CASE REPORT
Clinical Complete Response of Recurrent Gastric Cancer after Third-line CPT-11 Chemotherapy
2023 Volume 72 Issue 2 Pages 60-64
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2023 Volume 72 Issue 2 Pages 60-64
A 75-year-old man underwent distal gastrectomy for advanced gastric cancer in September 2018. During the adjuvant chemotherapy, computed tomography (CT) revealed recurrence sites in the liver and para-aortic lymph nodes. Therefore, chemotherapy was initiated. After first-line (capecitabine with oxaliplatin) and second-line (paclitaxel with ramucirumab) treatments, nivolumab was used as third-line chemotherapy. This treatment showed a strong effect against the tumor. However, following an immune-related adverse effect (irAE) because of nivolumab, the therapy was halted. The irAE was diagnosed with central adrenal insufficiency that was controllable by oral intake of steroids. CPT-11 was started and showed a similarly strong effect to that observed for nivolumab. Eventually, the recurrent tumor lesions became too small to be detected by CT. We discontinued CPT-11 at the request of the patient. Even after discontinuation, no recurrent sites have been observed, allowing us to declare a case of clinical complete response (cCR). In conclusion, even if irAEs occur in a patient, continuing chemotherapy should be considered. However, if cCR is achieved, discontinuation of chemotherapy might be a strategic treatment option.
Despite recent improvements in chemotherapy and associated advances in the treatment of gastric cancer,1,2,3,4 it is very rare for chemotherapy to lead to clinical complete response (cCR). The few described cases of cCR in advanced gastric cancer involved neoadjuvant chemotherapy or first-line chemotherapies.5 This case report presents a case of cCR of recurrent gastric cancer that was achieved after CPT-11 treatment. CPT-11 treatment was administered as a third-line chemotherapy for recurrent gastric cancer. Therefore, we present a rare case of cCR that was achieved after CTP-11 treatment alone.
A 75-year-old man underwent a distal gastrectomy with D2 lymph node dissection and cholecystectomy for advanced gastric cancer. Pathological findings included advanced gastric cancer, poorly differentiated adenocarcinoma with neuroendocrine differentiation, pT3, pN3b (24/67), M0, and pathological stage IIIC (Fig. 1). Adjuvant chemotherapy was initiated according to the Japanese Gastric Cancer Treatment Guidelines.6 Oral intake of TS-1 was administered as adjuvant chemotherapy to the patient from October 2018. Although we considered that capecitabine with oxaliplatin (CapeOX) or TS-1 with oxaliplatin may have been the most effective adjuvant chemotherapy, the patient chose TS-1 monotherapy.
Pathological findings.
(A) Macroscopic finding: the primary tumor (46 × 43 × 8 mm) was located on the middle third of the stomach, showing type 2 configuration. (B) Hematoxylin and eosin (HE) stain (×12.5), (B’) HE stain (×200): tumor cells are proliferating with alveolar, cord-like, or tubular pattern. High cellular atypia was observed and cytoplasm was often granular. (C) CD56 was positive (×200). (D) Synaptophysin was positive (×200). (Chromogranin A was negative; picture was not shown). These findings suggested moderately to poorly differentiated adenocarcinoma with neuroendocrine tumor differentiation.
In February 2019, the level of tumor markers (TM) increased. Computed tomography (CT) revealed recurrence sites in segment 6 of the liver, paraaortic lymph nodes, and abdominal fluid (Fig. 2,1A–1D). CapeOX was started as first-line chemotherapy in March 2019, and the patient’s HER2 status was negative. In August 2019, CT revealed tumor progression (Fig. 2, 2A–2D). Second-line treatment using paclitaxel with ramucirumab (PTX with RAM) was initiated. The tumor progression was observed again after achieving a partial response (Fig. 2, 3A–3D). In November 2019, nivolumab was initiated as a third-line chemotherapy. This treatment showed a good response against the tumor recurrence (Fig. 2, 4A–4D). In April 2020, the patient visited the hospital because of severe malaise. Blood tests showed extremely low levels of adrenocorticotropic hormone (<1.5 pg/mL) and cortisol (0.08 µg/mL). The levels of thyroid stimulating hormone, free thyroxine, and free triiodothyronine were normal. Magnetic resonance imaging detected no abnormalities in the pituitary. Based on these findings, we diagnosed central adrenal insufficiency caused by nivolumab as an immune-related adverse event (irAE).
Transition of computed tomography images from February 2019 (column 1) to September 2021 (column 6).
Yellow arrow indicates liver metastasis. Blue arrows indicate upper abdominal fluid. Orange arrow indicates para-aortic lymph node metastasis. Green arrows indicate pelvic fluid. Recurrent sites except for liver metastasis vanished in October 2020. Continuation of CTP-11 achieved further shrinkage of recurrent lesions in the liver.
Oral intake of hydrocortisone relieved these symptoms. Although nivolumab showed a good response against recurrent lesions, the liver recurrence sites could be detected with CT. Therefore, we recommended that the patient continue the chemotherapy using CPT-11 (Fig. 2, 5A–5D). CPT-11 treatment was initiated in May 2020. In October 2020, CT detected further shrinkage of recurrent lesions. In November 2020, the patient requested discontinuation of the chemotherapy because he was tired of the treatment, not because of the side effects of the drug. Since that time, the patient has not received any chemotherapy. CT revealed no recurrent sites, even after discontinuation of chemotherapy for 10 months (Fig. 2, 6A–6D). In addition, the TM level became normal (Fig. 3), which led us to define this case as cCR.
Clinical course and transition of tumor markers.
In this case, cancer antigen 125 (CA 125) was the most sensitive tumor marker. When cCR was declared, all tumor marker levels were normal. PD, Progressive Disease; CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19-9.
According to the consulting endocrinologist, the steroid dose could not be changed, even if nivolumab was halted. Therefore, we have prescribed hydrocortisone 20 mg/day since the irAE was diagnosed.
When informed consent for surgical procedures was obtained, the patient also provided general consent for publication and presentation of this case.
In recent decades, chemotherapy for unresectable and recurrent gastric cancer has improved because of the development of new drugs, such as ramucirumab and nivolumab.3,7 However, CPT-11 is a traditional drug used in the treatment of gastric cancer. Some reports have shown that cCR is achieved after CPT-11 administration.8 However, to the best of our knowledge, this is the first case report that showed cCR after third-line chemotherapy with CPT-11 for recurrent gastric cancer.
The Japanese Gastric Cancer Treatment Guidelines has determined CPT-11 as a third-line chemotherapy option.6 Although the recurrent lesions of the patient in the present case showed a good response to nivolumab, we could not continue nivolumab treatment because of the irAE. The cCR rate of nivolumab is reported as approximately 1%.4 This rate is not greatly different from other chemotherapy treatments, including TS-1 with oxaliplatin and paclitaxel with ramucirumab.2,3 If this patient had continued to use nivolumab, we consider that cCR may have been achieved. In addition, it is worth noting that the efficacy of nivolumab might have continued even if the treatment with nivolumab was stopped. Therefore, the reason for cCR in this study could not be identified, and we cannot conclude with certainty that the effect of CPT-11 alone or the continued effect of nivolumab with CPT-11 caused the observed cCR.9
There is a report suggesting that irAEs are correlated with a high response to nivolumab,10 which means that the occurrence of irAEs is associated with the high efficacy of nivolumab. Based on this reasoning and given that this patient had irAE, it is likely that the patient achieved a good response with nivolumab. In this patient, continuation of nivolumab could be an option because central adrenal insufficiency can be controlled by steroid intake. However, we chose to discontinue the use of nivolumab because we were concerned that other irAEs may have occurred.
In general, microsatellite instability-high (MSI-H) and tumor mutation burden (TMB) are regarded as good predictors for nivolumab.11,12,13 Although we should have measured these factors before starting nivolumab, we did not investigate them because tests for MSI or TMB were not mandatory. Kim et al. investigated predictors for nivolumab.14 In their report, normal serum sodium and low neutrophil lymphocyte ratio (NLR) were used as predictors of nivolumab response.14 In the present case, the patient showed normal sodium (140 mEq/L), and low NLR (0.82), which suggested that the patient was a good responder to nivolumab.15,16
Regarding pathological findings, this case did not have specific findings regarding nivolumab. For example, this case did not show high lymphocyte invasion to suggest Epstein Barr virus infection, which has been reported to be a predictive factor for nivolumab. A plausible explanation of good response to chemotherapy may be that this case had a neuroendocrine element. Some reports argue that neuroendocrine tumors respond well to CPT-11.17,18 In this case, we considered that neuroendocrine tumor involvement may have explained the good response to CPT-11.
After administration of CPT-11 for 12 months, recurrent lesions became undetectable. However, our strategy was to continue CPT-11 for as long as possible because we considered that the possibility of achieving cCR using only CPT-11 was very small.8 Eventually, we stopped chemotherapy in November 2020 in response to the patient’s request. By a strange coincidence, discontinuation of the chemotherapy revealed the cCR in this case. The Response Evaluation Criteria in Solid Tumors (RECIST) define cCR as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to less than 10 mm.19,20 This case met the definition of cCR according to the RECIST guidelines. Furthermore, although CPT-11 has been used to treat recurrent and unresectable gastric cancers, some doctors consider that the efficacy of this drug is not strong. In fact, chemotherapy regimens, including CPT-11 used decades ago are usually combinations of CPT-11 with other drugs, such as TS-1 or mitomycin.8 This supports our opinion. However, the progress of this case suggests that CPT-11 can lead to cCR after administration of nivolumab.
In this case, if there was a second recurrence, chemotherapy would be started again. This is because CPT-11 was not stopped because of resistance. In addition, resistance to nivolumab was not observed, although there remains the possibility of other irAEs. From this perspective, if cCR appears to be achieved, discontinuation of chemotherapy might be a positive option for patients.
In conclusion, we presented a case of recurrent gastric cancer in which cCR was achieved after using CPT-11 as third-line chemotherapy. If cCR is achieved, chemotherapy discontinuation might be a strategic treatment option.
We thank Mr. Samsudeen Saidu for English editing of this article.
The authors have no conflicts of interest to declare.
