In this patient, conversion surgery for initially unresectable GBC with peritoneal carcinomatosis resulted in good long-term survival without recurrence. There are few reports on conversion surgery for GBC, including BTC. In 2013, an initial study by Kato et al. [10] showed that chemotherapy with GEM significantly downsized initially unresectable, locally advanced BTC tumors and permitted surgical resection. The median survival times (MSTs) of patients treated with resection after downsizing chemotherapy and those treated with chemotherapy alone without resection were 19.3 and 7.5 months, respectively (p = 0.032) [10]. In 2015, the same group reported treatment of BTC using GC therapy rather than GEM monotherapy and found MSTs of 17.9 months for patients treated with resection following chemotherapy and 12.4 months for those treated with chemotherapy alone (p = 0.0378) [11]. Thus, the pathological response differed significantly with GC chemotherapy compared to GEM monotherapy. In 2020, a multicenter retrospective study of conversion surgery for initially unresectable BTC in Japan showed a 5-year survival rate following surgery of 38.2% with an MST of 34.3 months, which was significantly better than that for chemotherapy only (p < 0.001) [8]. Thus, conversion surgery for BTC seems to be beneficial for selected patients in whom lesion shrinkage permits curative surgery.
Evaluation of the validity of conversion surgery raises several clinical issues. The first is the surgical procedure and safety. Establishing an appropriate procedure is difficult because most cases are likely to be advanced locally with infiltration to major vessels or nearby organs, and distant metastasis may be present, even if curative resection is possible. A greater extent of resection also has a higher risk of postoperative complications, and such high-risk surgery may cause mortality. This factor should be taken into account when deciding to perform curative surgery.
The second issue is the optimal timing for conversion surgery. Noji et al. [8] performed conversion surgery at least 3 months after nonsurgical anticancer treatment, including chemotherapy, for initially unresectable BTC, and this resulted in stable disease or a partial response. However, other studies have reported no apparent criteria for the duration of chemotherapy before conversion surgery. Satoi et al. [7] found that the prognosis of conversion surgery for pancreatic cancer is significantly better in patients who received nonsurgical treatment for ≥ 240 days than in those treated for < 240 days, and many studies have subsequently used this finding as evidence for a preoperative treatment period of ≥ 8 months. However, whether the optimal treatment period for conversion surgery for pancreatic cancer is consistent with that for BTC is unclear. Tumor resistance to chemotherapy is also a concern, and ineffective regimens and forced changes often occur during chemotherapy for unresectable advanced cancer. Given the potential for the acquisition of tolerance to chemotherapy, macroscopic curative surgery should be performed before chemotherapy becomes ineffective.
There is also a need to identify potent chemotherapy for unresectable advanced GBC. In the ABC-02 trial, GC therapy had a significant survival advantage compared to gemcitabine alone, and this regimen has been established for unresectable BTC worldwide [13]. GS therapy [14] and GS plus CDDP (GCS) therapy are highly recommended for unresectable BTC in the guidelines for BTC treatment in Japan. The regimens differ among reports of conversion surgery for BTC [8,9,10,11]; however, they are primarily GEM-based. In addition, there is a need to consider the severe adverse events that can occur with GCS therapy, compared to those with GC and GS therapy. Therefore, it is difficult to compare regimens to determine which is more beneficial for conversion surgery.
It is important to evaluate the potential for macroscopic removal of lesions prior to conversion surgery, and this can be achieved with staging laparoscopy. However, we did not perform preoperative staging laparoscopy in this case because we thought that precise evaluation of expansion of the omentum lesions with laparoscopic observation would be difficult, and we determined preoperatively that we could achieve macroscopic radical resection of the target lesions by extended cholecystectomy and total omentectomy. However, since there was a possibility of liver metastases and other peritoneal lesions that were undetectable on imaging, staging laparoscopy may have been useful in this case. Peritoneal lavage cytology gave positive findings, but we were still able to achieve macroscopic resection and long-term survival. A recent report suggested that it may be acceptable to resect BTC without other non-curative factors, regardless of the peritoneal lavage cytology status [15], and this supports our treatment strategy for this patient. All of the above suggests that surgical macroscopic radical resection is highly conducive to positive patient outcomes.
The efficacy of conversion surgery for advanced cancer is oncologically understandable from the perspective of disease control. Macroscopic curative surgery for advanced cancer may be effective for certain patients in whom the number of malignant cells can be reduced with chemotherapy. Continued chemotherapy after surgery may be needed to eliminate residual microscopic cancer cells and prevent recurrence. We used the following criteria as the indication for conversion surgery for initially unresectable GBC: stabilization of tumor markers; and shrinkage or lack of growth of the tumor for ≥ 8 months, based on the finding for conversion surgery for pancreatic cancer described above [7]; and the potential for macroscopic curative resection. Scientific evidence for these criteria is still insufficient because of the lack of data. However, conversion surgery for patients with BTC who meet these two criteria does seem to be effective based on our results.