T. Asklund et al.

[6] van Steenbergen LN, Lemmens VE, Rutten HJ, Wymenga AN, Nortier JW, Janssen-Heijnen ML. Increased adjuvant treatment and improved survival in elderly stage III colon cancer patients in The Netherlands. Ann Oncol 2012;23:2805–11. [7] Chagpar R, Xing Y, Chiang YJ, Feig BW, Chang GJ, You YN, et al. Adherence to stage-specific treatment guidelines for patients with colon cancer. J Clin Oncol 2012;30:972–9. [8] Panchal JM, Lairson DR, Chan W, Du XL. Geographic variation and sociodemographic disparity in the use of oxaliplatin-containing chemotherapy in patients with stage III colon cancer. Clin Colorectal Cancer 2013;12:113–21. [9] Sanoff HK, Carpenter WR, Martin CF, Sargent DJ, Meyerhardt JA, Sturmer T, et al. Comparative effectiveness of oxaliplatin vs non-oxaliplatin-containing adjuvant chemotherapy for stage III colon cancer. J Natl Cancer Inst 2012;104:211–27. [10] Lund JL, Sturmer T, Sanoff HK, Brookhart A, Sandler RS, Warren JL. Determinants of adjuvant oxaliplatin receipt among older stage II and III colorectal cancer patients. Cancer 2013;119:2038–47. [11] Panchal JM, Lairson DR, Chan W, Du XL. Geographic variation and sociodemographic disparity in the use of oxaliplatin-containing chemotherapy in patients with stage III colon cancer. Clin Colorectal Cancer 2013;12:113–21. [12] Hershman DL, Buono D, McBride RB, Tsai WY, Neugut AI. Influence of private practice setting and physician characteristics on the use of breast cancer adjuvant chemotherapy for elderly women. Cancer 2009;115:3848–57. [13] Goldberg RM, Tabah-Fisch I, Bleiberg H, de Gramont A, Tournigand C, Andre T, et al. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin







administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol 2006;24:4085–91. Sanoff HK, Carpenter WR, Sturmer T, Goldberg RM, Martin CF, Fine JP, et al. Effect of adjuvant chemotherapy on survival of patients with stage III colon cancer diagnosed after age 75 years. J Clin Oncol 2012;30:2624–34. Hsiao FY, Mullins CD, Onukwugha E, Pandya N, Hanna N. Comparative effectiveness of different chemotherapeutic regimens on survival of people aged 66 and older with stage III colon cancer: A “real world” analysis using Surveillance, Epidemiology, and End Results-Medicare data. J Am Geriatr Soc 2011;59:1717–23. Tournigand C, Andre T, Bonnetain F, Chibaudel B, Lledo G, Hickish T, et al. Adjuvant therapy with fluorouracil and oxaliplatin in stage II and elderly patients (between ages 70 and 75 years) with colon cancer: Subgroup analyses of the Multicenter International Study of Oxaliplatin, Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer trial. J Clin Oncol 2012;30:3353–60. van Gils CW, Koopman M, Mol L, Redekop WK, Uyl-de Groot CA, Punt CJ. Adjuvant chemotherapy in stage III colon cancer: Guideline implementation, patterns of use and outcomes in daily practice in The Netherlands. Acta Oncol 2012;51:57–64. Abrams TA, Brightly R, Mao J, Kirkner G, Meyerhardt JA, Schrag D, et al. Patterns of adjuvant chemotherapy use in a population-based cohort of patients with resected stage II or III colon cancer. J Clin Oncol 2011;29:3255–62. Yothers G, O’Connell MJ, Allegra CJ, Kuebler JP, Colangelo LH, Petrelli NJ, et al. Oxaliplatin as adjuvant therapy for colon cancer: Updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol 2011;29:3768–74.

Durable stabilization of three chordoma cases by bevacizumab and erlotinib


of Radiation Sciences, Umeå University, Umeå, Sweden and 2Department of Pharmacology and Clinical Neurosciences, Umeå University, Umeå, Sweden To the Editor, Chordomas are rare tumors that arise from the vestigial or ectopic notochord, with an incidence of 0.5 to 0.8 per 1 000 000 [1,2]. About 50% originate from the sacrococcygeal region, 30% from the skull base and 15% from vertebral bodies [3]. A complete surgical resection is still considered the gold standard for treatment, when feasible. When this is not possible, high dose radiotherapy is often recommended [4]. Medical treatment has also been evaluated, but has mainly been reported as case studies. The rationale for

using drugs that interact with epidermal growth factor receptor (EGFR) is accumulating preclinical evidence that EGFR signaling is important in chordoma [5–7]. A few case reports have also indicated that EGFR inhibition may be of value in treating chordomas [8–11]. Although reliable data is limited, some reports support the hypothesis that regulators of angiogenesis, such as vascular endothelial growth factor (VEGF) and HIF-1α [8,12,13], play a role in the development of chordoma. In addition, imatinib has demonstrated clinically interesting effects in locally advanced tumors

Correspondence: T. Asklund, Department of Oncology, Norrlands University Hospital, 901 85 Umeå, Sweden. E-mail: [email protected] (Received 28 November 2013 ; accepted 17 December 2013) ISSN 0284-186X print/ISSN 1651-226X online © 2014 Informa Healthcare DOI: 10.3109/0284186X.2013.878472

Chordoma erlotinib bevacizumab


Figure 1. (A-D): 11C-methionine PET scans before and during chemotherapy. (A) In May 2009 after extensive radiotherapy, but before drug therapy, the scan showed enhanced uptake of methionine. (B) A treatment attempt with erlotinib in combination with cetuximab was made. Nevertheless, a slight increase in uptake was detected in July. (C) A clear reduction, even to subnormal levels, of methionine uptake in October compared to the previous exam was seen after replacement of cetuximab by bevacizumab, while erlotinib treatment continued. (D) The combination of erlotinib and bevacizumab continued until June 2010. The same month the methionine uptake level was unchanged compared to C.

that express platelet-derived growth factor β (PDGFB) and/or its receptor (PDGFRB) [14]. We report here the effects of erlotinib and bevacizumab in three consecutive patients with chordoma. While the clinical and neuroradiological characteristics were consistent with the diagnosis in one of the cases (Case 1), the diagnosis had been confirmed by histopathology in the remaining two cases (Cases 2 and 3). Case 1 We have described this case previously [8] and here supplement the data with a longer follow-up time. Briefly, a male patient aged 63 when he was diagnosed

in 2007 with a skull-base tumor that involved the clivus and dorsum sellae. An attempt to resect the tumor was complicated by severe life-threatening bradycardia as soon as the neurosurgeon manipulated the dura. Thus, no tissue-based diagnosis was available before radiotherapy, which was given between December 2007 and January 2008, and included fractionated stereotactic radiotherapy followed by a proton boost. Magnetic resonance imaging (MRI) follow-up showed disease progression, while an 11C-methionine positron emission tomography (PET) scan in May 2009 showed enhanced uptake in the tumor (Figure 1A). Treatment with erlotinib and cetuximab was started the same month and had no significant effect on methionine uptake.


T. Asklund et al.

Indeed, a slight increase in uptake occurred in a PET in July 2009 (Figure 1B). Cetuximab was replaced by bevacizumab in July, while erlotinib treatment continued. Interestingly, methionine uptake decreased significantly to slightly below normal in October 2009 (Figure 1C) and this level had persisted in a PET scan in June 2010 (Figure 1D). In addition, follow-up with MRI has shown a clear reduction in contrast enhancement and a slight decrease in tumor size. Treatment was stopped in June 2010 since the disease was stable, and the patient was experiencing treatment-related fatigue. Since then the patient has been treatment free. The most recent methionine PET scan was carried out in October 2010, and did not show any signs of enhanced uptake in the tumor. MRI in August 2013 showed stable disease, and the patient now has no clinical symptoms of the tumor six years after diagnosis and 4½ years after introducing erlotinib and bevacizumab.

Case 2 A female patient was 48 years old when diagnosed with a very large boneinfiltrating tumor mass in the sacrum in 2009. A laminectomy L4-S3 was performed in July 2009 and more extensive surgery in September 2009, with resection of approximately 80% of the extraosseous component. The decision to leave a residual tumor was based on the risk of causing

neurological damage, in the light of tumor infiltration of spinal nerves. The histopathological diagnosis was consistent with chordoma. An MRI follow-up in September 2010 showed pronounced tumor progression. Clinical symptoms had also increased, with pain in the right gluteal region and radiating pain in the right leg. Re-operation was considered to be of no benefit, as the major part of the tumor component was intraosseous in the sacrum. The only surgical intervention deemed feasible was a sacrectomy, but this would obviously be associated with severe neurological sequelae. Thus, the patient was treated with conventional photon radiotherapy with 2 Gy fractions, to a total of 66 Gy, applied to a gross tumor volume (GTV) of 214 cm3. This regimen was given in November–December 2010. A PET/computed tomography (CT) with 18F-FLT, as marker for proliferation, done in April 2011 showed proliferative activity in the tumor, mainly in the residual intraosseous component (Figure 2A, white continuous arrows). The non-tumor affected bone marrow also showed high FLT uptake, which is a normal finding in non-irradiated bone marrow (Figure 2A and B, white broken arrows). At this stage, May 2011, combination treatment with erlotinib and bevacizumab was initiated (erlotinib 150 mg once daily and bevacizumab 10 mg/kg once weekly), based on our previous experience [8]. In July 2011, no remaining FLT-uptake remained in

Figure 2. (A and B): 18F-FLT-PET/CT in April (A) and July (B) 2011. (A) FLT-uptake was high in the tumor, indicating enhanced proliferative activity (white continous arrows), before chemotherapy. The non-tumour affected bone marrow also showed high uptake (white broken arrows), but this is a normal finding. (B) In May erlotinib-bevacizumab was started, and in July no remaining FLT uptake could be seen in the tumor (white continous arrows). As expected, FLT-uptake in the non tumour affected bone marrow was still unchanged (white broken arrows).

Chordoma erlotinib bevacizumab


Figure 3. (A-C): Contrast enhanced T1 weighted MRI. (A) A contrast enhancing tumour with a size of 555 cm was observed in October 2008. (B) After treatment with cetuximab-erlotinib a clear decrease of contrast enhancement could be seen in March 2009. Due to toxicity cetuximab was stopped early, but treatment with erlotinib continued. (C) The contrast enhancement had decreased further in April 2010. The size of the tumour was unchanged.

the tumor (Figure 2B), while unchanged uptake could be seen in the bone marrow. The patient was at this time suffering from paronychias and a superficial infection close to the left elbow. These conditions were considered to be therapy-related, and the treatment was stopped in October 2011. The wounds subsequently healed and so did the infection in the elbow after surgical wound revision. An FLT-PET/CT in September 2012 showed no increased proliferation, and MRI in August 2013 showed stable disease. The patient was at that time walking with the help of a walker, whereas she had been confined to a wheelchair before the treatment. The pain was well controlled with methadone and gabapentine. Rehabilitation was ongoing, with the aim of enabling the patient to return to part-time work as a school teacher.

Case 3 A woman was 43 years of age when she was operated in September 2005 with a transsphenoidal approach for a clivus chordoma, which had been confirmed by histopathology. Complementary re-operation was carried out in January 2007, with a presigmoideal, transsphenoidal approach. Postoperative recovery and rehabilitation were initially complicated by meningitis and the development of hydrocephalus. A ventriculoperitoneal shunt was therefore implanted in February 2007. An MRI in December 2007 showed a residual tumor of less than 1 cm in size. However, a follow-up MRI in October 2008 showed a marked increase in size to 5  5  5 cm (Figure 3A). As the patient was reluctant to undergo radiotherapy, treatment with erlotinib was started in December 2008 at a dose of 100 mg daily and cetuximab at 250 mg/m2. Cetuximab was stopped after only four cycles due to rather severe skin reactions, while erlotinib was maintained at 100 mg daily. A significant reduction in contrast enhancement in the tumor was seen at follow-up, from October 2008 (before erlotinib) (Figure 3A),

compared to March 2009 (Figure 3B) and April 2010 (Figure 3C), which was interpreted as secondary to inhibition of EGFR signaling. Regular MRI follow-up for more than two years showed stable disease. Unfortunately, two subsequent MRI examinations in March and August 2011 showed significant tumor progression with an additional tumor component of size 1  1.5  1 cm in the epipharynx, adjacent to the carotid vessels. Re-operation was discussed, but was considered too hazardous. The symptom that caused most distress to the patient at this time was pronounced neuralgic pain along the distribution of the left trigeminal nerve. Bevacizumab 10 mg/kg every second week was added to the erlotinib in September 2011. The patient experienced significant relief from the neuralgic pain almost immediately. Bevacizumab was stopped in November 2012 due to radiologically stable disease, while erlotinib was maintained. MRI in September 2013 showed stable disease. At the most recent visit at our department in October she was still in a good clinical status, showing no signs of neurological deterioration. Discussion We describe here three cases of chordoma, one of them diagnosed on radiological and clinical grounds (Case 1), while two of them were histologically verified (Cases 2 and 3). These three patients demonstrated clinically meaningful responses to a combination of the VEGF inhibitor bevacizumab and the EGFR inhibitor erlotinib. Further surgical intervention was not a treatment option in any of the cases at this stage. Following initiation of the combination of erlotinib and bevacizumab, none of the patients in this report has neither experienced tumor progression nor clinical deterioration with follow-up times of 4½ years (Case 1), 2½ years (Case 2) and 2 years (Case 3). The combination of erlotinib and bevacizumab in relapsing non-operable chordoma may lead to


J. Y. Law et al.

disease stability and increased quality of life with significant pain relief for years, at the cost of mild to moderate toxicity. The approach is promising and it is worthy of further investigation in a prospective controlled setting. Conflict of interest: RH Member of the international steering committe of the Avaglio study evaluating bevacizumab (Roche®) for the treatment of gliobastoma. TA National investigator of the Avaglio study and the Tamiga study (Roche®) for the treatment of glioblastoma.






References [1] Eriksson B, Gunterberg B, Kindblom LG. Chordoma. A clinicopathologic and prognostic study of a Swedish national series. Acta Orthop Scand 1981;52:49–58. [2] McMaster ML, Goldstein AM, Bromley CM, Ishibe N,Parry DM. Chordoma: Incidence and survival patterns in the United States, 1973–1995. Cancer Cause Control 2001;12:1–11. [3] Cheng EY, Ozerdemoglu RA, Transfeldt EE, Thompson RC, Jr. Lumbosacral chordoma. Prognostic factors and treatment. Spine 1999;24:1639–45. [4] Zabel-du Bois A, Nikoghosyan A, Schwahofer A, Huber P, Schlegel W, Debus J, et al. Intensity modulated radiotherapy in the management of sacral chordoma in primary versus recurrent disease. Radiother Oncol 2010;97:408–12. [5] Shalaby A, Presneau N, Ye H, Halai D, Berisha F, Idowu B, et al. The role of epidermal growth factor receptor in





chordoma pathogenesis: A potential therapeutic target. J Pathol 2011;223:336–46. Dei Tos AP. Unveiling the molecular pathogenesis of chordoma: A new paradigm for molecular targeting of rare cancers. J Pathol 2011;223:565–6. Dewaele B, Maggiani F, Floris G, Ampe M, Vanspauwen V, Wozniak A, et al. Frequent activation of EGFR in advanced chordomas. Clin Sarcoma Res 2011;1:4. Asklund T, Danfors T, Henriksson R. PET response and tumor stabilization under erlotinib and bevacizumab treatment of an intracranial lesion non-invasively diagnosed as likely chordoma. Clin Neuropathol 2011;30:242–6. Launay SG, Chetaille B, Medina F, Perrot D, Nazarian S, Guiramand J, et al. Efficacy of epidermal growth factor receptor targeting in advanced chordoma: Case report and literature review. BMC Cancer 2011;11:423. Hof H, Welzel T, Debus J. Effectiveness of cetuximab/gefitinib in the therapy of a sacral chordoma. Onkologie 2006;29: 572–4. Linden O, Stenberg L, Kjellen E. Regression of cervical spinal cord compression in a patient with chordoma following treatment with cetuximab and gefitinib. Acta Oncol 2009; 48:158–9. Chen KW, Yang HL, Lu J, Wang GL, Ji YM, Wu GZ, et al. Expression of vascular endothelial growth factor and matrix metalloproteinase-9 in sacral chordoma. J Neurooncol 2011;101:357–63. Li X, Ji Z, Ma Y, Qiu X, Fan Q, Ma B. Expression of hypoxiainducible factor-1alpha, vascular endothelial growth factor and matrix metalloproteinase-2 in sacral chordomas. Oncol Lett 2012;3:1268–74. Stacchiotti S, Longhi A, Ferraresi V, Grignani G, Comandone A, Stupp R, et al. Phase II study of imatinib in advanced chordoma. J Clin Oncol 2012;30:914–20.

Simultaneous acute myeloid leukemia and mesothelioma diagnoses in a long-term survivor of the 1984 Bhopal gas leak


of Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, 2Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas and 3Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas To the Editor, The 1984 industrial accident in Bhopal, India led to the immediate deaths of thousands and resulted in long-term morbidity for survivors. Although unknown at the time, the health consequences of exposure to the released gas, methyl isocyanate, included

dysfunction of the central nervous system, pulmonary toxicity, and an increased risk of malignancy. The interval between exposure and development of clinically significant malignancies can be prolonged. We present a case of a woman diagnosed with both acute myeloid leukemia and mesothelioma 28 years

*These authors contributed equally. Correspondence: H. V. Naina, Division of Hematology-Oncology, Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Mail Code 8852, Dallas, Texas 75390-8852, USA. Tel:  1 214 6484180. Fax:  1 214 648 1955. E-mail: [email protected] (Received 9 November 2013 ; accepted 17 December 2013) ISSN 0284-186X print/ISSN 1651-226X online © 2014 Informa Healthcare DOI: 10.3109/0284186X.2013.879609

Copyright of Acta Oncologica is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.

Durable stabilization of three chordoma cases by bevacizumab and erlotinib.

Durable stabilization of three chordoma cases by bevacizumab and erlotinib. - PDF Download Free
8MB Sizes 1 Downloads 0 Views