Surgical debulking of gastrointestinal stromal tumors: Is it a reasonable option after second-line treatment with sunitinib?
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- Pantaleo, M.A., Di Battista, M., Catena, F. et al. J Cancer Res Clin Oncol (2008) 134: 625. doi:10.1007/s00432-007-0347-1
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After imatinib treatment, the surgical management of patients affected by gastrointestinal stromal tumor (GIST) has been widely reported and often considered by many oncologists in clinical practice. Surgical results are correlated with disease responsiveness to tyrosine kinase inhibitors and with complete extirpation of all tumor sites. By now, no report specifically addressing surgical management after second-line treatment with sunitinib is still available. Most patients have an unresectable disease and do not have any other therapeutical options except for clinical trials.
Materials and methods
We report two clinical cases of patients with metastatic GISTs, who underwent surgery after sunitinib, and discuss the surgical management option in this clinical setting.
Both our patients had a long, durable stable disease on sunitinib, but one developed a chronic mild bleeding that does not call for emergency surgical interventions and the other one developed chronic heart toxicity. They were proposed to undergo surgery despite the unresectable diseases and received an incomplete resection because of residual metastatic lesions. They restarted sunitinib after surgery.
The poor prognosis after sunitinib treatment and the absence of alternative validated options open the debate on the assessment of surgical management of metastatic GISTs in this setting. The role of surgery should be investigated in clinical trials; however, the enrollment may be difficult. In clinical practice and after a multidisciplinary case patient discussion, surgery could represent a reasonable choice for advanced GISTs especially if the risk of surgery-related death is not too high.
KeywordsGastrointestinal stromal tumorsSunitinibImatinibTK inhibitorsSurgery
Surgery is considered to be the principal treatment for the localized disease, gastrointestinal stromal tumors (GISTs). The 5-year survival rate is 40–60% for patients who undergo complete resection and 34% for patients with incomplete resection (DeMatteo et al. 2000; Ozguc et al. 2005). These survival rates are also influenced by standard prognostic factors, such as tumor size and mitotic rate (Ozguc et al. 2005). Approximately, there is a high-risk of 65% of GISTs relapsing (Nilsson et al. 2005; Pierie et al. 2001). At present, medical treatment with tyrosine kinase inhibitors (TK inhibitors), imatinib and sunitinib has changed the natural history of patients affected by recurrent, metastatic or inoperable diseases. About 80% of patients showed a durable response, 53.7% showed partial response and 27.9% had stable disease (Demetri et al. 2002). The usual recommended dose is 400 mg/die, but a significant benefit in terms of median PFS with an initial treatment at 400 mg twice a day has been demostrated (Verweij et al. 2004). Although most of the patients with GIST respond dramatically to imatinib mesylate, there is a little subset that exhibits primary resistance. Molecular mechanisms, such as exon 9 mutant isoform protein and no detectable mutation of c-kit, seem to be responsible for this event (Heinrich et al. 2003). A secondary drug resistance also occurs in 14% patients after a median of about 2 years, due to the acquisition of additional mutations of KIT or PDGFRα (Lux et al. 2000; Tamborini et al. 2004; Antonescu et al. 2005). This acquired resistance can be overcome by sunitinib, an oral multitargeted TK inhibitor with antiangiogenetic properties. Sunitinib leads to about 25% of responses and to a progression-free survival of about 7 months (Demetri et al. 2006).
The well-consolidated use of TK inhibitors in clinical pratice has also changed the role of surgery in patients affected by GIST. If patients with locally advanced diseases, considered inoperable at diagnosis, respond to pre-operative treatment with imatinib, the rate of complete surgical resection is high. (Bonvalot et al. 2006; Andtbacka et al. 2007; Gronchi et al. 2007; Raut et al. 2006; DeMatteo et al. 2007). While surgery after imatinib has been widely reported, any report that specifically addresses surgical management after sunitinib is not yet available.
We report two clinical cases of patients with metastatic GISTs who underwent surgery after sunitinib, and we discuss the management of patients in this clinical setting.
Case report 1
Because of the development of chronic bleeding resulting in mild anemia, on 30 November the patient underwent partial gastrectomy, partial pancreasectomy, resection of peritoenal nodules, left hepatectomy and wedge resections of multuple liver metaseases (VI–VIII segments). The residual disease was a multiple liver metastases, the bigger one on the seven segment. The histological evaluation confirmed the GIST diagnosis and the molecular analysis of c-kit (exons 9-11-13-17) and PDGFr-alfa (exons 12-14-18) did not reveal any mutations.
After surgery, the patient restarted medical treatment with sunitinib and developed progression of liver disease in 3 months. She is still alive and receiving sunitinib, despite the resistance, waiting for enrollment in a third-line clinical trial.
Case report 2
In November 2004, a 27 years old woman developed severe abdominal pain. She was submitted to abdominal ultrasound, chest X-ray and CT scan that showed a thickness of the gastric wall (lesser curve and fundus of stomach), multiple perigastric lymph nodes and multiple small liver and lung lesions. The biopsy performed during the endoscopy showed gastrointestinal stromal tumors (CD117+, EGFr+). In May 2005, she started systemic treatment with imatinib mesylate at a dose of 600 mg/die. At the first evaluation with a CT scan, the disease was stable. In June, she developed severe anemia (Hb 8.5 mg/dl) and required continue blood support. As a consequence, she was submitted to arteriography and embolization of gastro-epiploic arterial and continued treatment with imatinib. In October, a CT scan revealed a progression of gastric disease, and so she started sunitinib 37.5 mg/die from November 2005 to January 2007. The best response was stable disease, with only a mild reduction of the gastric mass (Fig 1e, f; g, h). However, she developed moderate toxicity with fatigue, thyroid function alteration and heart failure. In January 2007, the patient stopped the treatment. On 26 February 2007, she was submitted to surgery for gastrectomy with removal of the primary responsive tumor mass. The histological evaluation confirmed the diagnosis of GIST and the molecular analysis of c-kit (exons 9-11-13-17) and PDGFr-alfa (exons 12-14-18) did not show any mutations. She interrupted the treatment for 2 months and developed a progression of disease with the development of new lung lesions. At present, she has small multiple liver and lung lesions and has restarted treatment with sunitinib without relevant toxicity and with stable disease.
The role of surgery for patients affected by GIST has changed due to the neo-adjuvant use of imatinib (Bonvalot et al. 2006; Andtbacka et al. 2007; Gronchi et al. 2007; Raut et al. 2006; DeMatteo et al. 2007; Scaife et al. 2003; Wu et al. 2003; Rutkowski et al. 2006; Haller et al. 2007; Jamali et al. 2007). Imatinib may reduce the tumor size and increase the rate of complete resection of a large tumor mass, which was unresectable before systemic therapy (Andtbacka et al. 2007). These patients have longer median disease survival time compared to historical control, but they also received post-operative treatment with imatinib (Andtbacka et al. 2007). The impact of incomplete surgical resection on survival has not been studied well and it should be considered in selected patients with development of symptoms or with mixed response to imatinib.
No reports that focus specifically on surgical management after sunitinib therapy are available. Sunitinib is active in patients who are resistant or intolerant to imatinib and has recently been introduced as second-line therapy (Demetri et al. 2006). However, the response to sunitinib is not indefinitely maintained and progression-free survival is about 7 months. At this moment, for these patients, no other therapeutical options are available except for clinical trials or the reintroduction of imatinib, and for many oncologists, their management is really difficult in the absence of validated options. In this setting, some patients develop symptomatic disease, which does not always call for emergency surgical interventions, such as in the case of gastrointestinal bleeding or perforation, abdominal pain or bowel obstruction. Others may develop chronic toxicity, while some others may be asymptomatic and in good performance status, but with a progression of disease. Surgical approach in this setting needs to be investigated more.
To our knowledge, only few patients are reported in literature: 21 patients out of 69 and 3 out of 40 in Raut and De Matteo series respectively, but they are included in large general series of patients treated with TK inhibitors before surgery (Raut et al. 2006; DeMatteo et al. 2007). The results are related to all study population, also including those receiving imatinib, and so surgical outcome of sunitinib cases such as bulky residual, surgical complications, clinical outcome and post-operative treatments are not reported separately. In general, surgical results are correlated with disease responsiveness and disease extension before surgery. The benefit from surgery in patients with stable or responding diseases is well known (Gronchi et al. 2007; Raut et al. 2006). Regarding progressive disease, in Raut series, patients with “limited” but completely resectable progressive disease have a median progression-free survival (PFS) of 7.7 months. Patients with “generalized” progression, operated for symptomatic diseases or for emergency indications, have a median PFS of 2.9 months. The 12-month PFS rate was 3% and 0% and the 12-month overall survival (OS) rate was 86 and 0% for limited and generalized diseases, respectively, so the survival rates were significantly higher for patients with limited disease than those with generalized disease (both P < 0.0001 for PFS and OS; Raut et al. 2006). As a consequence, patients with limited progressive diseases may benefit from surgery only in case of complete extirpation of all tumor sites, and for patients with generalized progressive disease, surgery is not recommended except for the palliation of symptoms. The same considerations are reported by others authors (Andtbacka et al. 2007; Gronchi et al. 2007; Raut et al. 2006; DeMatteo et al. 2007). From a general point of view, the conclusions of these authors are acceptable. However, clinical practice often points out difficult therapeutical decisons. The majority of patients in this setting have a metastatic disease and a complete resection is impossible, independent of their responsiveness to medical treatment.
One of our patients was stable and underwent surgery for the development of mild bleeding without emergency indications. The other one was stable (only a minimal response of primary tumor) and underwent surgery because of the development of sunitinib toxicity. Both had an incomplete resection of their diseases because of residual metastatic lesions. At present, 10 and 7 months since surgery. they are still alive and continue to receive sunitinib. This good clinical outcome may be also associated with the wild-type (WT) status of the c-kit, even though the correlation between the mutation type and prognosis is still controversial for patients in the preimatinib era (Andersson et al. 2006).
Should oncologists be encouraged to refer patients with not completely resectable metastatic disease, even though asymptomatic, to surgeons? Some clinical reasons need to be considered.
First of all, currently, most patients after sunitinib treatment do not have any validated chance of cure. Not all patients have the opportunity to be enrolled in clinical trials and for those who may receive a third-line systemic therapy such as nilotinib, a debulking of residual disease should be probably a more suitable condition.
Incomplete resection of GIST after treatment with TK inhibitors
Thirdly, surgery has a rationale in cases of focal disease progression due to secondary focal resistance. The post-surgery re-administration of sunitinib may allow a durable stable condition for minimal disease.
In conclusion, the absence of validated cures and the poor prognosis after sunitinib could open the debate on the assessment of surgical management of metastatic GIST in this setting. No data from clinical trials involving surgery are available. In our opinion, in clinical practice and after a multidisciplinary case patient discussion, surgery could represent a possible choice for advanced GISTs after sunitinib, especially if the risk of surgery-related death is not superior to the estimated benefit and no third-line clinical trials are available.
We thank CARISBO (Fondazione Cassa di Risparmio Bologna) for supporting the research programs on gastrointestinal stromal tumors (GISTs)