Background: The current treatment for pseudomyxoma peritonei (PMP) consists of radical cytoreductive surgery (CRS) followed by hyperthermic intra-peritoneal chemotherapy (HIPEC). Aim: To assess PMP patients regarding the clinical and pathological characteristics, the treatment including surgery (CRS) and chemotherapy either HIPEC type or post-operative systemic chemotherapy aiming to evaluate end results regarding recurrence and survival. Patients and Methods: This retrospective study included 39 patients with PMP who were diagnosed, treated and followed-up from 2009-2014 at National Cancer Institute, Cairo, Egypt. Results: High grade mucinous adenocarcinoma was found in 23.1% of patients. Patients with low grade tumor showed higher survival rate compared with patients with high grade disease. The mean operative PCI score (peritoneal cancer index) that was done to all patients who were explored was 15.81. Our study reported success to achieve complete cytoreduction that was combined with HIPEC in 44% of patients who were planned for this modality. Treatment related postoperative grade (3 - 5) complications mainly surgery related developed in 17.3 of patients. Operative mortality was 22.2%. The follow up period in our study was quite short (mean 22.9). However the overall survival at the end of the follow up in our study was 48.7%, 1 year survival was 82%, and 2 year survival was 41%. The overall survival in patients treated with CRS and HIPEC was 66.6%, with 1 year and 2 year survival of 91% and 66.6% respectively. Only 2 patients developed recurrent disease during the follow up period. Conclusions: The outcome of PMP treatment process is extremely variable. Combined CRS and HIPEC is considered the best therapeutic approach for patients with PMP. Surgical experience combined with proper patient selection have to be built up together to improve the outcome. That could only be achieved through more centralization of patients’ treatment in specialized units or center.
Pseudomyxoma peritonei (PMP) is a rare intraperitoneal tumor, characterized by disseminated intraperitoneal tumor implants on peritoneal surfaces. The disseminated neoplastic cells produce mucin, which leads to the characteristic mucinous ascites [
Traditionally PMP has been treated with serial debulking procedures. This technique can provide relief for some time; however repeated debulking procedures become increasingly difficult, and lead to more complications [
Combining CRS and HIPEC can greatly improve survival with average 5 year survival rate around 76% [
The aim of this work was to assess patients with PMP regarding the clinical and pathological characteristics, the treatment including surgery (CRS) and chemotherapy either HIPEC type or post-operative systemic chemotherapy aiming to evaluate end results regarding recurrence and survival.
This is a retrospective study that was conducted at National Cancer Institute (NCI) in Cairo, Egypt. The study included patients with PMP who were diagnosed (radiologically and pathologically), treated and followed up in the period from 2009 to 2014.
MethodsHistologically proven PMP were identified at the histopathology department database. Patients’ files were retrieved from the biostatistics department. Data were extracted from the medical records, and selected variables were collected including; demographic characteristics included age and gender, patient medical history regarding diabetes mellitus and hypertension, history and number of previous surgeries that were related to PMP diagnosis and management, time between disease diagnosis and definitive surgery, number and types of lines of preoperative and postoperative systemic chemotherapy, and patients’ response, pathological features of the disease including type, grade, margins and lymph nodes involvement, preoperative evaluation including laboratory, radiological investigations including CT scan for the chest and abdomen, MRI, and PET CT if available, to estimate the preoperative PCI and metastasis, presence of extra-peritoneal metastasis, operative data (operative PCI score, whether complete or incomplete cytoreduction was done, data about hyperthermic intra peritoneal chemotherapy and type of chemotherapy, intraoperative morbidity, operative mortality), post-operative data (ICU admission and duration of ICU admission, hospital stay was calculated starting from date of operation till date of discharge, follow up data including disease progression and recurrence), survival data (event free survival was calculated from date of surgery till date of recurrence, progression or date of last follow up, overall survival was calculated from date of diagnosis of the primary cancer till date of death or date of last follow up if not died).
Date of diagnosis was determined by the date of the operation or by the date of the first pathology report if biopsy was taken. Histopathology of the tumor was classified according to the WHO classification, to low grade mucinous carcinoma and high grade mucinous carcinoma.
Tumor markers included in the study were CA125, CA19-9 and CEA. Data about completeness of cytoreduction was not documented according the CC score, so it was estimated according to R score; where R0 means no microscopic residuals at the end of the operation, R2 means macroscopic residual, while R1 means microscopic residuals detected as positive margin. Operative complications were considered as any deviation from the ideal operative and postoperative course, while operative mortality was defined as death within one month of the operation.
Progression and recurrence was diagnosed in case of marked rise of tumor markers and/or evidence of relapse in abdominal CT scan, or during laparotomy for any cause.
This study included 39 patients with pseudomyxoma peritonei. Their mean age was 53.8 years (
Descriptive Statistics | ||
---|---|---|
Range | Mean ± SD | |
Age (years) | 25 - 70 | 53.846 ± 12.014 |
Time between diagnosis and operation (months) | 1 - 15 | 4.577 ± 3.880 |
ICU stay (days) | 1 - 21 | 6.368 ± 5.387 |
Total hospital stay (days) | 1 - 68 | 11.115 ± 13.698 |
Follow up time (months) | 1 - 63 | 22.974 ± 15.875 |
panhystrectomy in 11 patients (33.3%), exploration in 13 patients (39.3%), appendectomy in 4 patients (30.3%), hernioplasty in 3 patients (9.1%), during caesarian section in one patient (3%), and iliopsoas mass in one patient (3%). Twenty three patients (58.9%) presented with abdominal or pelvic mass, 6 patients with abdominal or pelvic cysts while ascites was manifested in 66.7% of patients ranging from mild to massive. Extra-peritoneal metastasis was reported in 4 patients (10.2%) that included liver metastasis in 3 patients and one patient presented with spread along the insertion of iliopsoas muscle at the upper thigh.
CEA was elevated in 15/22 patients (68.1%) in whom the test was done while CA 19-9 was measured in 19 patients and it was elevated in 9 patients (47%). CA125 was measured in 14 patients and it was elevated in 6 patients (42%). Low grade mucinous adenocarcinoma was reported in 30 patients (76.9%), while high grade mucinous adenocarcinoma in 9 patients (23.1%).
In preoperative assessment, 32 patients (82%) had history of one previous surgery related to their illness, while 12% did not undergo any previous surgeries. The mean time between disease diagnosis and the operation was 4.6 months (range = 1 - 15). Twenty six patients (68%) were eligible and planned for combined CRS and HIPEC, and one patient for laparoscopic exploration. Only 12 patients (44.4%) underwent cytoreductive surgery and HIPEC, 6 patients were inoperable. Five patients had CRS without HIPEC; as their operations were aborted after completion of cytoreduction due to intraoperative complications or anesthetic limitations. However the operation was incomplete in 3 patients, and aborted before complete cytoreduction due to intraoperative morbidity. The mean operative PCI score was 15.8 (Range = 0 - 31).
The other 11 patients (28%) who were excluded from CRS and HIPEC were planned for follow up with or without systemic chemotherapy, or for best supportive care. One patient died before treatment. Among patients that underwent CRS with or without HIPEC, a macroscopic complete cytoreduction (R0) was reached in 13 patients (76.4%), R1 in 2 patients, and R2 in 2 patients. Bowel resection was done in 57.6% of patients who were planned for surgery.
During the study period, 8 patients (20.5%) received one line of systemic chemotherapy, 5 patients (12.8%) received two lines. The response of the disease to chemotherapy was progressive in 5 patients and stationary in the other 8 patients. The different lines of chemotherapy used in those patients are shown in
Intraoperative complications encountered in 8 patients (29%), the most common was bleeding in 6 patients. Treatment related postoperative grade (3 - 5) complications mainly surgery related developed in 4 patients (17.3%) that consisted of leakage in 2 patients, pulmonary embolism, and reactionary hemorrhage. Operative mortality was 22.2% (n = 6). Nineteen patients (70.4%) needed postoperative ICU admission with the mean ICU stay was 6.3 days (range 1 - 21), while the mean postoperative hospital stay was 11.1 days (range 1 - 68).
The mean follow up period was 22.9 months (range 1 - 63). At the end of the follow up 19 patients were alive and 20 patients (51.3%) died, the overall survival was 48.7%, 1 year overall survival rate was 82%, and 2 year overall survival rate was 41%. The 1 and 2 years overall survival in patients treated with CRS and HIPEC were 91%, and 66.6% respectively. Two patients (16.7%) developed disease recurrence that needed reoperation with cytoreductive surgery and HIPEC.
There was a significant relation between patients’ age and their final status or survival; young patients were associated with higher survival rates. In patients who underwent the operation after a period less than 6 months survival rate was 45%, 66.7% in operations within 6 - 12 months, and 0% in operations done within a period more than a year. However these results were insignificant. Overall survival in patients with low grade mucinous adenocarcinoma was 56.6% compared to 22.2% in patients with high grade mucinous adenocarcinoma but the difference was of borderline significance (P = 0.070). Patients with low grade tumor who underwent CRS and HIPEC showed significantly better overall survival when compared with those with high grade disease who underwent the same surgery (P = 0.028). Correlating the number of elevated preoperative tumor markers and survival showed no significant relation between the number of elevated tumor markers and the overall survival. In all patients who were explored the mean operative PCI score was 15.81 (range 1 - 30). The mean PCI score of those patients who were alive at the end of the follow up period was 13, compared to 18 in patients who died. Although the mean PCI score was higher in patients who died at the end of follow up period, the correlation between the mean PCI score and survival or recurrence in our study was not significant (
Chemotherapy line | Number of patients |
---|---|
Taxol-Carboplatin | 6 |
FOLFOX | 2 |
Taxol-Gemzar | 1 |
Cisplatin | 1 |
FU-xeloda | 1 |
Xeloda | 1 |
Oxaloplatin-xeloda | 2 |
IFL | 1 |
Alive | Death | t/x2 | P value | |||
---|---|---|---|---|---|---|
Operation Done | N | % | N | % | ||
CRS | 1 | 20.00 | 4 | 80.00 | 7.106 | 0.130 |
CRS + HIPEC | 8 | 66.67 | 4 | 33.33 | ||
Inoperable | 3 | 50.00 | 3 | 50.00 | ||
aborted | 0 | 0.00 | 3 | 100.00 | ||
Lap. Exploration | 1 | 100.00 | 0 | 0.00 | ||
Age (Range, Mean ± SD) | 25 - 61 47.42 ± 10.95 | 45 - 70 59.95 ± 9.73 | −3.782 | 0.001* | ||
Time Interval (N, %) | N | % | N | % | ||
1 to 6 | 9 | 45.00 | 11 | 55.00 | 2.205 | 0.332 |
6 to 12 | 2 | 66.67 | 1 | 33.33 | ||
>12. | 0 | 0.00 | 2 | 100.00 | ||
Path Grade (N, %) | N | % | N | % | ||
Low | 17 | 56.67 | 13 | 43.33 | 3.288 | 0.070 |
High | 2 | 22.22 | 7 | 77.78 | ||
Total | 19 | 48.72 | 20 | 51.28 | ||
Operation + grade (N, %) | N | % | N | % | ||
CRS + HIPEC with Low grade tumor | 8 | 80.00 | 2 | 20.00 | 4.800 | 0.028* |
CRS + HIPEC with High grate tumor | 0 | 0.00 | 2 | 100.00 | ||
Number of elevated markers (N, %) | N | % | N | % | ||
No | 4 | 57.14 | 3 | 42.86 | 0.152 | 0.985 |
One | 5 | 62.50 | 3 | 37.50 | ||
Two | 4 | 66.67 | 2 | 33.33 | ||
Three | 2 | 66.67 | 1 | 33.33 | ||
Total | 15 | 62.50 | 9 | 37.50 |
OP. PCI | ||||||
---|---|---|---|---|---|---|
Range, Mean ± SD | 1 - 31 13 ± 9.76 | 10 - 30 18.43 ± 5.50 | ||||
Operative Complications (N, %) | N | % | N | % | ||
No | 12 | 63.16 | 7 | 36.84 | 5.787 | 0.016* |
Yes | 1 | 12.50 | 7 | 87.50 | ||
Previous lines of CTH (N, %) | N | % | N | % | ||
No | 12 | 46.15 | 14 | 53.85 | 0.205 | 0.651 |
Yes | 7 | 53.85 | 6 | 46.15 |
Operative complications | Op Mortality | Chi-Square | ||||||
---|---|---|---|---|---|---|---|---|
No | Yes | Total | ||||||
N | % | N | % | N | % | X2 | P-value | |
No | 17 | 89.47 | 2 | 10.53 | 19 | 100.00 | 5.075 | 0.024* |
Yes | 4 | 50.00 | 4 | 50.00 | 8 | 100.00 | ||
Total | 21 | 77.78 | 6 | 22.22 | 27 | 100.00 |
The introduction of cytoreductive surgery followed by intraperitoneal chemotherapy as a more aggressive approach has resulted in a favorable impact on survival in patients with PMP. The pathological process of PMP is a subclinical event in the majority of patients, and pathological diagnosis is commonly made after laparotomy. Most of patients included in our study were diagnosed outside NCI, and were referred with at least one previous laparotomy. PMP is generally 2 - 3 times more common in females. Chua et al. [
Improving the outcome of surgery requires careful patient selection through the proper preoperative investigations. However accurate assessment of preoperative PCI is not often possible. The surgical PCI score is considered a strong prognostic factor, as it helps to predict the chance to achieve complete cytoreduction, which directly affects patients’ morbidity and survival [
Most of patients with PMP have elevation in one or more of the serum tumor markers. However it is non-specific to diagnose PMP but it is considered significant and independent prognostic factor regarding disease free survival and overall survival. A 5 year overall survival of 91% was reported in patients with no elevation in preoperative tumor markers compared to 60.8% overall survival in patients with elevated tumor markers [
The most recent pathological classification of PMP is according to the WHO classification, categorized the disease to low grade and high grade mucinous adenocarcinoma [
The histopathological grade is considered an important prognostic factor regarding patients’ outcome, as patients with high grade tumor demonstrated invasive component and had poor outcome compared with those with low grade disease.
Survival was much better with low grade tumor than those with high grade tumor. So a non-invasive histopathology is extremely important in selecting patients who are most likely to benefit from this treatment strategy [
The pathological process is mostly subclinical, and may be an incidental finding during laparotomy. Symptoms of appendicitis, increased abdominal girth, and ovarian mass are the most common presentation. Abdominal pain, hernia and ascites are less common presentations [
To identify appropriate surgical candidates and to predict tumor resectability, it was extremely important to do preoperative imaging. A full contrast abdomino-pelvic CT can provide information about the extent of the disease and to estimate the radiological PCI. CT sensitivity varies from 60% to 90%, depending on the quality of CT, size of tumor nodules, the regions examined and the interpretation of the radiologist. However an accurate assessment of radiological PCI is often not possible as it is poor at detecting nodules less than 5mm so the presence of milliary disease is a common cause of underestimation of PCI [
Extent of the disease reported with PCI score is the most important factor in predicting resectability and hence there is a strong relation between the PCI and the chance to achieve complete cytoreduction that is directly related to survival. Studies reported that when PCI score is greater than 20 the 5 year survival rate is less than 10% and here it is recommended to avoid cytoreductive surgery and HIPEC in PCI score more than 20 [
The most frequently used regimens in HIPEC are; Mitomycin C/doxorubicin, perfused intraperitoneal for 90 minutes (Sugarbaker’s protocol) [
This study reported success to achieve complete cytoreduction that was combined with HIPEC in only 44% of patients who were planned for this treatment modality. The chemotherapeutic regimen we used was Mitomycin C alone heated to 42˚C and perfused through closed abdomen technique.
In a series of patients, Smeenk et al. [
All available studies regarding the role of systemic chemotherapy are retrospective and limited to unresectable disease. Sugarbaker et al. [
Cytoreductive surgery combined with HIPEC is a quite complicated operation that carries significant rates of morbidity and mortality. This risk is acceptable in such lethal disease. And so many studies reported variable rates of operative and post-operative complications. In a systematic review on the efficacy of cytoreductive surgery and perioperative intraperitoneal chemotherapy for PMP, reported overall morbidity rate varied from 33% to 56%. And overall mortality rate ranged from 0% to 18%. With mean hospital stay ranged from 26 to 29 days, and median hospital stay from 16 to 21 days [
The incidence of complications depended more on the extent of the disease, number of peritonectomy procedures, and time required to complete the cytoreduction, rather than as a direct association with the intraperitoneal chemotherapy administration [
Smeek et al. [
In this study we reported intraoperative complications developed in 29% of patients. Operative mortality was 22.2%. Among patients who had any trial for CRS and HIPEC, operative complications were significantly related to post-operative mortality, and overall survival. Comparing these results with the previously mentioned studies results showed that we have an average operative complications rate. However small number of patients stands against reporting significant results.
A two-step approach may be used by doing HIPEC five days after CRS as a trial to decrease operative morbidity. The delayed HIPEC offers a chance to avoid long operation time for the patient and the surgeon, and also a chance to diagnose complications related to CRS as anastomotic leak that can be treated before HIPEC. However the long ICU stay and the cost of two operations are disadvantages limiting its use. Moreover adhesions and fibrin barrier limits the chemotherapy penetration to the tumor decreasing its cytotoxicity [
Survival and progression of the disease depends on multiple prognostic factors including PCI score, completeness of cytoreduction, tumor histology, prior surgical score, and previous lines of chemotherapy. These results showed no difference in short term survival between serial debulking and HIPEC. This finding suggested that CRS and HIPEC do not cause dramatic improvement in survival within the first 5 years. However in the long-term the survival benefits become more apparent, as the natural history of the disease is moderately slow. However survival is not the only aspect that matters. As number of reoperations were higher for the debulking era group than those for HIPEC era group (1.6 vs. 0.8). Andreasson et al. 2012 [
Development of the combined CRS and HIPEC, as a treatment, has significantly improved outcomes of PMP, regarding survival and disease free survival. The outcome of treatment depends on numerous factors that affect prognosis, and lack of homogeneity between centers makes a comparison of results across various studies difficult, this makes prediction of factors for short-term outcomes unclear.
In a multicenter study, Elias et al. [
The follow up period in our study was quite short. The mean follow up period was 22.9 months, along with the small number of patients, were two factors against reporting significant results regarding treatment outcome. The learning curve in different centers regarding PMP treatment is extremely long as it depends on various factors including; the procedure itself, surgeons and the way they achieve their experience and proficiency which depends mainly on external observer based fellowships, and number of principal surgeons per center ‘centers with more than 3 principal surgeons were at higher risk of their performance getting worse over time [
A limitation of this study remains the small number of patients that affected the significance of our final results and conclusion. So the need for more centralization through continuous cooperation between other centers, by referring PMP patients to more expert and specialized centers. Along with continuous collection of data over a long period of years is considered necessary for stronger and significant conclusions.
In order to identify the most effective follow up regimen, research is ongoing to identify patients at higher risk of recurrence and the risk factors. However currently, recurrence is diagnosed when there is marked rise in tumor markers, or evidence of relapse with CT [
The post-operative follow up protocol we use is to do CT scan and tumor markers every 3 months in year one, then every 6 months in year 2 and 3, then annually, with PET/CT once per year. Patients, with mucinous neoplasms, should be followed for years to detect PMP in early stage. A minimal follow up for 5 years consisting of physical examination, tumor markers, CEA and CA 19-9 and CT scan once a year or when indicated is reasonable. This is because of the long latency time and indolent tumor behavior [
The outcome of PMP treatment process is extremely variable. Combined CRS and HIPEC is considered the best therapeutic approach for patients with PMP. Surgical experience combined with proper patient selection have to be built up together to improve the outcome. That could only be achieved through more centralization of patients’ treatment in specialized units or center.
Gad, Z., Nassar, O., Soliman, H., Mohamed, S. and Mohamed, M. (2018) Outcome of Management of Pseudomyxoma Peritonei: National Cancer Institute Experience. Journal of Cancer Therapy, 9, 323-337. https://doi.org/10.4236/jct.2018.94030