Colorectal peritoneal metastases

What it means when colon cancer has reached the peritoneum

The peritoneum is the membrane that lines the inside of the abdomen and wraps the organs. When a colon tumour grows through the bowel wall, cells can shed from it and settle on that surface, where they implant and grow as nodules. This is called peritoneal carcinomatosis or, more precisely, peritoneal metastases.

It can appear in two ways. It is called synchronous when it is already there when the primary tumour is diagnosed, and metachronous when it appears months or years after the primary has been removed. The first is sometimes discovered in the operating theatre itself, during the colon operation; the second, on a follow-up scan or through a rising blood marker.

As for how common it is, the two population registries that have measured it best — one Swedish, one Dutch — find synchronous peritoneal metastases in around 4-5% of all colorectal cancers, and roughly as many again appearing later. Broader estimates, which include disease found only at reoperation or at autopsy, speak of up to a quarter of patients at some point in the illness. The exact figure depends on how hard one looks; what does not change is that it is not rare.

Segelman J, et al. Incidence, prevalence and risk factors for peritoneal carcinomatosis from colorectal cancer. Br J Surg, 2012 (Stockholm registry). Lemmens VE, et al. Predictors and survival of synchronous peritoneal carcinomatosis of colorectal origin: a population-based study. Int J Cancer, 2011 (Eindhoven registry).

Why it is not the same as a liver metastasis

A liver metastasis is a tumour that travelled through the bloodstream and grew inside an organ. A peritoneal metastasis is a tumour that fell onto a surface and stayed there. The difference sounds small and is enormous, for two opposite reasons.

The first works against you: peritoneal disease is scattered across many small points instead of concentrated in one or two large ones, so scans see it worse and intravenous chemotherapy reaches it worse. Historically, of the three metastatic sites of colorectal cancer, the peritoneum carried the worst prognosis under systemic treatment. In the pooled analysis of fourteen first-line chemotherapy trials, patients with peritoneal disease lived several months less, on median, than those with metastases elsewhere.

The second works in your favour: if all the disease sits on a surface a surgeon can reach with their hands, it can be removed in full. That is something a surgeon cannot do with multiple lung metastases and can do, in selected cases, with the peritoneum. It is the reason cytoreductive surgery exists.

Franko J, et al. Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: an analysis of individual patient data from prospective randomised trials from the ARCAD database. Lancet Oncology, 2016 (10,553 patients from 14 trials).

How it is found and how it is measured

The CT scan is the first test and also the most misleading one in this disease. It sees ascites, large nodules and thickening of the omentum well, but it systematically underestimates small-volume disease: nodules of a few millimetres scattered over the small bowel — precisely the ones that decide whether the operation can be completed — often escape it. A “clean” CT after a T4 or perforated tumour rules nothing out.

CEA, the blood marker, helps raise the suspicion of recurrence when it climbs during follow-up, but a normal value does not exclude it and a raised one does not say where the disease is.

That is why, when surgery is being considered, many units complete the work-up with a diagnostic laparoscopy: a short procedure through two or three small incisions to look directly at the peritoneum and the small bowel and score the disease before committing to an eight-hour operation. What is scored is the PCI, the peritoneal cancer index: thirteen regions of the abdomen, each graded 0 to 3 by the size of its largest nodule, added up to a total between 0 and 39.

CT sensitivity for small peritoneal nodules: Koh JL, et al. Evaluation of preoperative computed tomography in estimating peritoneal cancer index in colorectal peritoneal carcinomatosis. Ann Surg Oncol, 2009. PCI definition: Jacquet P, Sugarbaker PH. Cancer Treatment and Research, 1996.

Who is a candidate and who is not: the PCI and complete cytoreduction

The question that decides is not how much disease there is, but whether all of it can be removed. In colorectal origin, the answer has two thresholds worth knowing.

The first is volume. The French series that looked for the point beyond which surgery stops adding survival placed it between a PCI of 17 and 20: above that, the median of operated patients approached that of patients treated with chemotherapy alone, and the cost of the operation no longer paid off. The PRODIGE 7 trial did not admit patients with a PCI above 25. In practice most units use 20 as their reference, knowing it is a reference and not a border: where the disease sits and how it has behaved under chemotherapy matter too.

The second threshold is what remains at closure. The operation only counts if it ends in CC-0 — no visible disease — or, at most, CC-1, with residual nodules under 2.5 millimetres. An incomplete cytoreduction is not a partial version of the treatment: it is a major operation without the benefit that justifies it. In the European multicentre series of 506 patients with colorectal origin, median survival was 32.4 months with complete cytoreduction and 8.4 months when macroscopic disease was left behind.

Histology weighs as well. Signet ring cell tumours and, to a lesser extent, high-grade mucinous ones behave worse even with little disease and a flawless operation, and in many tumour boards they are a reason not to operate, or to demand a clear response to chemotherapy first.

And, in the opposite direction, the situations in which cytoreductive surgery is not indicated, written down so that nobody discovers them in the operating theatre:

• Extensive peritoneal disease, with a PCI clearly above 20, especially if it progresses during chemotherapy.
• Diffuse involvement of the small bowel or its mesentery that cannot be resected without leaving the patient with too little bowel.
• Metastases outside the abdomen — lung, bone, distant lymph nodes — that cannot be treated with curative intent. A small number of resectable liver metastases is not, on its own, a contraindication in experienced units.
• A general condition that cannot withstand a six- to ten-hour operation followed by weeks of recovery, or malnutrition that has not been corrected.
• Bowel obstruction or urinary tract obstruction by tumour at more than one site, which almost always signals more extensive disease than the CT shows.

PCI threshold: Elias D, et al. J Clin Oncol, 2010; Goéré D, et al. Extent of colorectal peritoneal carcinomatosis: attempt to define a threshold above which HIPEC does not offer survival benefit. Ann Surg Oncol, 2015. Complete versus incomplete cytoreduction: Glehen O, et al. J Clin Oncol, 2004. PRODIGE 7 inclusion criterion (PCI ≤ 25): Quénet F, et al. Lancet Oncol, 2021. Contraindications: PSOGI consensus and practice of reference units; combined liver and peritoneal metastases: Maggiori L, et al. Ann Surg, 2013.

What surgery achieves compared with chemotherapy alone

The figures, with their labels on. With systemic chemotherapy alone, in the pooled analysis of modern trials using oxaliplatin and irinotecan, patients whose only metastatic site was the peritoneum had a median survival of about 16 months. That is better than the five to seven months of the earlier era, and still the worst of the three sites.

With complete cytoreductive surgery, the French multicentre series of 523 patients gave a median of 30 months and five-year survival of 27%. In PRODIGE 7, with stricter selection and every patient operated on until the abdomen was clear, both arms reached medians of 41 months. And in the randomised trial that opened the field, in 2003, surgery gave 22.4 months against 12.6 with chemotherapy and palliative surgery — the oldest head-to-head comparison, with the technique and drugs of the time.

These figures have to be read honestly. Operated patients are selected: they have less disease, better general condition and, in many cases, have already shown that their tumour responds to chemotherapy. Part of the difference is due to that. But the part due to the operation is real, has been reproduced in dozens of series, and is the reason cytoreductive surgery for colorectal origin sits in European and American guidelines rather than in an experimental chapter.

Chemotherapy alone: Franko J, et al. Lancet Oncol, 2016. Operated series: Elias D, et al. J Clin Oncol, 2010 (523 patients, 23 centres); Quénet F, et al. Lancet Oncol, 2021 (PRODIGE 7). Randomised comparison: Verwaal VJ, et al. J Clin Oncol, 2003.

PRODIGE 7: what HIPEC adds and what it does not

It is the trial that has produced the most headlines in this disease, and the one most often told badly. It deserves a slow explanation.

PRODIGE 7 operated on 265 patients with colorectal peritoneal metastases until no visible disease remained. Half then received HIPEC with high-dose oxaliplatin for thirty minutes at the end of the operation; the other half were closed without it. Median survival was 41.7 months with HIPEC and 41.2 months without: the same. Serious complications at sixty days were more frequent with the bath, 26% against 15%.

What the trial demonstrates is which of the two acts does the work. Both arms had been operated on, and both lived roughly three times as long as patients did with chemotherapy alone. The therapeutic act is the complete cytoreduction. The oxaliplatin bath, in that schedule, added no survival and did add complications. To say “HIPEC does not work” from that result is as inaccurate as saying the operation does not work — the trial says the opposite of the latter.

And what it does not say. It did not test mitomycin C, the drug most American, Dutch and British units still use, in perfusions of sixty to ninety minutes. It did not test other tumours of origin. A later analysis suggested that the subgroup with an intermediate PCI, between 11 and 15, might benefit from the bath, but that is an exploratory finding that generates a hypothesis, not an indication. Today, in many European centres, oxaliplatin HIPEC is no longer routine in colorectal origin; mitomycin C HIPEC is still used, in the knowledge that its benefit in this indication has not been shown in a randomised trial. What is not in dispute is the operation.

Quénet F, et al. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncology, 2021. The confidence interval of the primary analysis is reported at 95.37% because of the alpha spent at the interim analysis.

Chemotherapy before and after, and what did not work as prevention

Surgery does not replace systemic chemotherapy; it accompanies it. In most patients chemotherapy is given before the operation, for a few months, for two reasons: to treat the microscopic disease no surgery reaches, and to see how the tumour responds. A tumour that progresses during chemotherapy is, in all likelihood, a tumour that surgery will not control either, and knowing that beforehand spares a futile operation. In patients with very little disease, some units operate first and give chemotherapy afterwards; the Dutch CAIRO6 trial was designed precisely to compare the two sequences.

In the other direction, HIPEC has been tried as a way of preventing carcinomatosis in high-risk patients — T4 or perforated tumours, ovarian metastases, or minimal carcinomatosis resected at the first operation — and the results have been negative. The PROPHYLOCHIP trial, which systematically reoperated on those patients after a year for a second look and HIPEC, did not improve disease-free survival compared with surveillance. The COLOPEC trial, which gave adjuvant oxaliplatin HIPEC after resection of T4 or perforated tumours, did not reduce the appearance of peritoneal metastases at eighteen months either.

The practical reading is that preventive HIPEC is not recommended outside a trial, and that in high-risk patients what does work is closer surveillance with a lower threshold for looking inside.

Goéré D, et al. Second-look surgery plus hyperthermic intraperitoneal chemotherapy versus surveillance in patients at high risk of developing colorectal peritoneal metastases (PROPHYLOCHIP-PRODIGE 15). Lancet Oncology, 2020. Klaver CEL, et al. Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer (COLOPEC). Lancet Gastroenterology & Hepatology, 2019. Chemotherapy sequence: Rovers KP, et al. (CAIRO6). JAMA Surgery, 2021.

Recurrence and repeat surgery

It is worth saying before the operation: even after a complete cytoreduction, most patients with colorectal origin relapse at some point, and in PRODIGE 7 median relapse-free survival was around a year in both arms. The tumour coming back does not mean the operation failed; it means the microscopic disease that could not be seen eventually grew.

Where it recurs matters. A relapse in the liver or the lung is treated like any colorectal metastasis at those sites, with surgery or local treatment where possible. A limited peritoneal relapse, in a patient who did well after the first operation and has had a long interval free of disease, can be operated on again: series of repeat surgery from high-volume centres show it is feasible with acceptable morbidity in well-selected patients, although they are small series and there are no survival figures that apply to everyone.

A particular case is the ovaries. In women, colorectal carcinomatosis frequently involves the ovaries, sometimes as the only visible site, which is why both are usually removed during cytoreductive surgery even when they look normal. It is a decision to discuss before the operation, especially in younger women.

Relapse-free survival in PRODIGE 7: Quénet F, et al. Lancet Oncol, 2021 (13.1 versus 11.1 months). Repeat surgery after peritoneal recurrence: practice of reference units and institutional series; no figure is given because results depend heavily on selection.

The phrase “nothing can be done”

Colorectal carcinomatosis is the indication for cytoreductive surgery with the most patients and, at the same time, the one most often dismissed without being assessed. The reason is simple: in a hospital without a peritoneal surgery unit, the word “carcinomatosis” on a CT report still means what it meant twenty-five years ago, and the patient goes straight to palliative chemotherapy.

That is correct in many cases, and not in others. The difference is not visible on the report: it is visible on the images, in the histology, in how the tumour has responded and, often, at laparoscopy. If you have been told nothing can be done and the case has not been through a tumour board with surgeons who operate on this disease routinely, asking for a second opinion is not distrusting anyone: it is completing an assessment that was left half done. In Spain there are designated reference centres for this disease, and the Hospital General Universitario Gregorio Marañón in Madrid is one of them.

What to send: the images in digital format, not the report; the pathology of the primary tumour with its molecular profile if it was done; the operative reports of previous surgery; and the list of treatments received with their dates. With that, a unit can say within a few days whether it makes sense to keep looking.