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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 7  |  Page : 1589-1593

Prolonged overall survival in metastatic gastric cancer treated with ipilimumab and lapatinib


Department of Oncology, Chinese PLA General Hospital, Beijing, China

Date of Web Publication19-Dec-2018

Correspondence Address:
Yanfang Ju
Department of Oncology, Chinese PLA General Hospital, Beijing 100853
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_508_17

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 > Abstract 


Objective: Gastric cancer is one of the most important common tumors in the world. It remains the second leading cause of cancer-related death worldwide. The prognosis of patients with unresectable or metastatic gastric cancer remains poor. New targeted drugs were evaluated in clinic, such as lapatinib. The potential for making beneficial progress is to investigate innovative therapeutic strategies, such as immunotherapy.
Methods: We used combination therapy including immunotherapy for treating gastric cancer. We treated a patient of metastatic gastric cancer for which lapatinib plus ipilimumab was effective after progression on trastuzumab.
Results: The patient has prolonged overall survival after treatment. Positron emission tomography-computed tomography examination showed that some of the cervical lymph nodes and retroperitoneal lymph nodes reduced and glucose metabolism decreased. In blood examination, the tumor marker (carcinoembryonic antigen) decreased. The patient has been lived for 4 years after multiple lymph node metastasis.
Conclusion: Targeted therapy combined with immunotherapy might be a useful option for metastatic gastric.

Keywords: Gastric cancer, immunotherapy, ipilimumab, lapatinib


How to cite this article:
Ju Y, Sun S, Jiao S. Prolonged overall survival in metastatic gastric cancer treated with ipilimumab and lapatinib. J Can Res Ther 2018;14:1589-93

How to cite this URL:
Ju Y, Sun S, Jiao S. Prolonged overall survival in metastatic gastric cancer treated with ipilimumab and lapatinib. J Can Res Ther [serial online] 2018 [cited 2019 Jan 24];14:1589-93. Available from: http://www.cancerjournal.net/text.asp?2018/14/7/1589/247720




 > Introduction Top


Gastric cancer is one of the most important common tumors in the world. It remains the second leading cause of cancer-related death worldwide although the incidence of gastric cancer has recently declined.[1] Surgery is considered as the only option for cure for resectable gastric cancer. However, 40%–60% of patients relapse after radical surgery.[2] Palliative chemotherapy for unresectable or metastatic gastric cancer is a treatment of choice. Different combination of chemotherapy has resulted in a median overall survival (OS) of 8–10 months.[3] Despite the chemotherapy, targeted therapy has been used in clinic. Trastuzumab has demonstrated a survival advantage in patients with human epidermal growth factor receptor 2-overexpressed gastric cancer.[4] Despite advances in the treatment of gastric cancer, the prognosis of patients with unresectable or metastatic gastric cancer remains poor. New targeted drugs were evaluated in clinic trial, such as lapatinib. The potential for making beneficial progress is to investigate innovative therapeutic strategies, such as immunotherapy. Here, we report a case of metastatic gastric cancer for which lapatinib plus ipilimumab was effective after progression on trastuzumab. The patients have prolonged OS over 4 years after treatment. The combined therapy with lapatinib plus ipilimumab was well accepted, with minimal adverse effects. This kind of treatment maybe a useful selection for advanced gastric cancer.


 > Case Report Top


In June 2010, a 71-year-old female was admitted to our hospital presenting with locally advanced gastric cancer. The patient underwent total gastrectomy with Billroth II anastomosis and D2 lymphadenectomy.

Immunohistological analysis identified an ulcer type highly differentiated adenocarcinoma, and metastases was identified in 8/23 dissected lymph nodes. Stage III cancer was diagnosed according to the sixth edition of the American Joint Committee on Cancer classification system. The patient received an adjuvant chemotherapy treatment including tegafur (60 mg, po, 2/day, d1-28). This regimen was repeated every 6 weeks. The patient presented diarrhea during the second cycle and then refused to continuous chemotherapy. Hence, the patient was regularly followed up every 3 months for the 1st year.

In June 2011, positron emission tomography-computed tomography (PET-CT) examination showed that the patient developed disease progression with cervical lymph nodes, mediastinal lymph nodes, and retroperitoneal lymph node metastasis. Immunohistological analysis and gene examination showed that human epidermal growth factor receptor 2 (HER2) 2+ and fluorescence in situ hybridization (FISH) +. Hence, the patient received 7 cycles of chemotherapy including herceptin and dicycloplatin every 2 weeks (4 mg/kg herceptin and 500 mg dicycloplatin). Four months later, the patient had progressed disease [Figure 1]a. The patient received the second chemotherapy including herceptin and capecitabine. During the second cycle, bevacizumab was added to the treatment. However, in blood examination, the carcinoembryonic antigen (CEA) increased 2 months later.
Figure 1: Positron emission tomography-computed tomography imaging during the treatment. (a) Positron emission tomography-computed tomography imaging showed intensely (18F) fluorodeoxyglucose-avid in left cervical lymph nodes and retroperitoneal lymph nodes after first-line treatment with herceptin and dicycloplatin for 7 cycles. (b) Positron emission tomography-computed tomography imaging showed decreased (18F) fluorodeoxyglucose-avid in the left retroperitoneal lymph nodes after treatment with lapatinib for 3 months. (c) After treatment with lapatinib for 9 months, positron emission tomography-computed tomography imaging showed decreased (18F) fluorodeoxyglucose-avid in cervical lymph nodes and left supraclavicular lymph nodes. The foci of cervical lymph nodes and left supraclavicular lymph nodes reduced and left retroperitoneal lymph nodes almost disappeared. (d) After treatment with lapatinib for 13 months, positron emission tomography-computed tomography imaging showed increased (18F) fluorodeoxyglucose-avid in some of the cervical lymph nodes and retroperitoneal lymph nodes. Some of the cervical lymph nodes enlarged. (e) After treatment with ipilimumab for four times, positron emission tomography-computed tomography imaging showed decreased (18F) fluorodeoxyglucose-avid in some of the cervical lymph nodes, left supraclavicular lymph nodes, and retroperitoneal lymph nodes. Some of the cervical lymph nodes, left supraclavicular lymph nodes, and retroperitoneal lymph nodes reduced. (f) After treatment with ipilimumab for 14 months (treatment with ipilimumab for six times), positron emission tomography-computed tomography imaging showed decreased (18F) fluorodeoxyglucose-avid in some of the cervical lymph nodes, left supraclavicular lymph nodes, and retro-peritoneal lymph nodes. Some of the cervical lymph nodes, left supraclavicular lymph nodes, and retroperitoneal lymph nodes reduced

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The patient refused to chemotherapy because of adverse effects. Then, the patient administered targeted therapy (lapatinib). After 3-month treatment, the patient had stable disease. Nine months later, according to the PET-CT examination [Figure 1]b, cervical lymph nodes shrinked and glucose metabolism reduced. Glucose metabolism of left retroperitoneal lymph nodes was reduced and almost disappeared. In blood examination, the tumor marker (CEA) decreased to the normal level [Figure 1]c. The treatment with lapatinib lasted for 13 months.

In May 2013, PET-CT examination showed that some of the cervical lymph nodes enlarged and glucose metabolism increased, glucose metabolism of left retroperitoneal lymph nodes increased [Figure 1]d. In blood examination, the tumor marker (CEA) increased. Hence, the patient received immunotherapy including ipilimumab (ipilimumab 50 mg) combined with lapatinib. Ipilimumab was administered every 3 weeks for three times. Four months later, the patient received ipilimumab combined with lapatinib. One month later, the patient received the combined therapy again. PET-CT examination showed that some of the cervical lymph nodes and retroperitoneal lymph nodes reduced and glucose metabolism decreased [Figure 1]e. In blood examination, the tumor marker (CEA) decreased [Figure 2]. Then, the patient received maintenance treatment every 3 months for three times. The patient had stable disease [Figure 1]f. The combined therapy had been lasted for 18 months until followed up. During the treatment, the patient seldom had the adverse effects. Occasionally, the patient felt slight weakness. The patient has been lived for over 4 years after multiple lymph node metastasis.
Figure 2: CEA changing during the treatment of ipilimumab combined with lapatinib

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 > Discussion Top


Gastric cancer is the second most common cause of cancer death worldwide. Gastric cancer is often diagnosed at an advanced stage. Systemic chemotherapy is the mainstay of treatment for these patients.[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18]

However, there is no accepted standard of care although studies showed some benefit from chemotherapy regimens including cisplatin, oxaliplatin, capecitabine, docetaxel, and irinotecan. OS remains poor for advanced gastric cancer.

Targeting agents have been widely tested. Trastuzumab was the first target drug developed. Trastuzumab is a recombinant humanized monoclonal antibody that targets the extracellular domain IV of HER2. HER2 is a receptor of tyrosine kinase and a member of the epidermal growth factor receptor (EGFR) family. EGFR overexpression has been found in different cancer including gastric cancer.

The ToGA trial was a large randomized multicenter Phase III trial that evaluated the addition of trastuzumab (Herceptin) to platinum-based chemotherapy in HER2-positive advanced gastric cancer, demonstrating improved survival for those patients receiving trastuzumab.[4] HER2 status can be measured by immunohistochemistry (IHC) or FISH. HER2 positive in the ToGA trial was defined as being either IHC3+ or FISH+.

In our study, the patient was diagnosed as advanced gastric cancer. Her-2 status was measured by IHC and FISH (HER-2 2+, FISH +). The patient received first-line therapy which included herceptin and chemotherapy (dicycloplatin). The time of disease control was 4 months. This was maybe related with the degree of HER-2 protein overexpression. The patient is IHC 2+ positive. In ToGA trial, researchers found that the effect of trastuzumab seems to be dependent on the degree of HER-2 protein overexpression, with the best median OS in the group of patients with IHC 3+.[19]

After first-line treatment, the patient received capecitabine combined with herceptin and bevacizumab. Angiogenic blockade strategy has been evaluated in the clinical trials and has been proved to benefit patients with metastatic cancers.[20],[21],[22],[23],[24],[25],[26] The disease also progressed. Then, the patient received lapatinib. Lapatinib is an oral tyrosine kinase inhibitor. It is an inhibitor of both EGFR and HER2. In preclinical experiment, the antitumor effect of lapatinib has been investigated in different gastric cancer cell lines. It could induce a selective and potent growth inhibition in two HER2-amplified gastric cancer cell lines. Hence, a Phase II clinical trial was performed in patients with advanced gastric cancer. The patients received lapatinib as monotherapy until disease progression or unacceptable toxicity. The response rate was 11% and the median OS was 4.8 months.[27]

In another clinical trial, patients were treated with lapatinib and capecitabine/oxaliplatin in first-line treatment. The combination therapy did not significantly improve the median OS compared with chemotherapy alone. However, in subgroup analysis, Asian patients seemed to benefit from lapatinib (median OS, 16.5 mo vs. 10.9).[28]

A randomized, open-label, Phase III study tested lapatinib in the second-line treatment of HER2-amplified advanced gastric cancer in Asian population. The addition of lapatinib to paclitaxel had no significant benefit in progress-free survival (PFS) and OS. However, there was significant benefit in both PFS (5.6 mo vs. 4.2 mo) and OS (14.0 mo vs. 7.6 mo) for patients with IHC 3+.[29]

In our treatment, the patient received lapatinib as monotherapy. The disease had been controlled for 13 months. The patient had long PFS time after treatment by lapatinib. Lapatinib maybe useful for treating the trastuzumab-resistant HER2-positive gastric cancer. A study described that lapatinib showed the antitumor effect for trastuzumab-resistant cell lines.[30]

However, after the treatment, the disease progressed again. There are no standard criteria for patients with advanced gastric cancer after multiple lines treatment. Researchers had to try other treatment, such as immunotherapy. However, early immunotherapies were limited by the lack of specificity and undefined molecular/cellular targets.

In recent years, ipilimumab had been evaluated in patients with advanced melanoma. Clinical trials showed that ipilimumab could improve OS of patients with advanced melanoma. Ipilimumab was the first therapy to improve OS of patients with advanced melanoma in recent clinical Phase III trials, and its success has ushered in a new era in the field of immuno-oncology. Immunotherapy has become the fourth pillar (along with surgery, radiotherapy, and chemotherapy) of the cancer treatment platform.[31]

Immunotherapy has become more and more important in recent years and has shown great benefits in many cancers.[32],[33],[34],[35],[36],[37]

Ipilimumab is a fully human monoclonal antibody that targets cytotoxic T-lymphocyte antigen-4 (CTLA-4) which can augment antitumor immune responses. CTLA-4 is a key negative regulator of T-cell activation which is serving as a natural braking mechanism. Scientists found that CTLA-4 blocking antibody could enhance antitumor immunity.[38]

Moreover, researchers found that CTLA-4 blockage had been successful clinically in advanced melanoma.[39],[40]

In a Phase III clinical trial, previously treated patients who received ipilimumab had significantly improved OS.[41]

Investigations of ipilimumab have also been undertaken in other solid tumors, such as unresectable or metastatic gastric cancer.[42]

In our study, the patient received ipilimumab combined with lapatinib after lapatinib monotherapy. The patient received eight times treatment of ipilimumab. She received maintenance therapy every 12 weeks to achieve long-standing antitumor effects after three times treatment of ipilimumab. The patient had stable disease for 23 months and she is still alive until follow-up now. This heavily pretreated patient with advanced gastric cancer has a long-time survival after treatment of ipilimumab combined with lapatinib. This case illustrates targeted therapy combined with immunotherapy maybe a useful selection for advanced gastric cancer.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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