2025/05/31 by Paul H. Sugarbaker · 1 voice
Medicine · #Endometriosis Research and Treatment #Intraperitoneal and Appendiceal Malignancies #Uterine Myomas and Treatments
paper · pdf · doi:10.1093/bjs/znaf081
openalex publication_date 2025/05/31 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/29
Armed with a new chemotherapy agent, mitomycin C, developed in Japan and sensitized by heat, three groups in Japan began successful experimental studies to treat gastric cancer patients at high risk of developing subsequent peritoneal metastatic disease1–3. At the Surgery Branch, National Institutes of Health, we did not have access to the mitomycin C. However, our pharmacologic studies with intraperitoneal 5-fluorouracil showed a marked local-regional dose intensification with a reduced systemic toxicity4. In the 1980s rectal cancer had a 40.0% local recurrence rate; a decision was made to perform an RCT of colorectal cancer patients that had a complete resection of their primary disease but were at high risk for subsequent peritoneal metastases. After carefully evaluating patients with a colorectal cancer resection who had advanced disease, they were randomized to receive either intravenous or intraperitoneal 5-fluorouracil over a one-year period5. The data from this trial were favourable regarding the local-regional effects of 5-fluorouracil. Progression of disease on abdominal and pelvic surfaces was significantly reduced. In contrast, the systemic component of colorectal cancer was the same in both groups. For colorectal cancer, despite the marked reduction in the incidence of peritoneal metastases in the intraperitoneal 5-fluorouracil group, there was no survival difference. In an attempt to utilize the positive data from this RCT, we began to recruit patients with pseudomyxoma peritonei for prolonged treatment with intraperitoneal 5-fluorouracil. This strategy is currently referred to as normothermic intraperitoneal chemotherapy long term or NIPEC long term. Pseudomyxoma peritonei patients did not develop liver or systemic metastases. The seemingly insurmountable obstacle to the benefit of our patients was the large volume of tumour on peritoneal surfaces that intraperitoneal chemotherapy failed to penetrate. The only way to utilize intraperitoneal 5-fluorouracil was to resect the extensive peritoneal mucinous tumour. A two-part treatment strategy was pursued. Following complete microscopic resection, the intraperitoneal chemotherapy would be used to eradicate microscopic residual disease. As it turned out, pseudomyxoma peritonei was a good choice for resection of large volumes of peritoneal surface tumour in preparation for flooding the peritoneal space, now visibly free of disease, with chemotherapy. The low-grade and minimally invasive mucinous tumour is characterized by the ‘redistribution phenomenon’. The glistening smooth visceral peritoneal surfaces are tightly bonded to underlying organs such as liver, spleen, and bowel surfaces. Also, the slippery smooth surface of the bowel and its mesentery are in continuous peristalsis. Mucinous tumour cells are relatively impaired from adherence, implantation, and vascularization on visceral as compared to parietal peritoneal surfaces6,7. This redistribution means that visceral resections are likely to be required only where the bowel is tethered. These anatomic sites for gross mucinous tumour to accumulate are the antrum of the stomach, the ileocecal valve region, and the upper rectum and rectosigmoid colon. The visceral resections at these anatomic sites are well described and reconstructions to achieve a complete resumption of gastrointestinal function are nearly always possible. For pseudomyxoma peritonei, the requirements for resections of parietal peritoneum infiltrated by mucinous tumour were much more demanding. However, a surgical myth concerning the resection of parietal peritoneum had to be dispelled before parietal peritoneum layered by pseudomyxoma could be removed. A surgical tradition of parietal peritoneal preservation was a prominent part of surgical education. When opening and closing the abdomen, I was instructed that the peritoneal layer of the abdominal wall was isolated and then meticulously closed with an absorbable suture. In performing a rectosigmoid or rectal resection, the pelvic peritoneum was preserved and then reconstructed to prevent small bowel obstructions from occurring in the pelvis. As more extensive parietal peritoneal resections were performed, no extraordinary complications with bowel obstruction from parietal peritonectomy were recorded. Unexpectedly, the combination of parietal peritoneal resections with NIPEC 5-fluorouracil long term resulted in few adhesions8. In patients with recurrence of pseudomyxoma who had perioperative intraperitoneal 5-fluorouracil, the prognosis was markedly improved. Probably the reoperative surgery was facilitated by a near absence of adhesions resulting from the index cytoreductive surgery (CRS)9. Fortunately, in patients with pseudomyxoma peritonei, the disease layered out on parietal peritoneal surfaces, often large volume, can be removed definitively by parietal peritonectomy procedures10. The mucinous tumour rarely penetrates the parietal peritoneal layer. Sometimes a lack of fibroareolar tissue beneath the parietal peritoneum that covers the central tendon of the right and left hemidiaphragm causes an invasion of this structure. Resection of the central tendon along with its overlying peritoneum is required to achieve a negative margin of resection. It is unusual to require resection of structures beneath the parietal peritoneum at other anatomic sites. As the six different parietal peritonectomy procedures were being tested in clinical trials regarding peritonectomy, several aspects of this new strategy quickly became apparent. First, the margin of resection beneath a peritonectomy procedure, although limited to a millimetre or less, when combined with perioperative intraperitoneal chemotherapy was very rarely a site of recurrent disease. If pseudomyxoma peritonei recurred it was on the visceral peritoneal surfaces11. The technology used to perform the peritonectomy procedure may have an impact on this very low incidence of recurrence beneath parietal peritoneal resections12. Second, the histologic subtype of the appendiceal tumour had a large impact on a long-term favourable outcome. Even though the complete removal of all visible disease by peritonectomy and visceral resections had occurred, not all patients with high-grade mucinous tumour remained disease-free in the abdomen and pelvis. The perioperative intraperitoneal adjuvant treatments, hyperthermic intraperitoneal chemotherapy (HIPEC) or early post-operative intraperitoneal chemotherapy (EPIC), were not able to preserve the surgical complete response that could be achieved by peritonectomy procedures and visceral resections. The two major components of successful management of established peritoneal metastases began to be accepted and placed into practice in the mid-1990s. CRS was the initial treatment. It required up to six parietal peritonectomy procedures and a selection of visceral resections. The goal of the CRS would evolve over time to be a complete visible clearing of the abdomen and pelvis of malignancy13. Combined with the CRS was perioperative intraperitoneal chemotherapy, whose goal was to preserve the surgical complete response long term. For surgeons treating peritoneal surface malignancy, HIPEC became the standard adjuvant treatment for CRS. However, from our analysis of treatment failure, for success long term, the absolute first requirement for benefit from CRS plus perioperative intraperitoneal chemotherapy was a complete versus an incomplete resection. Palliative surgery may be required and shows some benefit with an incomplete CRS. However, for a curative approach and for long-term benefit, resection of all macroscopic disease must occur. This fundamental principle demanding complete CRS presents the rationale for three articles in this issue. These include a review on nomenclature and boundaries of peritonectomies14, an international consensus statement15, and an educational paper on occult peritoneal spaces that may hide peritoneal implants which may be a cause of incomplete CRS and thereby hinder a long-term favourable result16. Complete CRS, a necessity of a long-term favourable result in the management of peritoneal metastases, will be facilitated by your study of this special issue. The author has no funding to declare. The author declares that there are no conflicts of interest. Research data are not shared.