INTRODUCTION
Gastric cancer (GC) is the fifth most common cancer and ranks fourth in terms of mortality.[1] Although surgical resection of GC, specifically in the early stages, is potentially curative, disease relapse still occurs in most patients.[2] Immunotherapy and antiangiogenic therapy have been increasingly used for treating GC. Moreover, studies have shown that combining both might increase the efficacy of immunotherapy and improve the patient’s prognosis.[3] A distinct tumor subclass, microsatellite instability-high (MSI-H), is highly susceptible to immunotherapy.[4,5] A first-time phase 2 trial proved the benefits of immune checkpoint inhibitors (ICI) for treating MSI-H tumors.[6] The KEYNOTE158 study confirmed that ICI ameliorates MSI-H/dM tumors, showing an 11-month median progression-free survival (PFS) and 46% response rate for the GC subgroup.[7] The onset time of immunotherapy is generally 2–3 months, with a maximum of 18 months.[8] Some unique responses, such as pseudoprogression (PsP), might occur.[9] As these patterns do not completely meet the RECIST1.1 criteria, which is clinically relevant for treatment decision-making, the immune response evaluation criteria (iRECIST)[10] was proposed. Although several reports have shown PsP, only a few have reported it in MSI-H GC. Herein, we present a case of postoperative recurrence of GC (with MSI-H status), which was significantly cured despite prolonged PsP during immunotherapy. We also reviewed some related literature.
CASE REPORT
In January 2015, a 59-year-old male was admitted to Shandong Provincial Qianfoshan Hospital complaining of a space-occupying lesion in his stomach. Abdominal pelvic computed tomography (CT) revealed that the fundus and cardia of the gastric wall were slightly thickened. Pathological analysis of the gastroscopic biopsy revealed gastric adenocarcinoma. The patient underwent radical proximal subtotal gastrectomy in January 2015, and the definitive diagnosis was gastric adenocarcinoma pT1N0M0, stage IA. No other antitumor treatment was administered after the surgery. His general state was very good.
In December 2020, the patient suddenly developed hematemesis and tarry stools. Pathological analysis of gastroscopic biopsy revealed gastric adenocarcinoma. Abdomen-enhanced CT showed thickened gastric wall, closely related to the front edge of the pancreatic body, with an unclear boundary and decreased local density. Tumor marker analysis revealed increased levels of carbohydrate antigen CA19-9, CA724, CA50, and CA242. The patient was evaluated with a clinical stage of rT4bN0M0 IIIA and underwent gastrectomy on December 16, 2020. The immunohistochemical profile was HER2(–), MLH1(–), and PMS2(–). Next-generation sequencing analysis indicated MSI-H. The final diagnosis was GC recurrence with pT4bN0M0, stage IIIA (according to the eighth edition of the American Joint Committee on Cancer TNM staging). On January 6 and 27, 2021, the patient underwent two cycles of chemotherapy with oxaliplatin and capecitabine. However, an abdomen magnetic resonance imaging (MRI) performed on February 26, 2021, revealed a tumor mass with diameter of 3.4 × 3.2 cm [Figure 1a], indicating GC recurrence.
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Figure 1: MRI of the tumor showing the original pancreatic invasion site. (a)The baseline tumor volume after operation;(b)tumor volume after concurrent chemoradiotherapy and two cycles of toripalimab; a continuous increase of the tumor after four cycles(c),six cycles(d) and eight cycles(e).(f) A decrease size of tumor after ten cycles. (g) The most recent MRI after 12 cycles of toripalimab
Subsequently, the pancreatic lesions were subjected to radiotherapy using intensity-modulated radiation therapy (dose total: planning gross tumor volume: 45 Gy/25 F). On March 3 and 25, 2021, the patient underwent concurrent treatments with toripalimab (240 mg every 3 weeks) and taxol liposome (135 mg/m2 every 3 weeks). The patient completed the radiotherapy on April 4, 2021. Imaging examination [Figure 1b] demonstrated partial response (PR) with over 30% shrinkage from the baseline (February 26, 2021) of the target lesions according to both RECIST1.1 and i(r) RECIST. Thus, the treatment continued and the tumor markers were within the normal range.
However, the abdomen MRI revealed an increase in the tumor size [Figure 1c] with the abnormal signal of the residual stomach [Figure 2a]. The tumor markers were also increased [Figure 3]. PD and unconfirmed progression (iUPD) were confirmed according to RECIST1.1 and i (r) RECIST, respectively. The patient’s ECOG Performance Status score was 0. Thus, we wanted to check for PsP. On June 2 and 26, and July 27, 2021, the patient received apatinib (250 mg/day), toripalimab, and taxol liposome in three cycles. The MRI conducted on July 26, 2021, showed that the target lesions (3.2 × 3 cm) were over 20% larger than their minimum and confirmed progression (iCPD) according to i (r) RECIST. Moreover, the tumor markers had also increased sharply. On August 18, 2021, apatinib, toripalimab, and irinotecan were administered. Two days after the treatment, the patient developed a fever (the highest body temperature = 39°C) with increased procalcitonin and C-reactive protein levels. The alanine aminotransferase and aspartate aminotransferase were abnormal. The patient was given anti-infection and hepatoprotective treatments, and irinotecan was canceled on the eighth day. Unfortunately, a reexamination showed postoperative recurrence of GC [Figure 1c] and continuous increase in the tumor near the pancreatic body (iCPD) [Figure 1e] with elevated CA19-9 levels [Figure 3]. The patient insisted on receiving immunotherapy and targeted therapy but refused chemotherapy. Thus, he received two cycles of toripalimab (240 mg, once every 3 weeks) and apatinib (250 mg/day) from September 15 to October 11, 2021. CA19-9 continued to rise during this period, but the ECOG score was 0. November 8, 2021, the MRI revealed that the mass (2.1 × 1.9 cm) at the target lesion and the residual gastric mass [Figure 2d] were smaller than before, and PR was considered. Noticeably, the tests for tumor markers all showed significant declines, although they were still above normal.
Figure 2: MRI (mDIXON and DWI) of the residual gastric mass. (a) Abnormal irregular signals in the remnant stomach after four cycles of immunotherapy, (b) after six cycles, (c) after eight cycles, (d) after ten cycles, and (e) after 12 cycles
Figure 3: Trends in the levels of tumor markers. The level of (a) CA19-9 and (b) CA724, CA50, and CA242 are shown
The last follow-up visit of this patient was conducted on January 4, 2022. His ECOG score was still 0. The levels of all tumor markers were within the normal range, and the MRI showed a continuous decrease size of tumors [Figures 1g, 2e, and 3]. Immunotherapy continues to be used in this patient. Based on the results presented, we believe that the patient’s repeated progress over treatment for up to 5 months is actually PsP. The entire treatment process and disease status of the patient are summarized in Figure 4.
Figure 4: Timeline of immunotherapy and the complete treatment process. RE, recurrence; PR, partial response; PD, progressive disease; iUPD, unconfirmed progression; iCPD, confirmed progression; S1, the first surgical treatment; S2, the second surgical treatment; GC, gastric cancer; (*) the patient refused chemotherapy
DISCUSSION
GC is a highly aggressive and heterogenous malignancy, where the median survival rate is less than 12 months in the advanced stage and is a significant global health problem. Although immunotherapy is a new treatment option for MSI-H tumors, reports on PsP in GC are rare.
PsP was first described in advanced melanoma patients receiving ipilimumab when tumor index lesions regressed after initial progression. Previous studies showed that the incidence of immune system-related PsP ranged from 0% to 15%, mostly around 10%, except for a renal cancer report of 14.8%.[11] As described before, tumor biopsies from patients who experienced PsP usually show fibrotic tissues and inflammatory markers without tumoral cells.[5] These novel responses were defined as progression based on standard RECIST to evaluate the efficacy of immunotherapy. Moreover, new immunotherapy-specific radiologic criteria were developed based on RECIST, including iRECIST, immune-related RECIST (irRECIST),[12] and immune-related response criteria (irRC).[13]
All these criteria introduced the concept of unconfirmed progressive disease, enabling treatment after progression with fresh radiological evaluation after at least 4–12 weeks. All of them conformed with RECIST in identifying objective responses (partial and complete responses) and can efficiently distinguish PsP from progression with few significant differences.[14] Coudert et al.[15] reported two renal cell carcinoma and endometrial adenocarcinoma cases with late onset of PsP after ICI initiation after 36 and 10 months, respectively. Our patients underwent regular imaging assessments after radiotherapy, chemotherapy, and immunotherapy. Based on this, we found that PsP occurred after four cycles of immunotherapy and persisted until the imaging examination revealed efficacy. During therapy, PsP can either be early (within the first 12 weeks) or delayed (after 12 weeks). Rika Satoyoshi et al.[16] reported the first PsP case in a GC patient undergoing immunotherapy with nivolumab in 2018. Although the disease progressed after four cycles of immunotherapy, tumor shrinkage was seen after cycle 10. The whole PsP lasted nearly 5 months. According to Hodi et al.,[12] PsP usually occurs when immunotherapy is started and lasts for 4–8 weeks, much less than 5 months. Similarly, Nishino et al.[17] reported that the time taken to shrink the tumor radiologically after progression could be very long, up to 6 months. Consistently, in our case, the whole PsP process lasted approximately 5 months, much longer than usual, making it a unique feature.
Previous studies have not reported unconventional models of response and progression to immunotherapy in conventional cytotoxic or targeted therapy. However, they are not affected by other treatment methods.[18] For cytotoxic agents and radiotherapy, tumor shrinkage represents the anti-tumoral efficacy and correlates with survival. Conversely, some targeted therapies, such as antiangiogenic agents, do not cause tumor shrinkage but improve survival.[19] In this case, although the patient received other treatments during immunotherapy, we still made an accurate judgment on PsP.
Previous case reports showed that despite the progression, most patients experiencing PsP exhibited good performance status (PS) without any clinical deterioration or even would experience improvement of tumoral symptoms.[20] Therefore, studies have shown that apart from pathologic review and radiologic evidence, the clinical assessment of patients is also important for making correct medical decisions for patients undergoing immunotherapy.[21] Moreover, several atypical PsP cases were reported, in which patients experienced new serious symptoms, such as lung tumor cavitation or a pericardial PsP. They reported a case where seven patients experienced symptomatic PsP during immunotherapy, including pain, syndrome vena cava superior, systemic inflammatory reaction, cardiac tamponade, hemoptysis, general deterioration, and respiratory insufficiency. As for our case, the patient was considered as PsP but always had a stable PS without any additional symptoms. Thus, the clinical criteria should be used carefully.
Several laboratory markers can distinguish this unique response toward ICI. For example, Tanizaki et al.[22] suggested that the level of carcinoembryonic antigen (CEA) was relevant to PsP as the CEA levels decreased under immunotherapy. Contrarily, in our case, we observed increased tumor burden along with altered tumor marker levels, including CEA, CA19-9, CA724, and CA50. During the whole PsP, their levels increased sharply (especially CA19-9). Until the last reexamination, the levels were restored to the normal range. As this has not been reported previously, we attempted to understand the underlying reason and the role of tumor markers in monitoring immunotherapy response but could not find any answers. Additionally, several authors hypothesized that the level of circulating tumor DNA, plasma interleukin-8 levels, chemokine (C-X-C motif) ligand (CXCL2), and matrix metalloproteinases 2 might help confirm PsP from true progression.[23,24] Since our patients did not undergo these tests, we could not evaluate these indicators.
MSI-H status is another notable feature of our patient. Le et al.[6] found that regardless of the tumor type, the mismatch repair-deficit tumors always respond better to PD-1 blockade. In May 2017, the FDA granted accelerated approval to pembrolizumab for adult and pediatric patients with MMR-deficient or MSI-H solid tumors. Until now, the FDA has approved several cancer treatments. Therefore, we chose immunotherapy. However, reports have not yet shown the relationship between MSI-H subtypes and the onset time of immunotherapy. Consequently, it cannot be concluded that the longer immune onset time of this GC in the patient is related to MSI-H.
PsP is an atypical response with ICIs, and several radiological and biological methods have successfully distinguished PsP from progression and hyperprogression. Moreover, the PS of patients has also been considered. However, reviewing all PsP case reports, these methods need to be validated in larger prospective cohorts. The misdiagnosis of this phenomenon as disease progression might lead to inappropriate decisions, including discontinuing ICIs.[25] In our case, the patient did not show efficacy until 8 months after receiving immunotherapy, while the PsP lasted nearly 5 months. The case report of the late onset of this immunotherapy is still rare. In 2020, Daniel Reinhorn et al.[26] retrospectively evaluated advanced non-small-cell lung cancer patients treated with ICI therapy, and of 207 patients, 22% patients received treatment beyond progression (TBP). Of these, 36% achieved a clinical benefit, while 27% had progression-free intervals over 6 months after receiving TBP. Won et al.[27] published a similar study showing that among 189 patients receiving ICI treatment, 3.7% had PsP (mostly 3 months after treatment). After continuing ICI treatment, the PFS of patients with PsP was significantly higher than that of patients without PsP. Eguren-Santamaria et al.[28] reported that NSCLC patients with brain metastasis who received ICI treatment also experienced temporary PsP, and the intensive immune infiltration was mainly composed of T lymphocytes, which improved after continuing ICI treatment. They revealed that ICI achieved a clinically meaningful response with durable disease control. Therefore, these studies confirmed the feasibility of continuing immunotherapy.
In conclusion, the prolonged PsP might occur during immunotherapy before it becomes clinically effective or might be accompanied by elevated tumor marker levels. It is more important to perform a clinical assessment, make a careful judgment, and then decide whether to continue the treatment plan.
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.
Acknowledgments
The study was supported by the National Natural Science Foundation of China [grant no. 81803043] and Science and Technology Development Plan of Shandong Province (no. ZR2021QH356 and no. ZR2021LSW023).
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