512 Short communication
Radiation recall dermatitis and radiation pneumonitis during treatment with vemurafenib Andrea Forschnera, Daniel Zipsb, Christina Schramlc, Martin Ro¨ckena, Eleni Iordanoua, Ulrike Leitera, Benjamin Weidea, Claus Garbea and Friedegund Meiera The basis of radiation recall reactions (RRR) is a subclinical radiation damage that is uncovered later by treatment with anticancer agents. Several drugs have been associated with RRR, in particular taxanes and anthracyclines. Recently, a few cases were reported concerning radiation recall dermatitis caused by vemurafenib. Up to now, there have been no reports of RRR in the lung induced by vemurafenib. We describe the occurrence of RRR in three melanoma patients who had undergone radiotherapy for metastases followed by systemic treatment with the BRAF inhibitor vemurafenib. Two patients developed radiation recall pneumonitis (RRP) and one patient developed radiation recall dermatitis (RRD) 5–7 weeks after the radiation treatment was finished and 2–4 weeks after vemurafenib was started. The early application of systemic (RRP) and topical corticosteroids (RRD) enabled us to continue the treatment with vemurafenib without dose
reduction. Caution is needed when vemurafenib is planned for patients who have undergone previous radiotherapy, and RRR of the skin and the lung have to be taken into c 2014 Wolters account. Melanoma Res 24:512–516 Kluwer Health | Lippincott Williams & Wilkins.
Introduction
Case reports
Radiation recall reactions (RRR) describe inflammatory reactions after a previous radiation treatment induced by a subsequent drug treatment. Typical radiation-induced inflammatory reactions occur during or directly after the irradiation procedure, whereas RRR typically manifest after a noninflammatory interval and only after the start of systemic drug treatment. The basis of RRR is a subclinical radiation damage that is uncovered later by treatment with anticancer agents. D’Angio et al. [1] was the first to describe the reactivation of ‘latent radiation effects in normal tissue’, induced by actinomycin D.
Patient 1
The skin is the easiest organ to observe; this might be the reason why most of the radiation recall phenomena are diagnosed on the skin, presenting with radiation recall dermatitis (RRD). If radiation recall involves previously irradiated pulmonary tissue, it is designated as radiation recall pneumonitis (RRP). Several drugs have been associated with RRR, in particular taxanes and anthracyclines [2–4]. Recently, a few cases were reported concerning RRD caused by vemurafenib [5,6]. To date, no reports of RRP induced by BRAF inhibitors have been published. We describe the occurrence of RRP in two melanoma patients and RRD in one melanoma patient who had undergone radiotherapy for metastases followed by systemic treatment with the BRAF inhibitor vemurafenib. c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0960-8931
Melanoma Research 2014, 24:512–516 Keywords: dermatitis, metastatic melanoma, pneumonitis, radiation recall, radiotherapy, vemurafenib Departments of aDermatology, bRadiooncology and cRadiology, Eberhard-Karls University of Tu¨bingen, Tu¨bingen, Germany Correspondence to Claus Garbe, MD, PhD, Department of Dermatology, Division of Dermatologic Oncology, Eberhard-Karls University of Tuebingen, Liebermeisterstr. 25, D-72076 Tu¨bingen, Germany Tel: + 49 07071 2987110; fax: + 49 07071 295187; e-mail: [email protected] Received 18 April 2013 Accepted 18 March 2014
A 71-year-old male patient had a complete resection of relapsing BRAF V600 E-positive lymph node melanoma metastases of the right axilla and subcutaneous metastases of the right pectoral side. Three weeks later, adjuvant radiotherapy of the right axilla, including the right supraclavicular, infraclavicular and pectoral regions, was given for 5 weeks with a cumulative dose of 50 Gy (International Commission on Radiation Units, 5 2 Gy/ week, CT-planned 3D-conformal radiotherapy, 15 MV photons, anterior and posterior beam arrangement with two fields, multileaf collimation). The estimated skin dose was between 30 and 40 Gy, which led to mild erythema (common toxicity criteria, grade 1) at the end of the therapy. The mean radiation doses to both lungs combined (mean lung dose) and the lung volume receiving 20 Gy (V20) were 6.9 Gy and 12.4%, respectively. Four weeks after completing the well-tolerated radiotherapy, systemic treatment with vemurafenib 960 mg twice a day was started for multiple melanoma metastases in the lung, the liver and the brain. The computed tomography (CT) before starting vemurafenib in August 2012 revealed no features of radiation-induced injury of the lung (Fig. 1b). After 3 weeks of vemurafenib treatment, the patient developed a dry and obsessing cough. The body temperature was normal. In the CT scan, parenchymal changes with predominant ground glass appearance of the right upper DOI: 10.1097/CMR.0000000000000078
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RRD, radiation pneumonitis under vemurafenib Forschner et al. 513
Fig. 1
(a)
(b)
(c)
(d)
lung, corresponding to the radiation dose distribution (Fig. 1a), had newly occurred. The diagnosis of radiation pneumonitis was established (Fig. 1c). We continued vemurafenib without any reduction of the dosage and added prednisolone 150 mg/day, accompanied by a prophylactic antibiotic therapy (amoxicillin and clavulanic acid) for 10 days. As the cough improved rapidly, the prednisolone dosage was reduced by 50 mg/week. Four weeks later, the infiltration of the right upper lung showed progressive consolidation consistent with a typical course in radiation pneumonitis (Fig. 1d). The patient was in a good general condition and subsequently did not have further pulmonary complaints. Patient 2
A 47-year-old female patient developed unresectable, BRAF V600 E-positive lymph node melanoma metastases of the upper mediastinum leading to an obstruction of the left main bronchus. The patient was supplied by stenting and radiotherapy for 4 weeks with a cumulative dose of 40 Gy (5 2.5 Gy/week)/shrinking field up to 50 Gy (5 2 Gy/week, CT-planned 3D-conformal radiotherapy, 6/15 MV photons, three beams anterior, posterior and oblique). The mean lung lode and the V20 were 17.4 Gy and 32.9%, respectively. During radiotherapy, the patient developed dysphagia and congestive cough with wheezing and humming. Her treatment consisted of dexamethasone 3 mg/day and an inhalation therapy with ambroxol. In March 2012, radiotherapy was completed. The CT scan did not reveal any radiation-induced injury of the lung (Fig. 2b). Three weeks later, we started treatment with vemurafenib 960 mg twice a day for lung, subcutaneous and peritoneal metastases. Four weeks later, the patient presented with heavy breathing and was hospitalized. In the CT scan of the thorax, groundglass opacities with consolidations, most prominent in the irradiated paramediastinal region according to the radiation dose distribution (Fig. 2a), were found and judged as radiation pneumonitis (Fig. 2c). A treatment with 60 mg prednisolone was started in combination with a prophylactic antibiotic therapy (amoxicillin and clavulanic acid) for 10 days. The symptoms improved promptly. Vemurafenib was continued. In June 2012, a CT scan revealed regression of the metastases and a consolidation of infiltrative changes (Fig. 2d). Patient 3
(a) The spatial radiation dose distribution with isodoses for 20, 30, 40 and 47.5 Gy (i.e. 95% of the prescribed dose) shown as red, blue, green and yellow lines, respectively. (b) Computed tomography 4 weeks after completing radiotherapy and before starting vemurafenib treatment (22.08.12). No features of radiation-induced injury of the lung. (c) Computed tomography after 4 weeks of vemurafenib treatment (25.09.12). Infiltrative changes of the right upper lung, corresponding to the irradiation area. (d) Computed tomography 4 weeks later (26.10.12). Consolidation of infiltrative changes.
A 37-year old male patient had excision of a BRAF V600 E-positive cerebral melanoma metastasis of the right frontal side. Two months later, an MRI of the brain revealed local recurrence and meningeosis. Therefore, whole-brain radiotherapy was performed with a cumulative dose of 30 Gy (5 3 Gy/week, 6 MV photons, 2D opposing lateral fields). The radiation was well tolerated without any skin toxicity. One week after completing radiotherapy, PET-CT revealed new inoperable lymph node metastases of the left axilla. Therefore, 3 weeks
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514 Melanoma Research 2014, Vol 24 No 5
Fig. 2
(a)
after completion of radiotherapy, in March 2012, systemic treatment with vemurafenib 960 mg twice a day was initiated. Two weeks after starting vemurafenib, the patient developed multiple itchy vesicles and papules on an erythematous swelling of the scalp, sharply defined to the prior irradiated area and consistent with RRD (Fig. 3a and b). We continued vemurafenib and treated him with topical corticosteroids. Six weeks later, RRD of the head had resolved, and after 2 months of vemurafenib treatment, a complete response was observed.
Discussion (b)
(c)
Enhanced sensitivity to systemically administrated drugs in the first week after completing radiotherapy is a frequent phenomenon, and it should be emphasized that acute responses to radiation therapy alone within 1 week are frequent. If the reactions appear after the first week, induced by subsequent drug treatment, they are called RRR [7,8]. The most reliable RRR is strongly confined to the former radiotherapy field and several years have passed since finishing the treatment. Several drugs have been reported to cause RRR: doxorubicin, epirubicin, adriamycin, etoposide, gemcitabine, paclitaxel, docetaxel, and vinorelbine [3,4,9–20]. In contrast to RRD, RRP is much rarer, and only 20 cases have been reported so far [4,10,12–14,17,18,20]. Vemurafenib appears to potentiate radiation effects in vitro [21]. Recently, a few clinical cases concerning radiosensitizing effects and RRD in patients under treatment with vemurafenib and radiotherapy were reported. Most of these patients developed skin toxicity, and one patient developed skin and liver toxicity [5,6,22,23]. Up to now, there have been no reports of RRR in the lung induced by vemurafenib.
(d)
(a) The spatial radiation dose distribution with isodoses for 20, 30, 40 and 47.5 Gy (i.e. 95% of the prescribed dose) shown as red, blue, green and yellow lines, respectively. (b) Computed tomography 3 weeks after completing radiotherapy and before starting vemurafenib treatment (22.03.12). No features of radiation-induced injury of the lung. (c) Computed tomography after 4 weeks of vemurafenib treatment (24.04.12). Ground-glass opacities most prominent in the irradiated paramediastinal region. (d) Computed tomography 7 weeks later (11.06.12). Consolidation of infiltrative changes with some remaining air bronchograms as typically observed over time in radiation-induced pneumonitis.
Lung toxicity represents an important dose-limiting side effect of thoracic radiotherapy [24,25]. The estimated risk of symptomatic radiation pneumonitis according to dosimetric parameters is less than 5% for patient one and about 15% for patient two [26]. Thus, on the basis of dosimetric considerations and the time course, it cannot be excluded that the radiation pneumonitis and vemurafenib treatment are independent events. However, the temporal association in both patients suggests that vemurafenib might have augmented or triggered the radiation response of the lung tissue. Whether this represents a single observation or a systematic interaction between vemurafenib and radiotherapy requires systematic evaluation. In our outpatient department, we further treated 28 patients with radiotherapy before starting systemical treatment with vemurafenib. Among these 28 patients, 10 patients had received a whole-brain radiation and five patients had undergone radiotherapy of the axillary region. Only one patient who started vemurafenib treatment the day after finishing whole-brain radiation
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
RRD, radiation pneumonitis under vemurafenib Forschner et al. 515
Fig. 3
(a)
(b)
(a, b) Multiple vesicles and papules on an erythematous swelling of the scalp, sharply defined to the prior irradiated area (11.05.12).
developed mild skin toxicity. All the other 27 patients remained inconspicuous. The median time interval between completion of radiation and the start of anticancer therapy in patients with RRD was about 39.5 days [8]. For RRP, this interval ranged from 12 days to 8 months [17,18]. A relatively short interval between the end of radiation and the start of systemic anticancer treatment was found to increase the risk for RRR. This interval is probably the most important factor influencing the manifestation of RRR [3,8,27,28]. The time interval between the start of anticancer therapy and the clinical manifestation of RRD and RRP ranged from several hours to 3 months [14,18,29,30]. In three patients, we started the treatment with vemurafenib 3–4 weeks after completing radiotherapy. The clinical symptoms appeared 2–4 weeks after the onset of vemurafenib treatment, that is the RRR occurred 5–7 weeks after radiotherapy had been completed and presumably were triggered by vemurafenib. Concerning the management of RRP and RRD, the most common and effective treatment would be discontinuation of the systemic therapy [8,17]. Symptomatic treatment options include either oral prednisolone 0.5–1.0 mg/kg body weight in RRP or topical glucocorticosteroids in RRD [17]. Alternatively, it was proposed to reduce the daily drug dose by 25% [30].
Because RRR may be life-threatening, particular care in radiotherapy planning, thorough patient counseling, interdisciplinary coordination and close follow-up are needed when potential modifiers of radiation response are considered. Unfortunately, for the majority of novel compounds, no data on potential interactions with radiotherapy are available [31,32]. Caution is needed when vemurafenib is planned for patients who have undergone previous radiotherapy. Taken together, potential interactions between molecularly targeted compounds and radiotherapy require special cooperation among the different specialists to assure patient safety. Nevertheless, in our three patients, vemurafenib could be continued without any reduction of the dosage. RRR resolved within 2–6 weeks after symptomatic treatment with local (RRD) or systemic steroids (RRP). Conclusion
RRR of the skin and lung have to be taken into account when vemurafenib treatment is initiated after radiotherapy. In contrast to dermatitis, which can easily be recognized, pulmonary reactions manifest with cough and require radiologic imaging for diagnosis. The early application of systemic and topical corticosteroids enabled us to continue anticancer therapy with vemurafenib without dose reduction.
Acknowledgements Study concept and design: Forschner, Garbe, Meier. Acquisition of data: Forschner, Zips, Schraml, Meier.
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516 Melanoma Research 2014, Vol 24 No 5
Analysis and interpretation of data: Forschner, Zips, Schraml, Ro¨cken, Meier, Garbe. Drafting of the manuscript: Forschner, Zips, Ro¨cken, Meier. Critical revision of the manuscript for important intellectual content: Forschner, Zips, Schraml, Ro¨cken, Iordanou, Leiter, Weide, Meier, Garbe. Study supervision: Garbe, Meier.
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Conflicts of interest
Andrea Forschner, Ulrike Leiter, Claus Garbe and Friedegund Meier are consultants, received honoraria for presentations on expert meetings and were sponsored for participation on melanoma conferences from Roche. Daniel Zips received honoraria and research grants from industry not related to the topic of the manuscript. Martin Ro¨cken is responsible for all industry sponsored events including studies sponsored by Roche. For the remaining authors there are no conflicts of interest.
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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Radiation recall dermatitis and radiation pneumonitis during treatment with vemurafenib Andrea Forschnera, Daniel Zipsb, Christina Schramlc, Martin Ro¨ckena, Eleni Iordanoua, Ulrike Leitera, Benjamin Weidea, Claus Garbea and Friedegund Meiera The basis of radiation recall reactions (RRR) is a subclinical radiation damage that is uncovered later by treatment with anticancer agents. Several drugs have been associated with RRR, in particular taxanes and anthracyclines. Recently, a few cases were reported concerning radiation recall dermatitis caused by vemurafenib. Up to now, there have been no reports of RRR in the lung induced by vemurafenib. We describe the occurrence of RRR in three melanoma patients who had undergone radiotherapy for metastases followed by systemic treatment with the BRAF inhibitor vemurafenib. Two patients developed radiation recall pneumonitis (RRP) and one patient developed radiation recall dermatitis (RRD) 5–7 weeks after the radiation treatment was finished and 2–4 weeks after vemurafenib was started. The early application of systemic (RRP) and topical corticosteroids (RRD) enabled us to continue the treatment with vemurafenib without dose
reduction. Caution is needed when vemurafenib is planned for patients who have undergone previous radiotherapy, and RRR of the skin and the lung have to be taken into c 2014 Wolters account. Melanoma Res 24:512–516 Kluwer Health | Lippincott Williams & Wilkins.
Introduction
Case reports
Radiation recall reactions (RRR) describe inflammatory reactions after a previous radiation treatment induced by a subsequent drug treatment. Typical radiation-induced inflammatory reactions occur during or directly after the irradiation procedure, whereas RRR typically manifest after a noninflammatory interval and only after the start of systemic drug treatment. The basis of RRR is a subclinical radiation damage that is uncovered later by treatment with anticancer agents. D’Angio et al. [1] was the first to describe the reactivation of ‘latent radiation effects in normal tissue’, induced by actinomycin D.
Patient 1
The skin is the easiest organ to observe; this might be the reason why most of the radiation recall phenomena are diagnosed on the skin, presenting with radiation recall dermatitis (RRD). If radiation recall involves previously irradiated pulmonary tissue, it is designated as radiation recall pneumonitis (RRP). Several drugs have been associated with RRR, in particular taxanes and anthracyclines [2–4]. Recently, a few cases were reported concerning RRD caused by vemurafenib [5,6]. To date, no reports of RRP induced by BRAF inhibitors have been published. We describe the occurrence of RRP in two melanoma patients and RRD in one melanoma patient who had undergone radiotherapy for metastases followed by systemic treatment with the BRAF inhibitor vemurafenib. c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0960-8931
Melanoma Research 2014, 24:512–516 Keywords: dermatitis, metastatic melanoma, pneumonitis, radiation recall, radiotherapy, vemurafenib Departments of aDermatology, bRadiooncology and cRadiology, Eberhard-Karls University of Tu¨bingen, Tu¨bingen, Germany Correspondence to Claus Garbe, MD, PhD, Department of Dermatology, Division of Dermatologic Oncology, Eberhard-Karls University of Tuebingen, Liebermeisterstr. 25, D-72076 Tu¨bingen, Germany Tel: + 49 07071 2987110; fax: + 49 07071 295187; e-mail: [email protected] Received 18 April 2013 Accepted 18 March 2014
A 71-year-old male patient had a complete resection of relapsing BRAF V600 E-positive lymph node melanoma metastases of the right axilla and subcutaneous metastases of the right pectoral side. Three weeks later, adjuvant radiotherapy of the right axilla, including the right supraclavicular, infraclavicular and pectoral regions, was given for 5 weeks with a cumulative dose of 50 Gy (International Commission on Radiation Units, 5 2 Gy/ week, CT-planned 3D-conformal radiotherapy, 15 MV photons, anterior and posterior beam arrangement with two fields, multileaf collimation). The estimated skin dose was between 30 and 40 Gy, which led to mild erythema (common toxicity criteria, grade 1) at the end of the therapy. The mean radiation doses to both lungs combined (mean lung dose) and the lung volume receiving 20 Gy (V20) were 6.9 Gy and 12.4%, respectively. Four weeks after completing the well-tolerated radiotherapy, systemic treatment with vemurafenib 960 mg twice a day was started for multiple melanoma metastases in the lung, the liver and the brain. The computed tomography (CT) before starting vemurafenib in August 2012 revealed no features of radiation-induced injury of the lung (Fig. 1b). After 3 weeks of vemurafenib treatment, the patient developed a dry and obsessing cough. The body temperature was normal. In the CT scan, parenchymal changes with predominant ground glass appearance of the right upper DOI: 10.1097/CMR.0000000000000078
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
RRD, radiation pneumonitis under vemurafenib Forschner et al. 513
Fig. 1
(a)
(b)
(c)
(d)
lung, corresponding to the radiation dose distribution (Fig. 1a), had newly occurred. The diagnosis of radiation pneumonitis was established (Fig. 1c). We continued vemurafenib without any reduction of the dosage and added prednisolone 150 mg/day, accompanied by a prophylactic antibiotic therapy (amoxicillin and clavulanic acid) for 10 days. As the cough improved rapidly, the prednisolone dosage was reduced by 50 mg/week. Four weeks later, the infiltration of the right upper lung showed progressive consolidation consistent with a typical course in radiation pneumonitis (Fig. 1d). The patient was in a good general condition and subsequently did not have further pulmonary complaints. Patient 2
A 47-year-old female patient developed unresectable, BRAF V600 E-positive lymph node melanoma metastases of the upper mediastinum leading to an obstruction of the left main bronchus. The patient was supplied by stenting and radiotherapy for 4 weeks with a cumulative dose of 40 Gy (5 2.5 Gy/week)/shrinking field up to 50 Gy (5 2 Gy/week, CT-planned 3D-conformal radiotherapy, 6/15 MV photons, three beams anterior, posterior and oblique). The mean lung lode and the V20 were 17.4 Gy and 32.9%, respectively. During radiotherapy, the patient developed dysphagia and congestive cough with wheezing and humming. Her treatment consisted of dexamethasone 3 mg/day and an inhalation therapy with ambroxol. In March 2012, radiotherapy was completed. The CT scan did not reveal any radiation-induced injury of the lung (Fig. 2b). Three weeks later, we started treatment with vemurafenib 960 mg twice a day for lung, subcutaneous and peritoneal metastases. Four weeks later, the patient presented with heavy breathing and was hospitalized. In the CT scan of the thorax, groundglass opacities with consolidations, most prominent in the irradiated paramediastinal region according to the radiation dose distribution (Fig. 2a), were found and judged as radiation pneumonitis (Fig. 2c). A treatment with 60 mg prednisolone was started in combination with a prophylactic antibiotic therapy (amoxicillin and clavulanic acid) for 10 days. The symptoms improved promptly. Vemurafenib was continued. In June 2012, a CT scan revealed regression of the metastases and a consolidation of infiltrative changes (Fig. 2d). Patient 3
(a) The spatial radiation dose distribution with isodoses for 20, 30, 40 and 47.5 Gy (i.e. 95% of the prescribed dose) shown as red, blue, green and yellow lines, respectively. (b) Computed tomography 4 weeks after completing radiotherapy and before starting vemurafenib treatment (22.08.12). No features of radiation-induced injury of the lung. (c) Computed tomography after 4 weeks of vemurafenib treatment (25.09.12). Infiltrative changes of the right upper lung, corresponding to the irradiation area. (d) Computed tomography 4 weeks later (26.10.12). Consolidation of infiltrative changes.
A 37-year old male patient had excision of a BRAF V600 E-positive cerebral melanoma metastasis of the right frontal side. Two months later, an MRI of the brain revealed local recurrence and meningeosis. Therefore, whole-brain radiotherapy was performed with a cumulative dose of 30 Gy (5 3 Gy/week, 6 MV photons, 2D opposing lateral fields). The radiation was well tolerated without any skin toxicity. One week after completing radiotherapy, PET-CT revealed new inoperable lymph node metastases of the left axilla. Therefore, 3 weeks
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
514 Melanoma Research 2014, Vol 24 No 5
Fig. 2
(a)
after completion of radiotherapy, in March 2012, systemic treatment with vemurafenib 960 mg twice a day was initiated. Two weeks after starting vemurafenib, the patient developed multiple itchy vesicles and papules on an erythematous swelling of the scalp, sharply defined to the prior irradiated area and consistent with RRD (Fig. 3a and b). We continued vemurafenib and treated him with topical corticosteroids. Six weeks later, RRD of the head had resolved, and after 2 months of vemurafenib treatment, a complete response was observed.
Discussion (b)
(c)
Enhanced sensitivity to systemically administrated drugs in the first week after completing radiotherapy is a frequent phenomenon, and it should be emphasized that acute responses to radiation therapy alone within 1 week are frequent. If the reactions appear after the first week, induced by subsequent drug treatment, they are called RRR [7,8]. The most reliable RRR is strongly confined to the former radiotherapy field and several years have passed since finishing the treatment. Several drugs have been reported to cause RRR: doxorubicin, epirubicin, adriamycin, etoposide, gemcitabine, paclitaxel, docetaxel, and vinorelbine [3,4,9–20]. In contrast to RRD, RRP is much rarer, and only 20 cases have been reported so far [4,10,12–14,17,18,20]. Vemurafenib appears to potentiate radiation effects in vitro [21]. Recently, a few clinical cases concerning radiosensitizing effects and RRD in patients under treatment with vemurafenib and radiotherapy were reported. Most of these patients developed skin toxicity, and one patient developed skin and liver toxicity [5,6,22,23]. Up to now, there have been no reports of RRR in the lung induced by vemurafenib.
(d)
(a) The spatial radiation dose distribution with isodoses for 20, 30, 40 and 47.5 Gy (i.e. 95% of the prescribed dose) shown as red, blue, green and yellow lines, respectively. (b) Computed tomography 3 weeks after completing radiotherapy and before starting vemurafenib treatment (22.03.12). No features of radiation-induced injury of the lung. (c) Computed tomography after 4 weeks of vemurafenib treatment (24.04.12). Ground-glass opacities most prominent in the irradiated paramediastinal region. (d) Computed tomography 7 weeks later (11.06.12). Consolidation of infiltrative changes with some remaining air bronchograms as typically observed over time in radiation-induced pneumonitis.
Lung toxicity represents an important dose-limiting side effect of thoracic radiotherapy [24,25]. The estimated risk of symptomatic radiation pneumonitis according to dosimetric parameters is less than 5% for patient one and about 15% for patient two [26]. Thus, on the basis of dosimetric considerations and the time course, it cannot be excluded that the radiation pneumonitis and vemurafenib treatment are independent events. However, the temporal association in both patients suggests that vemurafenib might have augmented or triggered the radiation response of the lung tissue. Whether this represents a single observation or a systematic interaction between vemurafenib and radiotherapy requires systematic evaluation. In our outpatient department, we further treated 28 patients with radiotherapy before starting systemical treatment with vemurafenib. Among these 28 patients, 10 patients had received a whole-brain radiation and five patients had undergone radiotherapy of the axillary region. Only one patient who started vemurafenib treatment the day after finishing whole-brain radiation
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RRD, radiation pneumonitis under vemurafenib Forschner et al. 515
Fig. 3
(a)
(b)
(a, b) Multiple vesicles and papules on an erythematous swelling of the scalp, sharply defined to the prior irradiated area (11.05.12).
developed mild skin toxicity. All the other 27 patients remained inconspicuous. The median time interval between completion of radiation and the start of anticancer therapy in patients with RRD was about 39.5 days [8]. For RRP, this interval ranged from 12 days to 8 months [17,18]. A relatively short interval between the end of radiation and the start of systemic anticancer treatment was found to increase the risk for RRR. This interval is probably the most important factor influencing the manifestation of RRR [3,8,27,28]. The time interval between the start of anticancer therapy and the clinical manifestation of RRD and RRP ranged from several hours to 3 months [14,18,29,30]. In three patients, we started the treatment with vemurafenib 3–4 weeks after completing radiotherapy. The clinical symptoms appeared 2–4 weeks after the onset of vemurafenib treatment, that is the RRR occurred 5–7 weeks after radiotherapy had been completed and presumably were triggered by vemurafenib. Concerning the management of RRP and RRD, the most common and effective treatment would be discontinuation of the systemic therapy [8,17]. Symptomatic treatment options include either oral prednisolone 0.5–1.0 mg/kg body weight in RRP or topical glucocorticosteroids in RRD [17]. Alternatively, it was proposed to reduce the daily drug dose by 25% [30].
Because RRR may be life-threatening, particular care in radiotherapy planning, thorough patient counseling, interdisciplinary coordination and close follow-up are needed when potential modifiers of radiation response are considered. Unfortunately, for the majority of novel compounds, no data on potential interactions with radiotherapy are available [31,32]. Caution is needed when vemurafenib is planned for patients who have undergone previous radiotherapy. Taken together, potential interactions between molecularly targeted compounds and radiotherapy require special cooperation among the different specialists to assure patient safety. Nevertheless, in our three patients, vemurafenib could be continued without any reduction of the dosage. RRR resolved within 2–6 weeks after symptomatic treatment with local (RRD) or systemic steroids (RRP). Conclusion
RRR of the skin and lung have to be taken into account when vemurafenib treatment is initiated after radiotherapy. In contrast to dermatitis, which can easily be recognized, pulmonary reactions manifest with cough and require radiologic imaging for diagnosis. The early application of systemic and topical corticosteroids enabled us to continue anticancer therapy with vemurafenib without dose reduction.
Acknowledgements Study concept and design: Forschner, Garbe, Meier. Acquisition of data: Forschner, Zips, Schraml, Meier.
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516 Melanoma Research 2014, Vol 24 No 5
Analysis and interpretation of data: Forschner, Zips, Schraml, Ro¨cken, Meier, Garbe. Drafting of the manuscript: Forschner, Zips, Ro¨cken, Meier. Critical revision of the manuscript for important intellectual content: Forschner, Zips, Schraml, Ro¨cken, Iordanou, Leiter, Weide, Meier, Garbe. Study supervision: Garbe, Meier.
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Conflicts of interest
Andrea Forschner, Ulrike Leiter, Claus Garbe and Friedegund Meier are consultants, received honoraria for presentations on expert meetings and were sponsored for participation on melanoma conferences from Roche. Daniel Zips received honoraria and research grants from industry not related to the topic of the manuscript. Martin Ro¨cken is responsible for all industry sponsored events including studies sponsored by Roche. For the remaining authors there are no conflicts of interest.
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