Comprehensive management of diffuse malignant peritoneal mesothelioma
Natural history
Mesothelioma arises from the serosal lining of the pleural, peritoneal and pericardial cavities. It is a rare neoplasm, but increasing in frequency. Peritoneal mesothelioma represents one fourth of all mesotheliomas.1–4 It is characterized macroscopically by thousands of whitish tumor nodules of variable size and consistency that may coalesce to form plaques, masses or layers to cover the entire peritoneal surface. Most patients have abdominal pain or ascites as a primary symptom. In most patients, the disease remains localized within the abdomen and pelvis throughout its course. In contrast to mucinous carcinomatosis from appendiceal or colorectal cancer, the pattern of distribution of cancer nodules from diffuse malignant peritoneal mesothelioma (DMPM) does not spare the visceral surface of the small bowel. Cytoreductive surgery (CRS) is thus difficult and less likely to be complete.#
Treatment results prior to CRS and hyperthermic intraoperative intraperitoneal chemotherapy (HIIC)
Before 2000, DMPM was treated at most cancer centers with a combination of systemic chemotherapy, palliative of tumor surgery and in a few patients total abdominal radiation. Median survival was approximately one year. Table 1 shows the results of treatment using palliative surgery and systemic treatment modalities for DMPM.5–11#
Treatment results of comprehensive therapy of CRS and HIIC
An aggressive treatment plan to surgically eradicate abdominal and pelvic disease combined with intraperitoneal chemotherapy to control residual disease has a strong rationale. When surgery is combined with a hyperthermic chemotherapy regimen, the results of treatment of DMPM improve. The median survival has approached 5years and seems to improve with subsequent reports12–20 (Table 2).#
Treatment of DMPM
We have performed 123 cytoreductive procedures for DMPM on 100 patients; this includes 100 initial cytoreductive procedures, 20 second-looks, and 3 third-look procedures.#
Perioperative intraperitoneal chemotherapy
HIIC with cisplatin (50mg/m2) and doxorubicin (15mg/m2) is given at 42°C in 1.5L/m2 of 1.5% dextrose peritoneal dialysis solution for 90min.16 The pharmacokinetics of cisplatin and doxorubicin administered intraperitoneally at 42°C are illustrated in Figs. 1 and 2. Doxorubicin is taken up into mesothelioma nodules.#
Early postoperative intraperitoneal chemotherapy with paclitaxel
Institutional survival results
In our series of 100 consecutive patients with peritoneal mesothelioma, the overall median survival was 50months (range 1–143months), with 1-, 3-, and 5-year survival rates of 77%, 53%, and 44%, respectively (Fig. 3). Fifty-two patients (52%) were alive at the last time of contact. Because the treatment plans are an evolution of increasingly aggressive protocols, not all patients early in our experience had all the treatments. In the group of 65 patients who underwent CRS combined with HIIC with cisplatin and doxorubicin and followed with early postoperative intraperitoneal paclitaxel the median survival was 79months (range 1–143months).20#
Feldman et al. at the National Cancer Institute, Bethesda have reported on several consecutive trials to evaluate treatment plans in DMPM patients. The most recent report of CRS plus HIIC included patients treated with cisplatin at 250mg/m2. At postoperative day 10, patients received 5-flourouracil and paclitaxel as an intraperitoneal dwell. The median overall survival for the 49 patients was 92months and the median progression-free survival was 17months. The 3-year survival was 59%.15#
Brigand et al. from Lyon, France recently reported 15 patients with DMPM who underwent CRS and HIIC with mitomycin C (0.5mg/kg) and cisplatin (0.7mg/kg) for 90min. The overall median survival was 46.7months, with 1-, 3- and 5-year survival of 71.5%, 49% and 36.8%, respectively.17#
Deraco et al. enrolled 49 patients to undergo CRS and HIIC with cisplatin (25mg/m2) and mitomycin C (3.3mg/m2) or cisplatin (43mg/L) and doxorubicin (15.25mg/L). The overall median survival has not been reached at the completion of the study and the progression-free survival was 40months.18#
Taub et al. carried out a prospective single-institution phase I–II trial on 27 patients with DMPM. The treatment regimen consisted of initial exploratory laparotomy with CRS and placement of indwelling intraperitoneal catheters. Surgery was followed by four intraperitoneal courses of doxorubicin (25mg) alternating with four intraperitoneal courses of cisplatin (100mg/m2). Four intraperitoneal doses of gamma-interferon were followed by a second laparotomy with biopsy verification of complete response or attempted resection of residual disease. HIIC with mitomycin (10mg/m2) plus cisplatin (75 to 100mg/m2) and finally whole abdominal radiation was added to the plan of management. The overall median survival was 68months with 3-year survival of 67%.19#
Prognostic indicators in DMPM
Eighteen potentially prognostic clinical and surgical factors were analyzed in the multivariate analysis for consecutive 100 DMPM patients treated at Washington Cancer Institute. Female gender, histologic type and adequacy of cytoreduction were independently associated with a better survival20 (Table 3).#
Female versus male
Females have a superior prognosis when compared to males with DMPM. Welch et al. suggested that direct exposure to asbestos was not a cause for peritoneal mesothelioma in women, but it was definitely related to the causation of peritoneal mesothelioma in men.21 Women may seek medical attention at an earlier stage, before symptoms, such as weight loss, related to a large volume of cancer, become evident.16 Kerrigan et al. also reported a favorable 30-month median survival in 25 female patients with peritoneal mesothelioma.14#
Histomorphology by nuclear size
Several studies have reported the poor outcome associated with the rarer biphasic or sarcomatoid histologic type.316192022 However, because only approximately 5% of patients show biphasic or sarcomatoid histologic type, this criterion is not useful as a prognostic indicator in a majority of patients. In addition to the histologic type, Cerruto and colleagues recently analyzed histomorphologic findings for their impact on survival of 62 patients with DMPM. In their multivariate analysis, the size of the nucleus of the mesothelioma cells was independently associated with a better survival (p<0.001).23#
Deraco and colleagues also studied histologic criteria as prognostic indicators in 49 patients with DMPM.18 Nuclear grade and mitotic count were correlated with survival in 49 patients with DMPM treated by CRS and HIIC. For both overall survival and disease-free survival, the mitotic count (per 50 high-power field) was a statistically significant determinant of survival (p=0.01 and p=0.03, respectively). Nuclear grade was a significant determinant of overall survival (p=0.02), but not of progression-free survival (p=0.10).#
Completeness of cytoreduction
At the end of the CRS, a completeness of cytoreduction score (CC) was recorded. In the 100 patients treated at the Washington Cancer Institute, 69 patients received adequate cytoreduction versus 31 patients who did not, and the 5-year survival was 59% versus 19%, respectively (p<0.001).20#
Completeness of cytoreduction was also found to be independently associated with a better survival in multivariate analysis by other major centers. Brigand and co-workers from Lyon defined an adequate cytoreduction as residual tumor nodules of ≤5mm. The median survival was not reached for patients with an adequate cytoreduction. It was 6.5months for patients with suboptimal cytoreduction (p<0.001 by univariate analysis).17 Deraco and colleagues compared the survival in patients who had optimal cytoreduction with those with a suboptimal result. Optimal cytoreduction was defined as residual tumor nodules of ≤2.5mm. In both univariate and multivariate analyses, CCR was a dominant treatment-related factor (p=0.01 and p<0.001, respectively).18#
Abdominal and pelvic CT to select patients for adequate cytoreduction
As indicated by the CCR data, this treatment-related factor has a major impact on the benefit expected from the comprehensive therapy. Using a radiologic test to help select patients for complete cytoreduction would be of great help to eliminate from elective treatment patients who will have suboptimal cytoreduction.#
We sought a correlation between the findings of the preoperative CT and completeness of cytoreduction.24 Data showed that the size of the tumor mass in the epigastric region and the interpretative findings of the small bowel/mesentery strongly correlated with the outcome of the surgery, i.e. adequate versus suboptimal cytoreduction (Table 4).#
Fig. 4 demonstrates the clinical pathway determined by preoperative CT for treating patients with peritoneal mesothelioma. According to this study, a patient with a tumor size >5cm in the epigastric region and Class III appearance of small bowel and its mesentery has a probability of 100% for a sub-optimal cytoreduction. A patient without either of these two preoperative CT findings has a 94% probability of an adequate cytoreduction.24 These data strongly suggest that preoperative abdominal and pelvic CT has an important role in the selection of patients for combined therapy.#
Morbidity and mortality
Little prospective morbidity and mortality data regarding CRS and perioperative intraperitoneal chemotherapy (PIC) in patients with peritoneal mesothelioma is available. In our series, 88 consecutive cases of CRS and PIC had a prospective assessment of the in-hospital morbidity and mortality. Grade III morbidity was defined as a complication requiring an invasive intervention, such as a CT guided drainage of intra-abdominal abscess. Grade IV morbidity required a return to the surgical intensive care unit or to the operating room.#
Of the 100 patients who underwent CRS and PIC for DMPM, five patients died postoperatively during their hospital stay: three died form sepsis and two died from pulmonary embolism. The Grade III morbidity rate was 24% with pleural effusion (5%) being the most common complication. Grade IV morbidity rate was 11% with early postoperative intra-abdominal bleeding (4%) being the most common complication.20#
These morbidity and mortality statistics may be quite similar to those reported for CRS and PIC for peritoneal surface malignancy treatment of patients with many different diagnoses. After cytoreductive surgery and PIC, the morbidity ranges from 20% to 50% and mortality varies between 1% and 10% in most published series.25–30 In the past, we reported a prospective morbidity and mortality analysis in the first 60 patients who underwent cytoreductive surgery and perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis.25 The Grade III/IV morbidity and in-hospital mortality rates were 35% and 5%, respectively. In 2003, the Grade III/IV morbidity and mortality rates of 68 mesothelioma patients who underwent this treatment were 23.5% and 7%, respectively.16 The most recent update showed little overall changes in the morbidity and mortality rates.20 This might reflect a position high on the learning curve for our group in the management of peritoneal mesothelioma. The Grade IV morbidity of 11% and mortality of 5% may be acceptable in light of current standards for management of gastrointestinal cancer, but can be reduced with improved patient selection, technical skills intraoperatively and postoperative care.#
Discussion
Many unanswered questions remain regarding the surgical options in the management of DMPM. Cytoreductive surgery and perioperative intraperitoneal chemotherapy produce longer survival and complete resolution of ascites in nearly all patients.#
The role of systemic chemotherapy in these patients remains to be settled. There are now Food and Drug Administration-approved treatment protocols using systemic chemotherapy. Currently, our patients who have a suboptimal cytoreduction with tumor nodules greater than 0.5cm (grade III or grade IV histology) remaining after surgery are recommended for systemic chemotherapy.#
The morbidity and mortality of this group of patients seems to be comparable to other major surgical procedures for gastrointestinal cancer but the cost is considerable. These prognostic indicators can be used to substantially improve the results of treatment both in terms of maximizing life years brought about by combined therapy and minimizing the complication rate and mortality rate in those patients unlikely to receive benefit.#
Figures and Tables
Table 1
| AuthorsRef. | Year | No. of patients | Median survival (months) |
| Chailleux et al.5 | 1988 | 11/167 | 10a |
| Antman et al.6 | 1988 | 37/180 | 15a |
| Sridhar et al.7 | 1992 | 13/50 | 9.5a |
| Markman et al.8 | 1992 | 19 | 9 |
| Yates et al.9 | 1997 | 14/272 | 14a |
| Neumann et al.10 | 1999 | 74 | 12 (mean) |
| Eltabbakh et al.11 | 1999 | 15b | 12.5 |
Table 2
| AuthorsRef. | Year | No. of patients | Median survival (months) |
| Park et al.12 | 1999 | 18 | 26 |
| Loggie et al.13 | 2001 | 12 | 34 |
| Kerrigan et al.14 | 2002 | 25a | 30 |
| Feldman et al.15 | 2003 | 49 | 92 |
| Sugarbaker et al.16 | 2003 | 67 | 68 |
| Brigand et al.17 | 2005 | 15 | 46.7 |
| Deraco et al.18 | 2005 | 49 | N/A |
| Wagmiller et al.19 | 2005 | 27 | 68 |
| Yan and Sugarbaker20 | 2005 | 65b | 79 |
| N/A, median survival has not been reached. |
Table 3
| Co-variate | b | SE | Sig | Exp(B) |
| Gender | 1.097 | 0.370 | 0.003 | 2.994 |
| Histopathological type | 1.761 | 0.445 | <0.001 | 5.817 |
| Completeness of cytoreduction | 1.296 | 0.308 | <0.001 | 3.653 |
| b, b regression coefficient; SE, standard error; Sig, significance; Exp(B), −eB. |
Table 4
| Class | Presence of ascites | Small bowel and mesentery involvement | Loss of mesenteric vessel clarity | CT interpretation |
| 0 | No | No | No | Normal appearance |
| I | Yes | No | No | Ascites only |
| II | Yes | Thickening | No | Solid tumor present |
| Enhancing | ||||
| III | Yes | Nodular thickening | Yes | Loss of normal architecture |
| Segmental obstruction |
References
4. K.E.Bani-HaniK.A.GharaibehMalignant peritoneal mesotheliomaJ Surg Oncol9120051725
10. V.NeumannK.M.MullerM.FischerPeritoneal mesothelioma—incidence and etiologyPathologe201999169176