Standard treatment for stage IV gastric cancer is basically chemotherapy. For HER2 positive stage IV gastric cancer patients, recommended treatment is trastuzumab-based chemotherapy [2]. According to the ToGA trial, the median OS was observed to extend to 13.8 months following trastuzumab therapy [2]. On the other hand, recent studies have shown the prognostic benefit of conversion surgery after chemotherapy in patients with unresectable gastric cancer [12,13,14,15,16,17,18,19]. Especially, some reports suggested prognostic importance of R0 resection after palliative chemotherapy in conversion surgery of stage IV gastric cancer patients who responded to the chemotherapy [15,16,17,18,19]. Therefore, we may recommend conversion surgery after chemotherapy of stage IV gastric cancer, if curative surgery is technically possible. However, regarding conversion surgery for HER2 positive stage IV gastric cancer, only a few case reports were published [3,4,5,6,7], and they did not assess prognostic importance of conversion surgery. Besides, no cohort study has ever been published on this subject because of the limited population of HER2 positive stage IV gastric cancer [2].
In this study, consecutive 11 HER2 positive stage IV gastric cancer patients treated with trastuzumab-based chemotherapy as the first line treatment were retrospectively investigated. Our study demonstrated a good treatment response of trastuzumab-based chemotherapy with 63.6% of response rate, and favorable OS of the conversion surgery group, while the OS of the chemotherapy alone group was almost the same as that of the ToGA trial (12.9 months vs. 13.8 months). Interestingly, the 3-year survival rate of patients who could achieve R0 resection was 100%, which is extremely high compared to that of stage IV gastric cancer patients treated with chemotherapy [20]. Compared to the ToGA trial, the OS of our patients was obviously better (31.5 months vs. 13.8 months). It might be because patients in the ToGA trial did not receive surgery after the chemotherapy, even though some of them might have a chance to receive R0 resection, because resection is not generally recommended for stage IV gastric cancer. Therefore, conversion surgery can be an effective treatment option for HER2 positive stage IV gastric cancer patients. However, our study just showed the prognosis of the conversion surgery group (all of them were treatment responders) and that of the chemotherapy alone group (half of them were non-responders). Therefore, even though we compared them, we could not demonstrate a true survival benefit of conversion surgery. However, the 3-year survival rate of patients who could achieve R0 resection was 100.0% (median OS, 51.8 months), which is extremely high compared to that of stage IV gastric cancer patients treated with chemotherapy [20]. Besides, a paper reported that the median OS of responders in advanced gastric cancer patients treated with trastuzumab was about 20 months [21], which is less than that of the conversion surgery group in our study. Therefore, we believe that our results indirectly suggest prognostic benefit of conversion surgery in HER2 positive stage IV gastric cancer, and we might say that our results were consistent with favorable results on conversion surgery for stage IV gastric cancer patients [12,13,14,15,16,17,18,19]. The indication for conversion surgery is still under discussion. Yoshida et al. proposed a new classification of stage IV gastric cancer according to the biological characteristics [15]. Their classification included four categories as following; category 1 is potentially resectable, category 2 is defined as gastric cancer with a marginally resectable metastasis, category 3 is gastric cancer with a potentially unresectable metastasis of peritoneal dissemination, and category 4 includes gastric cancer with non-curable metastasis. And they suggested that the indications for conversion therapy might include the patients from category 2, some patients from category 3 and a very small number of patients from category 4. In fact, our conversion surgery group included two “category 1” patients, three “category 2” patients, and one “category 4” patient. Thus, the addition of conversion surgery after chemotherapy may result in long term survival in selected patients, but it still remains unclear how is the indications and timing of the operation after the palliative chemotherapy, which should be studied in further investigation.
Besides, we demonstrated that HER2 expression of the primary tumor that was positive before the treatment became negative in all gastric cancer patients who received conversion surgery after trastuzumab-based chemotherapy. Miyake et al. reported that about 11 of 16 HER2 positive gastric cancer patients (about 70%) before first line chemotherapy lost HER2 expression after trastuzumab-based chemotherapy [22]. Moreover, regardless of HER2 expression after first line chemotherapy using trastuzumab, it was reported that continuous use of trastuzumab beyond progression failed to improve survival in a meta-analysis [23]. Therefore, it might be better not to use trastuzumab in adjuvant chemotherapy after conversion surgery, but further investigation will be needed.
Our study has limitations as follows. First, this study is based on single-center data, and the sample size is very small, even though the incidence of HER2-positive gastric cancer is relatively low. Second, retrospective nature is also a limitation of this study. The change of treatment strategy such as surgical technique and chemotherapy during a relatively long study period (7 years) may affect the results. Prospective multicenter study with larger patient population will be needed to confirm our findings in the future studies.