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Downstaging of a gastric GIST by neoadjuvant imatinib and endoscopic assisted laparoscopic resection
EJSO 33 (2007) 1044e1046
www.ejso.com
Lesson of the Month
Downstaging of a gastric GIST by neoadjuvant imatinib and endoscopic assisted laparoscopic resection D. Cavaliere a,*, A. Vagliasindi a, G. Mura a, M. Framarini a, G. Giorgetti a, G. Solfrini a, F. Tauceri a, F. Padovani b, C. Milandri c, A. Dubini b, L. Ridolfi c, E. Ricci d, G.M. Verdecchia a a
Department of Surgery, Chirurgia e Terapie Oncologiche Avanzate, Ospedale ‘‘Morgagni-Pierantoni’’ di Forlı`, Italy b Department of Pathology, Ospedale ‘‘Morgagni-Pierantoni’’ di Forlı`, Italy c Department of Medical Oncology, Ospedale ‘‘Morgagni-Pierantoni’’ di Forlı`, Italy d Gastroenterology and Digestive Endoscopy, Ospedale ‘‘Morgagni-Pierantoni’’ di Forlı`, Italy Accepted 12 March 2007 Available online 30 April 2007
Keywords: Gastrointestinal stromal tumours (GISTs); Gastric neoplasm; Imatinib; Laparoscopic resection
Background Gastrointestinal stromal tumours (GISTs) are rare malignancies characterized by a specific histological and immunohistochemical pattern.1 The management of these tumours has been recently revised by the introduction of imatinib (GlivecÒ, formerly STI-571; Novartis Pharma AG, Basel, Switzerland), an orally administered tyrosine kinase inhibitor blocking most activated KIT proteins. Up to 85% of the patients respond to the treatment (controlled tumour growth) with a 50% or greater reduction of the tumour mass in 35e53%.2,3 A planned interim analysis of a randomized phase III trial comparing two doses of imatinib in patients with advanced GISTs, showed complete tumour responses in 2% and 3% according to the dosage, after a median follow-up of 8.4 months.4 Promising results of surgery to remove residual GIST masses in patients who had an objective response to initial therapy with imatinib have already been reported5 and have led to clinical trials of imatinib as an adjuvant or neoadjuvant therapy with surgery.6 We report a case of a marginally resectable primitive gastric GIST
* Corresponding author. U.O. Chirurgia e Terapie Oncologiche Avanzate, Dipartimento di Chirurgia, Ospedale ‘‘GB Morgagni-L Pierantoni’’, Via C. Forlanini 34, 47100 Forlı`, Italia. Tel.: þ39 0543 735502; fax: þ39 0543 735760. E-mail address: [email protected] (D. Cavaliere). 0748-7983/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2007.03.011
treated with imatinib with a neoadjuvant intent, and late endoscopic assisted laparoscopic radical resection. Case presentation A 64-year-old man presented with a 15 10 cm solid perigastric mass with blurred margins. Gastric endoscopy reported an ab-extrinsic subcardial lesion. Biopsy confirmed the diagnosis of GIST. The patient was referred for imatinib therapy (400 mg/ day) on a neoadjuvant basis, before subsequent surgical resection. An important morphologic and clinical response was rapidly obtained. The pharmacologic debulking was monitored by means of echography, positron emission tomography with [18F] fluorodeoxyglucose (FDG-PET) and CT. Restaging was performed after 6 months and revealed a reduction in tumour diameter of approximately 50% with complete metabolic response. The lesion presented central aerial cavitations as with necrotic tissue. The search for hepatic or peritoneal metastatic lesions by means of radiological imaging was negative. He continued the treatment with imatimib for 12 months. A surgical operation was performed on the residual disease. A laparoscopic approach was attempted. The lesion was located at the gastric fundus, in tight proximity of the cardia; an intra-operative endoscopy was performed and, under laparoscopic and endoscopic combined control, the linear stapler was placed.
D. Cavaliere et al. / EJSO 33 (2007) 1044e1046
Transillumination by the gastroscope was useful to obtain a tumour-free margin and an adequate luminal preservation. A partial gastric resection was performed. Operative time was 115 min. Estimated blood loss was less than 100 mL. Recovery was uneventful. Pathological evaluation of the resected specimen showed regular structure of the mucosa and sub-mucosa. The muscular layer presented a tumour mass with diffuse fibrotic regression, haemorrhagic areas and focal calcifications. Residual viable foci of tumour mass were found in few areas with spindle cells; the nuclei were bland lengthened with pale cytoplasm. The cells show immupositivity for CD117 and CD34, were negative for SMA, desmin and s-100. Three weeks after the operation imatimib treatment was resumed with 400 mg/day. Twelve months have elapsed from the surgical resection and the patient continues imatinib treatment, he is asymptomatic and there is no radiological or clinical evidence of disease resumption.
Discussion GIST management is in continuous evolution, as the first solid tumour for which a targeted therapy can modify the natural history positively.2e4 This case report is distinguished by the fact that the surgical resection has been accomplished by a laparoscopic
1045
approach after the success of the pharmacological debulking for a tumour initially deemed marginally operable. The type and the extent of operation becomes a problem for the GIST located in an esophago-gastric junction. Upon diagnosis (baseline TC imaging, Fig. 1A) there were some doubt about the invasion to the diaphragm and splenic hilum. The tumour, in consideration of the anatomical location, the extension and the relationships with the contiguous organs, required an extended surgery. Resection of multiple intra-abdominal organs and surgery for tumour debulking are not warranted and provide no appreciable benefit, except perhaps for palliation of localized bleeding or obstruction in patients whose performance status is otherwise excellent.7 The consensus meeting for the management of GIST of 20e21 March 2004,8 suggests to use imatinib therapy with neoadjuvant purpose when function sparing surgery is the goal. However, some patients who have either unresectable GIST or GIST for which surgery would lead to a marked loss of organ function, may be treated with neoadjuvant imatinib in an attempt to achieve cytoreduction and organ preservation. Furthermore, evidence-based treatment guidelines recommend imatinib as first-line therapy in cases of marginally resectable pathology-confirmed GISTs, with surgery and postoperative imatinib administration advised if imatinib response improves respectability.9 After the farmacologic debulking (CT and MR imaging, Fig. 1CeD; laparoscopic view, Fig. 2) the tumour was
Figure 1. Computed tomography scans at baseline (A) and after 6 (B) and 12 (C) months of therapy with imatinib. The magnetic resonance imaging (D) at 12 months of imatinib demonstrating inhomogeneous enhancement with cavitations and necrotic degeneration of the mass.
1046
D. Cavaliere et al. / EJSO 33 (2007) 1044e1046
Competing interests The authors declare that they have no competing interests. Acknowledgements Written consent was obtained from the patient for publication of this case report. References
Figure 2. Laparoscopic view of the tumor and the esophago-gastric junction after the pharmacologic debulking. The line delimits the resection margin.
clearly operable and a curative partial resection was enabled. Given that GISTs rarely involve lymph nodes, they appear safely amenable to laparoscopic excision.10 The combined use of endoscopic with transillumination and laparoscopy is an effective, simple tool to allow easy detection of the clear margin.11 Thanks to these new multimodal and multidisciplinary approaches, we were able to perform a curative treatment with visceral and functional preservation. Conclusions Currently, the combined expertise of medical oncologists and surgeons, with the support of radiologists, endoscopists and of pathologists, in a multidisciplinary setting, is proving to be the winning strategy, capable of supplying the best perspectives for the treatment and prevention of disease progression. Laparoscopy combined with intraoperative endoscopy is effective and safe in selected cases of advanced gastric stromal tumours after pharmacologic debulking with imatinib, leading the attempt of a functional and organ preserving surgery.
1. Fletcher C, Berman JJ, Corless C. Diagnosis of gastrointestinal stromal tumours: a Consensus approach. Hum Pathol 2002;33:459–65. 2. Van Oosterom AT, Judson I, Verweij J, et al. Safety and efficacy of imatinib (ST571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 2001;358:1421–3. 3. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumours. N Engl J Med 2002 Aug 15;347(7):472–80. 4. Verwej J, Casali P, Zalcberg J, et al. Early efficacy comparison of two doses of imatinib for the treatment of advanced gastrointestinal stromal tumor (GIST): interim results of a randomized phase III trial from the EORTC-STBSG, ISG and AGITG. Proc Am Soc Clin Oncol 2003;22:814. 5. Hohenberger P, Bauer S, Schneider U, et al. Tumor resection following imatinib pre-treatment in GI stromal tumors. Proc Am Soc Clin Oncol 2003;22:818. 6. Eisemberg BL, Judson I. Surgery and imatinib in the management of GIST: emerging approach to adjuvant and neoadjuvant therapy. Ann Surg Oncol 2004;11:465–75. 7. Blanke CD, Eisemberg BL, Heinrich MC. Gastrointestinal stromal tumors. Curr Treat Options Oncol 2001;2:485–91. 8. Blay JY, Bonvalot S, Casali P, et al. GIST consensus meeting panellists: consensus meeting for the management of gastrointestinal stromal tumor. Report of the GIST consensus Conference of 20e21 March 2004, under the auspice of ESMO. Ann Oncol 2005;16:566–78. 9. Demetri GD, Benjamin R, Blanke CD, et al. NCCN Task force report: optimal management of patients with gastrointestinal stromal tumors (GIST) e expansion and update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 2004;2(Suppl 1):S1–S26. 10. Matthews BD, Walsh RM, Kercher KW, et al. Laparoscopic vs open resection of gastric stromal tumors. Surg Endosc 2002;16(5): 803–7. 11. Bouillot JL, Bresler L, Fagnez PL, Samama G, Champault G, Parent Y. Laparoscopic resection of benign submucosal gastric tumors. Gastroenterol Clin Biol 2003;27:272–6.
www.ejso.com
Lesson of the Month
Downstaging of a gastric GIST by neoadjuvant imatinib and endoscopic assisted laparoscopic resection D. Cavaliere a,*, A. Vagliasindi a, G. Mura a, M. Framarini a, G. Giorgetti a, G. Solfrini a, F. Tauceri a, F. Padovani b, C. Milandri c, A. Dubini b, L. Ridolfi c, E. Ricci d, G.M. Verdecchia a a
Department of Surgery, Chirurgia e Terapie Oncologiche Avanzate, Ospedale ‘‘Morgagni-Pierantoni’’ di Forlı`, Italy b Department of Pathology, Ospedale ‘‘Morgagni-Pierantoni’’ di Forlı`, Italy c Department of Medical Oncology, Ospedale ‘‘Morgagni-Pierantoni’’ di Forlı`, Italy d Gastroenterology and Digestive Endoscopy, Ospedale ‘‘Morgagni-Pierantoni’’ di Forlı`, Italy Accepted 12 March 2007 Available online 30 April 2007
Keywords: Gastrointestinal stromal tumours (GISTs); Gastric neoplasm; Imatinib; Laparoscopic resection
Background Gastrointestinal stromal tumours (GISTs) are rare malignancies characterized by a specific histological and immunohistochemical pattern.1 The management of these tumours has been recently revised by the introduction of imatinib (GlivecÒ, formerly STI-571; Novartis Pharma AG, Basel, Switzerland), an orally administered tyrosine kinase inhibitor blocking most activated KIT proteins. Up to 85% of the patients respond to the treatment (controlled tumour growth) with a 50% or greater reduction of the tumour mass in 35e53%.2,3 A planned interim analysis of a randomized phase III trial comparing two doses of imatinib in patients with advanced GISTs, showed complete tumour responses in 2% and 3% according to the dosage, after a median follow-up of 8.4 months.4 Promising results of surgery to remove residual GIST masses in patients who had an objective response to initial therapy with imatinib have already been reported5 and have led to clinical trials of imatinib as an adjuvant or neoadjuvant therapy with surgery.6 We report a case of a marginally resectable primitive gastric GIST
* Corresponding author. U.O. Chirurgia e Terapie Oncologiche Avanzate, Dipartimento di Chirurgia, Ospedale ‘‘GB Morgagni-L Pierantoni’’, Via C. Forlanini 34, 47100 Forlı`, Italia. Tel.: þ39 0543 735502; fax: þ39 0543 735760. E-mail address: [email protected] (D. Cavaliere). 0748-7983/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2007.03.011
treated with imatinib with a neoadjuvant intent, and late endoscopic assisted laparoscopic radical resection. Case presentation A 64-year-old man presented with a 15 10 cm solid perigastric mass with blurred margins. Gastric endoscopy reported an ab-extrinsic subcardial lesion. Biopsy confirmed the diagnosis of GIST. The patient was referred for imatinib therapy (400 mg/ day) on a neoadjuvant basis, before subsequent surgical resection. An important morphologic and clinical response was rapidly obtained. The pharmacologic debulking was monitored by means of echography, positron emission tomography with [18F] fluorodeoxyglucose (FDG-PET) and CT. Restaging was performed after 6 months and revealed a reduction in tumour diameter of approximately 50% with complete metabolic response. The lesion presented central aerial cavitations as with necrotic tissue. The search for hepatic or peritoneal metastatic lesions by means of radiological imaging was negative. He continued the treatment with imatimib for 12 months. A surgical operation was performed on the residual disease. A laparoscopic approach was attempted. The lesion was located at the gastric fundus, in tight proximity of the cardia; an intra-operative endoscopy was performed and, under laparoscopic and endoscopic combined control, the linear stapler was placed.
D. Cavaliere et al. / EJSO 33 (2007) 1044e1046
Transillumination by the gastroscope was useful to obtain a tumour-free margin and an adequate luminal preservation. A partial gastric resection was performed. Operative time was 115 min. Estimated blood loss was less than 100 mL. Recovery was uneventful. Pathological evaluation of the resected specimen showed regular structure of the mucosa and sub-mucosa. The muscular layer presented a tumour mass with diffuse fibrotic regression, haemorrhagic areas and focal calcifications. Residual viable foci of tumour mass were found in few areas with spindle cells; the nuclei were bland lengthened with pale cytoplasm. The cells show immupositivity for CD117 and CD34, were negative for SMA, desmin and s-100. Three weeks after the operation imatimib treatment was resumed with 400 mg/day. Twelve months have elapsed from the surgical resection and the patient continues imatinib treatment, he is asymptomatic and there is no radiological or clinical evidence of disease resumption.
Discussion GIST management is in continuous evolution, as the first solid tumour for which a targeted therapy can modify the natural history positively.2e4 This case report is distinguished by the fact that the surgical resection has been accomplished by a laparoscopic
1045
approach after the success of the pharmacological debulking for a tumour initially deemed marginally operable. The type and the extent of operation becomes a problem for the GIST located in an esophago-gastric junction. Upon diagnosis (baseline TC imaging, Fig. 1A) there were some doubt about the invasion to the diaphragm and splenic hilum. The tumour, in consideration of the anatomical location, the extension and the relationships with the contiguous organs, required an extended surgery. Resection of multiple intra-abdominal organs and surgery for tumour debulking are not warranted and provide no appreciable benefit, except perhaps for palliation of localized bleeding or obstruction in patients whose performance status is otherwise excellent.7 The consensus meeting for the management of GIST of 20e21 March 2004,8 suggests to use imatinib therapy with neoadjuvant purpose when function sparing surgery is the goal. However, some patients who have either unresectable GIST or GIST for which surgery would lead to a marked loss of organ function, may be treated with neoadjuvant imatinib in an attempt to achieve cytoreduction and organ preservation. Furthermore, evidence-based treatment guidelines recommend imatinib as first-line therapy in cases of marginally resectable pathology-confirmed GISTs, with surgery and postoperative imatinib administration advised if imatinib response improves respectability.9 After the farmacologic debulking (CT and MR imaging, Fig. 1CeD; laparoscopic view, Fig. 2) the tumour was
Figure 1. Computed tomography scans at baseline (A) and after 6 (B) and 12 (C) months of therapy with imatinib. The magnetic resonance imaging (D) at 12 months of imatinib demonstrating inhomogeneous enhancement with cavitations and necrotic degeneration of the mass.
1046
D. Cavaliere et al. / EJSO 33 (2007) 1044e1046
Competing interests The authors declare that they have no competing interests. Acknowledgements Written consent was obtained from the patient for publication of this case report. References
Figure 2. Laparoscopic view of the tumor and the esophago-gastric junction after the pharmacologic debulking. The line delimits the resection margin.
clearly operable and a curative partial resection was enabled. Given that GISTs rarely involve lymph nodes, they appear safely amenable to laparoscopic excision.10 The combined use of endoscopic with transillumination and laparoscopy is an effective, simple tool to allow easy detection of the clear margin.11 Thanks to these new multimodal and multidisciplinary approaches, we were able to perform a curative treatment with visceral and functional preservation. Conclusions Currently, the combined expertise of medical oncologists and surgeons, with the support of radiologists, endoscopists and of pathologists, in a multidisciplinary setting, is proving to be the winning strategy, capable of supplying the best perspectives for the treatment and prevention of disease progression. Laparoscopy combined with intraoperative endoscopy is effective and safe in selected cases of advanced gastric stromal tumours after pharmacologic debulking with imatinib, leading the attempt of a functional and organ preserving surgery.
1. Fletcher C, Berman JJ, Corless C. Diagnosis of gastrointestinal stromal tumours: a Consensus approach. Hum Pathol 2002;33:459–65. 2. Van Oosterom AT, Judson I, Verweij J, et al. Safety and efficacy of imatinib (ST571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 2001;358:1421–3. 3. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumours. N Engl J Med 2002 Aug 15;347(7):472–80. 4. Verwej J, Casali P, Zalcberg J, et al. Early efficacy comparison of two doses of imatinib for the treatment of advanced gastrointestinal stromal tumor (GIST): interim results of a randomized phase III trial from the EORTC-STBSG, ISG and AGITG. Proc Am Soc Clin Oncol 2003;22:814. 5. Hohenberger P, Bauer S, Schneider U, et al. Tumor resection following imatinib pre-treatment in GI stromal tumors. Proc Am Soc Clin Oncol 2003;22:818. 6. Eisemberg BL, Judson I. Surgery and imatinib in the management of GIST: emerging approach to adjuvant and neoadjuvant therapy. Ann Surg Oncol 2004;11:465–75. 7. Blanke CD, Eisemberg BL, Heinrich MC. Gastrointestinal stromal tumors. Curr Treat Options Oncol 2001;2:485–91. 8. Blay JY, Bonvalot S, Casali P, et al. GIST consensus meeting panellists: consensus meeting for the management of gastrointestinal stromal tumor. Report of the GIST consensus Conference of 20e21 March 2004, under the auspice of ESMO. Ann Oncol 2005;16:566–78. 9. Demetri GD, Benjamin R, Blanke CD, et al. NCCN Task force report: optimal management of patients with gastrointestinal stromal tumors (GIST) e expansion and update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 2004;2(Suppl 1):S1–S26. 10. Matthews BD, Walsh RM, Kercher KW, et al. Laparoscopic vs open resection of gastric stromal tumors. Surg Endosc 2002;16(5): 803–7. 11. Bouillot JL, Bresler L, Fagnez PL, Samama G, Champault G, Parent Y. Laparoscopic resection of benign submucosal gastric tumors. Gastroenterol Clin Biol 2003;27:272–6.