Peritoneal Surface Oncology: A progress report
Introduction
The Fourth International Workshop on Peritoneal Surface Malignancy took place in Madrid (Spain) on December 2–4, 2004. This scientific event brought together 132 physicians (primarily surgical oncologists, but also pathologists, gynecologists and medical oncologists) as well as nurses from around the world interested in the study and management of peritoneal neoplasms. Participants included internationally renowned experts in the field, team members of existing peritoneal surface malignancy treatment centers and healthcare professionals interested in starting new programs. Workshop participation has been suggested as a requirement for the initiation of a program in peritoneal surface oncology.1#
The scientific program included diagnostic pathology, technology of hyperthermic peritoneal perfusion, quantitative prognostic indicators, accreditation of treatment programs, ovarian cancer, gastric cancer, peritoneal mesothelioma, appendiceal mucinous tumors, colorectal cancer, morbidity and mortality. Selected topics presented at the Workshop are covered in detail by the articles contained in this monograph and authored by the speakers who presented each of them. A final half-day of the meeting was exclusively devoted to summary, consensus building and discussion of future directions in the field. These submissions are edited to reflect these final goals of the meeting. It is hoped that these papers serve as general guidelines to direct the work of established treatment centers until the celebration of the next Workshop, to be held in Milan (Italy) in December of 2006.#
Proposals of standardized nomenclature
Multiple names and its acronyms have been used in the scientific literature to refer to the intraoperative administration of hyperthermic intraperitoneal chemotherapy, often causing confusion. Among the Workshop participants a favored term was “HIPEC” (Hyperthermic IntraPeritoneal Chemotherapy), as proposed by the Dutch group.2 Similarly, there is a need to unify the description of prognostic indicators related to the histopathologic grading of peritoneal surface neoplasms, distribution, volume of peritoneal carcinomatosis, and the completeness of cytoreductive surgery. The Workshop dedicated a session to this topic, only to demonstrate once again the variety of nomenclatures and classifications used. No consensus regarding a standardized group of indicators was evident at the close of the meeting; this issue was identified as a need for further study.#
Proposal for an International Peritoneal Surface Oncology Group
International collaboration has been a prominent part of the progress in peritoneal surface oncology. This collaboration has occurred spontaneously among treatment centers, often to support and promote the initiation of new treatment programs in different countries. However, for scientifically sound progress to occur in this field, as it has occurred in other diseases, prospective multicenter trials are desirable. These are especially important in a group of diseases that include low-incidence conditions such as pseudomyxoma peritonei or peritoneal mesothelioma and require highly specialized treatment modalities not easily available in many institutions. Since the initiation of the International Workshops in London in 1998, a biannual meeting of a core group of interested centers and individuals has occurred. The continuation of an “International Peritoneal Surface Oncology Group” (IPSOG) was suggested and plans for a subsequent workshop definitely addressed. In order to facilitate, foster and speed up communication among individuals and groups from different countries interested in peritoneal surface oncology, the Internet platform www.peritonectomy.com was inaugurated. It is encouraged that significant information regarding research initiatives, protocols and other pertinent information be posted at this web site, coordinated and created by Dr. H. Müller (Hammelburg, Germany).#
Need for accreditation and selection of centers for peritoneal surface malignancy treatment programs
Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy is a demanding and resource-consuming procedure with a steep learning curve, and an acceptable, but not negligible, morbidity and mortality. Adequate prior training and a sustained interest in the technical, surgical and scientific features of peritoneal surface oncology is a must for success. It is desirable that guidelines be set up for a quality-control and accreditation process carried out by peers by which to certify the ability of interested centers to perform these procedures with adequate guarantees. An international working group chaired by Sarah T. O'Dwyer (Manchester, UK) was assembled to address this issue. Currently, centers are self-selected sometimes by their capability to provide the highly specialized services of peritonectomy and intraoperative hyperthermic chemotherapy. The limited capacity of resources required for the care of these patients (intensive care beds, operating time, chemotherapy in the operating room, etc.) and the possibility for an adverse outcome with deficient methodology mandates a knowledgeable patient selection.#
Consensus and differences expressed at the Workshop
There are different modalities for perioperative intraperitoneal chemotherapy administration. Some centers exclusively use a hyperthermic intraoperative perfusion (HIPEC), others only early postoperative administration, and others use both sequentially. There is no clinical data to support one option over the other and the question remains whether a trial to clarify this issue would be necessary.#
Debate on the technique for HIPEC (open versus closed) has not rendered any new conclusions. Differences in local-regional failure and survival may become apparent but require long-term follow-up and management of a large number of patients with a single disease. All centers were comfortable with the option they currently use and did not feel compelled for a change.#
Regarding the chemotherapy drug choice for HIPEC, most programs participating in the Workshop use mitomycin C for carcinomatosis of appendiceal or colonic origin; the option of intraperitoneal oxaliplatin plus concomitant intravenous 5-fluorouracil was strongly advocated by D. Elias.3 There is an ongoing debate around the dosage of mitomycin C that should be used in HIPEC for an optimal therapeutic index. The combination of cisplatin and doxorubicin is almost unanimously used in HIPEC for advanced ovarian cancer.#
It was agreed that the desirable intra-abdominal temperature range to maintain during HIPEC is 41.5 to 42.5°C.#
Long-term intraperitoneal chemotherapy administration following cytoreductive surgery outside the perioperative period is not likely to be pursued by IPSOG because of uneven distribution due to adhesions. However, in a preoperative setting where few if any adhesions exist, exploration of the use of intraperitoneal chemotherapy in the neoadjuvant setting is following Yonemura's recent studies (NIPS protocol for gastric cancer).4#
Specific diseases and their peritoneal surface component
Peritoneal mesothelioma
An expected rise in the incidence of peritoneal mesothelioma will occur in the decades to come given the latency period between asbestos exposure and the onset of the disease. Emphasis was made on the significant differences between pleural and peritoneal mesothelioma, stressing the need to consider them different disease processes. A proposal for a new pathologic grading system of peritoneal mesothelioma based on nuclear features (size and nucleoli) was presented by the Washington Hospital Center group.#
Successful phase II experiences56 with the management of peritoneal mesothelioma by cytoreductive surgery and perioperative intraperitoneal chemotherapy suggest that patient selection (based on pathology, disease burden and other features) is key for good treatment outcomes and that small volume macroscopic residual disease after cytoreduction would not preclude satisfactory treatment results if adequate perioperative intraperitoneal chemotherapy is used. There seems to be an increased drug uptake by these residual mesothelioma nodules.#
Stage III epithelial ovarian cancer
The gynecologic oncology community was scarcely represented at the Workshop. Emphasis was expressed on the need for specialized surgeons (surgical or gynecologic oncologists) to deal with this disease, rather than general gynecologists.#
Despite the fact that the value of intraperitoneal chemotherapy in advanced ovarian cancer has been successfully tested in phase II and phase III trials, this treatment modality has still not gained acceptance as “standard of care”.7 However, the recent publication of a third prospective randomized trial confirming the superiority of intraperitoneal over systemic cisplatin-based chemotherapy after adequate surgical cytoreduction (reference∗∗<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Armstrong+DK%22%5BAuthor%5D> Armstrong DK, <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Bundy+B%22%5BAuthor%5D> Bundy B, <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Wenzel+L%22%5BAuthor%5D> Wenzel L, <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Huang+HQ%22%5BAuthor%5D> Huang HQ, <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Baergen+R%22%5BAuthor%5D> Baergen R, <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Lele+S%22%5BAuthor%5D> Lele S, et al. Intraperitoneal cisplatin and paciltaxel in ovarian cancer.<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16394306&itool=pubmed_Abstract> N Engl J Med. 2006;354:77-9.) is already setting a turning point in the current treatment recommendations for this disease process. Dr. M. Deraco (Milan, Italy) invited attending centers to join a recently opened phase III multicenter trial coordinated by his group. It is designed for stage III/IV epithelial ovarian cancer with macroscopic disease after first line systemic chemotherapy, comparing an aggressive loco-regional approach (secondary cytoreductive surgery plus HIPEC) followed by systemic chemotherapy versus systemic chemotherapy alone.#
Gastric cancer
The role of adjuvant perioperative intraperitoneal chemotherapy in curatively resected primary gastric cancer was reviewed by Dr. Yu (Taegu, Korea), principal investigator of a successful randomized trial published on this topic.8 T3, T4 and lymph node positive cases are the ones that show a significant survival advantage over surgery alone. A proposal for a new multricentric randomized trial addressing this topic in order to revalidate these results was made. Participating centers should perform over 20 gastrectomies per year and should be proficient in the administration of early postoperative intraperitoneal chemotherapy (having done over 10 cases before joining the trial). Inclusion would be reserved only for stage III gastric cancer, and therefore a reliable clinical indicator for pT3 and pT4 tumors would need to be identified.#
A novel neoadjuvant approach to peritoneal carcinomatosis of gastric origin, combining intraperitoneal and systemic chemotherapy (NIPS)4 was presented by Dr. Yonemura (Shizuoka, Japan). This induction treatment is followed by cytoreductive surgery, HIPEC and early postoperative intraperitoneal chemotherapy. Promising initial results, especially encouraging in cases where a complete cytoreduction is achieved, warrant further research in this direction for such a challenging problem in gastrointestinal oncology.#
Peritoneal carcinomatosis of colorectal origin
The positive results of the randomized trial recently published9 by the Dutch group led by Dr. Zoetmulder has boosted the interest of the oncologic community in the use of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy (Mitomycin C HIPEC alone in this case) to treat colorectal carcinomatosis. It must be kept in mind that the systemic chemotherapy combination that was employed in the trial was 5-fluorouracil plus leucovorin, which was the standard regimen employed for metastatic colorectal cancer at the time the trial was designed. However, two questions still remain unanswered after this study: does HIPEC add anything to a complete cytoreduction? And what is the most effective HIPEC regimen for peritoneal carcinomatosis of colorectal origin?#
Again, new trials should be conducted for these questions to be answered. The first question would need a trial in which patients would be randomized after cytoreduction to HIPEC with mitomycin C or no HIPEC, both arms followed by systemic chemotherapy (FOLFOX). The second question would compare treatment with oxalipalin HIPEC against an arm with mitomycin C HIPEC, both followed by systemic chemotherapy (FOLFOX). Only patients with an optimal cytoreduction (to nodules less than 2.5 mm in maximal diameter; e.g. CC-0 or CC-1) would be randomized. The proposed inclusion criteria would be for patients with adenocarcinoma of the colon whose primary tumor was located above the peritoneal reflection, limited peritoneal dissemination, absence of distant metastases and no systemic chemotherapy administered within the preceding 12 months. Appendix cancer cases would be excluded. Workshop participants did not show a significant preference for one or the other protocol designs described above.#
Very selected cases of colon cancer with peritoneal dissemination and liver metastases can benefit from combined liver resection and peritonectomy procedures provided they can be rendered macroscopically disease free by this surgical procedure, supplemented by HIPEC. Dr. D. Elias (Villejuif, France) showed limited but very promising phase II results and the proposed selection criteria to consider a patient amenable to this therapeutic option. After extensive pharmacologic studies, Dr. Elias' group has also pioneered and described the therapeutic details for the use of Oxaliplatin HIPEC combined with intravenous 5-fluorouracil, an option that can already be considered an alternative to Mitomycin C HIPEC. Combined Oxaliplatin plus Irinotecan HIPEC regimens are currently being investigated at his service.10#
Cytoreductive surgery and perioperative intraperitoneal chemotherapy as standard of care
There was an unquestionable consensus that this combined treatment can be presently considered standard of care for all cases of mucinous appendiceal neoplasms with peritoneal dissemination (regardless of their description as “pseudomyxoma peritonei” or not) in an otherwise fit patient in the absence of distant metastases (liver or extra-abdominal sites).#
There was strong support by at least half of the attendees that this treatment strategy may be indicated in selected cases of treatment-resistant advanced ovarian cancer (ideally platinum-resistant cases with prolonged disease-free intervals). In these cases this therapeutic option should be considered a strong recommendation or suggestion, but not a consensus agreement by the Workshop participants.#