Int. I
Rodialion
Oncology
Biol
Phys
1977. Vol. 2. pp. 325-331
Pergamon Press.
Prmted in the U.S.A.
??Brief Communication
ADRIAMYCIN-IRRADIATION
CUTANEOUS
COMPLICATIONSt
SILVIO A. ARISTIZABAL, M.D.,+ ROBERT C. MILLER, M.D.,S A. LEE SCHLICHTEMEIER, M.D.,9 STEPHEN E. JONES, M.D.7 and MAX L. M. BOONE M.D., Ph.D.” Department of Radiology, Division of Radiation Oncology, (SAA, RCM, ALS, MLMB) and Department of Internal Medicine, (Secion of Hematology and Medical Oncology), (SEJ) The University of Arizona College of Medicine, Tucson, AR 85721, U.S.A. Four cases of abnormally severe skin reactions including an instance of skin necrosis occurred in patients with breast cancer who were treated with cyclophosphamide, adriamycin and irradiation concurrently following mastectomy. These unusual skin reactions apparently resulted from the interaction of radiation with adriamycin and prompted us to modify both the radiation dose and the timing of administration of chemotherapy. To date, no unusual or severe skin reactions have been observed in 14 patients who have received chemotherapy with adriamycin plus radiation in accord with this modified treatment plan. Adriamycin,
Irradiation,
Skin reactions.
INTRODUCTION
have employed both modalities of therapy routinely in patients with the highest risk of recurrence (e.g. 4 or more involved axillary lymph nodes); we are studying the effect of adding radiation therapy to chemotherapy in patients with a somewhat lower risk of recurrence (e.g. l-3 involved axillary nodes). In the course of this program, several patients received adriamycin, cyclophosphamide and radiation therapy concurrently and we observed a number of unusually severe skin reactions as reported here.
The initial management of breast cancer frequently has included the use of postoperative irradiation to reduce the likelihood of local or regional recurrences.’ Recent reports have indicated that adjuvant chemotherapy immediately after mastectomy in women who have metastatic involvement of axillary lymph nodes, dramatically reduces the number of early cancer recurrences.*A Based on our experience in advanced or recurrent breast cancer where we found that the 2-drug combination of adriamycin and cyclophosphamide produced objective cancer regressions as often or more often than other currently available drug combinations,‘.“” in 1974, we initiated an adjuvant breast cancer program employing these two agents.” Although the exact current role for postoperative irradiation in conjunction with adjuvant chemotherapy has yet to be defined, we
METHODS
AND MATERIALS
Between September of 1975 and April of 1976, twenty patients with carcinoma of breast were referred to the Arizona Medical Center for postoperative adjuvant treatment. Their median age was 55 years (range 30-68). Eleven patients had undergone radical mastectomy while 9 had modified radical mastectomy. All
tSupported in part by Public Health Service Grants CA-17094 and CA-17343-01 from the National Cancer Institute, Bethesda, Maryland. *Assistant Professor of Radiology.
§Instructor of Radiology. TAssociate Professor of Internal rProfessor of Radiology. 325
Medicine.
326
Radiation
Oncology
0 Biology 0 Physics
had pathologically involved axillary nodes but no evidence of disseminated metastases (Stage II). Diagnostic tests before treatment included routine blood counts, liver function tests, serum calcium, chest X-ray and bone scan. The original schedule for radiation therapy was to deliver 5,OOOrad in 25 daily equal fractions over 5 weeks to the chest wall (using tangential parallel opposed wedged fields; dose calculated at appropriate combined isodose curve), supraclavicular-axillary areas and internal mammary chain (through direct anterior fields, dose calculated at 1 cm, depth of maximum dose). Bolus material (1 cm thick) was used over the chest wall on alternate days to 4000 rad. The treatment was delivered with an isocenter 4 MeV linear accelerator. Chemotherapy consisted of 21 administered of adriamycin day cycles intravenously (30 mg per m’) on day one and oral cyclophosphamide (150 mg per m’) daily on days 3-6; these doses as employed in our adjuvant program are 75% of the usual full doses.” The first 3 patients were treated currently with full doses of irradiation and chemotherapy. For the next 17 patients the radiation dose was reduced to 4400rad using the same technique and fractionation regimen. Among the patients receiving reduced radiation dose, 2 received combination chemotherapy concurrently and one other patient was treated with only a 3 day time interval between completion of irradiation and the beginning of Table
1. Sequence
and
Treatment Concurrent irradiation (5000 rad) and adriamycin Concurrent irradiationt (4400 rad) and adriamycin 7 days separation between both agents (4400 rad)
timing
March-April
1977, Volume
chemotherapy. Thus for the purpose of analysis, 6 patients were felt to have received concurrent radiation therapy and chemotherapy. Our present plan for combined modality adjuvant treatment is to administer 2 cycles of chemotherapy followed by a 7-10 days rest and then 4400 rad in 4-5 weeks. Seven to 10 days after completion of the course of irradiation, chemotherapy is resumed for an additional 6 cycles. RESULTS The results are summarized in Table 1. Four of 6 patients who received concurrent chemotherapy and irradiation developed acute skin reactions, 2 of them in spite of the reduced radiation dose (4400rad). However, of the 14 patients who were treated sequentially, (with at least 7 days separating irradiation (4400 rad) and chemotherapy) none experienced enhanced radiation reactions of the skin; these are significant differences statistically (p = 0.01). The augmentation of radiation response observed in our patients has been of considerable clinical significance. The exact sequence of treatment as well as the duration and intensity of skin complication is summarized in Fig. 1. In patient 1, the acute skin reaction that progressed from erythema to moist epithelitis to superficial ulceration and necrosis covering an area of 5 x 6 cm (Fig. 2) caused considerable discomfort for the period of 4 months during which healing took place.
of adriamycin-radiation complications
No.
of
patients
3
2
3
2
14
2, No. 3 and No. 4
administration
and
Complications Skin necrosis (Patient 1) Moist epithelitis and esophagitis (Patient 2) Extensive moist epithelitis and slough (Patient 3) Moist desquamation (Patient
4)
O$
tPatient 3 was started on adriamycin 3 days after completion of irradiation. *Difference in results between concurrently and sequentially treated cases is statistically significant (4/6 vs O/14, p = 0.01).
Adriamycin-irradiation
cutaneous
Patlent 1
complications
9/15
327
0 S. A. ARISTIZABAL et al.
IO/V
lrradlatlon Chemotherapy Skin Effect Patlent 2
8/6 tt
8,26 tt
e t+
II/5 tt ‘I-
6 ++ 5
I*/* ++ 4
I/7 tt 4
tt 7 7 Sk,”“eCrOI,l
‘l/1,
VI0
lrradlatlon tt
Chemotherapy
500 tt
+I
Skin Effect Patient 3 lrradiatlon Chemotherapy
I/20
2/20
-123 tt
6
Z/22 +t
‘?/I2 tt
5/3 tt
5/24 tt
6/M
tt
T
Skin Effect Patlent 4 lrradlatlon Chemotherapy
I/5 10/Z? +T
IO,24 tt
12,s
II/14
tt
I/26
12/26 F
tt
tt
+t
_E
Sktn Effect 0
10
30
50
70
90
110
130
. 150
170
Days
Fig. 1. Timing of combined modality therapy for breast cancer in those patients who developed severe cutaneous reactions. Key: t t Adriamycin (30 mg m’) cyclophosphamide (150 mg m’). Skin reaction score scale: 1 = Barely detectable change. 2 = Erythema over 50% of area. 3 = Dry desquamation. 4 = Focal areas of moist reaction. 5 = Moist reaction over 50% of area. 6 = Moist reaction over 80% of area. 7 = Skin necrosis.
Fig. 2. Skin necrosis
in Lt. axilla (Patient
1).
328
Radiation
Oncology
0 Biology 0 Physic\
March-April
Patient 2 developed a severe moist reaction over the entire chest wall field which took 5 weeks to subside. She also experienced symptoms of esophagitis which persisted for 2 months. In patient 3 the acute moist desquamation with skin slough involved 80% of the irradiated chest wall skin (Fig. 3) was of short duration but quite painful. The moist skin reaction in patient 4 spread to the entire in a moist state for 2 chest wall, persisted weeks and healed over the next 2 weeks; the irradiation course had to be discontinued at 3200rad. Despite their severity all of these observed acute skin reactions have been completely reversible over time without skin grafting.
Fig. 3. Extensive
moist
epithelitis
DISCUSSION The skin reactions we observed are sufficiently severe and unusual that we are convinced they are the result of interaction between adriamycin and irradiation administered concurrently. It is well known that antibiotic cancer chemotherapeutic agents like actinomycin D and adriamycin (both “DNA
1977, Volume
2, No.
3 and No. 4
binders”) may enhance the effect of ionizing radiation; complications may occur when these agents are combined with doses of irradiation which would otherwise be well tolerated. This type of interaction with regard to adriamycin has been documented in several experimental and clinical reports in the literature.“‘.14.‘h The role of cyclophosphamide as a radiation enhancer is not clear. Experimental data suggest only an enhanced effect in the lungs of laboratory animals receiving irradiation plus cyclophosphamide.‘” In patients, no augmentation of normal tissue damage (either acute in terms of skin reactions or delayed in terms of fibrosis) was observed with combined
and slough in Rt. chest
wall (Patient
3).
treatment with chemotherapy (cyclophosphamide and vincristine) and irradiation.’ Before the introduction of adjuvant cheinotherapy in our institution, the standard plan for postoperative radiation therapy included 5000rad in 25 daily fractions over 5 weeks. This radiation regimen usually produces a mild erythema and dry desquamation of the
Adriamycin-irradiation
cutaneous
complications
chest wall skin. Occasional patients may develop small areas of moist desquamation. Extensive acute epithelitis or actual skin necrosis are quite rare complications. Because of the severe skin reactions we introduced observed, we have several modifications in our breast cancer treatment plan in an effort to minimize the apparent adriamycin-irradiation interactions. After we recognized an augmented radiation effect (patients 1 and 2, Fig. 3) and scattered reports appeared in the literature describing similar observations,7.‘h.‘7 we reduced the irradiation dose from 5000 to 4400rad in 4.5 weeks. This reduction was based on clinical’ and experimental (mathematical model) data4 which suggested that a dose of 4500rad in 5 weeks could eliminate at least 90% of occult deposits in adenocarcinoma of the breast. We also anticipate that adriamycin will enhance radiation effects in neoplastic as well as normal tissue and the frequency of local recurrence will remain unchanged despite the reduction of radiation dose. In as much as the dose reduction alone did not seem to solve the problems of exuberant radiation reaction as exemplified by patients 3 and 4 (Fig. l), a further modification of the treatment plan was undertaken. Based on in vitro data suggesting that adriamycin inhibits the repair of irradiation damage’4.‘7 and that the sequence and the timing of adriamycin in relation to irradiation might be crucial, we began separating the administration of both modalities by at least 7 days. It is apparent from Fig. 1 that there did not seem to be any correlation between the amount of adriamycin and modification of the irradiation reaction. Patients 2 and 3 had received only one dose of the drug prior to development of complications. The reduction of the irradiation dose per se or in combination with only a three-day separation from drug administration did not affect the results; an acute reaction still developed in 2 of 3 patients. However, when this dose reduction was coupled with at least a 7-day separation between administration of drugs and irradiation, no additional skin reactions have been observed. The short duration of the acute skin reaction following 3 days separation between
0 S. A. ARISTIZABAL
et al.
329
modalities was the first indication of the importance of the “time factor” in relation to complications. Our subsequent experiencetotal absence of acute skin effects when both modalities separated by at least 7 daysfurther suggests that the temporal relationship of administration of both agents plays a more important role than the absolute dose of either one. It is not yet possible on the basis of our data, to determine if indeed a decrease in the radiation dose (to 4400 rad) is necessary if we simply observe the time separation of 7 days between chemotherapy and irradiation. Nonetheless, because these skin reactions were so severe, we have elected to continue with our present combined schedule until more information is available. A review of the literature dealing with adriamycin-irradiation skin toxicity reveals that most patients have been treated concurrently3.1”.‘3 and some sequentially’.” but not in a systematic fashion, either in terms of dose of drug, dose and time factors of irradiation or in temporal relationship to each other to allow for any conclusions. Efforts to determine the factor by which it would be necessary to reduce the amount of irradiation have been fraught with the same difficulties. In this regard, Phillips has suggested the use of the dose-effect factor (DEF) which is the ratio of the radiation dose required in the absence of the drug to the radiation dose required for the same level of damage in the presence of the drug.14 Dose-effect factors for different normal tissues and various combinations of single or multi agent chemotherapy and irradiation have been estimated from available clinical and experimental data.14 Experimentally derived DEF values for skin and mucous membranes exist only for bleomycin (1.2-1.5) and clinically derived values are available for actinomycin (1.7), methotrexate (1.58-1.88), and 6-mercaptopurine (1.18- 1 .32).14 Quantitative information however is lacking especially in relation to adriamycin and DEF values for this agent are still unknown. These values may be of importance in planning future combined chemotherapy and radiotherapy treatment
330
Radiation
Oncology
when one is concerned normal tissues. From
our
ed sequentially,
data
in the a DEF
0 Biology
with last
the
??Physics
safety
14 patients
of treat-
of 1.14 has been calcul-
ated for the chest wall skin of adult women. It is obvious that this value (DEF) varies with whether the patient is treated concurrently or sequentially and also with the length of the time interval between modalities. Although this report is concerned with cutaneous reactions, other organs (lung, heart, esophagus, trachea, thyroid, spinal cord) are included partly within the volume irradiated in the treatment of patients with breast cancer; therefore, they are subject to various degrees of potential damage from radiationadriamycin interaction. Indeed, mediastinal irradiation in cancer patients who receive adriamycin appears to be a risk factor for the subsequent development of cardiomyophathy.‘,”
March-April
1977, Volume
2, No. 3 and No. 4
Enhanced radiation reactions of the esophagus”’ and lungI also have been reported. In our series, except for one instance of severe esophagitis (patient 2), no acute damage to any of these organs has been observed. Not known as yet are the late tissue effects that may result from this therapeutic combination; however, the incidence of late effects usually runs parallel to that of acute reactions.” Consequently, any decrease in the rate of acute reactions should be reflected in a reduced frequency of long term complications. Only additional clinical experience will determine whether our modifications of combined modality therapy will result in satisfactory local and distant control of micrometastases in patients with Stage II breast cancer.
REFERENCES 1. Blum, R.H., Carter, S.K.: Adriamycin: a new anticancer drug with significant clinical activity. Ann. Intern. Med. 80: 249-259, 1974. 2. Bonadonna, G., Brusamolino, E., Valagussa, P., Rossi, A., Brugnatelli, L., Brambilla, C., Delena, M., Tancini, G., Bajetta, E., Musumeci, R., Veronesi, V.: Combination chemotherapy as an adjuvant treatment in inoperable breast cancer. N. Engl. J. Med. 294: 405-410, 1976. 3. Cassady, J.R., Richter, M.P., Piro, A.J., Jaffe, N.: Radiation-adriamycin interactions-Preliminary clinical observations. Cancer 36: 946949, 1975. 4. Cohen, L.: Theoretical iso survival formulae for fractionated radiation therapy. Bri. J. Radiol. 41: 522-528, 1968. 5. Ewy, G.A., Jones, S.E., Groves, B.M.: Adriamycin heart disease. Arizona Med. 33: 274278, 1976. 6. Fisher, B., Carbone, P., Economou, S.G., Frelick, R., Glass, A., Lerner, H., Redmand, C., Zelen, M., Band, P., Katrych, P.L., WoImark, N., Fisher, E.R.: L-Phenylalanine mustard (L-PAM) in the management of primary breast cancer: A report of early findings. N. EngI. J. Med. 292: 117-122, 1975. 7. Fletcher, G.H.: Local results of irradiation in the primary management of localized breast cancer. Cancer 29: 545-551, 1972. Rivkin, S.E., Spigel, S.C., 8. Gottlieb, J.A., Hoogstraten, B., O’Bryan, R.M., Delaney,
9.
10.
Il.
12.
13.
14.
15.
16.
F.C., Singhakowinta, A.: Superiority of adriamycin over oral nitrosoureas in patients with advanced breast carcinoma. Cancer 33: 519526, 1974. Johnson, R.: Discussions: Combined Radiotherapy and Chemotherapy. Cancer 37: 12141215, 1976. Johnson, R.E., Brereton, H.D., Kent, C.H.: Small cell cancer of the lung: Attempt to remedy causes of past therapeutic failure. Lancet 2: 289-291, 1976. Jones, S.E., Durie, B.G.M., Salmon, S.E.: Combination chemotherapy with adriamycin and cyclophosphamide for advanced breast cancer. Cancer 36: 90-97, 1975. Minow, R.A., Benjamin, R.S., Gottlieb, J.A.: cardiomyopathy-an Adriamycin overview with determination of risk factors. Cancer Chemother. Rep. 6: 195-202, 1975. Phillips, T.L., Fu, K.K.: Quantification of combined radiation therapy and chemotherapy effects on critical normal tissues. Cancer 37: 1186-1200, 1976. Phillips, T.L., Wharam, M.D., Margolis, L.W.: Modification of radiation injury to normal tissues by chemotherapeutic agents. Cancer 35: 1678-1684, 1975. Salmon, S.E.: Progress in adjuvant chemotherapy of early breast cancer. Arizona Med. 32: 108-110, 1975. Tefft, M., Lattin, P.B., Jereb, B., Cham, W., Ghavimi, F., Rosen, G., Exelby, P., Marcove,
Adriamycin-irradiation
cutaneous
complications 0 S. A.
R., Murphy, M.L., D’Angio, G.J.: Acute and late effects on normal tissues following combined chemotherapy and radiation therapy for childhood rhabdomyosarcoma and Ewing’s sarcoma. Cancer 37: 1201-1213, 1976.
ARISTIZABAL et al.
331
17. Watring, W.G., Byfield, J.E., Lagasse, L.D., Lee, Y.D., Juillard, G., Jacobs, M., Smith M.L.: Combination adriamycin and radiation therapy in gynecologic cancers. Gynec. Oncol. 2: 518-526, 1974.
Rodialion
Oncology
Biol
Phys
1977. Vol. 2. pp. 325-331
Pergamon Press.
Prmted in the U.S.A.
??Brief Communication
ADRIAMYCIN-IRRADIATION
CUTANEOUS
COMPLICATIONSt
SILVIO A. ARISTIZABAL, M.D.,+ ROBERT C. MILLER, M.D.,S A. LEE SCHLICHTEMEIER, M.D.,9 STEPHEN E. JONES, M.D.7 and MAX L. M. BOONE M.D., Ph.D.” Department of Radiology, Division of Radiation Oncology, (SAA, RCM, ALS, MLMB) and Department of Internal Medicine, (Secion of Hematology and Medical Oncology), (SEJ) The University of Arizona College of Medicine, Tucson, AR 85721, U.S.A. Four cases of abnormally severe skin reactions including an instance of skin necrosis occurred in patients with breast cancer who were treated with cyclophosphamide, adriamycin and irradiation concurrently following mastectomy. These unusual skin reactions apparently resulted from the interaction of radiation with adriamycin and prompted us to modify both the radiation dose and the timing of administration of chemotherapy. To date, no unusual or severe skin reactions have been observed in 14 patients who have received chemotherapy with adriamycin plus radiation in accord with this modified treatment plan. Adriamycin,
Irradiation,
Skin reactions.
INTRODUCTION
have employed both modalities of therapy routinely in patients with the highest risk of recurrence (e.g. 4 or more involved axillary lymph nodes); we are studying the effect of adding radiation therapy to chemotherapy in patients with a somewhat lower risk of recurrence (e.g. l-3 involved axillary nodes). In the course of this program, several patients received adriamycin, cyclophosphamide and radiation therapy concurrently and we observed a number of unusually severe skin reactions as reported here.
The initial management of breast cancer frequently has included the use of postoperative irradiation to reduce the likelihood of local or regional recurrences.’ Recent reports have indicated that adjuvant chemotherapy immediately after mastectomy in women who have metastatic involvement of axillary lymph nodes, dramatically reduces the number of early cancer recurrences.*A Based on our experience in advanced or recurrent breast cancer where we found that the 2-drug combination of adriamycin and cyclophosphamide produced objective cancer regressions as often or more often than other currently available drug combinations,‘.“” in 1974, we initiated an adjuvant breast cancer program employing these two agents.” Although the exact current role for postoperative irradiation in conjunction with adjuvant chemotherapy has yet to be defined, we
METHODS
AND MATERIALS
Between September of 1975 and April of 1976, twenty patients with carcinoma of breast were referred to the Arizona Medical Center for postoperative adjuvant treatment. Their median age was 55 years (range 30-68). Eleven patients had undergone radical mastectomy while 9 had modified radical mastectomy. All
tSupported in part by Public Health Service Grants CA-17094 and CA-17343-01 from the National Cancer Institute, Bethesda, Maryland. *Assistant Professor of Radiology.
§Instructor of Radiology. TAssociate Professor of Internal rProfessor of Radiology. 325
Medicine.
326
Radiation
Oncology
0 Biology 0 Physics
had pathologically involved axillary nodes but no evidence of disseminated metastases (Stage II). Diagnostic tests before treatment included routine blood counts, liver function tests, serum calcium, chest X-ray and bone scan. The original schedule for radiation therapy was to deliver 5,OOOrad in 25 daily equal fractions over 5 weeks to the chest wall (using tangential parallel opposed wedged fields; dose calculated at appropriate combined isodose curve), supraclavicular-axillary areas and internal mammary chain (through direct anterior fields, dose calculated at 1 cm, depth of maximum dose). Bolus material (1 cm thick) was used over the chest wall on alternate days to 4000 rad. The treatment was delivered with an isocenter 4 MeV linear accelerator. Chemotherapy consisted of 21 administered of adriamycin day cycles intravenously (30 mg per m’) on day one and oral cyclophosphamide (150 mg per m’) daily on days 3-6; these doses as employed in our adjuvant program are 75% of the usual full doses.” The first 3 patients were treated currently with full doses of irradiation and chemotherapy. For the next 17 patients the radiation dose was reduced to 4400rad using the same technique and fractionation regimen. Among the patients receiving reduced radiation dose, 2 received combination chemotherapy concurrently and one other patient was treated with only a 3 day time interval between completion of irradiation and the beginning of Table
1. Sequence
and
Treatment Concurrent irradiation (5000 rad) and adriamycin Concurrent irradiationt (4400 rad) and adriamycin 7 days separation between both agents (4400 rad)
timing
March-April
1977, Volume
chemotherapy. Thus for the purpose of analysis, 6 patients were felt to have received concurrent radiation therapy and chemotherapy. Our present plan for combined modality adjuvant treatment is to administer 2 cycles of chemotherapy followed by a 7-10 days rest and then 4400 rad in 4-5 weeks. Seven to 10 days after completion of the course of irradiation, chemotherapy is resumed for an additional 6 cycles. RESULTS The results are summarized in Table 1. Four of 6 patients who received concurrent chemotherapy and irradiation developed acute skin reactions, 2 of them in spite of the reduced radiation dose (4400rad). However, of the 14 patients who were treated sequentially, (with at least 7 days separating irradiation (4400 rad) and chemotherapy) none experienced enhanced radiation reactions of the skin; these are significant differences statistically (p = 0.01). The augmentation of radiation response observed in our patients has been of considerable clinical significance. The exact sequence of treatment as well as the duration and intensity of skin complication is summarized in Fig. 1. In patient 1, the acute skin reaction that progressed from erythema to moist epithelitis to superficial ulceration and necrosis covering an area of 5 x 6 cm (Fig. 2) caused considerable discomfort for the period of 4 months during which healing took place.
of adriamycin-radiation complications
No.
of
patients
3
2
3
2
14
2, No. 3 and No. 4
administration
and
Complications Skin necrosis (Patient 1) Moist epithelitis and esophagitis (Patient 2) Extensive moist epithelitis and slough (Patient 3) Moist desquamation (Patient
4)
O$
tPatient 3 was started on adriamycin 3 days after completion of irradiation. *Difference in results between concurrently and sequentially treated cases is statistically significant (4/6 vs O/14, p = 0.01).
Adriamycin-irradiation
cutaneous
Patlent 1
complications
9/15
327
0 S. A. ARISTIZABAL et al.
IO/V
lrradlatlon Chemotherapy Skin Effect Patlent 2
8/6 tt
8,26 tt
e t+
II/5 tt ‘I-
6 ++ 5
I*/* ++ 4
I/7 tt 4
tt 7 7 Sk,”“eCrOI,l
‘l/1,
VI0
lrradlatlon tt
Chemotherapy
500 tt
+I
Skin Effect Patient 3 lrradiatlon Chemotherapy
I/20
2/20
-123 tt
6
Z/22 +t
‘?/I2 tt
5/3 tt
5/24 tt
6/M
tt
T
Skin Effect Patlent 4 lrradlatlon Chemotherapy
I/5 10/Z? +T
IO,24 tt
12,s
II/14
tt
I/26
12/26 F
tt
tt
+t
_E
Sktn Effect 0
10
30
50
70
90
110
130
. 150
170
Days
Fig. 1. Timing of combined modality therapy for breast cancer in those patients who developed severe cutaneous reactions. Key: t t Adriamycin (30 mg m’) cyclophosphamide (150 mg m’). Skin reaction score scale: 1 = Barely detectable change. 2 = Erythema over 50% of area. 3 = Dry desquamation. 4 = Focal areas of moist reaction. 5 = Moist reaction over 50% of area. 6 = Moist reaction over 80% of area. 7 = Skin necrosis.
Fig. 2. Skin necrosis
in Lt. axilla (Patient
1).
328
Radiation
Oncology
0 Biology 0 Physic\
March-April
Patient 2 developed a severe moist reaction over the entire chest wall field which took 5 weeks to subside. She also experienced symptoms of esophagitis which persisted for 2 months. In patient 3 the acute moist desquamation with skin slough involved 80% of the irradiated chest wall skin (Fig. 3) was of short duration but quite painful. The moist skin reaction in patient 4 spread to the entire in a moist state for 2 chest wall, persisted weeks and healed over the next 2 weeks; the irradiation course had to be discontinued at 3200rad. Despite their severity all of these observed acute skin reactions have been completely reversible over time without skin grafting.
Fig. 3. Extensive
moist
epithelitis
DISCUSSION The skin reactions we observed are sufficiently severe and unusual that we are convinced they are the result of interaction between adriamycin and irradiation administered concurrently. It is well known that antibiotic cancer chemotherapeutic agents like actinomycin D and adriamycin (both “DNA
1977, Volume
2, No.
3 and No. 4
binders”) may enhance the effect of ionizing radiation; complications may occur when these agents are combined with doses of irradiation which would otherwise be well tolerated. This type of interaction with regard to adriamycin has been documented in several experimental and clinical reports in the literature.“‘.14.‘h The role of cyclophosphamide as a radiation enhancer is not clear. Experimental data suggest only an enhanced effect in the lungs of laboratory animals receiving irradiation plus cyclophosphamide.‘” In patients, no augmentation of normal tissue damage (either acute in terms of skin reactions or delayed in terms of fibrosis) was observed with combined
and slough in Rt. chest
wall (Patient
3).
treatment with chemotherapy (cyclophosphamide and vincristine) and irradiation.’ Before the introduction of adjuvant cheinotherapy in our institution, the standard plan for postoperative radiation therapy included 5000rad in 25 daily fractions over 5 weeks. This radiation regimen usually produces a mild erythema and dry desquamation of the
Adriamycin-irradiation
cutaneous
complications
chest wall skin. Occasional patients may develop small areas of moist desquamation. Extensive acute epithelitis or actual skin necrosis are quite rare complications. Because of the severe skin reactions we introduced observed, we have several modifications in our breast cancer treatment plan in an effort to minimize the apparent adriamycin-irradiation interactions. After we recognized an augmented radiation effect (patients 1 and 2, Fig. 3) and scattered reports appeared in the literature describing similar observations,7.‘h.‘7 we reduced the irradiation dose from 5000 to 4400rad in 4.5 weeks. This reduction was based on clinical’ and experimental (mathematical model) data4 which suggested that a dose of 4500rad in 5 weeks could eliminate at least 90% of occult deposits in adenocarcinoma of the breast. We also anticipate that adriamycin will enhance radiation effects in neoplastic as well as normal tissue and the frequency of local recurrence will remain unchanged despite the reduction of radiation dose. In as much as the dose reduction alone did not seem to solve the problems of exuberant radiation reaction as exemplified by patients 3 and 4 (Fig. l), a further modification of the treatment plan was undertaken. Based on in vitro data suggesting that adriamycin inhibits the repair of irradiation damage’4.‘7 and that the sequence and the timing of adriamycin in relation to irradiation might be crucial, we began separating the administration of both modalities by at least 7 days. It is apparent from Fig. 1 that there did not seem to be any correlation between the amount of adriamycin and modification of the irradiation reaction. Patients 2 and 3 had received only one dose of the drug prior to development of complications. The reduction of the irradiation dose per se or in combination with only a three-day separation from drug administration did not affect the results; an acute reaction still developed in 2 of 3 patients. However, when this dose reduction was coupled with at least a 7-day separation between administration of drugs and irradiation, no additional skin reactions have been observed. The short duration of the acute skin reaction following 3 days separation between
0 S. A. ARISTIZABAL
et al.
329
modalities was the first indication of the importance of the “time factor” in relation to complications. Our subsequent experiencetotal absence of acute skin effects when both modalities separated by at least 7 daysfurther suggests that the temporal relationship of administration of both agents plays a more important role than the absolute dose of either one. It is not yet possible on the basis of our data, to determine if indeed a decrease in the radiation dose (to 4400 rad) is necessary if we simply observe the time separation of 7 days between chemotherapy and irradiation. Nonetheless, because these skin reactions were so severe, we have elected to continue with our present combined schedule until more information is available. A review of the literature dealing with adriamycin-irradiation skin toxicity reveals that most patients have been treated concurrently3.1”.‘3 and some sequentially’.” but not in a systematic fashion, either in terms of dose of drug, dose and time factors of irradiation or in temporal relationship to each other to allow for any conclusions. Efforts to determine the factor by which it would be necessary to reduce the amount of irradiation have been fraught with the same difficulties. In this regard, Phillips has suggested the use of the dose-effect factor (DEF) which is the ratio of the radiation dose required in the absence of the drug to the radiation dose required for the same level of damage in the presence of the drug.14 Dose-effect factors for different normal tissues and various combinations of single or multi agent chemotherapy and irradiation have been estimated from available clinical and experimental data.14 Experimentally derived DEF values for skin and mucous membranes exist only for bleomycin (1.2-1.5) and clinically derived values are available for actinomycin (1.7), methotrexate (1.58-1.88), and 6-mercaptopurine (1.18- 1 .32).14 Quantitative information however is lacking especially in relation to adriamycin and DEF values for this agent are still unknown. These values may be of importance in planning future combined chemotherapy and radiotherapy treatment
330
Radiation
Oncology
when one is concerned normal tissues. From
our
ed sequentially,
data
in the a DEF
0 Biology
with last
the
??Physics
safety
14 patients
of treat-
of 1.14 has been calcul-
ated for the chest wall skin of adult women. It is obvious that this value (DEF) varies with whether the patient is treated concurrently or sequentially and also with the length of the time interval between modalities. Although this report is concerned with cutaneous reactions, other organs (lung, heart, esophagus, trachea, thyroid, spinal cord) are included partly within the volume irradiated in the treatment of patients with breast cancer; therefore, they are subject to various degrees of potential damage from radiationadriamycin interaction. Indeed, mediastinal irradiation in cancer patients who receive adriamycin appears to be a risk factor for the subsequent development of cardiomyophathy.‘,”
March-April
1977, Volume
2, No. 3 and No. 4
Enhanced radiation reactions of the esophagus”’ and lungI also have been reported. In our series, except for one instance of severe esophagitis (patient 2), no acute damage to any of these organs has been observed. Not known as yet are the late tissue effects that may result from this therapeutic combination; however, the incidence of late effects usually runs parallel to that of acute reactions.” Consequently, any decrease in the rate of acute reactions should be reflected in a reduced frequency of long term complications. Only additional clinical experience will determine whether our modifications of combined modality therapy will result in satisfactory local and distant control of micrometastases in patients with Stage II breast cancer.
REFERENCES 1. Blum, R.H., Carter, S.K.: Adriamycin: a new anticancer drug with significant clinical activity. Ann. Intern. Med. 80: 249-259, 1974. 2. Bonadonna, G., Brusamolino, E., Valagussa, P., Rossi, A., Brugnatelli, L., Brambilla, C., Delena, M., Tancini, G., Bajetta, E., Musumeci, R., Veronesi, V.: Combination chemotherapy as an adjuvant treatment in inoperable breast cancer. N. Engl. J. Med. 294: 405-410, 1976. 3. Cassady, J.R., Richter, M.P., Piro, A.J., Jaffe, N.: Radiation-adriamycin interactions-Preliminary clinical observations. Cancer 36: 946949, 1975. 4. Cohen, L.: Theoretical iso survival formulae for fractionated radiation therapy. Bri. J. Radiol. 41: 522-528, 1968. 5. Ewy, G.A., Jones, S.E., Groves, B.M.: Adriamycin heart disease. Arizona Med. 33: 274278, 1976. 6. Fisher, B., Carbone, P., Economou, S.G., Frelick, R., Glass, A., Lerner, H., Redmand, C., Zelen, M., Band, P., Katrych, P.L., WoImark, N., Fisher, E.R.: L-Phenylalanine mustard (L-PAM) in the management of primary breast cancer: A report of early findings. N. EngI. J. Med. 292: 117-122, 1975. 7. Fletcher, G.H.: Local results of irradiation in the primary management of localized breast cancer. Cancer 29: 545-551, 1972. Rivkin, S.E., Spigel, S.C., 8. Gottlieb, J.A., Hoogstraten, B., O’Bryan, R.M., Delaney,
9.
10.
Il.
12.
13.
14.
15.
16.
F.C., Singhakowinta, A.: Superiority of adriamycin over oral nitrosoureas in patients with advanced breast carcinoma. Cancer 33: 519526, 1974. Johnson, R.: Discussions: Combined Radiotherapy and Chemotherapy. Cancer 37: 12141215, 1976. Johnson, R.E., Brereton, H.D., Kent, C.H.: Small cell cancer of the lung: Attempt to remedy causes of past therapeutic failure. Lancet 2: 289-291, 1976. Jones, S.E., Durie, B.G.M., Salmon, S.E.: Combination chemotherapy with adriamycin and cyclophosphamide for advanced breast cancer. Cancer 36: 90-97, 1975. Minow, R.A., Benjamin, R.S., Gottlieb, J.A.: cardiomyopathy-an Adriamycin overview with determination of risk factors. Cancer Chemother. Rep. 6: 195-202, 1975. Phillips, T.L., Fu, K.K.: Quantification of combined radiation therapy and chemotherapy effects on critical normal tissues. Cancer 37: 1186-1200, 1976. Phillips, T.L., Wharam, M.D., Margolis, L.W.: Modification of radiation injury to normal tissues by chemotherapeutic agents. Cancer 35: 1678-1684, 1975. Salmon, S.E.: Progress in adjuvant chemotherapy of early breast cancer. Arizona Med. 32: 108-110, 1975. Tefft, M., Lattin, P.B., Jereb, B., Cham, W., Ghavimi, F., Rosen, G., Exelby, P., Marcove,
Adriamycin-irradiation
cutaneous
complications 0 S. A.
R., Murphy, M.L., D’Angio, G.J.: Acute and late effects on normal tissues following combined chemotherapy and radiation therapy for childhood rhabdomyosarcoma and Ewing’s sarcoma. Cancer 37: 1201-1213, 1976.
ARISTIZABAL et al.
331
17. Watring, W.G., Byfield, J.E., Lagasse, L.D., Lee, Y.D., Juillard, G., Jacobs, M., Smith M.L.: Combination adriamycin and radiation therapy in gynecologic cancers. Gynec. Oncol. 2: 518-526, 1974.
