Practical Radiation Oncology (2012) 2, e65–e68
www.practicalradonc.org
Teaching Case
Radiation recall reaction with anastrozole treatment in breast cancer Ayfer Haydaroglu MDa , Fatma Sert MDa,⁎, Ali Can Kazandi MDb , Idil Unal MDb a
Department of Radiation Oncology, Ege University, Izmır, Turkey Department of Dermatology, Ege University, Izmir, Turkey
b
Introduction Radiation recall reactions (RRR) are acute inflammatory tissue reactions that may develop in the preirradiated areas following the administration of certain triggering agents.
Case presentation Our case is a 68-year-old postmenopausal female patient with suspicion of cancer in the right breast. Cancer was detected by mammography. Partial mastectomy and axillary dissection (in physical examination she had palpable lymph nodes in right axillary) were performed in February 2010. Pathologic staging of the patient was pT2N0M0. Diagnosis was invasive ductal carcinoma, with the tumor 4.5 cm in size, located in the lower inner quadrant; cellular grade, 3; nuclear grade, 2; modified Bloom and Richardson grade, 2. None of the 24 axillary nodes displayed metastatic involvement. Surgical margin was 1 cm. In immunohistochemical analysis, it was reported that estrogen receptor was 20% (+2), progesterone receptor 40% (+3), p53 10%, c-erb B2 (-), and Ki 67 30%. Chemotherapy was not considered due to the patient's comorbidities (heart failure, diabetes mellitus) but radiotherapy, and afterward hormonal therapy regimens, were Conflicts of interest: None. ⁎ Corresponding author. Faculty of Medicine, Department of Radiation Oncology, Ege University, Izmır, Turkey. E-mail address: [email protected] (F. Sert).
planned. With 3-dimensional conformal RT, a dose of 50 Gy photons was delivered to the whole breast in tangential field with 6 MV, and an additional 10 Gy electron boost to the tumor bed with 10-MeV electron energy. RT was completed without a problem except for grade 1 radiation dermatitis. Following RT, hormonal therapy was planned for the patient with a hormonesensitive tumor, and an aromatase inhibitor (AI), anastrozole, was started the day that was the end of RT, with the dose of 1 mg once a day, for a period of 5 years. At the first follow-up control (3 months after the RT), the patient reported that she did not have any complaints just after the treatment, but redness and itching started while she used anastrozole on a regular basis. In the physical examination, irradiated areas were observed hyperemic, with erythematous lesions. It was initially considered as radiodermatitis, and local treatment was recommended. Due to the significant increase in complaints, the patient was readmitted again in 2 weeks. In her re-examination, increased hyperemia and papular lesions were observed in the irradiated fields, heat and color differences were detected between the 2 breasts, and the lesions were somewhat diffused out of the radiation field (Fig 1). In the meantime, the patient continued to use anastrozole. In dermatologic examination, hyperpigmented plaques, with purpuric, papular lesions, and partly faint erythematous areas were observed at the right thoracic area of the patient, including only the breast area (so it was differentiated from the drug side effect). In the biopsy specimens taken from these skin lesions, increased pigmentation and vacuolar degeneration at the basal layer of the epidermis, and a few melanophages in the
1879-8500/$ – see front matter © 2012 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.prro.2012.03.001
e66
A. Haydaroglu et al
Practical Radiation Oncology: October-December 2012
Figure 1
Two months after radiotherapy.
superficial dermis were observed. Methylprednisolone aseponate cream, 10% urea cream, and fusidic acid cream were started. The histopathologic findings obtained in the biopsy were found compatible with late-stage lesions of drug eruptions and related mild hyperpigmentation. Together with the histopathologic findings and clinical history of the patient, clinical diagnosis was concluded as radiation recall reaction (Fig 2). Discontinuation of the inducing drug was recommended by the dermatologists. They did not consider this to be a situation that required hospitalization. Due to the diagnosis, anastrozole treatment was discontinued. Treatment regimen recommended by dermatologists was continued and 100% palliation was achieved in dermatologic symptoms (Fig 3).
Discussion RRR was first described by D'Angio in 1959, 1 as the inflammatory skin reaction that may occur in the previously irradiated fields following actinomycin-D treatment. 1-3 The etiology and the pathogenesis of RRR are not clearly understood. In the literature, the incidence
Figure 2
rate was reported as 1 in 49 cases by Sears et al, 4 and similar to 8 in 91 cases by Kodym et al. 5 RRR due to the use of tamoxifen has been rarely reported in breast cancer, while RRR due to the use of AI has never been reported. Therefore, our patient is the first RRR case induced by the use of AI. Boström et al, 3 who focused on vascular damage, specified that local vascular permeability or proliferative changes induced by RT, may influence the pharmacokinetics of the related drugs. Camidge and Price 2 disagreed and indicated that vascular changes could not be detected in the affected tissues. Hellman and Botnick, 6 who have supported the pathogenesis related with stem cell deficiency and increased sensitivity, emphasized that initial RT can reduce the number of epithelial stem cells and epithelial proliferation capacity. Seymour et al 7 modified this hypothesis, and indicated that susceptibility to some drugs may be seen in the irradiated fields due to the permanent changes, even though stem cells develop following RT. Thus, skin reactions occur when stem cells are exposed to the triggering agent. Abadir and Liebmann 8 pointed out the remaining stem cells in the field of radiation, with adequate function, but increased sensitivity.
Histopathologic findings.
Practical Radiation Oncology: October-December 2012
Figure 3
e67
Three months after discontinuation of anastrozol treatment.
Camidge and Price, 2 who argued for “drug hypersensitivity reaction,” emphasized this phenomenon was related, rather than cytotoxic properties of the drug, with particularly idiopathic drug reactions, considering the incidence and rate of occurrence of the reactions, and also the occurrence with various drugs. Considering the rate of occurrence of the reactions, nonimmune mechanisms should remain at the forefront. It generally occurs following mega-voltage RT. Radiation threshold dose causing RRR is not exactly known. In the literature, it was stated that RRR may develop within the radiation dose range of 10 to 81 Gy. 9 RRR may develop much later in the fields irradiated with a low dose, compared with high-dose RT. 10 RRR was noted to develop with many cytotoxic and noncytotoxic drugs such as actinomycin D, doxorubicin (Adriamycin), bleomycin, docetaxel, 5-fluorouracil, etoposide, gemcitabine, isoniazid, rifampicin, and tamoxifen. 1-3 The period between the completion of RT and the development of RRR may differ from several days to several years. In some reports, this interval was between 1 week and 15 years. 1,2,5,11 In our case, RRR developed in 1 month. It is important to differentiate RRR from acute skin reactions occurring after RT. When the period mentioned above is shorter, differential diagnosis may Table 1
RRR with anastrozole treatment in breast cancer
Grading system for the radiation recall reaction
Grade 0: No adverse event Grade 1: Faint erythema or dry desquamation Grade 2: Moderate to severe erythema or a patchy wet desquamation, mostly limited to skin folds and wrinkles; moderate edema Grade 3: Confluent wet desquamation, ≥1.5 cm diameter, not limited to skin folds; pitting edema Grade 4: Skin necrosis or ulceration of full thickness dermis; may be bleedings induced by minor trauma.
become much more difficult. 3 Even though histopathologic characteristics are clearly identified in the literature, epidermal increase of p53 expression following recovery of skin eruptions may be detected by immunohistochemical analysis. 3,5 Dermal atypical vascular dilatation and epidermal necrotic keratinocytes may be detected under direct microscopic examination. Similarly, histopathologic findings related to the internal organs are also nonspecific. Common Toxicity Criteria version 2 is recommended as the grading system for the RRR (Table 1). 1-15 Even though standard treatment of RRR is not yet clearly defined, many researchers recommend discontinuation of anti-inflammatory treatments and administration of the triggering agent. 3 In addition to discontinuation or dose reduction of the drug, topical or systemic steroids, nonsteroidal anti-inflammatory agents, and antihistamines may be recommended according to the severity of reactions. 1-15
Conclusions By means of medical treatments given after RT, RRR developed early in the irradiated fields should be differentiated from acute radiation reactions. It should be particularly noticed that RRR occurs after the recovery of acute reactions and with the administration of the triggering drug, and disappears with the discontinuation of the triggering drug. In our patient with breast cancer, we identified for the first time the RRR induced by AI administered following RT. We differentiated the RRR case from acute skin reactions, proved it by a biopsy, and demonstrated regression of the symptoms by discontinuation of the triggering AI. We concluded that, in addition to some recognized chemotherapeutic agents, administration of anastrozole (an aromatase inhibitor) may also cause RRR.
e68
A. Haydaroglu et al
References 1. D'Angio GJ. Clinical and biological studies of actinomycin D and roentgen irradiation. Am J Roentgenol Radium Ther Nucl Med. 1962;87:106-109. 2. Camidge R, Price A. Characterizing the phenomenon of radiation recall dermatitis. Radiother Oncol. 2001;59:237-245. 3. Boström A, Sjölin-Forsberg G, Wilking N, Bergh J. Radiation recall: another call with tamoxifen. Acta Oncol. 1999;38:955-959. 4. Sears ME. Erythema in areas of previous irradiation in patients treated with hydroxyurea (NSC-32065). Cancer Chemother Rep. 1964;40:31-32. 5. Kodym E, Kalinska R, Ehringfeld C, Sterbik-Lamina A, Kodym R, Hohenberg G. Frequency of radiation recall dermatitis in adult cancer patients. Onkologie. 2005;28:18-21. 6. Hellman S, Botnick LE. Stem cell depletion: an explanation of the late effects of cytotoxins. Int J Radiat Oncol Biol Phys. 1977;2: 181-184. 7. Seymour CB, Mothersill C, Alper T. High yields of lethal mutations in somatic mammalian cells that survive ionizing radiation. Int J Radiat Biol Relat Stud Phys Chem Med. 1986;50:167-179.
Practical Radiation Oncology: October-December 2012 8. Abadir R, Liebmann J. Radiation reaction recall following simvastatin therapy: a new observation. Clin Oncol (R Coll Radiol). 1995;7:325-326. 9. Greco FA, Brereton HD, Kent H, Zimbler H, Merrill J, Johnson RE. Adriamycin and enhanced radiation reaction in normal esophagus and skin. Ann Intern Med. 1976;85:294-298. 10. Greco FA, Oldham RK. Adriamycin and radiation reactions. Ann Intern Med. 1977;86:655-656. 11. Aristizabal SA, Miller RC, Schlichtemeier AL, Jones SE, Boone MLM. Adriamycin-irradiation cutaneous complications. Int J Radiat Oncol Biol Phys. 1977;2:325-331. 12. Phillips TL, Fu KK. Quantification of combined radiation therapy and chemotherapy effects on critical normal tissues. Cancer. 1976;37(2 Suppl):1186-1200. 13. Burstein HJ. Side effects of chemotherapy. Case 1. Radiation recall dermatitis from gemcitabine. J Clin Oncol. 2000;18:693-694. 14. Fontana JA. Radiation recall associated with VP-16-213 therapy. Cancer Treat Rep. 1979;63:224-225. 15. Yeo W, Leung SF, Johnson PJ. Radiation-recall dermatitis with docetaxel: establishment of a requisite radiation threshold. Eur J Cancer. 1997;33:698-699.
www.practicalradonc.org
Teaching Case
Radiation recall reaction with anastrozole treatment in breast cancer Ayfer Haydaroglu MDa , Fatma Sert MDa,⁎, Ali Can Kazandi MDb , Idil Unal MDb a
Department of Radiation Oncology, Ege University, Izmır, Turkey Department of Dermatology, Ege University, Izmir, Turkey
b
Introduction Radiation recall reactions (RRR) are acute inflammatory tissue reactions that may develop in the preirradiated areas following the administration of certain triggering agents.
Case presentation Our case is a 68-year-old postmenopausal female patient with suspicion of cancer in the right breast. Cancer was detected by mammography. Partial mastectomy and axillary dissection (in physical examination she had palpable lymph nodes in right axillary) were performed in February 2010. Pathologic staging of the patient was pT2N0M0. Diagnosis was invasive ductal carcinoma, with the tumor 4.5 cm in size, located in the lower inner quadrant; cellular grade, 3; nuclear grade, 2; modified Bloom and Richardson grade, 2. None of the 24 axillary nodes displayed metastatic involvement. Surgical margin was 1 cm. In immunohistochemical analysis, it was reported that estrogen receptor was 20% (+2), progesterone receptor 40% (+3), p53 10%, c-erb B2 (-), and Ki 67 30%. Chemotherapy was not considered due to the patient's comorbidities (heart failure, diabetes mellitus) but radiotherapy, and afterward hormonal therapy regimens, were Conflicts of interest: None. ⁎ Corresponding author. Faculty of Medicine, Department of Radiation Oncology, Ege University, Izmır, Turkey. E-mail address: [email protected] (F. Sert).
planned. With 3-dimensional conformal RT, a dose of 50 Gy photons was delivered to the whole breast in tangential field with 6 MV, and an additional 10 Gy electron boost to the tumor bed with 10-MeV electron energy. RT was completed without a problem except for grade 1 radiation dermatitis. Following RT, hormonal therapy was planned for the patient with a hormonesensitive tumor, and an aromatase inhibitor (AI), anastrozole, was started the day that was the end of RT, with the dose of 1 mg once a day, for a period of 5 years. At the first follow-up control (3 months after the RT), the patient reported that she did not have any complaints just after the treatment, but redness and itching started while she used anastrozole on a regular basis. In the physical examination, irradiated areas were observed hyperemic, with erythematous lesions. It was initially considered as radiodermatitis, and local treatment was recommended. Due to the significant increase in complaints, the patient was readmitted again in 2 weeks. In her re-examination, increased hyperemia and papular lesions were observed in the irradiated fields, heat and color differences were detected between the 2 breasts, and the lesions were somewhat diffused out of the radiation field (Fig 1). In the meantime, the patient continued to use anastrozole. In dermatologic examination, hyperpigmented plaques, with purpuric, papular lesions, and partly faint erythematous areas were observed at the right thoracic area of the patient, including only the breast area (so it was differentiated from the drug side effect). In the biopsy specimens taken from these skin lesions, increased pigmentation and vacuolar degeneration at the basal layer of the epidermis, and a few melanophages in the
1879-8500/$ – see front matter © 2012 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.prro.2012.03.001
e66
A. Haydaroglu et al
Practical Radiation Oncology: October-December 2012
Figure 1
Two months after radiotherapy.
superficial dermis were observed. Methylprednisolone aseponate cream, 10% urea cream, and fusidic acid cream were started. The histopathologic findings obtained in the biopsy were found compatible with late-stage lesions of drug eruptions and related mild hyperpigmentation. Together with the histopathologic findings and clinical history of the patient, clinical diagnosis was concluded as radiation recall reaction (Fig 2). Discontinuation of the inducing drug was recommended by the dermatologists. They did not consider this to be a situation that required hospitalization. Due to the diagnosis, anastrozole treatment was discontinued. Treatment regimen recommended by dermatologists was continued and 100% palliation was achieved in dermatologic symptoms (Fig 3).
Discussion RRR was first described by D'Angio in 1959, 1 as the inflammatory skin reaction that may occur in the previously irradiated fields following actinomycin-D treatment. 1-3 The etiology and the pathogenesis of RRR are not clearly understood. In the literature, the incidence
Figure 2
rate was reported as 1 in 49 cases by Sears et al, 4 and similar to 8 in 91 cases by Kodym et al. 5 RRR due to the use of tamoxifen has been rarely reported in breast cancer, while RRR due to the use of AI has never been reported. Therefore, our patient is the first RRR case induced by the use of AI. Boström et al, 3 who focused on vascular damage, specified that local vascular permeability or proliferative changes induced by RT, may influence the pharmacokinetics of the related drugs. Camidge and Price 2 disagreed and indicated that vascular changes could not be detected in the affected tissues. Hellman and Botnick, 6 who have supported the pathogenesis related with stem cell deficiency and increased sensitivity, emphasized that initial RT can reduce the number of epithelial stem cells and epithelial proliferation capacity. Seymour et al 7 modified this hypothesis, and indicated that susceptibility to some drugs may be seen in the irradiated fields due to the permanent changes, even though stem cells develop following RT. Thus, skin reactions occur when stem cells are exposed to the triggering agent. Abadir and Liebmann 8 pointed out the remaining stem cells in the field of radiation, with adequate function, but increased sensitivity.
Histopathologic findings.
Practical Radiation Oncology: October-December 2012
Figure 3
e67
Three months after discontinuation of anastrozol treatment.
Camidge and Price, 2 who argued for “drug hypersensitivity reaction,” emphasized this phenomenon was related, rather than cytotoxic properties of the drug, with particularly idiopathic drug reactions, considering the incidence and rate of occurrence of the reactions, and also the occurrence with various drugs. Considering the rate of occurrence of the reactions, nonimmune mechanisms should remain at the forefront. It generally occurs following mega-voltage RT. Radiation threshold dose causing RRR is not exactly known. In the literature, it was stated that RRR may develop within the radiation dose range of 10 to 81 Gy. 9 RRR may develop much later in the fields irradiated with a low dose, compared with high-dose RT. 10 RRR was noted to develop with many cytotoxic and noncytotoxic drugs such as actinomycin D, doxorubicin (Adriamycin), bleomycin, docetaxel, 5-fluorouracil, etoposide, gemcitabine, isoniazid, rifampicin, and tamoxifen. 1-3 The period between the completion of RT and the development of RRR may differ from several days to several years. In some reports, this interval was between 1 week and 15 years. 1,2,5,11 In our case, RRR developed in 1 month. It is important to differentiate RRR from acute skin reactions occurring after RT. When the period mentioned above is shorter, differential diagnosis may Table 1
RRR with anastrozole treatment in breast cancer
Grading system for the radiation recall reaction
Grade 0: No adverse event Grade 1: Faint erythema or dry desquamation Grade 2: Moderate to severe erythema or a patchy wet desquamation, mostly limited to skin folds and wrinkles; moderate edema Grade 3: Confluent wet desquamation, ≥1.5 cm diameter, not limited to skin folds; pitting edema Grade 4: Skin necrosis or ulceration of full thickness dermis; may be bleedings induced by minor trauma.
become much more difficult. 3 Even though histopathologic characteristics are clearly identified in the literature, epidermal increase of p53 expression following recovery of skin eruptions may be detected by immunohistochemical analysis. 3,5 Dermal atypical vascular dilatation and epidermal necrotic keratinocytes may be detected under direct microscopic examination. Similarly, histopathologic findings related to the internal organs are also nonspecific. Common Toxicity Criteria version 2 is recommended as the grading system for the RRR (Table 1). 1-15 Even though standard treatment of RRR is not yet clearly defined, many researchers recommend discontinuation of anti-inflammatory treatments and administration of the triggering agent. 3 In addition to discontinuation or dose reduction of the drug, topical or systemic steroids, nonsteroidal anti-inflammatory agents, and antihistamines may be recommended according to the severity of reactions. 1-15
Conclusions By means of medical treatments given after RT, RRR developed early in the irradiated fields should be differentiated from acute radiation reactions. It should be particularly noticed that RRR occurs after the recovery of acute reactions and with the administration of the triggering drug, and disappears with the discontinuation of the triggering drug. In our patient with breast cancer, we identified for the first time the RRR induced by AI administered following RT. We differentiated the RRR case from acute skin reactions, proved it by a biopsy, and demonstrated regression of the symptoms by discontinuation of the triggering AI. We concluded that, in addition to some recognized chemotherapeutic agents, administration of anastrozole (an aromatase inhibitor) may also cause RRR.
e68
A. Haydaroglu et al
References 1. D'Angio GJ. Clinical and biological studies of actinomycin D and roentgen irradiation. Am J Roentgenol Radium Ther Nucl Med. 1962;87:106-109. 2. Camidge R, Price A. Characterizing the phenomenon of radiation recall dermatitis. Radiother Oncol. 2001;59:237-245. 3. Boström A, Sjölin-Forsberg G, Wilking N, Bergh J. Radiation recall: another call with tamoxifen. Acta Oncol. 1999;38:955-959. 4. Sears ME. Erythema in areas of previous irradiation in patients treated with hydroxyurea (NSC-32065). Cancer Chemother Rep. 1964;40:31-32. 5. Kodym E, Kalinska R, Ehringfeld C, Sterbik-Lamina A, Kodym R, Hohenberg G. Frequency of radiation recall dermatitis in adult cancer patients. Onkologie. 2005;28:18-21. 6. Hellman S, Botnick LE. Stem cell depletion: an explanation of the late effects of cytotoxins. Int J Radiat Oncol Biol Phys. 1977;2: 181-184. 7. Seymour CB, Mothersill C, Alper T. High yields of lethal mutations in somatic mammalian cells that survive ionizing radiation. Int J Radiat Biol Relat Stud Phys Chem Med. 1986;50:167-179.
Practical Radiation Oncology: October-December 2012 8. Abadir R, Liebmann J. Radiation reaction recall following simvastatin therapy: a new observation. Clin Oncol (R Coll Radiol). 1995;7:325-326. 9. Greco FA, Brereton HD, Kent H, Zimbler H, Merrill J, Johnson RE. Adriamycin and enhanced radiation reaction in normal esophagus and skin. Ann Intern Med. 1976;85:294-298. 10. Greco FA, Oldham RK. Adriamycin and radiation reactions. Ann Intern Med. 1977;86:655-656. 11. Aristizabal SA, Miller RC, Schlichtemeier AL, Jones SE, Boone MLM. Adriamycin-irradiation cutaneous complications. Int J Radiat Oncol Biol Phys. 1977;2:325-331. 12. Phillips TL, Fu KK. Quantification of combined radiation therapy and chemotherapy effects on critical normal tissues. Cancer. 1976;37(2 Suppl):1186-1200. 13. Burstein HJ. Side effects of chemotherapy. Case 1. Radiation recall dermatitis from gemcitabine. J Clin Oncol. 2000;18:693-694. 14. Fontana JA. Radiation recall associated with VP-16-213 therapy. Cancer Treat Rep. 1979;63:224-225. 15. Yeo W, Leung SF, Johnson PJ. Radiation-recall dermatitis with docetaxel: establishment of a requisite radiation threshold. Eur J Cancer. 1997;33:698-699.
