustard. Topical chemotherapy is easy to use and accessible to patients in communities where TSEI is not available.42,44 Vonderheid et a1.44report remissions in 70% of 140 patients with pre-tumorous infiltrative MF. However, disease-free survival at three years is only 13% and topical chemotherapy as currently used is not curative. Five of 16 patients, who discontinuing treatment after three years’ continuous complete remission, relapsed shortly thereafter. Permanent maintenance therapy has been recommended.44 Frequent cutaneous hypersensitivity limits the usefulness of this treatment when patients cannot be successfully desensitized.42 A randomized clinical trial is necessary to settle the outstanding questions of optimal techniques and timedose parameters in TSEl for MF. Because of the rarity of the disease, the cooperation of several centers will be necessary. Our results suggest several possibilities where adjuvants to TSEI should be tested. Patients given TSEI for plaque disease (T,_,N,) rarely die from MF, and the majority relapse in skin. A systemic adjuvant is unnecessary in this group, and inclusion of this low-risk group in a trial of systemic adjuvants could obscure any benefit accruing to high-risk subgroups. A non-cross-resistant local adjuvant might decrease the failures in skin and prolong freedom from symptoms. Adjuvant topical nitrogen mustard does not significantly prolong disease-free survival.2.29 Since both alkylators and ionizing radiation have a common mode of cellular action, this failure is not surprising.’ Photochemotherapy with methoxsalen (PUVA) or with hematoporphyrin derivative may be worth testing as local adjuvants to TSE1.7.‘0,23.3’
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