Case Report
Radiation Recall Reaction With Letrozole Therapy in Breast Cancer Lauren M. Foster,1 Mary Ellen Mahoney,2 Michael W. Harmon,3 Jeffrey W. Allen,4 Join Y. Luh5 Clinical Practice Points Radiation recall reaction is a rare inflammatory skin
condition that occurs in a previously irradiated field and is prompted by the administration of certain drugs. We report a case of a 74-year-old woman with stage IIA cancer of the right breast who was treated with lumpectomy and radiation and experienced
radiation recall reaction after starting adjuvant letrozole. Discontinuing letrozole led to resolution of the skin reaction, after which the patient was able to resume the medication without complications. The pathophysiologic characteristics of radiation recall reaction are discussed.
Clinical Breast Cancer, Vol. 14, No. 3, e95-7 ª 2014 Elsevier Inc. All rights reserved. Keywords: Letrozole, Radiation recall reaction, Radiation therapy
Introduction Radiation recall reaction is a rare inflammatory condition of the skin similar in appearance to the acute erythema that occurs as a side effect of radiation therapy. The radiation recall reaction occurs in the previously irradiated field and is prompted by the administration of certain drugs. A recall reaction can occur over a broad time frame, ranging from days to years after the radiation treatment.1 However, once the patient is exposed to the recall-activating drug, the reaction develops within a couple of minutes to days.1 Numerous chemotherapy agents are associated with recall, but here we describe a case associated with the nonsteroidal aromatase inhibitor letrozole. To our knowledge, this is the first report of radiation recall reaction with this medication.
Case Report The patient is a 74-year-old postmenopausal woman who presented with an abnormal screening mammogram on May 1, 2012. The mammogram showed a new 1-cm density in the right breast in 1
Lyman Briggs College, Michigan State University, East Lansing, MI Department of General Surgery, St. Joseph Hospital, Eureka, CA; Stanford Cancer Institute, Stanford, CA 3 Department of Radiation Oncology, St. Joseph Hospital, Eureka, CA 4 Humboldt Medical Specialists HematologyeOncology, Eureka, CA 5 Department of Radiation Oncology, St. Joseph Hospital, Eureka, CA; University of Texas Health Science Center at San Antonio, Cancer Therapy and Research Center 2
Submitted: Oct 15, 2013; Revised: Dec 25, 2013; Accepted: Dec 26, 2013; Epub: Jan 3, 2014 Address for correspondence: Join Y. Luh, MD, St. Joseph Hospital, 2700 Dolbeer St, Eureka, CA 95501 Fax: 7070-269-3849; e-mail contact: [email protected]
1526-8209/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2013.12.011
the retroareolar region. A follow-up mammogram and ultrasonogram of the right breast performed on May 11, 2012 were read as Breast Imaging Reporting and Data System (BI-RADS) 4, and an ultrasonographically guided biopsy on May 30, 2012 showed grade 1 invasive ductal carcinoma that was strongly estrogen receptor/ progesterone receptor positive and human epidermal growth factor receptor 2 (HER2) negative (immunohistochemical score of 2þ; fluorescence in situ hybridization negative) with a low proliferative index (Ki-67, 9%). She underwent a lumpectomy and axillary lymph node dissection on July 2, 2012. The final pathologic staging of the patient was pT2N0(i-)M0 (stage IIA). Given the favorable prognostic factors, chemotherapy was not recommended and the patient received whole breast radiation therapy from August 13, 2012 until September 27, 2012. The whole breast received a dose of 5040 cGy in tangential fields with an additional boost to the tumor bed of 1000 cGy using a wedge pair field. Side effects of the radiation therapy included a grade 2 brisk erythema (Common Terminology Criteria for Adverse Events, version 2.0) within the treatment field and increased pigmentation near the right axilla, as well as some fatigue. After several weeks, the skin reaction resolved completely. Approximately 2 months after radiation therapy, the patient began hormonal therapy with the nonsteroidal aromatase inhibitor letrozole at a dose of 2.5 mg daily. She did well until approximately 1 month after starting letrozole. She presented for follow-up on December 10, 2012 with a recurrence of grade 2 erythema and itching in her right breast (Fig. 1). The skin reaction was similar to the reaction she had experienced during radiation therapy and had the shape of the previous radiation portals. The use of topical creams gave no relief. The clinical
Clinical Breast Cancer June 2014
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Radiation Recall Reaction and Letrozole Figure 1 Recall Reaction in Right Breast
Table 1 Grading System for the Radiation Recall Reaction Grade 0 Grade 1 Grade 2 Grade 3 Grade 4
assessment was that the patient was experiencing a recall skin reaction resulting from previous radiation therapy. Discontinuation of the inducing drug, letrozole, was recommended for 10 days and the patient was to return for follow-up after that time. She returned for a follow-up visit 8 days later and continued to have erythema of the right breast, but the itching in the involved skin had ceased. Letrozole treatment continued to be withheld. Approximately 3 weeks later, on January 9, 2013, she was seen for an evaluation of the recall reaction; the skin reaction had dramatically improved. The right breast had increased pigmentation but no erythema, dry desquamation, or moist desquamation. Letrozole was then restarted. At her next follow-up appointment in April 2013, she was tolerating letrozole well. The recall reaction had completely resolved and she now had only slight hyperpigmentation within her previous treatment fields, which is normal for patients who have undergone breast radiation therapy. Physical examination revealed a good cosmetic outcome and no evidence of recurrent tumor in the breast.
Discussion
e96
-
Radiation recall reactions are a phenomenon whose exact mechanism is unclear. However, there are many hypotheses based on the existing knowledge of the reaction and the evidence presented by case reports. There are several potential causes that stand out as most plausible. The most commonly used grading system for the radiation recall reaction has been the Common Terminology Criteria for Adverse Events, version 2.0 (Table 1).1-7 There have since been several updates to this system, the current being version 4.03.8 One hypothesis is that radiation produces an inadequacy of epithelial stem cells. Hellman and Botnick suggested that radiation depletes the number of epithelial stem cells and a full recovery does not occur.2 Seymour et al hypothesized that stem cells are present after radiation but are made inadequate by changes after irradiation, including impairment of the cells’ capability to proliferate and function as normal stem cells.3 Abadir and Leibmann proposed the mechanism of epithelial stem cell sensitivity.4 The increased sensitivity is based on the assumption
Clinical Breast Cancer June 2014
No adverse event Faint erythema or dry desquamation Moderate to severe erythema or a patchy wet desquamation, mostly limited to skin folds and wrinkles; moderate edema Confluent wet desquamation 1.5 cm diameter not limited to skin folds; pitting edema Skin necrosis or ulceration of full-thickness dermis; may be bleeding induced by minor trauma
that stem cells remain functional after radiation-induced depletion by cycling at a faster rate. Drugs that are active in rapidly reproducing cells would have a more detrimental effect on these cells, and they would therefore be more prone to damage. Vascular damage is another proposed mechanism of the recall reaction. Bostrom et al offered the explanation that irradiation induces changes in local vascular permeability, affecting the pharmacokinetics of the triggering drugs.5 Based on the rate of onset of the recall reaction after exposure to an inducing drug, Camidge and Price proposed a method related to drug hypersensitivity.1 Nonimmune mechanisms are favored in this hypothesis over immune mechanisms because of the speed of the onset of reaction symptoms. Drug hypersensitivity in conjunction with radiation-induced cellular sensitivity best theorizes the mechanism behind the radiation recall reaction. Recall reactions are rare. Reactions have been reported to occur with many cytotoxic and noncytotoxic drugs, such as actinomycin D, doxorubicin, bleomycin, docetaxel, 5-fluorouracil, etoposide, gemcitabine, isoniazid, rifampicin, and tamoxifen.1,5,6 There have been several documented cases involving the use of tamoxifen in adjuvant therapy for patients with breast cancer. There has been one published report in which the nonsteroidal aromatase inhibitor anastrozole caused a recall reaction.7 However, there have been no previously documented cases involving letrozole. Therefore, to our knowledge, our patient is the first reported case of a recall reaction in response to letrozole and the second reported case of a reaction caused by a nonsteroidal aromatase inhibitor. We are unaware of any published reports on recall reactions caused by the steroidal aromatase inhibitor exemestane. Recall reactions can develop within a wide time frame after radiation therapy. In our case, the patient developed the reaction 2 months after irradiation. She was advised to discontinue letrozole, and after 1 month without taking the inducing drug, the skin reaction had completely resolved. Once letrozole was restarted, she had no recurrence of the reaction and was able to continue her treatment, suggesting that recall reaction and not an allergic reaction is the likely explanation for this phenomenon. An IgE-mediated allergic reaction would have likely resulted in a worse and more intense reaction on reinitiation of letrozole. Clinically, our case is significant because it demonstrates that once a recall reaction is resolved, a patient can restart hormonal therapy. Completing the recommended duration of hormonal therapy decreases the patient’s odds of having a tumor recurrence. The patient in the case of anastrozole-induced radiation recall reaction discontinued the medication permanently.7 To our
Lauren M. Foster et al knowledge, ours is the first reported case in which a patient was successfully restarted on an aromatase inhibitor after a recall reaction.
Conclusion
We present the first reported case in the United States, to our knowledge, of radiation recall reaction in response to the nonsteroidal aromatase inhibitor letrozole, and the first case in which the patient was able to resume the drug successfully after a short interruption in therapy. Radiation recall reactions occur in response to an inducing drug and arise in the previously irradiated field. This skin reaction is separate from the acute radiation reaction and occurs after the acute reaction has resolved. The discontinuation of the inducing drug allows the reaction to cease. After the resolution of the skin reaction, the drug can be restarted and treatment can be resumed without the recurrence of the recall reaction. The ability to resume treatment has significant therapeutic advantages
and distinguishes radiation recall reaction from an allergic reaction.
References 1. Camidge R, Price A. Characterizing the phenomenon of radiation recall dermatitis. Radiother Oncol 2001; 59:237-45. 2. Hellman S, Botnick LE. Stem cell depletion: an explanation of the late effects of cytotoxins. Int J Radiat Oncol Biol Phys 1977; 2:181-4. 3. Seymour CB, Mothersill C, Alper T. High yields of lethal mutations in somatic mammalian cells that survive ionizing radiation. Int J Radiat Biol 1986; 50: 167-79. 4. Abadir R, Liebmann J. Radiation reaction recall following simvastatin therapy: a new observation. Clin Oncol 1995; 7:325-6. 5. Bostrom A, Sjolin-Forsberg G, Wilking N, Bergh J. Radiation recall: another call with tamoxifen. Acta Oncol 1999; 38:955-9. 6. D’Angio GJ. Clinical and biological studies of actinomycin D and roentgen irradiation. Am J Roentgenol Radium Ther Nucl Med 1962; 87: 106-9. 7. Haydaroglu A, Sert F, Kazandi A, Unal I. Radiation recall reaction with anastrozole treatment in breast cancer. Practical Radiat Onco 2012; 2:65-8. 8. US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Available at: http://evs.nci.nih.gov/ ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed: September 16, 2013.
Clinical Breast Cancer June 2014
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Radiation Recall Reaction With Letrozole Therapy in Breast Cancer Lauren M. Foster,1 Mary Ellen Mahoney,2 Michael W. Harmon,3 Jeffrey W. Allen,4 Join Y. Luh5 Clinical Practice Points Radiation recall reaction is a rare inflammatory skin
condition that occurs in a previously irradiated field and is prompted by the administration of certain drugs. We report a case of a 74-year-old woman with stage IIA cancer of the right breast who was treated with lumpectomy and radiation and experienced
radiation recall reaction after starting adjuvant letrozole. Discontinuing letrozole led to resolution of the skin reaction, after which the patient was able to resume the medication without complications. The pathophysiologic characteristics of radiation recall reaction are discussed.
Clinical Breast Cancer, Vol. 14, No. 3, e95-7 ª 2014 Elsevier Inc. All rights reserved. Keywords: Letrozole, Radiation recall reaction, Radiation therapy
Introduction Radiation recall reaction is a rare inflammatory condition of the skin similar in appearance to the acute erythema that occurs as a side effect of radiation therapy. The radiation recall reaction occurs in the previously irradiated field and is prompted by the administration of certain drugs. A recall reaction can occur over a broad time frame, ranging from days to years after the radiation treatment.1 However, once the patient is exposed to the recall-activating drug, the reaction develops within a couple of minutes to days.1 Numerous chemotherapy agents are associated with recall, but here we describe a case associated with the nonsteroidal aromatase inhibitor letrozole. To our knowledge, this is the first report of radiation recall reaction with this medication.
Case Report The patient is a 74-year-old postmenopausal woman who presented with an abnormal screening mammogram on May 1, 2012. The mammogram showed a new 1-cm density in the right breast in 1
Lyman Briggs College, Michigan State University, East Lansing, MI Department of General Surgery, St. Joseph Hospital, Eureka, CA; Stanford Cancer Institute, Stanford, CA 3 Department of Radiation Oncology, St. Joseph Hospital, Eureka, CA 4 Humboldt Medical Specialists HematologyeOncology, Eureka, CA 5 Department of Radiation Oncology, St. Joseph Hospital, Eureka, CA; University of Texas Health Science Center at San Antonio, Cancer Therapy and Research Center 2
Submitted: Oct 15, 2013; Revised: Dec 25, 2013; Accepted: Dec 26, 2013; Epub: Jan 3, 2014 Address for correspondence: Join Y. Luh, MD, St. Joseph Hospital, 2700 Dolbeer St, Eureka, CA 95501 Fax: 7070-269-3849; e-mail contact: [email protected]
1526-8209/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2013.12.011
the retroareolar region. A follow-up mammogram and ultrasonogram of the right breast performed on May 11, 2012 were read as Breast Imaging Reporting and Data System (BI-RADS) 4, and an ultrasonographically guided biopsy on May 30, 2012 showed grade 1 invasive ductal carcinoma that was strongly estrogen receptor/ progesterone receptor positive and human epidermal growth factor receptor 2 (HER2) negative (immunohistochemical score of 2þ; fluorescence in situ hybridization negative) with a low proliferative index (Ki-67, 9%). She underwent a lumpectomy and axillary lymph node dissection on July 2, 2012. The final pathologic staging of the patient was pT2N0(i-)M0 (stage IIA). Given the favorable prognostic factors, chemotherapy was not recommended and the patient received whole breast radiation therapy from August 13, 2012 until September 27, 2012. The whole breast received a dose of 5040 cGy in tangential fields with an additional boost to the tumor bed of 1000 cGy using a wedge pair field. Side effects of the radiation therapy included a grade 2 brisk erythema (Common Terminology Criteria for Adverse Events, version 2.0) within the treatment field and increased pigmentation near the right axilla, as well as some fatigue. After several weeks, the skin reaction resolved completely. Approximately 2 months after radiation therapy, the patient began hormonal therapy with the nonsteroidal aromatase inhibitor letrozole at a dose of 2.5 mg daily. She did well until approximately 1 month after starting letrozole. She presented for follow-up on December 10, 2012 with a recurrence of grade 2 erythema and itching in her right breast (Fig. 1). The skin reaction was similar to the reaction she had experienced during radiation therapy and had the shape of the previous radiation portals. The use of topical creams gave no relief. The clinical
Clinical Breast Cancer June 2014
- e95
Radiation Recall Reaction and Letrozole Figure 1 Recall Reaction in Right Breast
Table 1 Grading System for the Radiation Recall Reaction Grade 0 Grade 1 Grade 2 Grade 3 Grade 4
assessment was that the patient was experiencing a recall skin reaction resulting from previous radiation therapy. Discontinuation of the inducing drug, letrozole, was recommended for 10 days and the patient was to return for follow-up after that time. She returned for a follow-up visit 8 days later and continued to have erythema of the right breast, but the itching in the involved skin had ceased. Letrozole treatment continued to be withheld. Approximately 3 weeks later, on January 9, 2013, she was seen for an evaluation of the recall reaction; the skin reaction had dramatically improved. The right breast had increased pigmentation but no erythema, dry desquamation, or moist desquamation. Letrozole was then restarted. At her next follow-up appointment in April 2013, she was tolerating letrozole well. The recall reaction had completely resolved and she now had only slight hyperpigmentation within her previous treatment fields, which is normal for patients who have undergone breast radiation therapy. Physical examination revealed a good cosmetic outcome and no evidence of recurrent tumor in the breast.
Discussion
e96
-
Radiation recall reactions are a phenomenon whose exact mechanism is unclear. However, there are many hypotheses based on the existing knowledge of the reaction and the evidence presented by case reports. There are several potential causes that stand out as most plausible. The most commonly used grading system for the radiation recall reaction has been the Common Terminology Criteria for Adverse Events, version 2.0 (Table 1).1-7 There have since been several updates to this system, the current being version 4.03.8 One hypothesis is that radiation produces an inadequacy of epithelial stem cells. Hellman and Botnick suggested that radiation depletes the number of epithelial stem cells and a full recovery does not occur.2 Seymour et al hypothesized that stem cells are present after radiation but are made inadequate by changes after irradiation, including impairment of the cells’ capability to proliferate and function as normal stem cells.3 Abadir and Leibmann proposed the mechanism of epithelial stem cell sensitivity.4 The increased sensitivity is based on the assumption
Clinical Breast Cancer June 2014
No adverse event Faint erythema or dry desquamation Moderate to severe erythema or a patchy wet desquamation, mostly limited to skin folds and wrinkles; moderate edema Confluent wet desquamation 1.5 cm diameter not limited to skin folds; pitting edema Skin necrosis or ulceration of full-thickness dermis; may be bleeding induced by minor trauma
that stem cells remain functional after radiation-induced depletion by cycling at a faster rate. Drugs that are active in rapidly reproducing cells would have a more detrimental effect on these cells, and they would therefore be more prone to damage. Vascular damage is another proposed mechanism of the recall reaction. Bostrom et al offered the explanation that irradiation induces changes in local vascular permeability, affecting the pharmacokinetics of the triggering drugs.5 Based on the rate of onset of the recall reaction after exposure to an inducing drug, Camidge and Price proposed a method related to drug hypersensitivity.1 Nonimmune mechanisms are favored in this hypothesis over immune mechanisms because of the speed of the onset of reaction symptoms. Drug hypersensitivity in conjunction with radiation-induced cellular sensitivity best theorizes the mechanism behind the radiation recall reaction. Recall reactions are rare. Reactions have been reported to occur with many cytotoxic and noncytotoxic drugs, such as actinomycin D, doxorubicin, bleomycin, docetaxel, 5-fluorouracil, etoposide, gemcitabine, isoniazid, rifampicin, and tamoxifen.1,5,6 There have been several documented cases involving the use of tamoxifen in adjuvant therapy for patients with breast cancer. There has been one published report in which the nonsteroidal aromatase inhibitor anastrozole caused a recall reaction.7 However, there have been no previously documented cases involving letrozole. Therefore, to our knowledge, our patient is the first reported case of a recall reaction in response to letrozole and the second reported case of a reaction caused by a nonsteroidal aromatase inhibitor. We are unaware of any published reports on recall reactions caused by the steroidal aromatase inhibitor exemestane. Recall reactions can develop within a wide time frame after radiation therapy. In our case, the patient developed the reaction 2 months after irradiation. She was advised to discontinue letrozole, and after 1 month without taking the inducing drug, the skin reaction had completely resolved. Once letrozole was restarted, she had no recurrence of the reaction and was able to continue her treatment, suggesting that recall reaction and not an allergic reaction is the likely explanation for this phenomenon. An IgE-mediated allergic reaction would have likely resulted in a worse and more intense reaction on reinitiation of letrozole. Clinically, our case is significant because it demonstrates that once a recall reaction is resolved, a patient can restart hormonal therapy. Completing the recommended duration of hormonal therapy decreases the patient’s odds of having a tumor recurrence. The patient in the case of anastrozole-induced radiation recall reaction discontinued the medication permanently.7 To our
Lauren M. Foster et al knowledge, ours is the first reported case in which a patient was successfully restarted on an aromatase inhibitor after a recall reaction.
Conclusion
We present the first reported case in the United States, to our knowledge, of radiation recall reaction in response to the nonsteroidal aromatase inhibitor letrozole, and the first case in which the patient was able to resume the drug successfully after a short interruption in therapy. Radiation recall reactions occur in response to an inducing drug and arise in the previously irradiated field. This skin reaction is separate from the acute radiation reaction and occurs after the acute reaction has resolved. The discontinuation of the inducing drug allows the reaction to cease. After the resolution of the skin reaction, the drug can be restarted and treatment can be resumed without the recurrence of the recall reaction. The ability to resume treatment has significant therapeutic advantages
and distinguishes radiation recall reaction from an allergic reaction.
References 1. Camidge R, Price A. Characterizing the phenomenon of radiation recall dermatitis. Radiother Oncol 2001; 59:237-45. 2. Hellman S, Botnick LE. Stem cell depletion: an explanation of the late effects of cytotoxins. Int J Radiat Oncol Biol Phys 1977; 2:181-4. 3. Seymour CB, Mothersill C, Alper T. High yields of lethal mutations in somatic mammalian cells that survive ionizing radiation. Int J Radiat Biol 1986; 50: 167-79. 4. Abadir R, Liebmann J. Radiation reaction recall following simvastatin therapy: a new observation. Clin Oncol 1995; 7:325-6. 5. Bostrom A, Sjolin-Forsberg G, Wilking N, Bergh J. Radiation recall: another call with tamoxifen. Acta Oncol 1999; 38:955-9. 6. D’Angio GJ. Clinical and biological studies of actinomycin D and roentgen irradiation. Am J Roentgenol Radium Ther Nucl Med 1962; 87: 106-9. 7. Haydaroglu A, Sert F, Kazandi A, Unal I. Radiation recall reaction with anastrozole treatment in breast cancer. Practical Radiat Onco 2012; 2:65-8. 8. US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Available at: http://evs.nci.nih.gov/ ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed: September 16, 2013.
Clinical Breast Cancer June 2014
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