Annals of Surgical Oncology 14(6):1807–1817

DOI: 10.1245/s10434-007-9350-7

Educational Review

Selection of Patients with Colorectal Peritoneal Carcinomatosis for Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy Tristan D. Yan, BSc (Med) MBBS, Junyang Sim, BSc (Med), and David L. Morris, MD, PhD

Nationally Funded Peritonectomy Center, Department of Surgery, University of New South Wales, St. George Hospital, Sydney, Australia

Background: Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy has been suggested as a treatment option for patients with colorectal peritoneal carcinomatosis. However, the survival benefit is achieved at the expense of moderate to high perioperative morbidity and mortality. Methods: This review summarized the important prognostic factors for survival; outlined the patient selection process from major peritonectomy centers, paying particular attention to preoperative evaluation; and identified areas for potential improvement. Emphasis was placed on a strict patient selection process to avoid futile aggressive treatments. Results: Currently, contrast-enhanced computed tomography, magnetic resonance imaging, positron emission tomography, and laparoscopy have been utilized in the preoperative evaluation process to identify potential surgical candidates. Patients with good performance status, low volume of peritoneal disease, and absence of extra-abdominal metastases are more likely to benefit from the combined treatment. Conclusions: Quantitative assessment of the extent of disease is possible and should be performed at the time of primary cancer operation. Careful selection of patients to identify surgical candidates with favorable prognostic indicators is important. Key Words: Patient selection—Colorectal carcinoma—Peritoneal carcinomatosis—Cytoreductive surgery—Intraperitoneal chemotherapy.

lated CRPC treated by the modern systemic chemotherapy. At the same time, it has been realized that peritoneal carcinomatosis is a form of local-regional cancer dissemination and not another manifestation of systemic metastasis.5 On the basis of the better understanding of the natural history, in recent years, a targeted local-regional treatment for CRPC has been suggested, which integrates cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC) into one treatment strategy. This combined treatment approach attempts to target both macroscopic and microscopic disease involving the peritoneal cavity. Some evidence has suggested that this management option could potentially achieve survival benefits in the proportion of patients that meet strict

Traditionally, systemic chemotherapy was routinely used for patients with colorectal peritoneal carcinomatosis (CRPC), whereas surgery was only offered to palliate complications such as intestinal obstruction. Over the past decade, an evolving role of modern systemic chemotherapy and biological agents with improved response rates has occurred for colorectal metastases.1–4 However, there is a lack of data regarding survival of the subset of patients with isoReceived November 20, 2006; accepted January 2, 2007; published online March 8, 2007. Address correspondence and reprint requests to: David L. Morris, MD, PhD; E-mail: [email protected] Published by Springer Science+Business Media, Inc.
2007 The Society of Surgical Oncology, Inc.

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selection criteria.6–8 In 2004, an international registry study on 506 patients from 28 institutions showed a median survival of 19 months, with 3- and 5-year survival of 39% and 19%, respectively.6 More importantly, a recent randomized controlled trial (RCT), conducted in Holland, demonstrated that CRS combined with hyperthermic intraperitoneal chemotherapy (HIPEC) was associated with better survival than traditional systemic chemotherapy.7 Although there is more evidence demonstrating the efficacy of the combined treatment, the current opinions on the standard of care for patients with CRPC are polarized. Many medical and surgical oncologists are still insisting on more proof before accepting the combined approach. In contrast, others, including most specialist peritonectomy surgeons, think it is inappropriate or even unethical to conduct further randomized trials when there is no reported evidence demonstrating the efficacy of modern systemic chemotherapy in this group of patients. The Fifth International Peritoneal Oncology Meeting was held on December 4–6, 2006, in Milan, Italy. One of the main objectives of the meeting was to reach a consensus, through the Delphi process,9 on methodology, preoperative investigations, and treatment strategies for CRPC. The question has arisen as to the next logical step to take, before further comparative data become available. From a peritonectomy surgeonÕs standpoint, more emphasis needs to be placed on stringent patient selection to identify most appropriate surgical candidates and avoid futile aggressive treatments. The aims of this review are to summarize the important prognostic factors for survival in CRPC patients after the combined treatment; to outline patient selection process from major peritonectomy centers, paying particular attention to preoperative evaluation; and to identify areas for potential improvement.

METHODS To provide a comprehensive review on important prognostic indicators affecting survival, a systematic electronic literature search with Medline, PubMed, and EMBASE covering the period from January 1966 to August 2006 was performed in September 2006, to include experimental and observational studies that used CRS and PIC for CRPC. All studies selected were human trials published in English. Studies that included other cancer diagnoses when reporting aggregate outcomes were excluded. Ann. Surg. Oncol. Vol. 14, No. 6, 2007

A total of 39 relevant articles were identified. Twenty-five articles analyzed potential prognostic indicators for survival.6,7,10–32 There was one RCT comparing CRS and HIPEC with traditional systemic chemotherapy,7 and the remaining 24 articles were observational case series.6,10–32 Prognostic Indicators In the early efforts to manage CRPC, patients were scored as carcinomatosis present versus absent. In the former group, no survival at 5 years was expected. It was soon realized that not all patients with peritoneal carcinomatosis were the same. Especially in the past 5 years, specialist centers have adopted the combined treatment for CRPC.8 Because more patients are now managed in a relatively uniform manner, the data regarding important prognostic indicators reported by one center can be shared by others. It has been found that the use of quantitative prognostic indicators allows a more precise prediction of treatment outcomes.33 Four different scoring systems by which to quantify CRPC have been described: the Sugarbaker Peritoneal Cancer Index (PCI), the Dutch Simplified Peritoneal Cancer Index (SPCI), the Lyon Staging System, and the Completeness of Cytoreduction (CCR) score. Peritoneal Cancer Index PCI is an assessment combining lesion size (LS-0 to LS-3) with tumor distribution in 13 abdominopelvic regions (AR-0 to AR-12), to quantify the extent of disease as a numerical score (PCI-0 to PCI-39).34 Many prospective studies have used this scoring system and demonstrated marked survival advantages with a low PCI.6,10–19 However, there are some caveats in the use of PCI in CRPC. Currently, the cutoff of a low PCI associated with a favorable survival has not been clearly defined, in that the available clinical evidence does not allow reliable prediction on when it is suitable to proceed with the combined treatment solely on the basis of the value of PCI. Gomes da Silva and Sugarbaker14 reported that the median survival for PCI of <20 was 41 months, compared with 16 months for PCI of >20. Elias and colleagues15 found that the survival difference was between PCI of £ 15 and PCI of >15. Yan et al.18 and Kecmanovic et al.19 reported a marked survival difference comparing PCI of £ 13 with PCI of >13. At the Milan Peritoneal Oncology Consensus Meeting, 67% of the voters did not regard a PCI of >20 as an absolute exclusion criterion for the combined treatment, especially when considering low-grade

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tumors or young patients without mesenteric or liver involvement. Unlike appendiceal mucinous neoplasms, CRPC is a more invasive cancer. Therefore, the window of opportunity to potentially eradicate the disease when it is confined to the peritoneal cavity is narrow. Progressive disease may result in cancer invasion along the mesenteric border between the small bowel and the small bowel mesentery or at numerous sites on the small bowel surface. Lymph node metastases in groups unrelated to the primary cancer, representing lymphatic dissemination from peritoneal carcinomatosis (i.e., metastases from metastases), may also present. These situations confer a poor prognosis. Thus, cancer at crucial anatomic sites may override a favorable PCI score. Simplified Peritoneal Cancer Index and Lyon Staging System The Dutch SPCI registers presence versus absence of tumors in seven abdominal areas: left and right subdiaphragmatic spaces, subhepatic space, omentum/transverse colon, small intestine/mesentery, ileocolic region, and pelvis.20 This system is routinely used at the Netherlands Cancer Institute for prognostic assessment.7,20,21 The Lyon Staging System describes five stages of peritoneal carcinomatosis in terms of its size and distribution.33 Stage 0 indicates no macroscopic disease; stage 1 indicates tumors up to 5 mm localized in one abdominal region; stage 2 indicates tumors up to 5 mm diffused throughout the whole abdomen; stage 3 indicates tumors up to 2 cm; and stage 4 indicates tumors greater than 2 cm. In all prospective studies reported from the Lyon group, there were important differences between the prognosis of stage 1 and 2 versus stage 3 and 4.6,22–25 CCR Score Use of the International Union Against Cancer score measuring the extent of residual disease after cytoreduction is possible, but it is preferentially used for surgical resection of primary cancers. Even after a complete cytoreduction, a microscopic confirmation, R0, for peritoneal carcinomatosis is not practical. Jacquet and Sugarbaker34 proposed a CCR score that quantifies the extent of residual disease into four categories. CCR-0 indicates no visible evidence of residual tumor; CCR-1 indicates residual tumors £ 2.5 mm in diameter; CCR-2 indicates residual tumors between 2.5 mm and 2.5 cm; and CCR-3 indicates residual tumors >2.5 cm or a confluence of disease present at any site.

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Nearly all treatment centers agree that in both noninvasive and invasive peritoneal disease, the CCR score is the principle prognostic indicator for survival.6,7,10–14,16–22,26–32 One interesting observation is that the definition of a complete or adequate cytoreduction may vary when assessing different disease processes. In CRPC, complete cytoreduction may require a CCR-0 score.6,7,10–14,16–22,26–32 In the Dutch randomized trial, 17 of 18 patients who had CCR-0 cytoreduction were still alive at the completion of the study.7 In 1996, Elias and coworkers35 attempted a randomized study comparing CRS and early postoperative intraperitoneal chemotherapy (EPIC) versus CRS without EPIC. The trial was terminated prematurely as a result of recruitment difficulties. Although EPIC did not have any measurable effect, both arms demonstrated a 2-year survival of 60% in patients who had CCR-0 cytoreduction. The authors concluded that CCR-0 was a prerequisite for longterm survival.35 A recent update from the same group reported a 5-year survival of 49% in 30 patients who received CCR-0 cytoreduction and heated intraoperative oxaliplatin.36 In the registry study by Glehen et al.,6 271 patients had CCR-0 cytoreduction and their median survival was 32 months, with a 3-year survival of 47%. These results were far better than CCR-1 or CCR-2 (Table 1). The role of intraperitoneal chemotherapy in CCR-1 and CCR-2 cytoreduction is questionable. Modern systemic chemotherapy with or without biological agents should be considered in these patients. By comparison, in less invasive malignancy such as pseudomyxoma peritonei, a complete cytoreduction may include both CCR-0 and CCR-1.37 Currently most patients with pseudomyxoma peritonei seen at peritonectomy centers are usually the ones with large volume of disease and/or extensive prior surgery. As a result, CCR-0 is rarely achievable. A recent report by Yan and colleagues38 showed that of 402 patients who received complete cytoreduction, 395 patients (98%) had CCR-1 and only 7 patients (2%) has CCR0 cytoreduction. However, this broader definition of complete cytoreduction does not seem to affect the overall survival outcome, in that the 10-year survival rate was 85% for the entire cohort of 402 patients.38 Furthermore, when considering peritoneal mesothelioma, a disease that rarely spares small bowel, the ability to achieve a complete cytoreduction is even more limited. But interestingly, even a CCR-2 cytoreduction may offer some patients long-term benefit.39,40 International experience has consistently shown that 5-year survival ranges from 30% to 60%

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TABLE 1. Survival after cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) and/or early postoperative intraperitoneal chemotherapy for colorectal peritoneal carcinomatosis

Study 7

Verwaal et al. * 6

Glehen et al. **

Center

Median follow-up (mo) Groupa n

Amsterdam

22

Multiple centers 52

Gomes da Silva and Sugarbaker14 Washington Amsterdam Verwaal et al.21**

60 46

Glehen et al.22**

Lyon

60

Elias et al36 Shen et al.31**

Villejuif Winston-Salem

55 15

Pilati et al.47 Yan et al.18*

Padova Sydney

15 12

HIPEC Control Overall CCR-0 CCR-1 CCR-2 CCR-0 Overall CCR-0 CCR-1 CCR-2 Overall CCR-0 CCR-1 CCR-2 CCR-0 Overall CCR-0 CCR-1 Overall Overall CCR-0 CCR-1

54 51 506 271 106 129 70 117 59 41 17 53 23 11 19 30 77 37 40 46 30 21 9

Survival rates (%) Median survival (mo) 1 year 2 years 3 years 5 years 22 13 19 32 24 8 33 22 43 17 5 13 33 13 8 60 16 28 6 18 29 NR 10

67 56 72 87 79 38 88 75 94 66 21 55 85 55 22 – 56 77 37 – 72 85 69

44 22 – – – – – – – – – 32 54 35 5 73 – 52 19 31 64 71 46

– – 39 47 29 6 44 28 56 9 0 – – – – 53 25 42 8 – – – –

– – 19 31 15 0 32 19 43 2 – 11 22 10 – 49 17 35 4 – – – –

a

Overall, all patients included; CCR, Completeness of Cytoreduction score. * P = .03. ** P < .001.

after an adequate cytoreduction and PIC for peritoneal mesothelioma.41–45 CCR score is related to the pretreatment tumor load and the surgeonÕs ability to eradicate gross disease. It is likely that if the disease is detected and treated early, the tumor volume may be small at the time of cytoreduction, and therefore, a complete removal of all tumors may be more feasible. Considering the current lack of clinical evidence on the efficacy of modern systemic chemotherapy for isolated CRPC, these patients should be recommended early to a peritonectomy center for assessment before embarking on systemic chemotherapy alone.8 More importantly, an accurate documentation of the extent of peritoneal disease by using PCI at the time of primary cancer resection is extremely useful. This could greatly facilitate the patient selection process when considering the combined treatment. Other Prognostic Indicators In addition to these quantitative prognostic indicators, several clinical and histopathological parameters have also been shown to influence the prognosis. These include: age,6 performance status,31 intestinal obstruction,31 malignant ascites,31 preoperative sysAnn. Surg. Oncol. Vol. 14, No. 6, 2007

temic chemotherapy,6 adjuvant systemic chemotherapy,6 repeat surgery,6,46 disease-free interval,46 tumor differentiation,6,20,22,47 signet-ring cell,20 mucinous adenocarcinoma,11,18 lymph node status,6,14 and solid organ metastases.6,15,31,48 It is known that poor tumor differentiation and lymph node metastases in patients with primary colorectal cancer indicate a poor prognosis. They may reflect the aggressive biological behaviors of the disease and a propensity for systemic metastases. Some centers perform synchronous resection of regional lymph nodes and/or liver metastases. As a result of limited data, the current evidence does not preclude these patients from the combined treatment. Recently, Elias and coworkers48 showed a 3-year overall survival of 42% and disease-free survival of 24% in 24 patients with synchronous peritoneal and liver metastases from colorectal cancer. Because colorectal cancer spreads not only by the transcoelomic route but also via lymphatic and hematogenous dissemination, the containment of disease only with targeted local-regional therapy in high-risk patients is inadequate. Best systemic chemotherapy with or without biological agents should be considered in these patients. The prognostic significance of mucinous versus nonmucinous colorectal adenocarcinoma is not well

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understood. Some reports showed that mucinous type was associated with a reduced survival,49–51 but others did not support such findings.52,53 Mucinous colorectal adenocarcinoma has a tendency to cause peritoneal dissemination.11,18 This phenomenon may be related to the physical property of mucinous tumors, in that the mucin may act as a transport vehicle that facilitates tumor cell distribution within the peritoneal cavity. In a recent study, 7 of 30 patients with mucinous histology were found to have a larger volume of disease at the time of cytoreduction.18 Their 2-year survival was 26%, as compared with 80% in the nonmucinous group. Although this survival difference might be related to the extent of peritoneal disease (PCI), it might also be due to some biological differences between mucinous and nonmucinous tumors. Table 2 summarizes all important prognostic indicators for survival, identified systematically from the original studies in the current literature. It shows that quantitative prognostic indicators, such as PCI and CCR, have proven to be useful in predicting survival. Although other clinical and histopathological parameters seem to correlate with prognosis, these parameters should be evaluated further to allow a more reliable prediction.

PATIENT SELECTION In most series, patients with limited peritoneal carcinomatosis are likely to receive a complete cytoreduction and considered the best candidates for this combined local-regional approach. When CRS turns out to be technically impossible, it seems that patients might be better off with systemic chemotherapy. It is especially the case when considering the moderate to high perioperative morbidity and mortality.54–58 Therefore, it is important to detect and stage peritoneal carcinomatosis in view of treatment planning and to predict whether a complete cytoreduction is likely to be performed. In the current clinical practice, this is achieved by preoperative abdominopelvic computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) or PET/CT, and/or laparoscopy. However, all of these investigation modalities have major limitations. Preoperative Investigations The sensitivity of multislice CT in diagnosing peritoneal carcinomatosis varies from 60% to

TABLE 2. Prognostic indicators for survival after cytoreductive surgery and perioperative intraperitoneal chemotherapy for colorectal peritoneal carcinomatosis Prognostic indicators

Reference

Quantitative factors Peritoneal Cancer Index Simplified Peritoneal Cancer Index Lyon Staging System Completeness of Cytoreduction score Clinical factors Age Performance status Intestinal obstruction Malignant ascites Preoperative systemic chemotherapy Adjuvant systemic chemotherapy Repeat surgery Disease-free interval Histopathological factors Tumor differentiation Signet-ring cell Mucinous adenocarcinoma Lymph nodal status Solid organ metastases

6, 7, 6, 6,

10–19 20, 21 22–25 7, 10–14, 16–22, 26–32

6 31 31 31 6 6 6, 46 46 6, 20, 22, 47 20 11, 18 6, 14 6, 15, 31, 48

90%,59–62 which depends on the quality of CT, the size of tumor nodules, the abdominopelvic regions examined, and the interpretation of the radiologist.59,63,64 In general, CT is easier to perform, provides a higher spatial resolution, and is more familiar to clinicians. It is limited, however, by its difficulty in small nodule detection, especially in the absence of ascites. This may be the case in many patients with early tumor dissemination. Gadolinium-enhanced MRI with its superior contrast resolution is an attractive alternative to CT.65–67 However, MRI requires longer scanning time and is more easily influenced by movement artifacts as a result of respiration and bowel peristalsis. During surgery, most sites of peritoneal tumor infiltration, including omentum, diaphragms, and pelvis, can be satisfactorily managed with peritonectomy procedures, as described by Sugarbaker.68 Also ileocecal involvement is well treated with intestinal resection. Therefore, tumor deposits in these areas, even when missed by preoperative CT or MRI scans, usually have limited impact on prediction of successfulness of cytoreduction. Yet disease infiltration into the small bowel and its mesentery is a major limiting factor for complete cytoreduction. Yan et al.69 defined interpretive CT findings of small bowel and small bowel mesentery into four classes (class 0–III) according to the spectrum of disease severity. This radiologic classification is useful in determining the operability for peritoneal mesothelioma. In class Ann. Surg. Oncol. Vol. 14, No. 6, 2007

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III disease, whereby the configuration of the small bowel on CT appears thickened and distorted, it usually means that an adequate cytoreduction is unable to be achieved. The application of this CT classification in CRPC is currently being evaluated prospectively in a multi-institutional study.70 It is likely that CT features indicating small bowel obstruction, distortion, bowel wall thickening, and enhancement may correlate strongly with a poor prognosis, because the disease at this stage is usually too far advanced for salvage treatment with cytoreduction.59,69 However, these anatomic imaging techniques (CT and MRI) can diagnose pathologic processes only after they reach a detectable size, become contour deforming, or have abnormal enhancement after intravenous contrast administration. PET with 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) can differentiate tumors more easily from adjacent structures because of the focally increased FDG tracer uptake. PET has an overall sensitivity of >85% in the detection of colorectal metastases in the entire body, according to a recently published meta-analysis.71 But the high sensitivity is associated with a lower specificity as a result of other areas of normal physiologic accumulation of FDG and the lack of anatomical registration. This major drawback of PET is overcome by the availability of integrated wholebody PET/CT imaging systems, yielding intrinsically fused morphological and functional data sets. However, PET/CT may be limited by its high cost and availability. Given a spatial resolution of 4–6 mm available in the PET/CT systems and the fact that FDG is an unspecific radioactive tracer, negative PET/CT results would still not exclude micrometastases. Currently, all noninvasive imaging modalities have major limitations in the assessment of low-volume disseminated peritoneal disease and may fail to detect early localized disease at a stage where treatment is most likely to be beneficial. Laparoscopic exploration is a reliable way of assessing tumor severity in the peritoneal cavity and may supplement the information provided by the imaging techniques. Recent studies showed that laparoscopy is safe to diagnose and stage peritoneal carcinomatosis.72–74 However, it is important to acknowledge that this technique is difficult to assess patients with extensive prior surgery and lymph nodes involving in the retroperitoneal space.75,76 The spread of malignant cells through the trocar tract is another major concern. Table 3 provides a summary of the advantages and disadvantages of CT, MRI, PET, and laparoscopy. Ann. Surg. Oncol. Vol. 14, No. 6, 2007

Considering these current investigational modalities, a high-quality cross-sectional imaging study, either contrast-enhanced multislice CT or gadolinium-enhanced MRI, should be performed routinely. Although these two modalities have similar diagnostic accuracy, the simplicity and better spatial resolution make CT a more widely used imaging tool for detection of peritoneal tumors. FDG-PET, or preferably PET/CT, should be at least selectively considered as part of preoperative workup in high-risk patients. Laparoscopic exploration may supplement imaging modalities to allow direct visualization. However, the use of these investigations should be individualized and planned as part of a multidisciplinary approach. One of the key consensus points regarding preoperative investigations from the Milan Peritoneal Oncology Meeting was that contrast-enhanced multislice CT is the fundamental imaging modality, whereas MRI, PET, laparoscopy, and serum tumor markers are supplementary investigational modalities in preoperative evaluation of candidates undergoing the combined treatment. Selection Criteria Various patient selection criteria have been used by different institutions. At the Washington Cancer Institute, the preoperative workup was aimed at quantitative evaluation of the abdominopelvic disease, ruling out extraabdominal dissemination.11 Clinical examination, laboratory tests including carcinoembryonic antigen and contrast-enhanced chest and abdominopelvic CT, were routinely performed. All patients had biopsy-confirmed diagnosis of CRPC. Patients with unresectable liver metastases or lymph node involvement along the aorta or vena cava, or in the celiac group, as per abdominopelvic CT scan, were considered unsuitable for the combined treatment. Patients with prior abdominal radiotherapy were ineligible for the combined therapy. In Amsterdam, patients with histologically proven CRPC, without clinical or radiological evidence of liver or lung metastases, who were <70 years old and fit to undergo major surgery, were eligible for this therapy.20 In their RCT, which had a median followup of 22 months, the median survival was 22 months in the cytoreduction group and 13 months in the control arm (P = .032).7 In a more recent update on 117 CRPC patients, after a median follow-up of 46 months, the median survival was 22 months.21 In Lyon, all patients underwent physical examination, routine blood tests (serum electrolytes and

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TABLE 3. Advantages and disadvantages of current investigational modalities for colorectal peritoneal carcinomatosis Modality

Advantage

Disadvantage

Contrast-enhanced multislice CT

    

 Low sensitivity for small tumors  Low sensitivity with mesenteric deposits  Lower contrast resolution

MRI

 Superior contrast resolution  Multiple imaging types  Manipulation of signal intensities

   

Low sensitivity for small tumors Longer imaging times Movement artifacts Lower spatial resolution

PET or PET/CTs*

   

Functional activity Higher sensitivity Detection of occult metastases Anatomical localization*

    

Low sensitivity for small tumors Lower specificity Increased cost Limited availability Mismatched fusion*

Laparoscopy

   

Direct visualization High sensitivity for small tumors Supplement to imaging Biopsy

    

Relatively more invasive Technical difficulty with adhesions Failure to assess retroperitoneal space Risk of port track seeding Increased cost

Superior spatial resolution Shorter imaging times Less movement artifacts Readily available Clinical familiarity

CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography. *PET/CT.

liver function tests), cardiac echocardiogram, spirometry, hepatic ultrasound, and cerebral, thoracic, and abdominopelvic CT.22 The inclusion criteria were: age <70 years, primary colorectal adenocarcinoma, peritoneal carcinomatosis confirmed by cytological and/or pathological examination, synchronous or metachronous CRPC, absence of extraabdominal dissemination, and absence of liver metastases as per preoperative investigations. The exclusion criteria were: renal or myocardial impairment, administration of systemic chemotherapy in the month before inclusion, central nervous system disease (vascular or tumor), and World Health Organization performance status score of >2. By using these selection criteria, only 53 of 152 patients with CRPC were eligible for the combined treatment. After a median follow-up of 60 months, the overall median survival was 13 months.22 In Villejuif, the preoperative workup included a clinical examination, measurements of carcinoembryonic antigen levels, chest and abdominopelvic CT, and colonoscopy.35 The eligibility criteria for CRS and intraperitoneal hyperthermic oxaliplatin were good performance status (Eastern Cooperative Oncology Group status 1–2), age <65 years, no extra-abdominal tumors, no evidence of intestinal obstruction, no debilitating ascites, and no clinical or radiological evidence of bulky or irresectable peritoneal carcinomatosis.35 All their patients had already received neoadjuvant systemic chemotherapy for at least 3 months. Patients were excluded from the

combined treatment if they experienced rapid progressive disease while receiving systemic chemotherapy and/or if a complete cytoreduction could not be achieved. After a median follow-up of 55 months, 30 patients had a median survival of 60 months and 5-year overall and disease-free survival of 49% and 34%, respectively.36 In Padova, patients with CRPC underwent total body CT and/or PET. Most patients underwent exploratory laparotomy.47 Patients with lymph nodal or solid organ metastases were not considered for the therapy, and those with incomplete cytoreduction were ineligible for intraperitoneal chemotherapy. The median survival was 18 months in 46 patients after a 15-month follow-up.47 In Sydney, patients underwent physical examinations, contrast-enhanced total body CT, and PET to assess the extent of the disease.18 The inclusion criteria consisted of age >18 and £ 80 years; patients diagnosed with peritoneal carcinomatosis from colorectal carcinoma, and signed informed consent. The exclusion criteria consisted of World Health Organization performance status of >2; bleeding diatheses not responding to medical treatments, and extra-abdominal colorectal metastases. After a median follow-up of 12 months, the overall median survival of 30 patients was 29 months, with 2-year survival of 64%.18 The differences in the survival results among all institutions were partly due to factors such as variations in recruitment criteria, treatment protocols, Ann. Surg. Oncol. Vol. 14, No. 6, 2007

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surgical experience, and length of follow-up. The results from the Milan Peritoneal Oncology Consensus Meeting suggest that patients who have a good performance status (£ 2), absence of extra-abdominal metastases, resectable regional lymph nodes or hepatic metastases, low peritoneal disease involvement, and potential complete cytoreduction candidates, as per contrast-enhanced multislice CT with or without PET and laparoscopy, should be considered for the combined treatment. Ninety-two percent of the voters would consider CRS and HIPEC followed by best adjuvant systemic chemotherapy for patients with limited peritoneal carcinomatosis found at the time of resection of primary disease (T4 N0 M1). Because evidence on excluding patients with resectable synchronous regional lymph nodes and/or hepatic metastases is lacking, all voters would consider either neoadjuvant or adjuvant systemic chemotherapy combined with CRS and HIPEC as an appropriate treatment for patients with limited peritoneal carcinomatosis and positive lymph nodes (T4 N2 M1). Sixty-seven percent of the voters did not consider liver metastases as an exclusion criterion.

FUTURE DIRECTIONS Currently, only one RCT has been performed.7 Many oncologists are insisting on more proof before accepting the combined treatment as the standard of care. There are no published data that specifically demonstrate the efficacy of modern systemic chemotherapy for patients with CRPC. The historical controls mainly include 5-fluorouracil–based chemotherapeutic regimens. Although patients with a complete cytoreduction have a more favorable prognosis, again, the current evidence is insufficient to conclude whether the survival advantage is entirely due to surgery or is associated with the features which predispose these patients to a complete cytoreduction. However, given the promising results currently achieved, recruiting patients to undergo more RCTs comparing CRS and HIPEC with modern systemic chemotherapy alone may not be practical, partly because patients are relatively well informed about the promising results of the combined treatment. Also, there may be an unwillingness of peritonectomy surgeons to participate in such randomized trials. In 1996, the French group tried to compare CRS with EPIC versus CRS without EPIC, but only 35 patients enrolled in 4 years, and the study was terminated prematurely before it reached the required 90 patients.35 According to the investigators, the Ann. Surg. Oncol. Vol. 14, No. 6, 2007

discontinuation of the trial was related to promising results found in CRS with HIPEC at the time. It was also suggested from this trial that the period of time required to recruit an adequate number of patients is likely to extend over different evolutions of both the intervention and the comparator. Although only a small number of patients may be required to achieve adequate statistical power to detect a proposed large difference in outcomes, the precision of the estimate of effectiveness in a small trial is likely to be low. However, the fact that RCTs are difficult to perform should not constitute a plea against randomization. Perhaps at this point an important question to ask is, what is the additional value of HIPEC? An RCT comparing CRS and HIPEC with no HIPEC, both followed by best systemic chemotherapy, may be a more feasible proposal in the current medical setting. Alternatively, conducting a prospective, comparative, nonrandomized trial with a clearly defined protocol for patient group, intervention, comparator, and endpoints may also be potentially meaningful. This high-quality prospective observational data collection may provide more accurate estimates of outcomes for the procedure, in addition to information of prognostic factors associated with a favorable prognosis. Importantly, outcomes must be recorded on an intention-to-treat basis, i.e., for all patients in whom complete cytoreduction and HIPEC is attempted, regardless of whether or not peritonectomy is performed and whether or not optimal cytoreduction is achieved or an open-and-close procedure is carried out. Many centers only report outcomes in patients who received complete cytoreduction or in patients who had both CRS and HIPEC. Although this may be predictive of outcome, it only applies to selected patients, usually with favorable prognostic features, and is not useful in terms of patient selection. Currently, a prospective multi-institutional phase II registry study by using CRS and HIPEC with mitomycin C followed by modern adjuvant systemic chemotherapy for patients with isolated CRPC is in process.70 This study involves 66 peritoneal surface malignancy surgeons from 46 institutions in 16 countries. In this study, PCI is the designated scoring system, and preoperative workup includes contrastenhanced multislice chest and abdominopelvic CT. PET is considered for exclusion of extra-abdominal disease. In patients who have received neoadjuvant modern systemic chemotherapy with or without biological agents, if they respond to the systemic therapy and have a good performance status, CRS and HIPEC is then considered. In theory, this chemoselection approach may enable selection of a biologically

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favorable group that responds to chemotherapy, allowing patients who develop progressive disease during this interval of reevaluation to avoid a major surgery. It needs to be acknowledged that although response to preoperative chemotherapy as a patient selection criterion has been suggested in the management of multiple colorectal liver metastases, the evidence of this chemoselection approach in CRPC is not clear, but it could potentially be a favorable patient selection criterion.36 However, in reality, many patients referred to specialist peritonectomy centers have already been treated by medical oncologists. These patients have disease that has failed to respond to systemic chemotherapy, so they seek combined treatment as a last resort. After the RCT by the Dutch group, and until further convincing evidence on systemic chemotherapy or other treatment options demonstrating superior results becomes available, it may be fair to suggest an early referral for the potential surgical candidates to specialist peritonectomy centers for evaluation before embarking on systemic therapy alone. As emphasized in the present review, CRS with HIPEC is not indicated for all patients with CRPC, and the results achieved by international experts in this field may not be replicated in routine clinical practice. However, it is clear that the mere documentation of presence versus absence of peritoneal disease is no longer adequate. Quantitative assessment of the extent of disease is now possible and should be performed at the time of primary cancer operation, so that adjuvant treatments for appropriately selected patients can be followed. Patients with good performance status, low volume of peritoneal disease, and absence of extra-abdominal metastases are more likely to benefit from the combined treatment. This is very much dependent on early diagnosis, early referral to specialist peritonectomy centers for staging, and prompt intervention. A collaborative effort from medial oncologists, colorectal surgeons, and peritoneal surface malignancy treatment centers is required. ACKNOWLEDGMENT There are no potential conflicts of interests.

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