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Bevacizumab Schedule in a Patient with Metastatic Desmoplastic Small Round-cell Tumour Refractory to Chemotherapy
Clinical Oncology (2005) 17: 393–396
Correspondence doi:10.1016/j.clon.2005.03.009
References
Cowden Syndrome: A Rare, but Recognisable Cancer Predisposition Disorder
1 National Institute of Clinical Excellence. Clinical guideline 14. Familial breast cancer. May 2004. 2 Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 2003;72:1117–1130. 3 Bushby KM, Cole T, Matthews JN, et al. Centiles for adult head circumference. Arch Dis Child 1992;67:1286–1287. 4 Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet 2000;37:828–830.
Sir d The understanding of hereditary cancer syndromes among oncologists and other health professionals is increasing. The recently published NICE guidelines for familial breast cancer give recommendations on referral pathways and subsequent investigation and management [1]. In particular, mutations in the BRCA1 or BRCA2 genes are well known to be associated with an increased lifetime risk of breast cancer of as much as 80%, and of ovarian cancer from 20–40% [2]. By taking an adequate family history, patients at high risk of harbouring such mutations can be identified. However, there are rarer genetic cancer predisposition syndromes, which are not well known to non-geneticists, but can be identified from clinical features and appropriate history taking. A caucasian woman, known to our centre, first presented at the age of 27 years with unilateral thyroid enlargement. A thyroid lobectomy was carried out, and histology showed numerous small adenomatous areas considered to be of borderline malignancy. Two years later, she developed a 1 cm follicular cancer at the thyroid isthmus, which was excised. A local recurrence 12 years later was treated with further surgery and radioactive iodine, and has not subsequently recurred. At the age of 33 years, she was diagnosed with ductal carcinoma of the left breast treated with wide local excision, postoperative radiotherapy and adjuvant chemotherapy. She developed a further carcinoma in the same breast 9 years later, which was treated with mastectomy and adjuvant tamoxifen. At the age of 41 years, she underwent a right radical nephrectomy for a classical clear-cell renal carcinoma. In view of the history of three separate primary cancers at a young age, the woman was referred to the local cancer genetics service. Macrocephaly was noted, with a cranial circumference of 61.5 cm being above the 97th centile [3]. Small papules were present on the right cheek and left upper lip. There was a single papule on the tongue. There was no history of cancer in other close family members. Mutational analysis was carried out to assess the BRCA1, BRCA2 and PTEN ( phosphate and tensin homologue) genes. A four base-pair deletion was identified in the PTEN gene, which was predicted to introduce a stop codon leading to premature truncation of the PTEN protein. Metastatic sites of disease were present by the age of 44 years, with biopsy-confirmed renal metastastis in the left scapula, and cerebral metastases from breast cancer. Further palliative treatments with radiotherapy, chemotherapy and endocrine therapy were given. Cowden syndrome occurs in people with mutations in the PTEN gene located on chromosome 10q23.3. The PTEN protein negatively regulates the phosphoinositide-3-kinase signaling pathway. Inactivation of the gene leads to increased cellular proliferation. Clinical diagnostic criteria have been published, which include facial trichilemmomas, acral keratoses, papillomatous mucocutaneous lesions, macrocephaly, gastrointestinal hamartomas, and cancers of the breast, thyroid, endometrium and kidney [4]. Gene mutations show an autosomal dominant inheritance pattern. Denovo cases can occur. The incidence of Cowden syndrome has been reported as 1 in 200 000. However, the true incidence is likely to be greater than this owing to probable under-diagnosis, and clinicians should bear this diagnosis in mind when seeing patients with unusual patterns of disease. J. W. ADLARD
Cookridge Hospital, Leeds, West Yorkshire, UK
0936-6555/05/000000C04 $35.00/0
doi:10.1016/j.clon.2005.03.010
Failure of a Cetuximab/Bevacizumab Schedule in a Patient with Metastatic Desmoplastic Small Round-cell Tumour Refractory to Chemotherapy Sir d A 23-year-old man presented in late 2002 with abdominal swelling and pain. Ultrasound and computed tomography showed multiple intra-abdominal masses, the largest measuring 16 cm in the pelvis, three liver lesions, and small mediastinal lymph nodes. Ultrasound-guided biopsy documented small round neoplastic cells with hypercromatic nuclei and a high mitotic activity (Fig. 1a and b). Immunohistochemical stains resulted positive for low molecular keratin CAM 5.2, desmin and WT-C19, but negative for WT-180. The final diagnosis was of desmoplastic small round-cell tumour (Fig. 1a). From January to May 2003, the patient underwent six cycles of chemotherapy with epirubicin and ifosfamide, obtaining a partial response. In July 2003, he underwent debulking surgery, with minimal lymph nodes residual disease and to four cycles of methotrexate/cisplatin regimen up to December 2003, with progressive disease. In January 2004, he underwent docetaxel/dacarbazine chemotherapy and then, after tumour progression, epirubicin/ifosfamide/dexrazoxane for four cycles, with a further progression of disease. On the basis of tumour RNA tests, which showed overexpression of epidermal growth factor receptor and vascular endothelial growth factor receptor, in October 2004 the patient received cetuximab (loading dose 400 mg/m2 and then 250 mg/m2 weekly) in combination with bevacizumab (7.5 mg/kg every 2 weeks). This regimen was well tolerated, with grade 3/4 acneiform rash as the only toxicity (Fig. 1c). After 3 months of treatment, a computed tomography documented disease progression (Fig. 1d). Desmoplastic small round-cell tumours are aggressive neoplasms of adolescents and young adults, with a mean survival of 29 months [1]. The family includes Ewing’ sarcoma, peripheral primitive neuroectodermal tumours, rabdomyosarcomas and desmoplastic small round-cell tumours [2]. Desmoplastic small round-cell tumours probably arise from a multipotent neural crest stem cell [2,3]. Histologically, there is a prominent desmoplastic stromal reaction and multi-immunophenotypic differentiation [2]. Desmoplastic small round-cell tumours are generally refractory to conventional treatments, including high-dose chemotherapy [4]. Recently, some poor prognostic factors have been identified: metastasis at diagnosis other than lung, a tumour volume of more than 100 cc, axial site involvement, lack of response to first-line chemotherapy or early relapsing disease [4,5]. The unique chromosomal rearrangement identified in desmoplastic small round-cell tumours, t (11; 22) ( p13; q12), juxtaposes
Ó 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
394
CLINICAL ONCOLOGY
Fig. 1
two genes, the EWS, on chromosome 22, and WT-1 gene, at 11p13 [2,5]. The chimeric product of the fusion presents transforming in-vitro and invivo properties by a disregulation of a critical group of target genes, such as platelet-derived growth factor-A, which stimulates fibroblasts and stromal desmoplastic reaction [5]. The presence of this specific fusion transcript may represent a possible target for selective molecular targeting therapies. This is the first reported case of a patient with a metastatic desmoplastic small round-cell tumour, refractory to chemotherapy, treated with a combination of two monoclonal antibodies directed against specific molecular targets overexpressed by tumour cells. This combined schedule showed good tolerability, but was ineffective. The only evident side-effect was a severe and diffuse acneiform rash but, contrary to clinical trials in colorectal cancer, the efficacy of cetuximab was not correlated to skin toxicity in such a case. R. LONGO* F. TORINO* A. MORABITO* S. AMICI* D. GATTUSO* L. MANENTEy G. GASPARINI*
*Division of Medical Oncology, San Filippo Neri Hospital, Italy; yU.O.C.di Anatomia ed Istologia Patologica, San Filippo Neri Hospital, Rome, Italy
References 1 Gil A, Gomez Portilla A, Brun EA, Sugarbaker PH. Clinical perspective on desmoplastic small round-cell tumor. Oncology 2004;67:231–242.
2 Bertuzzi A, Castagna L, Nozza A, et al. High-dose chemotherapy in poor-prognosis adult small round-cell tumors: clinical and molecular results from a prospective study. J Clin Oncol 2002;20:2181–2188. 3 Lae ME, Roche PC, Jin L, et al. Desmoplastic small round-cell tumor: a clinicopathologic, immunohistochemical, and molecular study of 32 tumors. Am J Surg Pathol 2002;26:823–835. 4 Kushner BH, Laquaglia MP, Wollner N, et al. Desmoplastic small round-cell tumor: prolonged progression survival with aggressive multimodality therapy. J Clin Oncol 1996;14:1526–1531. 5 Gerald WL, Rosai J, Ladany M. Characterization of the genomic breakpoint and chimeric transcripts in the EWS-WT1 gene fusion of desmoplastic small round-cell tumor. Proc Natl Acad Sci U S A 1995;92: 1028–1032.
doi:10.1016/j.clon.2005.04.004
Radiolabelled Octreotide Scintigraphy in Patients with Lymphoma d Does it have a Role in Receptor-mediated Radiotherapy? Sir d Targeted radiotherapy (e.g. radioimmunotherapy) has shown promising results in lymphoma. Tumour cell killing is predominantly by targeted radiation, although antibody effects and the ‘bystander effect’ are likely to contribute significantly [1,2]. Somatostatin receptors (SSTRs) have been identified in malignant lymphomas [3,4]. Octreotide is a synthetic somatostatin analogue, which is
Correspondence doi:10.1016/j.clon.2005.03.009
References
Cowden Syndrome: A Rare, but Recognisable Cancer Predisposition Disorder
1 National Institute of Clinical Excellence. Clinical guideline 14. Familial breast cancer. May 2004. 2 Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 2003;72:1117–1130. 3 Bushby KM, Cole T, Matthews JN, et al. Centiles for adult head circumference. Arch Dis Child 1992;67:1286–1287. 4 Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet 2000;37:828–830.
Sir d The understanding of hereditary cancer syndromes among oncologists and other health professionals is increasing. The recently published NICE guidelines for familial breast cancer give recommendations on referral pathways and subsequent investigation and management [1]. In particular, mutations in the BRCA1 or BRCA2 genes are well known to be associated with an increased lifetime risk of breast cancer of as much as 80%, and of ovarian cancer from 20–40% [2]. By taking an adequate family history, patients at high risk of harbouring such mutations can be identified. However, there are rarer genetic cancer predisposition syndromes, which are not well known to non-geneticists, but can be identified from clinical features and appropriate history taking. A caucasian woman, known to our centre, first presented at the age of 27 years with unilateral thyroid enlargement. A thyroid lobectomy was carried out, and histology showed numerous small adenomatous areas considered to be of borderline malignancy. Two years later, she developed a 1 cm follicular cancer at the thyroid isthmus, which was excised. A local recurrence 12 years later was treated with further surgery and radioactive iodine, and has not subsequently recurred. At the age of 33 years, she was diagnosed with ductal carcinoma of the left breast treated with wide local excision, postoperative radiotherapy and adjuvant chemotherapy. She developed a further carcinoma in the same breast 9 years later, which was treated with mastectomy and adjuvant tamoxifen. At the age of 41 years, she underwent a right radical nephrectomy for a classical clear-cell renal carcinoma. In view of the history of three separate primary cancers at a young age, the woman was referred to the local cancer genetics service. Macrocephaly was noted, with a cranial circumference of 61.5 cm being above the 97th centile [3]. Small papules were present on the right cheek and left upper lip. There was a single papule on the tongue. There was no history of cancer in other close family members. Mutational analysis was carried out to assess the BRCA1, BRCA2 and PTEN ( phosphate and tensin homologue) genes. A four base-pair deletion was identified in the PTEN gene, which was predicted to introduce a stop codon leading to premature truncation of the PTEN protein. Metastatic sites of disease were present by the age of 44 years, with biopsy-confirmed renal metastastis in the left scapula, and cerebral metastases from breast cancer. Further palliative treatments with radiotherapy, chemotherapy and endocrine therapy were given. Cowden syndrome occurs in people with mutations in the PTEN gene located on chromosome 10q23.3. The PTEN protein negatively regulates the phosphoinositide-3-kinase signaling pathway. Inactivation of the gene leads to increased cellular proliferation. Clinical diagnostic criteria have been published, which include facial trichilemmomas, acral keratoses, papillomatous mucocutaneous lesions, macrocephaly, gastrointestinal hamartomas, and cancers of the breast, thyroid, endometrium and kidney [4]. Gene mutations show an autosomal dominant inheritance pattern. Denovo cases can occur. The incidence of Cowden syndrome has been reported as 1 in 200 000. However, the true incidence is likely to be greater than this owing to probable under-diagnosis, and clinicians should bear this diagnosis in mind when seeing patients with unusual patterns of disease. J. W. ADLARD
Cookridge Hospital, Leeds, West Yorkshire, UK
0936-6555/05/000000C04 $35.00/0
doi:10.1016/j.clon.2005.03.010
Failure of a Cetuximab/Bevacizumab Schedule in a Patient with Metastatic Desmoplastic Small Round-cell Tumour Refractory to Chemotherapy Sir d A 23-year-old man presented in late 2002 with abdominal swelling and pain. Ultrasound and computed tomography showed multiple intra-abdominal masses, the largest measuring 16 cm in the pelvis, three liver lesions, and small mediastinal lymph nodes. Ultrasound-guided biopsy documented small round neoplastic cells with hypercromatic nuclei and a high mitotic activity (Fig. 1a and b). Immunohistochemical stains resulted positive for low molecular keratin CAM 5.2, desmin and WT-C19, but negative for WT-180. The final diagnosis was of desmoplastic small round-cell tumour (Fig. 1a). From January to May 2003, the patient underwent six cycles of chemotherapy with epirubicin and ifosfamide, obtaining a partial response. In July 2003, he underwent debulking surgery, with minimal lymph nodes residual disease and to four cycles of methotrexate/cisplatin regimen up to December 2003, with progressive disease. In January 2004, he underwent docetaxel/dacarbazine chemotherapy and then, after tumour progression, epirubicin/ifosfamide/dexrazoxane for four cycles, with a further progression of disease. On the basis of tumour RNA tests, which showed overexpression of epidermal growth factor receptor and vascular endothelial growth factor receptor, in October 2004 the patient received cetuximab (loading dose 400 mg/m2 and then 250 mg/m2 weekly) in combination with bevacizumab (7.5 mg/kg every 2 weeks). This regimen was well tolerated, with grade 3/4 acneiform rash as the only toxicity (Fig. 1c). After 3 months of treatment, a computed tomography documented disease progression (Fig. 1d). Desmoplastic small round-cell tumours are aggressive neoplasms of adolescents and young adults, with a mean survival of 29 months [1]. The family includes Ewing’ sarcoma, peripheral primitive neuroectodermal tumours, rabdomyosarcomas and desmoplastic small round-cell tumours [2]. Desmoplastic small round-cell tumours probably arise from a multipotent neural crest stem cell [2,3]. Histologically, there is a prominent desmoplastic stromal reaction and multi-immunophenotypic differentiation [2]. Desmoplastic small round-cell tumours are generally refractory to conventional treatments, including high-dose chemotherapy [4]. Recently, some poor prognostic factors have been identified: metastasis at diagnosis other than lung, a tumour volume of more than 100 cc, axial site involvement, lack of response to first-line chemotherapy or early relapsing disease [4,5]. The unique chromosomal rearrangement identified in desmoplastic small round-cell tumours, t (11; 22) ( p13; q12), juxtaposes
Ó 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
394
CLINICAL ONCOLOGY
Fig. 1
two genes, the EWS, on chromosome 22, and WT-1 gene, at 11p13 [2,5]. The chimeric product of the fusion presents transforming in-vitro and invivo properties by a disregulation of a critical group of target genes, such as platelet-derived growth factor-A, which stimulates fibroblasts and stromal desmoplastic reaction [5]. The presence of this specific fusion transcript may represent a possible target for selective molecular targeting therapies. This is the first reported case of a patient with a metastatic desmoplastic small round-cell tumour, refractory to chemotherapy, treated with a combination of two monoclonal antibodies directed against specific molecular targets overexpressed by tumour cells. This combined schedule showed good tolerability, but was ineffective. The only evident side-effect was a severe and diffuse acneiform rash but, contrary to clinical trials in colorectal cancer, the efficacy of cetuximab was not correlated to skin toxicity in such a case. R. LONGO* F. TORINO* A. MORABITO* S. AMICI* D. GATTUSO* L. MANENTEy G. GASPARINI*
*Division of Medical Oncology, San Filippo Neri Hospital, Italy; yU.O.C.di Anatomia ed Istologia Patologica, San Filippo Neri Hospital, Rome, Italy
References 1 Gil A, Gomez Portilla A, Brun EA, Sugarbaker PH. Clinical perspective on desmoplastic small round-cell tumor. Oncology 2004;67:231–242.
2 Bertuzzi A, Castagna L, Nozza A, et al. High-dose chemotherapy in poor-prognosis adult small round-cell tumors: clinical and molecular results from a prospective study. J Clin Oncol 2002;20:2181–2188. 3 Lae ME, Roche PC, Jin L, et al. Desmoplastic small round-cell tumor: a clinicopathologic, immunohistochemical, and molecular study of 32 tumors. Am J Surg Pathol 2002;26:823–835. 4 Kushner BH, Laquaglia MP, Wollner N, et al. Desmoplastic small round-cell tumor: prolonged progression survival with aggressive multimodality therapy. J Clin Oncol 1996;14:1526–1531. 5 Gerald WL, Rosai J, Ladany M. Characterization of the genomic breakpoint and chimeric transcripts in the EWS-WT1 gene fusion of desmoplastic small round-cell tumor. Proc Natl Acad Sci U S A 1995;92: 1028–1032.
doi:10.1016/j.clon.2005.04.004
Radiolabelled Octreotide Scintigraphy in Patients with Lymphoma d Does it have a Role in Receptor-mediated Radiotherapy? Sir d Targeted radiotherapy (e.g. radioimmunotherapy) has shown promising results in lymphoma. Tumour cell killing is predominantly by targeted radiation, although antibody effects and the ‘bystander effect’ are likely to contribute significantly [1,2]. Somatostatin receptors (SSTRs) have been identified in malignant lymphomas [3,4]. Octreotide is a synthetic somatostatin analogue, which is