Recurrent peritoneal serous carcinoma that was unmanageable with paclitaxel-carboplatin therapy responded to autologous formalin-fixed tumor vaccine.

Paclitaxel-carboplatin therapy (TC) usually controls primary peritoneal serous carcinoma (PPSC) but not recurrent disease. In this case, PPSC recurred after three courses of TC, responded dramatically to additional autologous formalin-fixed tumor vaccine (AFTV), and resulted in prolonged, progression-free survival without visible lesions detected by positron emission tomography-computed tomography.

Introduction

Primary peritoneal serous carcinoma (PPSC) has a clinical profile similar to ovarian cancer 1. Adjuvant paclitaxel–carboplatin therapy (TC) showed almost identical, favorable results regarding survival rates in patients with PPSC and ovarian cancer 2; however, once recurrence happens, PPSC becomes difficult to manage with TC alone.

Active, specific immunotherapy using the patient's tumor cells can elicit a long-term cell-mediated immune response and succeeds in treating melanoma and colon cancer 3,4. Formalin-fixed cells and paraffin-embedded tumor tissues are also good sources of alternative tumor-associated antigens for autologous cytotoxic T-cell induction 5,6. Autologous formalin-fixed tumor vaccine (AFTV) was developed on the basis of this principle 7,8. A prospective randomized clinical trial showed that AFTV significantly decreased the incidence of early recurrence in patients with hepatocellular carcinoma who had undergone hepatic resection alone 9. Other pilot and phase I/IIa studies for glioblastoma multiforme indicated that such therapy was effective without notable complications 10,11. Therefore, AFTV has been considered to be applicable to many types of solid tumors, such as high-grade malignant fibrous histiocytoma in combination with radiotherapy 12. In this background, we tried to treat a case of tertiary-recurrent PPSC with TC and AFTV, which seemed difficult to manage with TC alone.

Case Report

A 57-year-old woman presented an abnormal endometrial pap smear, which was suspicious for adenocarcinoma and was systemically explored. However, no malignant lesion was confirmed by total endometrial curettage or computed tomography. The CA125 level was within the normal range. She underwent laparoscopic laparotomy, which identified adenocarcinoma on the surfaces of her ovary, omentum, and peritoneum. After undergoing a total abdominal hysterectomy, bilateral salpingo-oophorectomy, total omentectomy, pelvic lymphadenectomy, and exploratory excision of the right crus of diaphragm, she was histologically diagnosed with PPSC.

She had an elevated CA125 level (1335 U/mL) after 26 months of time to progression (TTP) by the first postoperative paclitaxel (180 mg/m2) plus carboplatin (CBDCA; area under the curve 6) therapy (TC) comprising six courses. Positron emission tomography-computed tomography (PET-CT) showed recurrence at the small bowel, which was observed only on the surface of the ileum. As a result, a 3-cm ileostomy was performed. A second TC comprising six courses was administered; however, after 20 months of TTP, the CA125 level was elevated again (84 U/mL). She underwent TC a third time, which comprised five courses. After resulting 8.3 months of TTP, the CA125 level continuously increased from 17.9 U/mL (day 0) to 2586 U/mL (day 91) (see Fig.1). PET-CT revealed multiple hot spots around the right crus of the diaphragm, liver, and mesentery (day 85) (see Fig.2, left). TC was again attempted; however, after initiation of the fourth TC (day 97), the CA125 level increased to 3571 U/mL (day 105). At that point, a decision was made to combine TC and AFTV.

Figure 1

Changes in CA125 levels after TC and AFTV therapy. The CA125 level continuously increased from 17.9 U/mL (day 0) to 2586 U/mL (day 91). TC (solid arrows) began on day 97, and intradermal injections of AFTV (open arrows) commenced on day 116. Following initiation of this therapy, CA125 levels dramatically decreased from 3571 U/mL (day 105) to 244 U/mL (day 133). Levels continued to decrease from 53.6 U/mL (day 161) to 29.3 U/mL (day 189) to 15.8 U/mL (day 281). AFTV, autologous formalin-fixed tumor vaccine; TC, paclitaxel–carboplatin therapy.

Figure 2

Response to TC and AFTV therapy assessed by PET-CT. PET-CT images before and after TC and AFTV. Left: Multiple hot spots around the right crus of the diaphragm, liver, and mesentery are visible. Right: No recurrent hot spots detected after TC and AFTV. AFTV, autologous formalin-fixed tumor vaccine; TC, paclitaxel–carboplatin therapy; PET-CT, positron emission tomography-computed tomography.

The AFTV was prepared as has been described 10. First the formalin-fixed, histologically confirmed neoplastic tissue was thoroughly fragmented and centrifuged. Then, an alcohol extract preparation of freeze-dried Bacillus Calmette–Guérin vaccine (Japan BCG Laboratory, Tokyo. Tokyo, Japan) was added, washed, and suspended in 1 ml of saline with 250 ng of tuberculin microparticles and 250 ng of soluble tuberculin (Japan BCG Laboratory, Tokyo).

After obtaining informed consent from the patient, AFTV were initiated (day 116). She received three intradermal injections of AFTV at 2-week intervals. The day after the third AFTV injection, skin erythema and induration were observed, suggesting delayed-type hypersensitivity reaction around inoculated points; this finding persisted for only 7 days.

The blood CA125 levels dramatically decreased to 244 U/mL (day 133), 53.6 U/mL (day 161), 20.4 U/mL (day 224), 17.9 U/mL (day 251), and 15.8 U/mL (day 281) (Fig.1). PET-CT revealed no visible mass (day 189) (Fig.2, right). However, CA125 levels dramatically increased again from 24.8 U/mL (day 310) to 830 U/mL (day 344). Because the entire specimen was used to prepare the three AFTV, additional chemotherapy without AFTV was performed with TC (only one course; no response), followed by gemcitabine monotherapy (no response), and finally, topotecan (no response). The patient died 16.5 months after undergoing TC and AFTV treatment.

Discussion

When comparing clinical profiles of PPSC and ovarian cancer, many similarities exist. For example, TC affects patient survival rates in a similar and favorable manner 2. A traditional phase II study evaluating the efficacy of TC for platinum-sensitive recurrent ovarian cancers demonstrated an observable response in 75.6% (26.8% complete response, 48.8% partial response) of cases 13, but incidence of the response to TC decreased in the context of PPSC recurrence.

In this case study, the patient's TTP was 26, 20, and 8.3 months after the first, second, and third TC, respectively. When PPSC recurred after the third TC, the CA125 level continued to elevate to 3571 U/mL even after initiating a fourth TC; this response pattern differed from those of the former TC applications in which the CA125 level decreased in response to therapy. Thus, TC alone could not manage the fourth recurrent PPSC in this case.

When TC was combined with AFTV, the patient responded dramatically to the additional AFTV and did not develop severe adverse effects. In addition, the patient showed a TTP of 11.5 months, which was longer than that of the third TTP. Because formalin fixation preserves the specific antigenicity of tumor cells 5 and preparation of AFTV from resected and fixed tumor tissues 10,11 is simple, AFTV therapy is a viable option for clinical applications. Furthermore, after the patient received TC and AFTV, no visible lesions were detected by PET-CT. These findings suggest that TC and AFTV could serve as a new strategy for recurrent PPSC, which is unmanageable with TC alone.

The feasibility and efficacy of complete laparoscopic staging was demonstrated in early stage ovarian cancer 14; however, in advanced stage, the role of laparoscopy has been limited in cytoreductive procedures. In this case, cancer mass was observed on the surfaces of the ovary, omentum, peritoneum, and right crus of diaphragm, and laparotomy was rationally indicated for optimal maximum cytoreduction. The efficacy of intraperitoneal (IP) chemotherapy preceded by cytoreductive surgery was reported in advanced ovarian cancer 15. In this case, consecutive cytoreductive laparotomy after laparoscopic survey was seemed to be appropriate, and we do not adopt IP chemotherapy due to the possibility in severe adverse events, such as grade 3–4 pain, ileus, diarrhea, or an associated complication of IP catheter, which might worsen quality of life in spite of the expected promising survival by IP 16. Latest immunotherapeutic advancements in the treatment of tumors 17–19 should be taken in consideration for this type of patients.

Conclusion

In this case study, the patient gained approximately a year of progression-free survival time after the recurrence of TC-resistant PPSC, which implies that this type of immunotherapy may be a viable treatment option for chemo-refractory recurrent PPSC.

Patient Consent

Written informed consent was obtained from the patient for publication of this Case report and accompanying images.