VOLUME
32
䡠
NUMBER
8
䡠
MARCH
10
2014
JOURNAL OF CLINICAL ONCOLOGY
Imiquimod in the Treatment of Breast Cancer Skin Metastasis Introduction Breast cancer is the most frequently diagnosed cancer in women and the second leading cause of cancer death in women. Of all tumor types, it tends to have a propensity to metastasize to the skin, causing a significant degree of morbidity.1,2 A review of the literature reveals a single case report describing the use of topical imiquimod, a synthetic small nucleotide-like compound of the imidazoquinoline family, to successfully treat breast cancer skin metastasis.2 The exact mechanism of action of imiquimod is not known, but it is an immune response modifier and it has been hypothesized to enhance an immune response against tumors by stimulating dendritic cells and macrophages and by activating inflammatory cytokines and chemokines through toll-like receptors.3,4 There is also some evidence that it has antiangiogenic properties5 and that it can stimulate intrinsic apoptosis.6-8 Originally used on genital warts, it has proven beneficial in the treatment of basal cell carcinoma9 and can be useful in the treatment of skin metastasis from malignant melanoma.7,10,11 We report a case of breast cancer skin metastasis that was successfully treated with imiquimod when radiotherapy and several chemotherapy regimens were unsuccessful and excision was not a viable therapeutic option. In addition to regression of the lesion and an improvement in esthetic appearance, the patient also described a significant reduction in pain from the skin metastasis. Case Report Our patient first presented at 26 years of age with a grade 3, estrogen receptor (ER) –positive (90%, 3⫹), progesterone receptor (PR) –positive (10%, 1⫹), and human epidermal growth factor receptor 2 (HER2) –negative (2⫹, fluorescent in situ hybridization [FISH] ratio, 1.2) invasive ductal carcinoma of the right breast that was clinically staged as T2N3. She was given fluorouracil, epirubicin, and cyclophosphamide plus docetaxel neoadjuvantly. This was followed by a right modified radical mastectomy and a lymph node dissection; only two cytokeratin-positive cells, thought to be residual malignant cells, were found within a single lymph node of the 15 lymph nodes resected. The excised right breast had significant fibrotic changes with no evidence of residual disease. The patient subsequently received adjuvant radiotherapy to the right chest wall and internal mammary lymph nodes (50.4 Gy in 28 fractions) along with the full right axilla (45 Gy in 25 fractions). She began receiving tamoxifen, and although a genetics assessment was negative for mutations in BRCA1, BRCA2, p53, and CHK2 genes, the patient went on to have a total abdominal hysterectomy/bilateral salpingo- oophorectomy and a left prophylactic mastectomy. After 1 year of treatment with tamoxifen, she was switched to treatment with letrozole and goserelin, which she continued to receive as maintenance therapy. e22
© 2014 by American Society of Clinical Oncology
D I A G N O S I S
I N
O N C O L O G Y
Three years later, the patient was found to have enlarged lymph nodes in the contralateral left axilla and left lower neck. Staging revealed that this was the only site of disease. She underwent a lymph node dissection that revealed 19 of 20 nodes were positive for invasive ductal carcinoma (ER negative [1%], PR negative [1%], and HER2 positive [3⫹]) with extracapillary extension. Given her disease-free interval of more than 3 years, along with the negative staging scans and the change in hormonal and HER2 status from the previous rightsided breast cancer, the finding was considered a new primary lesion of the breast. She then received adjuvant docetaxel, cyclophosphamide, and trastuzumab for eight cycles. Soon after completing chemotherapy, and while undergoing maintenance therapy with trastuzumab, the patient developed four skin lesions in the left axilla along with left axillary, left supraclavicular, and left cervical adenopathy. Biopsy of the skin lesions revealed invasive ductal carcinoma (ER negative [0%], PR negative [0%], and HER2 negative [1⫹; FISH ratio, 1.1]). She was treated with external-beam radiotherapy to the left lower neck, left supraclavicular region, and left axilla (50 Gy in 25 fractions) with concomitant capecitabine and experienced reduction in lymph node size and resolution of the skin lesions. She suffered grade 3 dermatitis with significant blistering, which led to the discontinuation of capecitabine and limited the number of radiotherapy treatments with bolus to seventeen (ie, for the last eight treatments, the bolus was omitted). Within days after the completion of radiotherapy, the patient developed new skin lesions in the left axilla but outside of the radiation field. She began receiving dose-reduced capecitabine and lapatinib, but within a few months she developed a malignant pleural effusion, lung nodules, and new skin metastases in the anterior neck, left supraclavicular area, and left upper back. Biopsy of the skin lesions confirmed triple-negative breast cancer (ER negative, PR negative, and HER2 negative [2⫹; FISH ratio, 1.1]). Because her skin lesions continued to progress despite being treated sequentially with gemcitabine and carboplatin, paclitaxel, paclitaxel nanoparticle albumin bound (Abraxane; Abraxis Bioscience, Los Angeles, CA), and oral cyclophosphamide, she was again treated with radiation to the left neck/left supraclavicular area with 17 Gy in two fractions, given that there was overlap with the previous area. However, the lesions continued to progress despite the radiation treatment. The skin lesions circumferentially occupied the patient’s left upper back, left supraclavicular area, and the front of her neck (Figs 1A and 1B). The lesions were painful, and the patient described them as continuous electric shocks and burning despite the use of opioids and pregabalin. She was then administered imiquimod 5% to apply three times per week. Within one week of using the imiquimod cream, there was a decrease in the intensity and thickness of the lesion, and the surface area was stable (Fig 2). The following week, there was a decrease in surface area and a further reduction in intensity and thickness (Fig 3), with no reported adverse effects. Three weeks after the start of imiquimod, the patient reported her pain intensity had lessened from a score of 8 of 10 to 6 of 10. She was able to discontinue oxycodone long-acting 5 mg and was solely using hydromorphone 1 mg orally as Journal of Clinical Oncology, Vol 32, No 8 (March 10), 2014: pp e22-e25
Information downloaded from jco.ascopubs.org and provided by at Gazi Universitesi on October 4, 2014 from 194.27.18.18 Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Diagnosis in Oncology
A
A
B
B
Fig 2.
Fig 1.
needed. The patient then stopped applying imiquimod for approximately 2 to 3 weeks, and the lesions quickly began to progress. Restarting imiquimod again led to regression. During the next 4 months, the skin lesions and pain continued to improve with the use of topical imiquimod (Fig 4). Over the same time period, the visceral disease of the patient was somewhat controlled with the use of the aforementioned chemotherapy agents, but leptomeningeal disease eventually developed. She received radiotherapy and was given eribulin, but despite this, her CNS disease continued to progress and she passed away. Discussion The patient case described above suggests that imiquimod topical cream can be an effective treatment for cutaneous metastasis from www.jco.org
breast cancer and possibly other cancers. Metastatic skin lesions can be a significant source of pain and can also be damaging to a patient’s self-esteem, which in turn affects the patient’s overall well-being and can lead to significant emotional distress.12,13 Surgical excision is often not possible and/or is ineffective. Radiation therapy may also not be effective and can have important adverse effects. Imiquimod has already proven effective in the treatment of external genital warts14 and actinic keratosis precancerous skin lesions,15 as well as superficial basal cell carcinoma.9 Other studies have reported some efficacy in metastatic melanoma.11 More recently, a case report was published describing the use of imiquimod to treat a renal cell carcinoma skin metastasis, with a significant reduction in the lesion after 2 months and no recurrence after 12 months.16 Our findings suggest that imiquimod can be used as a viable alternative in the treatment of breast skin metastasis and that a response may be achieved even if the lesion is refractory to chemotherapy and radiation. Although our patient was receiving chemotherapy while also being treated with imiquimod, the timing of response of the skin lesions seemed to coincide quite clearly with the start of imiquimod, especially when progression of the skin lesions was noted on chemotherapy. We cannot definitively rule out a complimentary action between the chemotherapy and imiquimod; © 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at Gazi Universitesi on October 4, 2014 from 194.27.18.18 Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
e23
Henriques et al
A
A
B
B
Fig 4.
Fig 3.
however, the skin lesions continued to improve with the topical cream alone, even while the patient was not receiving chemotherapy. More studies are required to better understand how this immune modifier acts on skin metastasis from breast cancer and other cancers, and a randomized clinical trial would be important to demonstrate efficacy. Imiquimod’s reported ability to treat a variety of different skin cancers and tumor metastases suggests that its immunemodifying properties result in a nonspecific antitumor response that may be intense and local. A recent study suggests that imiquimod’s stimulation of dermal mast cells through toll-like receptors leads to the expression of chemokine-2, which results in the migration of large numbers of plasmacytoid dendritic cells (pDCs) into the vicinity of the tumor.4 The activated pDCs then produce type I interferons that act in an autocrine manner to upregulate expression of granzyme B and tumor necrosis factor–related apoptosis-inducing ligand, transe24
© 2014 by American Society of Clinical Oncology
forming the pDCs into killer dendritic cells. Still, some reports have suggested that imiquimod may lead to an intrinsic apoptosis of tumor cells independent of its associated immune response, possibly by downregulating myeloid cell leukemia 1 and B-cell lymphoma/leukemia 2 proteins, among other antiapoptotic proteins, although the exact mechanism leading to tumor cell apoptosis is still not clear.6-8 Additional studies are needed to elucidate imiquimod’s exact mechanism of action, and we will begin analysis of skin samples of treated patients in the near future. In this case report, we demonstrate that imiquimod seems to provide a noninvasive and easily tolerated means of treatment of skin lesions from metastatic breast cancer and can lead to a significant improvement in pain, disease burden, and esthetic appearance.
Lisa Henriques Faculte´ de Medicine de l’Universite´ de Montre´al, Montreal, Quebec, Canada
Michael Palumbo, Marie-Pascale Guay, Boris Bahoric, Mark Basik, Petr Kavan, and Gerald Batist Sir Mortimer B. Davis Jewish General Hospital, McGill University, Segal Cancer Centre, Montreal, Quebec, Canada
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at Gazi Universitesi on October 4, 2014 from 194.27.18.18 Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Diagnosis in Oncology
REFERENCES 1. Krathen RA, Orengo IF, Rosen T: Cutaneous metastasis: A meta-analysis of data. South Med J 96:164-167, 2003 2. Hengge UR, Roth S, Tannapfel A: Topical imiquimod to treat recurrent breast cancer. Breast Cancer Res Treat 94:93-94, 2005 3. Hemmi H, Kaisho T, Takeuchi O, et al: Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 3:196-200, 2002 4. Drobits B, Holcmann M, Amberg N, et al: Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells. J Clin Invest 122:575-585, 2012 5. Li VW, Li WW, Talcott KE, et al: Imiquimod as an antiangiogenic agent. J Drugs Dermatol 4:708-717, 2005 6. Huang SW, Chang CC, Lin CC, et al: Mcl-1 determines the imiquimodinduced apoptosis but not imiquimod-induced autophagy in skin cancer cells. J Dermatol Sci 65:170-178, 2012 7. Scho¨n MP, Wienrich BG, Drewniok C, et al: Death receptor-independent apoptosis in malignant melanoma induced by the small-molecule immune response modifier imiquimod. J Invest Dermatol 122:1266-1276, 2004 8. Smith EB, Schwartz M, Kawamoto H, et al: Antitumor effects of imidazoquinolines in urothelial cell carcinoma of the bladder. J Urol 177:23472351, 2007
9. Smits EL, Ponsaerts P, Berneman ZN, et al: The use of TLR7 and TLR8 ligands for the enhancement of cancer immunotherapy. Oncologist 13:859-875, 2008 10. Hesling C, D’Incan M, Mansard S, et al: In vivo and in situ modulation of the expression of genes involved in metastasis and angiogenesis in a patient treated with topical imiquimod for melanoma skin metastases. Br J Dermatol 150:761-767, 2004 11. Wolf IH, Smolle J, Binder B, et al: Topical imiquimod in the treatment of metastatic melanoma to skin. Arch Dermatol 139:273-276, 2003 12. Moussas GI, Papadopoulou AG, Christodoulaki AG, et al: Psychological and psychiatric problems in cancer patients: Relationship to the localization of the disease [in Greek]. Psychiatrike 23:46-60, 2012 13. Battie C, Verschoore M: Dermatology, cosmetic and well-being [in French]. Ann Dermatol Venereol 138:294-301, 2011 14. Moore RA, Edwards JE, Hopwood J, et al: Imiquimod for the treatment of genital warts: A quantitative systematic review. BMC Infect Dis 1:3, 2001 15. Torres A, Storey L, Anders M, et al: Immune-mediated changes in actinic keratosis following topical treatment with imiquimod 5% cream. J Transl Med 5:7, 2007 16. Asakura M, Miura H: Imiquimod 5% cream for the treatment of nasal lesion of metastatic renal cell carcinoma. Dermatol Ther 24:375-377, 2011
DOI: 10.1200/JCO.2012.46.4883; published online ahead of print at www.jco.org on January 13, 2014
■ ■ ■
www.jco.org
© 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at Gazi Universitesi on October 4, 2014 from 194.27.18.18 Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
e25
32
䡠
NUMBER
8
䡠
MARCH
10
2014
JOURNAL OF CLINICAL ONCOLOGY
Imiquimod in the Treatment of Breast Cancer Skin Metastasis Introduction Breast cancer is the most frequently diagnosed cancer in women and the second leading cause of cancer death in women. Of all tumor types, it tends to have a propensity to metastasize to the skin, causing a significant degree of morbidity.1,2 A review of the literature reveals a single case report describing the use of topical imiquimod, a synthetic small nucleotide-like compound of the imidazoquinoline family, to successfully treat breast cancer skin metastasis.2 The exact mechanism of action of imiquimod is not known, but it is an immune response modifier and it has been hypothesized to enhance an immune response against tumors by stimulating dendritic cells and macrophages and by activating inflammatory cytokines and chemokines through toll-like receptors.3,4 There is also some evidence that it has antiangiogenic properties5 and that it can stimulate intrinsic apoptosis.6-8 Originally used on genital warts, it has proven beneficial in the treatment of basal cell carcinoma9 and can be useful in the treatment of skin metastasis from malignant melanoma.7,10,11 We report a case of breast cancer skin metastasis that was successfully treated with imiquimod when radiotherapy and several chemotherapy regimens were unsuccessful and excision was not a viable therapeutic option. In addition to regression of the lesion and an improvement in esthetic appearance, the patient also described a significant reduction in pain from the skin metastasis. Case Report Our patient first presented at 26 years of age with a grade 3, estrogen receptor (ER) –positive (90%, 3⫹), progesterone receptor (PR) –positive (10%, 1⫹), and human epidermal growth factor receptor 2 (HER2) –negative (2⫹, fluorescent in situ hybridization [FISH] ratio, 1.2) invasive ductal carcinoma of the right breast that was clinically staged as T2N3. She was given fluorouracil, epirubicin, and cyclophosphamide plus docetaxel neoadjuvantly. This was followed by a right modified radical mastectomy and a lymph node dissection; only two cytokeratin-positive cells, thought to be residual malignant cells, were found within a single lymph node of the 15 lymph nodes resected. The excised right breast had significant fibrotic changes with no evidence of residual disease. The patient subsequently received adjuvant radiotherapy to the right chest wall and internal mammary lymph nodes (50.4 Gy in 28 fractions) along with the full right axilla (45 Gy in 25 fractions). She began receiving tamoxifen, and although a genetics assessment was negative for mutations in BRCA1, BRCA2, p53, and CHK2 genes, the patient went on to have a total abdominal hysterectomy/bilateral salpingo- oophorectomy and a left prophylactic mastectomy. After 1 year of treatment with tamoxifen, she was switched to treatment with letrozole and goserelin, which she continued to receive as maintenance therapy. e22
© 2014 by American Society of Clinical Oncology
D I A G N O S I S
I N
O N C O L O G Y
Three years later, the patient was found to have enlarged lymph nodes in the contralateral left axilla and left lower neck. Staging revealed that this was the only site of disease. She underwent a lymph node dissection that revealed 19 of 20 nodes were positive for invasive ductal carcinoma (ER negative [1%], PR negative [1%], and HER2 positive [3⫹]) with extracapillary extension. Given her disease-free interval of more than 3 years, along with the negative staging scans and the change in hormonal and HER2 status from the previous rightsided breast cancer, the finding was considered a new primary lesion of the breast. She then received adjuvant docetaxel, cyclophosphamide, and trastuzumab for eight cycles. Soon after completing chemotherapy, and while undergoing maintenance therapy with trastuzumab, the patient developed four skin lesions in the left axilla along with left axillary, left supraclavicular, and left cervical adenopathy. Biopsy of the skin lesions revealed invasive ductal carcinoma (ER negative [0%], PR negative [0%], and HER2 negative [1⫹; FISH ratio, 1.1]). She was treated with external-beam radiotherapy to the left lower neck, left supraclavicular region, and left axilla (50 Gy in 25 fractions) with concomitant capecitabine and experienced reduction in lymph node size and resolution of the skin lesions. She suffered grade 3 dermatitis with significant blistering, which led to the discontinuation of capecitabine and limited the number of radiotherapy treatments with bolus to seventeen (ie, for the last eight treatments, the bolus was omitted). Within days after the completion of radiotherapy, the patient developed new skin lesions in the left axilla but outside of the radiation field. She began receiving dose-reduced capecitabine and lapatinib, but within a few months she developed a malignant pleural effusion, lung nodules, and new skin metastases in the anterior neck, left supraclavicular area, and left upper back. Biopsy of the skin lesions confirmed triple-negative breast cancer (ER negative, PR negative, and HER2 negative [2⫹; FISH ratio, 1.1]). Because her skin lesions continued to progress despite being treated sequentially with gemcitabine and carboplatin, paclitaxel, paclitaxel nanoparticle albumin bound (Abraxane; Abraxis Bioscience, Los Angeles, CA), and oral cyclophosphamide, she was again treated with radiation to the left neck/left supraclavicular area with 17 Gy in two fractions, given that there was overlap with the previous area. However, the lesions continued to progress despite the radiation treatment. The skin lesions circumferentially occupied the patient’s left upper back, left supraclavicular area, and the front of her neck (Figs 1A and 1B). The lesions were painful, and the patient described them as continuous electric shocks and burning despite the use of opioids and pregabalin. She was then administered imiquimod 5% to apply three times per week. Within one week of using the imiquimod cream, there was a decrease in the intensity and thickness of the lesion, and the surface area was stable (Fig 2). The following week, there was a decrease in surface area and a further reduction in intensity and thickness (Fig 3), with no reported adverse effects. Three weeks after the start of imiquimod, the patient reported her pain intensity had lessened from a score of 8 of 10 to 6 of 10. She was able to discontinue oxycodone long-acting 5 mg and was solely using hydromorphone 1 mg orally as Journal of Clinical Oncology, Vol 32, No 8 (March 10), 2014: pp e22-e25
Information downloaded from jco.ascopubs.org and provided by at Gazi Universitesi on October 4, 2014 from 194.27.18.18 Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Diagnosis in Oncology
A
A
B
B
Fig 2.
Fig 1.
needed. The patient then stopped applying imiquimod for approximately 2 to 3 weeks, and the lesions quickly began to progress. Restarting imiquimod again led to regression. During the next 4 months, the skin lesions and pain continued to improve with the use of topical imiquimod (Fig 4). Over the same time period, the visceral disease of the patient was somewhat controlled with the use of the aforementioned chemotherapy agents, but leptomeningeal disease eventually developed. She received radiotherapy and was given eribulin, but despite this, her CNS disease continued to progress and she passed away. Discussion The patient case described above suggests that imiquimod topical cream can be an effective treatment for cutaneous metastasis from www.jco.org
breast cancer and possibly other cancers. Metastatic skin lesions can be a significant source of pain and can also be damaging to a patient’s self-esteem, which in turn affects the patient’s overall well-being and can lead to significant emotional distress.12,13 Surgical excision is often not possible and/or is ineffective. Radiation therapy may also not be effective and can have important adverse effects. Imiquimod has already proven effective in the treatment of external genital warts14 and actinic keratosis precancerous skin lesions,15 as well as superficial basal cell carcinoma.9 Other studies have reported some efficacy in metastatic melanoma.11 More recently, a case report was published describing the use of imiquimod to treat a renal cell carcinoma skin metastasis, with a significant reduction in the lesion after 2 months and no recurrence after 12 months.16 Our findings suggest that imiquimod can be used as a viable alternative in the treatment of breast skin metastasis and that a response may be achieved even if the lesion is refractory to chemotherapy and radiation. Although our patient was receiving chemotherapy while also being treated with imiquimod, the timing of response of the skin lesions seemed to coincide quite clearly with the start of imiquimod, especially when progression of the skin lesions was noted on chemotherapy. We cannot definitively rule out a complimentary action between the chemotherapy and imiquimod; © 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at Gazi Universitesi on October 4, 2014 from 194.27.18.18 Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
e23
Henriques et al
A
A
B
B
Fig 4.
Fig 3.
however, the skin lesions continued to improve with the topical cream alone, even while the patient was not receiving chemotherapy. More studies are required to better understand how this immune modifier acts on skin metastasis from breast cancer and other cancers, and a randomized clinical trial would be important to demonstrate efficacy. Imiquimod’s reported ability to treat a variety of different skin cancers and tumor metastases suggests that its immunemodifying properties result in a nonspecific antitumor response that may be intense and local. A recent study suggests that imiquimod’s stimulation of dermal mast cells through toll-like receptors leads to the expression of chemokine-2, which results in the migration of large numbers of plasmacytoid dendritic cells (pDCs) into the vicinity of the tumor.4 The activated pDCs then produce type I interferons that act in an autocrine manner to upregulate expression of granzyme B and tumor necrosis factor–related apoptosis-inducing ligand, transe24
© 2014 by American Society of Clinical Oncology
forming the pDCs into killer dendritic cells. Still, some reports have suggested that imiquimod may lead to an intrinsic apoptosis of tumor cells independent of its associated immune response, possibly by downregulating myeloid cell leukemia 1 and B-cell lymphoma/leukemia 2 proteins, among other antiapoptotic proteins, although the exact mechanism leading to tumor cell apoptosis is still not clear.6-8 Additional studies are needed to elucidate imiquimod’s exact mechanism of action, and we will begin analysis of skin samples of treated patients in the near future. In this case report, we demonstrate that imiquimod seems to provide a noninvasive and easily tolerated means of treatment of skin lesions from metastatic breast cancer and can lead to a significant improvement in pain, disease burden, and esthetic appearance.
Lisa Henriques Faculte´ de Medicine de l’Universite´ de Montre´al, Montreal, Quebec, Canada
Michael Palumbo, Marie-Pascale Guay, Boris Bahoric, Mark Basik, Petr Kavan, and Gerald Batist Sir Mortimer B. Davis Jewish General Hospital, McGill University, Segal Cancer Centre, Montreal, Quebec, Canada
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at Gazi Universitesi on October 4, 2014 from 194.27.18.18 Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Diagnosis in Oncology
REFERENCES 1. Krathen RA, Orengo IF, Rosen T: Cutaneous metastasis: A meta-analysis of data. South Med J 96:164-167, 2003 2. Hengge UR, Roth S, Tannapfel A: Topical imiquimod to treat recurrent breast cancer. Breast Cancer Res Treat 94:93-94, 2005 3. Hemmi H, Kaisho T, Takeuchi O, et al: Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 3:196-200, 2002 4. Drobits B, Holcmann M, Amberg N, et al: Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells. J Clin Invest 122:575-585, 2012 5. Li VW, Li WW, Talcott KE, et al: Imiquimod as an antiangiogenic agent. J Drugs Dermatol 4:708-717, 2005 6. Huang SW, Chang CC, Lin CC, et al: Mcl-1 determines the imiquimodinduced apoptosis but not imiquimod-induced autophagy in skin cancer cells. J Dermatol Sci 65:170-178, 2012 7. Scho¨n MP, Wienrich BG, Drewniok C, et al: Death receptor-independent apoptosis in malignant melanoma induced by the small-molecule immune response modifier imiquimod. J Invest Dermatol 122:1266-1276, 2004 8. Smith EB, Schwartz M, Kawamoto H, et al: Antitumor effects of imidazoquinolines in urothelial cell carcinoma of the bladder. J Urol 177:23472351, 2007
9. Smits EL, Ponsaerts P, Berneman ZN, et al: The use of TLR7 and TLR8 ligands for the enhancement of cancer immunotherapy. Oncologist 13:859-875, 2008 10. Hesling C, D’Incan M, Mansard S, et al: In vivo and in situ modulation of the expression of genes involved in metastasis and angiogenesis in a patient treated with topical imiquimod for melanoma skin metastases. Br J Dermatol 150:761-767, 2004 11. Wolf IH, Smolle J, Binder B, et al: Topical imiquimod in the treatment of metastatic melanoma to skin. Arch Dermatol 139:273-276, 2003 12. Moussas GI, Papadopoulou AG, Christodoulaki AG, et al: Psychological and psychiatric problems in cancer patients: Relationship to the localization of the disease [in Greek]. Psychiatrike 23:46-60, 2012 13. Battie C, Verschoore M: Dermatology, cosmetic and well-being [in French]. Ann Dermatol Venereol 138:294-301, 2011 14. Moore RA, Edwards JE, Hopwood J, et al: Imiquimod for the treatment of genital warts: A quantitative systematic review. BMC Infect Dis 1:3, 2001 15. Torres A, Storey L, Anders M, et al: Immune-mediated changes in actinic keratosis following topical treatment with imiquimod 5% cream. J Transl Med 5:7, 2007 16. Asakura M, Miura H: Imiquimod 5% cream for the treatment of nasal lesion of metastatic renal cell carcinoma. Dermatol Ther 24:375-377, 2011
DOI: 10.1200/JCO.2012.46.4883; published online ahead of print at www.jco.org on January 13, 2014
■ ■ ■
www.jco.org
© 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at Gazi Universitesi on October 4, 2014 from 194.27.18.18 Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
e25
