Long-lasting complete response status of advanced stage IV gall bladder cancer and colon cancer after combined treatment including autologous formalin-fixed tumor vaccine: two case reports

The prognosis of advanced cancer (notably late stage IV cancer) of the digestive organs remains very poor despite the advances in surgical treatment and chemotherapy, even with the latest immune checkpoint inhibitors (as discussed in the Educational Session: What’s next in Cancer Immunotherapy, American Society of Clinical Oncology, June 6, 2016). We have previously reported a case of advanced breast cancer with bone metastasis that was successfully treated [1] with combined treatments including autologous formalin-fixed tumor vaccine (AFTV) [2, 3]. Herein, we report the success of this approach in cases of advanced gall bladder cancer (stage IV, liver metastasis) and colon cancer (stage IV, abdominal and lung metastases).

Gall bladder cancer and abdominal wall-metastasized colon cancer have a poor prognosis despite the advances in surgical techniques, chemotherapy, and radiation therapy. Patients with progressive cancer are waiting for new additional therapies, such as the combination of irradiation and immunotherapy. We have already reported on the success of combined treatments including AFTV for advanced breast cancer with bone metastasis [1]. Therefore, this is the second report of a long-lasting complete response of stage IV cancer after combined treatments including AFTV from our institution.

Gall bladder cancer is an uncommon disease in most parts of the world, despite being the most common and aggressive malignancy of the biliary tree [4]. The management of advanced gall bladder cancer remains a challenge for tumors invading the serosa and/or adjacent organs (T3) and those that invade the main portal vein or hepatic artery, or two or more extrahepatic organs/structures (T4). The benefits of surgical treatment remain unclear compared with potential survival owing to the high rate of surgical invasion; therefore, the therapy should be carefully selected considering the issues with surgery. Surgical resection is only recommended when a curative R0 resection is possible [5]. Given the poor prognosis of gall bladder cancer patients with T ≥ 2 and/or node-positive disease, adjuvant therapy is recommended. For optimal adjuvant therapy, 6 months of gemcitabine- or fluoropyrimidine-based chemotherapy with or without fluorouracil-based chemoradiation can be considered [5]. Most large studies of gall bladder cancer have demonstrated only a 2.7–15% overall 5-year survival rate in the USA and in European countries [6‐8]. In a Japanese study on 4774 patients, the 5-year survival rates for stage III, IVA, and IVB cancers were 29, 12.4, and 2.5, respectively [9]. The reason for this reported difference may be the more extensive resection routinely performed by Japanese surgeons, although patient selection bias, differences in pathologic staging, and other variables might have caused this difference in the survival rate [10]. In the context of the case of stage IV gall bladder cancer, it is difficult to mention the real cause of improved survival. However, case 1 was diagnosed with multiple liver metastases and lymph node metastasis, and we should consider that undetectable latent cancer cells spread widely around the primary tumor. Thus, the initial R0 surgery may not have completely removed the entire tumor burden. Therefore, it is highly probable that the combination of AFTV and chemotherapy has been suppressing any recurrence, as confirmed on CT, for more than 5 years.

The case fatality rates for stage I, II, III, and IV colorectal cancers have been reported to be approximately 6, 11, 30, and 79%, respectively [11]. In particular, the 5-year survival rate of synchronous peritoneal carcinomatosis (PC) from colorectal cancer (8.1%) was worse than that of metachronous PC from colorectal cancer (25.4%) [12]. The presence of PC from colorectal cancer is frequently diagnosed during surgery, and 91% of cases of PC from colorectal cancer are not preoperatively detected [13]. The operating surgeon has to select the appropriate treatment strategy, which can include systemic chemotherapy, complete cytoreductive surgery, intraperitoneal chemotherapy, and systemic chemotherapy; temporary surgery, such as a stoma; systemic chemotherapy alone or best supportive care; etc. [14]. In case 2, adjuvant chemotherapy was stopped because of cerebral infarction. The combination of irradiation and immunotherapy with AFTV, as a new additional therapy, did not cause any grade 2–4 adverse effects and ensured long-lasting complete remission. The effect of AFTV could be further explored in other similar cases. In addition, hyperthermic intraperitoneal chemotherapy (HIPEC) surgery is another option for cases in which first-line chemotherapy fails to downstage the cancer [15].

It has been reported that X-ray irradiation upregulates glioma cell immunogenicity [16], and this phenomenon suggests that the combination of irradiation and immunotherapy may be a good therapeutic candidate against malignant cells [17‐19]. Moreover, it has been shown that this combination treatment can enhance antitumor effects [20‐22]. Active immunotherapy can induce tumor-specific cytotoxic T lymphocytes (CTLs) and achieve a long-term antitumor immune response, and the autologous fixed tumor tissue is expected to provide many tumor antigens that may be recognized by a patient’s immune system resulting in a specific antitumor response [23, 24]. Thus, the treatment course of the present patients with the additional immunotherapy (AFTV) is considered to be well justified.

As delayed-type hypersensitivity (DTH) testing is commonly used to measure specific antitumor cellular immune reactivity, it can be used to evaluate the antitumor cellular immune status immediately before and then after AFTV treatment. The reactivity was found to be positive 2 weeks after the last AFTV injection in both of the present cases. Therefore, the cellular immune response against the carcinoma was induced by the AFTV treatment; however, the effect was weak and slow, and we assume that radiation and chemotherapy contributed to the eradication of the carcinoma with metastasis [1].

Generally, the prognoses of stage IV gall bladder cancer and abdominal wall-metastasized colon cancer are very poor, despite the conventional treatments. At present, the quality of life of our patients is very good, without any recurrence. Moreover, the adverse effects of AFTV were less than grade 2 according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) [25]. Therefore, combination therapy including AFTV should be considered for cases of advanced cancer, although larger-scale randomized and pivotal clinical trials are necessary to confirm the efficacy of AFTV.

In summary, we report the success of combination therapy including AFTV in cases of stage IV heavily metastasized gall bladder cancer and abdominal wall-metastasized colon cancer. Both patients experienced long-lasting, complete remission. Therefore, combination therapy including AFTV should be considered in patients with advanced cancer of the digestive organs.