Cytoreductive Surgery and Intraperitoneal Hyperthermic Chemotherapy for Peritoneal Surface Malignancy: Non-Colorectal Indications

Cytoreductive Surgery and Intraperitoneal Hyperthermic Chemotherapy for Peritoneal Surface Malignancy: Non-Colorectal Indications isseminated malignant peritoneal surface disease (PSD) or “carcinomatosis” has traditionally and justifiably been approached with therapeutic nihilism. Patients typically progress to death due to bowel obstruction in less than a year.1 PSD results from intracavitary dissemination of tumor from a variety of primary pathologic lesions. Such findings are all too common for gastrointestinal and ovarian carcinomas, sarcoma, and mesothelioma. Frequently, PSD is confined to the peritoneal cavity without extra-abdominal disease. Thus, a regional approach for selected patients with PSD is reasonable. Beginning approximately 30 years ago, aggressive treatments of PSD were explored. Centers explored treatment options such as peritonectomy procedures,2 supplemented with intraperitoneal (IP) adjuvant therapies.3-5 Hyperthermic intraperitoneal chemotherapy (HIPEC) and early postoperative IP chemotherapy have emerged as the most commonly used IP adjuvants.6-8 Over the past decade, there has been ever-increasing interest in regional therapy for PSD. This has been further stimulated by publication of a prospective randomized trial for PSD from colorectal sources9 as well as recent successes with IP chemotherapy for PSD from ovarian cancer.10,11 The optimal management of patients with PSD from noncolonic sources is a matter of intense debate. Systemic chemotherapy for PSD from these lesions has improved in recent years, but remains limited, in part because of its limited entry into the peritoneum. The localization of tumor within the peritoneum without distant metastasis makes an aggressive regional approach appealing. Several groups have treated peritoneal surface extension of appendiceal tumors with debulking procedures.12-14 However, it is clear that these procedures are frequently unable to remove all microscopic tumors, thus making the use of IP adjuvants attractive.

D

Curr Probl Cancer 2009;33:168-193. 0147-0272/2009/$34.00 ⫹ 0 doi:10.1016/j.currproblcancer.2009.06.005

168

Curr Probl Cancer, May/June 2009

Our approach to selected patients with PSD has been to combine aggressive cytoreductive surgery (CS) (the goal being resection of all gross disease) with chemoperfusion to address microscopic residual disease. A chemotherapy perfusion done at the same time as CS has several advantages over systemic therapy. First, the chemotherapy is delivered at a time when the disease is at its minimum (immediately after CS). Next, intracavitary chemotherapy achieves drug levels 20- to 1000-fold greater (depending on the agent used) than can be obtained with even the most ambitious intravenous administration. This may overcome relative intrinsic drug resistance. Further, following CS, all peritoneal surfaces are exposed, which allows for better drug distribution (vs postoperative) as all adhesions are lysed. Additionally, the single intraoperative dose eliminates significant compliance/tolerance issues encountered with postoperative administration of several cycles of treatment.10,11,15 We have previously reported our early experience8 and our expanded experience with 501 procedures, in addition to subsets of patients treated with CS and HIPEC for PSD from appendiceal,16,17 colorectal,18,19 gastric,20 and small bowel21 carcinomas as well as mesothelioma.22 This manuscript updates our experience and reviews relevant literature for noncolorectal patients PSD undergoing CS and HIPEC for PSD.

Methods Patients who underwent CS and HIPEC for PSD at Wake Forest University School of Medicine Baptist Hospital between December 1991 and April 2009 were identified from a prospective database. This database and analysis have been approved by the institutional review board at Wake Forest University. All patients were evaluated in the Surgical Oncology Clinics preoperatively. Evaluations included (at a minimum): a complete history, examination, pathologic review, computed tomography (CT) imaging, blood counts, and renal and liver functions. To be considered for CS and HIPEC, patients needed to have normal organ function (serum creatinine ⬍2 mg/dL, alkaline phosphatate and serum aspartate transaminase or alanine transaminase ⬍3 times the upper limit of normal, white blood cell count ⱖ4000/mm3, and platelet count ⱖ100,000 mm3). Evaluation of preoperative CT imaging focused on the absence of extra-abdominal metastasis, parenchymal hepatic metastasis (hepatic surface lesions allowed), bulky small bowel disease, multistation bowel obstruction, and ureteral or biliary obstruction. Tumors were categorized according to the primary site of origin. Prior to CS and Curr Probl Cancer, May/June 2009

169

HIPEC, patients had their pathology reviewed by the Wake Forest University Department of Pathology. This was compared with final pathology from specimens garnered at the time of CS to reach a final diagnosis for the database. Patients with bulky pelvic disease or multiple previous pelvic procedures were routinely considered for urological consultation for ureteral stent placement at the start of the procedure to facilitate retroperitoneal dissection. Clinical data on all patients were recorded in a database and maintained by a dedicated data management unit.

Cytoreductive Surgery The goal of CS was resection of all gross disease in all cases. CS consisted of the removal of gross tumor and involved organs, peritoneum, or tissue deemed technically feasible and safe for the patient. This included routine supracolic omentectomy in all cases where not previously performed. Peritonectomy procedures were performed as indicated.2 Any tumors adherent or invasive to structures that could not be removed were cytoreduced using the cavitational ultrasonic surgical aspirator (CUSA; Valleylab, Boulder, CO). The resection status of patients was judged after CS using the following classification: R0, complete removal of all visible tumor and negative cytologic findings or microscopic margins; R1, complete removal of all visible tumor and positive postperfusion cytologic findings or microscopic margins; R2a, minimal residual tumor, nodule(s) measuring 0.5 cm or less; R2b, gross residual tumor, nodule ⬎0.5 cm but ⱕ2 cm; and R2c, extensive disease remaining, nodules ⬎2 cm.

Intraperitoneal Hyperthermic Chemotherapy (HIPEC) After completion of CS, patients were passively cooled to a core temperature of approximately 34-35°C. This was accomplished by not warming airway gases or intravenous solutions and cooling the room. After CS was completed, peritoneal perfusion inflow and outflow catheters were placed percutaneously into the abdominal cavity. Temperature probes were placed on the inflow and outflow catheters just outside the exit sites from the abdomen. The abdominal skin incision was closed temporarily with a running cutaneous suture to prevent leakage of peritoneal perfusate (closed technique). A perfusion circuit was established with approximately 3 L of Ringer’s lactate. Flow rates of approximately 1 L/minute were maintained using a roller pump managed by the perfusionist. The circuit continued from the single roller pump, through a heat exchanger, and then to the patient. 170

Curr Probl Cancer, May/June 2009

Temperature was monitored at a core site as well as the perfusate going in and out of the fluid warmer. Once a stable perfusion circuit was established and outflow temperature exceeded 38.5°C, the chemotherapy was introduced into the perfusion circuit. A maximum inflow temperature of 42.5°C was tolerated during perfusion, with a target outflow temperature at the pelvis of 40°C. The abdomen was gently massaged throughout perfusion to improve drug distribution to all peritoneal surfaces. Total planned perfusion time after the initial addition of antineoplastic agent (most commonly mitomycin C [MMC]) was 120 minutes, although several chemotherapeutic agents were used. The MMC was dosed based on volume of perfusate necessary to establish a stable circuit at 10 mg/L of perfusate at the initiation of the HIPEC, and at 60 minutes, an additional 10 mg of MMC was added to keep MMC perfusate concentrations higher than 5 ␮g/mL. Dose reductions were given by decreasing the dose of agent and/or perfusion time at the discretion of the surgeon (such as elderly individuals, marrow depletion from extensive previous chemotherapy, etc). Other chemotherapeutic agents were also used based on primary tumor site and previous systemic therapy. Since 2004, we have used cisplatin, 250 mg/M2 in the perfusate with sodium thiosulfate (administered intravenously) for mesothelioma cases. Ovarian cases used cisplatin or carboplatin. Sarcoma cases (and GIST before the introduction of imatinib) were perfused with MMC ⫾ mitoxantrone.

Clinical Follow-Up Clinical follow-up occurred at 1 month and then at least every 6 months thereafter for up to 5 years. After 5 years from the last HIPEC, follow-up was annually. Blood counts, liver functions, and tumor markers (as appropriate), as well as abdominal and pelvic CT scans with oral and intravenous contrast, were obtained with each follow-up visit and when clinically indicated. Patients were typically followed jointly with medical oncologists. Some patients received systemic chemotherapy at the discretion of their medical oncologists.

Statistical Analysis All data were collected prospectively; descriptive statistics were generated for all measures, including means, ranges, and standard deviations for continuous measures and frequencies and proportions for categorical data. Overall survival (OS) was calculated from the date of CS and HIPEC to the last known date of follow-up or date of death. Estimates of survival were calculated using the Kaplan-Meier (product-limit) method; analysis using Cox proportional hazards was performed on all pertinent Curr Probl Cancer, May/June 2009

171

TABLE 1. Listing of organs resected as part of the CS in addition to peritoneal resections* Resected

N

Percent

Diaphragm Colon Rectum Small bowel Stomach Spleen Uterus Ovaries Gallbladder Pancreas Appendix Omentum Kidney Lung Liver Bladder

28 215 39 176 60 166 29 73 89 37 45 296 9 1 33 5

5.6 42.9 7.8 35.1 12.0 33.1 5.8 14.6 17.8 7.4 9.0 59.1 1.8 0.2 6.6 1.00

*Omentectomy (supracolic) was performed routinely if not previously resected (N ⫽ 501). Reprinted with permission from Levine et al: Cytoreductive surgery and intraperitoneal hyperthermic chemotherapy for peritoneal surface malignancy: experience with 501 procedures. J Am Coll Surg 2007;204(5):943–953.

clinicopathologic variables to determine each one’s association with survival. Group comparisons of OS were performed using the approximate ␹2 statistic for the log-rank test. Additionally, the Cox proportional hazards regression model was used in a stepwise fashion to perform a multivariate analysis of clinicopathologic factors to determine an overall model of independent predictors of OS. Statistical significance was defined as a P ⱕ 0.05.

Results Patients and Clinicopathologic Features A total of 734 HIPEC procedures were performed on 680 patients with peritoneal surface malignancy who underwent the procedures between December 30, 1991 and April 2009. The mean age was 53 (range 15-87 years of age) with a slight female preponderance. Second HIPEC was performed on approximately 10% of selected cases with recurrent/ persistent disease.23 Approximately 20% of patients had an ileostomy (12%) or colostomy (8%) created. The organs resected as part of the CS are listed in Table 1. The median hospital stay was 9 days with an average of 15.3 (⫾18) days. Most patients were admitted to the ICU with an average stay of 2 days. Performance status (ECOG scoring system) was 0 in 35%, 1 in 46%, 2 in 15%, 3 in 4%, and 4 in ⬍1%. 172

Curr Probl Cancer, May/June 2009

FIG 1. Overall survival (Kaplan-Maier) by primary tumor site, differences significant; P ⫽ 0.0001, N ⫽ 602.

FIG 2. Overall survival (Kaplan-Maier) by performance status, differences significant; P ⫽ 0.01. Curr Probl Cancer, May/June 2009

173

FIG 3. Overall survival (Kaplan-Maier) by resection status for gastric, small bowel, ovarian, and mesothelioma, differences significant; P ⫽ 0.0001.

Primary sites of origin for the patients were as follows: adrenal (0.2%), appendix (35.4%), colorectal (28.9%), gall bladder (0.7%), gastric (9.1%), gastrointestinal stromal tumor (2%), mesothelioma (6%), ovary (10%), pancreas (cystic neoplasm and IPMT) (1%), sarcoma 11 (2%), small bowel 6 (1%), urachal 5 (1%), and unknown (2%). The median survival (months) was significantly different by site of origin as follows: appendix 63.5, colorectal 16.4, gastric 6.1, mesothelioma 27.1, ovary 28.5, and sarcoma 28.1; P ⫽ 0.0001. For other histologic sites of origin, the series had too few cases for meaningful analysis. Our current results are shown in Figure 1. Performance status was a significant prognostic indicator for all patients undergoing HIPEC (Fig 2). The organs resected are in Table 1. The length of the operation ranged from 4 to 16 hours depending on the extent and location of disease, but averaged just under 10 hours. The quantity of residual disease was recorded by the primary surgeon and was scored according to the R status for residual disease.24 The resection status was a significant predictor of survival; P ⫽ 0.0001 (Fig 3). For the purposes of survival calculations, R0 and R1 were combined due to the difficulties clearly separating them in the setting of PSD. Our outcomes for patients treated with HIPEC for gastric, small bowel ovarian, and mesothelioma cancer are shown in Figures 4, 5, 6, and 7, respectively. 174

Curr Probl Cancer, May/June 2009

FIG 4. Overall survival (Kaplan-Maier) for gastric subset; N ⫽ 43.

FIG 5. Overall survival (Kaplan-Maier) for small bowel subset; N ⫽ 13.

Morbidity and Mortality The 30-day postoperative morbidity and mortality were approximately 43% and 4%, respectively. Wound infection, hematologic toxicity, sepsis, respiratory failure, anastomotic leak, pneumonia, and enterocutaneous fistula accounted for most of the postoperative complications in this cohort of patients. Curr Probl Cancer, May/June 2009

175

FIG 6. Overall survival (Kaplan-Maier) for ovarian subset; N ⫽ 50.

FIG 7. Overall survival (Kaplan-Maier) for mesothelioma subset; N ⫽ 40.

Survival and Follow-Up For the cohort (with a median follow-up of ⬎55 months), the median OS was 22.2 months. One-, three-, and five-year OS were 66.8%, 40.0%, and 27.8%, respectively (Fig 2). The survival rates include operative mortality. Figures 1, 2, and 7 depict the Kaplan-Maier actuarial survival 176

Curr Probl Cancer, May/June 2009

TABLE 2. Univariate and multivariate analysis of prognostic significance of clinicopathologic variables, based on stepwise regression analysis Univariate variables Race Dose of MMC Resection status Sex Complications Length of operation Previous CS and HIPEC Age Temperature of perfusate Length of chemotherapy Primary tumor histology (site) Performance status Multivariate variables Resection status Performance status Primary tumor histology (site) Complications

0.87 0.82 0.0001 0.24 0.002 0.12 0.006 0.19 0.80 0.22 0.0007 0.0001 0.001 0.0012 0.0001 0.0006

Reprinted with permission from Levine et al: Cytoreductive surgery and intraperitoneal hyperthermic chemotherapy for peritoneal surface malignancy: experience with 501 procedures. J Am Coll Surg 2007;204(5):943–953.

curves for these factors. Kaplan-Maier plots for patients treated with HIPEC for mesothelioma, gastric, small bowel, and ovarian cancer are shown in Figures 3, 4, 5, and 6, respectively. Table 2 shows univariate and multivariate analysis of factors related to outcomes for HIPEC.

Discussion PSD represents a substantial challenge for patients and physicians alike. The experience with CS and HIPEC is now rich for PSD originating from appendiceal and colorectal sites. Most centers (ours included) have most such cases related to these sites of origin. However, there is significantly less data available for noncolorectal sources. The following discussion reviews our experience, current approaches, and relevant literature. CS and HIPEC represent a substantial operative undertaking for both patient and surgeon. Average operative times are approximately 10 hours followed by long ICU and hospital stays, which consume substantial resources. Morbidity and mortality is significant; therefore, straight forward preoperative discussions with the patient and family are mandatory. However, properly selected patients have a real chance at long-term survival, which is rarely, if ever, realized without such aggressive efforts. PSD arising from cancers of the appendix, colon or ovary, and mesothelioma have the best outcomes. We have avoided addressing PSD from Curr Probl Cancer, May/June 2009

177

hepatic biliary, pancreatic sources principally due to difficulty in obtaining control of the primary lesion. Systemic chemotherapy for peritoneal surface malignancies is limited in effect by its limited entry into the peritoneum. Any systemic chemotherapy for IP disease must overcome the plasma–peritoneal partition. Pharmacokinetic studies have confirmed the presence of this peritoneal– plasma partition by demonstrating that drugs delivered into the peritoneal cavity have a clearance that is inversely proportional to the square root of its molecular weight.25-27 The addition of IP chemotherapy can be viewed as a tool to overcome this drug resistance as well as toxicity associated with systemic administration. Due to this partition, drugs without lipophilic properties and high molecular weights have optimal characteristics for IP application. The pharmacokinetic advantage of IP perfusion can be seen by the area under the curve ratios of peritoneal fluid to plasma that favor retention of drug in the peritoneum.28-35 In addition to the pharmacokinetic advantage that IP chemotherapy infusion after maximal tumor debulking offers, the addition of hyperthermia affects cell membranes, cytoskeletons, synthesis of macromolecules, and DNA repair mechanisms.36,37 Many institutions, including this one, have used primarily MMC. The synergy between MMC and hyperthermia occurs independent of the cell cycle, thus allowing for significant tumoricidal activity with brief exposures.38-40 In this study we evaluated various clinical, treatment, and pathologic characteristics that potentially impact survival for patients undergoing CS and HIPEC with MMC for peritoneal surface neoplasms. Pathologic characteristics clearly impact the clinical outcomes of patients with PSD. For appendiceal tumors, surgical series, patients with low grade mucinous carcinoma peritonei (which is also described as disseminated peritoneal adenomucinosis or pseudomyxoma peritonei [PMP]) experience better clinical outcomes than those with higher grade nonmucinous appendiceal malignancies.41-47 In this study, the survival rate in patients with high-grade lesions was significantly lower than for the low-grade PSD. This is not an unexpected finding based on the biological and molecular differences between low- and high-grade nonmucinous appendiceal tumors.16,17 PMP has been considered the classic indication for HIPEC. Five-year survival after HIPEC for PMP has ranged from 66% to 97%, and our experience is consistent with those results.43-46 Patients undergoing complete CS before HIPEC had superior outcomes compared with those who underwent incomplete CS regardless of site of the primary lesion. The 3-year survival rate for patients with a R0/1 178

Curr Probl Cancer, May/June 2009

resection was 59.9% ⫾ 3.9%, whereas 3-year survival for R2a, R2b, and R2c resections was 38.7% ⫾ 5.3%, 15.0% ⫾ 5.3%, and 14.0% ⫾ 4.2%, respectively (P ⫽ 0.0001). This finding confirms data from our institution, and others, that demonstrate a significant survival advantage for patients undergoing R0/R1 resection compared with those with R2 resections.18,48-50 In a review of 506 patients, Glehen and coworkers analyzed the survival of patients with peritoneal surface malignancies from colorectal primary tumors undergoing incomplete CS followed by HIPEC, and found that this treatment paradigm resulted in limited long-term survival. Patients who are unable to undergo significant CS (R2a or better) at laparotomy may be spared the potential toxicity of HIPEC. Whereas the above are generally applicable to patients undergoing CS and HIPEC from any source of PSD, the following discussion will focus on noncolorectal sources.

Gastric Cancer Gastric cancer accounts for nearly 10% of new cancer diagnoses and is the second leading cause of cancer-related mortality worldwide.51 PSD is a common cause of death in patients with gastric carcinoma, as well as other gastrointestinal malignancies.52-55 Its development is invariably fatal.22,55-58 Advanced disease is often present at the time the primary tumor is diagnosed22,59,60; even when curative gastrectomy is performed, peritoneal recurrence develops in nearly 50% of patients.53,54,59,61 The median survival in this patient population ranges from 2.2 to 8.8 months,52 with a 5-year survival of 0%.55,56 Although there have been randomized trials that have shown benefit for chemotherapy or chemoradiotherapy in the adjuvant setting, PSD remains a key site of failure.62,63 Therefore, aggressive therapy aimed at preventing PSD from gastric cancer is relevant and needed. Decades ago, it was found that PSD from gastric sources may occur following curative resection.56-59,61,64-66 The etiology of the PSD is thought to be sloughing of cells from the surface of tumors that have invaded the serosa of the stomach to account for most peritoneal metastasis.52,59,61 It has been shown that the area of serosal tumor invasion is positively correlated with the detection rate of IP free cancer cells.64 Further, simple irrigation with saline solution has been shown to be ineffective in removing any neoplastic cells that may have contaminated the peritoneal cavity during the course of surgery.56 IP instillation of chemotherapy has been shown to prevent the development of peritoneal carcinomatosis after implantation of neoplastic cells in an animal model.61 When instilled directly into the peritoneal cavity, peak tissue Curr Probl Cancer, May/June 2009

179

concentrations of agent are much higher than those attained through the intravenous route.66 Current options for the treatment of peritoneal recurrences are limited. In large randomized trials, neither intravenous chemotherapy nor radiation has been shown significant survival advantage for this disease.59 Although systemic chemotherapy improved since the turn of the century, it has limited efficacy against metastatic gastric cancer in general and PSD in particular. This may be due to poor penetration of agents given intravenously through the peritoneum. One recent Japanese study suggested that a combination of intravenous methotrexate and 5-fluorouracil was effective in alleviating the sequelae of peritoneal carcinomatosis; however, median survival time (9.2 months) was not substantially improved.65 The significant risk of PSD from gastric cancer has led to substantial literature using IP adjuvants for resectable (but without proven PSD) disease. HIPEC has been extensively studied in Japan.55,59,64,67 Several small, but prospective and randomized trials have been completed with conflicting results. A meta-analysis has been performed for adjuvant IP therapy for respectable gastric cancer.68 This analysis reveals a significant survival advantage for IP adjuvant therapy (HIPEC with and/or without EPIC) versus surgery alone. The hazard rate for survival was 0.60 with a 95% confidence interval of 0.43-0.83 (P ⫽ 0.002).68 However, no consistent decrease in peritoneal failure was found in these studies or the meta-analysis, and patients undergoing HIPEC (or similar type procedures) did have a higher complication rate after surgery.68 The results of the Medical Research Council trial adjuvant gastric infusional chemotherapy trial (also called the “MAGIC” trial) suggested that patients with operative gastric cancer benefit from perioperative systemic chemotherapy with epirubicin, cisplatin, and fluorouracil. Additionally, the Southwest Oncology Group trial 9008/Intergroup 0116 trial found that postoperative chemoradiotherapy significantly improved outcomes for patients with resected stage IB to III gastric cancer, and should be considered a standard of care. With proven adjuvant therapy now available for high-risk gastric cancer (without known peritoneal dissemination), how adjuvant HIPEC fits into current therapy is unclear. Patients with PSD from gastric cancer have also been investigated for CS and HIPEC type IP adjuvant therapy. Although there have been several reports, the results to date have been mixed.69-71 Perioperative morbidity is significant and complete cytoreduction is achieved in less than half of the cases. Long-term survival in most series is ⬍10% but has been reported to be as high as 27% in optimally cytoreduced patients 180

Curr Probl Cancer, May/June 2009

undergoing HIPEC.71 Median survival ranges from 10 to 23 months. These studies clearly show that complete cytoreduction correlates with longer survival, but highlight the limited efficacy of surgery with HIPEC in this setting. Consequently, based on our experience, we recommend that patients with PSD from gastric cancer be carefully selected for this procedure. Our current criteria include otherwise healthy patients with good preoperative functional status and no evidence of extraperitoneal or hepatic metastasis. Further, imaging should suggest that an R0/1 resection is possible. Patients with full thickness gastric wall resection without evidence of peritoneal carcinomatosis are also potential candidates. If an R1 resection cannot be achieved, one must have engaged in a discussion with the patient before surgery as to the patient’s wishes at this point. We do not recommend this procedure in a patient in whom resection of all gross disease is not possible. Although palliative resection in selected stage IV patients has been suggested to be of value, this is a decision that we feel is best made when both physician and patient understand both the limitations and implications of such procedures. A confirmatory prospective, randomized trial comparing resection with adjuvant HIPEC versus curative resection alone for less advanced gastric carcinoma (stage II and III) is needed to more fully evaluate this method of treatment for patients presenting with gastric cancer. However, with the recent data showing efficacy from adjuvant chemotherapy or chemoradiation, we do not believe such a study will be supported in the United States in the foreseeable future.

Small Bowel Small bowel carcinoma represents 1-3% of all gastrointestinal malignancies, with adenocarcinoma being the most frequent histologic variant.72-75 Approximately 2500 new cases are diagnosed each year in the United States.72 Typically, these tumors present after significant delays in diagnosis due to the vagueness of associated presenting symptoms and the difficulty of imaging to identify small bowel cancers at an early stage.72 Late identification of small bowel adenocarcinoma has contributed to its poor prognosis, which has been reported to be between 10 and 40 months, with a 5-year survival rate ranging from 10% to 45%, considering all stages at diagnosis.72 PSD has been identified as the most common form of disease progression for small bowel adenocarcinoma. However, local failure, abdominal wall recurrence, and hepatic metastases remain significant concerns as well.75 The rarity of small bowel carcinoma makes Curr Probl Cancer, May/June 2009

181

experience with PSD from this site extremely limited. The purpose of this study is to add data to the literature on the prognosis of PSD from small adenocarcinoma treated with CS and HIPEC. Our published series of six patients with PSD from a small bowel primary showed a median survival of 45.1 months after treatment with CS and HIPEC. This is a significant improvement from the median survival of only 3.1 months documented for patients with PSD originating from all nongynecologic malignancies who received only traditional treatment. Specifically, small bowel adenocarcinoma has a poor prognosis, regardless of progression to PSD. Additionally, the median survival of 45.1 months in this series is an improvement on previously reported median survival data of 12 months for PSD from small bowel adenocarcinoma after treatment with CS and HIPEC.76 The only other study on the topic we are aware of is one by Marchettini and Sugarbaker (coincidentally also 6 patients) which recommended CS and HIPEC for small bowel adenocarcinoma with PSD, and these two series support that recommendation.76 There are, of course, limited conclusions that can be drawn from 2 series each with only 6 patients. However, we have updated our published experience with an additional 7 cases, bringing our total series to 13. The median survival is now 29.4 months in our experience. Despite these additional cases, it still remains difficult to determine the effects of systemic therapy treatments both before and after CS and HIPEC on OS. For example, half of our patients received systemic chemotherapy before CS and HIPEC, and half after. The rarity of small bowel carcinoma makes large clinical trials impractical. Currently, systemic therapy is largely extrapolated from the experience with colorectal cancer. Clearly, systemic therapy has a significant role in the treatment of patients with PSD from the small bowel, and newer agents hold promise (even if developed for colorectal cancer). Further, this experience with CS and HIPEC parallels that seen with PSD from colorectal cancer.19-21 Progression of small bowel adenocarcinoma to PSD portends a poor prognosis, and raises a difficult question in terms of treatment. Although much is still unknown on how best to treat patients with PSD, CS and HIPEC seem to be an effective and attractive option in a very difficult situation. The limited data suggest that CS and HIPEC should be considered in selected patients with PSD from small bowel adenocarcinoma. Our current approach is to initiate treatment with the best available systemic chemotherapy for no more than six cycles and then proceed with CS and HIPEC in patients who do not progress. 182

Curr Probl Cancer, May/June 2009

Ovarian Cancer There are approximately 26,600 new cases of ovarian carcinoma and 14,500 related deaths annually in the United States. Most patients have advanced disease at the time of diagnosis that remains confined to the peritoneal cavity for extended periods. Treatment involves surgical cytoreduction followed by systemic platinum-based chemotherapy. Although cisplatin was originally used in combination systemic therapy with paclitaxel, carboplatin has replaced cisplatin with equivalent efficacy and an improved toxicity profile.77 Three randomized prospective trials in optimally cytoreduced ovarian cancer have been performed comparing chemotherapy combinations incorporating cyclic IP cisplatin to systemic therapy alone. An improved progression-free interval and OS advantage were associated with IP therapy.78-80 In addition, carboplatin has also been evaluated as IP therapy with two phase II trials demonstrating a complete response rate of approximately 25% in patients with minimal residual disease after initial platinum-based therapy.81,82 The results of these trials suggest that IP (vs intravenous) chemotherapy yields superior outcomes. This led the National Cancer Institute to take the unusual step of declaring it the standard of care in 2006.10 The advantages of IP chemotherapy for ovarian cancer are clear for progression-free and OS. However, this advantage is at the cost of triple the infection and thrombocytopenia rates, with higher rates of neutropenia and lower rates of completing therapy.10 It is notable that only 42% of patients randomized to receive IP chemotherapy actually received it.10 This low rate of tolerability makes HIPEC an attractive modality for patients with PSD from ovarian cancer. There has not been a randomized trial that compared conventional IP chemotherapy for resected ovarian cancer to HIPEC. Approximately 400 cases of HIPEC have now been reported in the world with literature from over 20 centers. The reported studies are mostly small, containing heterogeneous populations, and the data are often difficult to interpret.83 Clearly, with randomized trials showing advantages to IP chemotherapy, this should be the standard of care. However, there remains a potential role for HIPEC in this setting. Specifically, patients being considered for adjuvant therapy or who are unlikely or unwilling to be able to complete IP therapy may be well served with HIPEC (with systemic therapy). Further, patients who recur or progress on IP therapy and have disease limited to the abdomen which is amenable to CS, and retain a good performance status, may be candidates for HIPEC with secondary cytoreduction. Curr Probl Cancer, May/June 2009

183

When HIPEC is considered for PSD from ovarian sources, the optimal agent is unclear. MMC and cisplatin have been reported from several centers.83 We recently published a phase I trial evaluating carboplatin as the agent in the perfusate for HIPEC.84 This found no maximally tolerated dose, but suggested a dose of, 1000 mg/M2, and this has become our standard agent and dose for ovarian HIPEC. Our survival of ⬃25% at 5 years of follow-up is quite competitive with results from other centers treating predominantly platinum-resistant recurrent disease.83,85 Clearly, much work remains to be done with HIPEC in consideration of PSD from ovarian cancer. Although large-scale randomized trials evaluating HIPEC in this setting are not underway, cooperative groups should definitely consider them.

Mesothelioma Malignant mesothelioma is a rare, aggressive malignancy that arises from mesothelial surfaces such as the pleura, peritoneum, and the pericardium. It is more common in males (M:F ratio of 4:1) and classically affects middle-aged to elderly patients with a mean age of 58.86 Its occurrence has been linked to asbestos exposure since 1960, although its role in peritoneal mesothelioma is less clear.87 The specific role of additional cofactors, such as simian virus 40, has yet to be determined. Although its incidence in the United States has likely peaked at 15 cases per million people per year, the worldwide incidence of malignant mesothelioma continues to rise and is not expected to peak for another 15-20 years.88 Malignant mesothelioma is a rapidly fatal disease, and if left untreated, survival rarely extends past a year. Traditional therapies such as palliative surgery, systemic chemotherapy, and whole body radiation offer little, if any, survival benefit.89-92 Approximately 20% of malignant mesothelioma arises from the peritoneal cavity. Patients with malignant peritoneal mesothelioma (MPM) most often present with abdominal distension, ascites, abdominal pain, weight loss, and/or bowel obstruction, and widespread peritoneal dissemination is common at the time the patient is diagnosed.93 Over the past 10-15 years, CS combined with perioperative IP chemotherapy has been shown to improve survival and provide a potential cure in some patients with MPM. Mitomycin, cisplatin, doxorubicin, paclitaxel, and 5-FU have been used intraperitoneally to treat MPM as an adjunct to CS; however, the most efficacious perioperative chemotherapy regimen has yet to be determined. Primary peritoneal mesothelioma is a much less common entity than the pleural malignancy, with only a few hundred cases expected in the United 184

Curr Probl Cancer, May/June 2009

States annually. Although the molecular characteristics of peritoneal disease differ only slightly from the pleural disease, the clinical courses are disparate.88,94 Peritoneal disease typically presents with ascites, abdominal pain, and eventually bowel obstruction. The disease tends to remain within the abdominal cavity until late in the course, and distant metastasis is distinctly uncommon, thus making this an excellent candidate for CS and HIPEC. We and others have previously reported experience with this modality,22,95-97 which represents a great improvement over best systemic therapy.22,88,95-97 In our initial report, we used MMC as the agent,22 but have changed to cisplatin after the reports from the surgery branch of the National Cancer Institute.95,96 In a recent meta-analysis combining results from 7 studies, the clinical outcomes of 240 patients who received CS plus perioperative IP chemotherapy were reported. Median survival in these studies ranged from 34 to 92 months with 5-year survival rates ranging from 29% to 59%.98 We believe that mesothelioma represents one of the strongest cases for combining HIPEC with CS.

Conclusions PSD represents a substantial oncological problem, which can be addressed with CS and HIPEC. It is estimated that only a handful of patients who are potential candidates for this therapy actually receive it, which is underscored by the relatively small number of patients accrued to the phase II studies for peritoneal carcinomatosis at large “perfusion centers.” It is clear that expanding the number of centers should be done by surgical oncologists who have more than a passing knowledge of systemic chemotherapy and are comfortable with the rigors of aggressive operative procedures in the abdomen.23 This has led to a consensus statement by a group of surgeons with an interest in CS and HIPEC which outlines an evaluation strategy for PSD from colorectal carcinoma.98 While reported results from “perfusion centers” represent a substantial improvement in duration and likely quality of life,99-101 most patients undergoing these procedures will experience tumor recurrence. Evaluating patients for second cytoreduction and additional chemoperfusion will become an ever more common problem as patients with PMP often require multiple procedures.23,102 We, and others, believe that in selected patients, a second cytoreductive procedure and chemoperfusion may be of value. In evaluating patients for second cytoreduction, the same criteria that are used to select patients for the first remain important. Specifically, the patients must remain medically fit to tolerate a major operative procedure, be free of extra-abdominal parenchymal metastases, and have Curr Probl Cancer, May/June 2009

185

disease that seems amenable to complete cytoreduction. Additionally, the time to recurrence after initial cytoreduction and the completeness of the initial cytoreduction should be considered in deciding to proceed with another procedure. Patients with bulk residual disease after an initial cytoreduction for PSD should not be considered candidates for second cytoreductive procedures.23,102 Several issues surround the future of CS and HIPEC for PSD. Chief among them is how to make such therapy standardized and available to large numbers of patients. At present there are approximately 50 active centers in the United States and less than a dozen with experience of greater than 100 cases. The operative procedures required for aggressive cytoreduction are lengthy, challenging, morbid, and use a great deal of hospital, blood bank, and surgical house officer resources. Resource use (and safety) of chemotherapy in the operating room is a significant concern for many centers. Additionally, great care needs to be taken in selecting patients to undergo this procedure, and there is a learning curve for surgeons/centers that impacts outcome. Further, for most primary site tumors, the optimal time, dose, temperature, and chemotherapeutic agents for perfusion are not based on class I data. Fundamental questions regarding HIPEC for PSD need to be addressed. Foremost among these is whether the addition of HIPEC after CS is of value. Obviously, the value of HIPEC depends on the tumor being treated. There are only completed randomized trials for CS and HIPEC evaluated patients with PSD from colorectal and gastric primary lesions. That trial compared CS and HIPEC with standard systemic chemotherapy to standard systemic therapy (fluorouracil and leucovorin) and found the CS and HIPEC doubled the survival.9 Clearly, it would be desirable to evaluate the value of HIPEC versus CS alone, in a multicenter prospective randomized trial. However, such randomized controlled trials have proven difficult to complete and efforts have previously failed.103 Specifically, many patients presenting themselves for evaluation to specialized centers refuse to consider such a randomization.103 Efforts to bring CS and HIPEC to multicenter trials have not been embraced by the cooperative oncology groups to date. Such difficulties in performing randomized trials do not mean they should not be pursued. The advancement of centers of excellence as well as the initiation of cooperative group trials will help to define the optimal treatment approach for peritoneal spread for PSD. The future of CS and HIPEC for PSD lies in a multi-center and randomized trials that not only investigate response and survival, but also standardization of techniques, quality of life, and integration with ever-improving systemic therapy. 186

Curr Probl Cancer, May/June 2009

Acknowledgments We wish to acknowledge the substantial contributions of house officers, perfusionists, nurses, enterostomal therapists, psychosocial oncologists, urologists, and radiologists who contributed to the care of these patients. We would also like to thank Joan Feder for her editorial support and Mary Cromer for her ongoing support of the database.

REFERENCES 1. Sadeghi B, Arvieux C, Glehen O, Beaujard AC, Rivoire M, Baulieux J, et al. Peritoneal carcinomatosis from non-gynecologic malignancies: results of the EVOCAPE 1 multicentric prospective study. Cancer 2000;88:358-63. 2. Sugarbaker PH. Peritonectomy procedures. Ann Surg 1995;221:29-42. 3. Torisu M, Katano M, Kimura Y, Itoh H, Takesue M. New approach to management of malignant ascites with a streptococcal preparation OK 432. I. Improvement of host immunity and prolongation of survival. Surgery 1983;93:357-64. 4. Hendren SK, Hahn SM, Spitz FR, Bauer TW, Rubin SC, Zhu T, et al. Phase II trial of debulking surgery and photodynamic therapy for disseminated intraperitoneal tumors. Ann Surg Oncol 2001;8:65-71. 5. Sindelar WF, DeLaney TF, Tochner Z, Thomas GF, Dachoswki LJ, Smith PD, et al. Technique of photodynamic therapy for disseminated intraperitoneal malignant neoplasms. Phase I study. Arch Surg 1991;126:318-24. 6. Sugarbaker PH, Jablonski KA. Prognostic features of 51 colorectal and 130 appendiceal cancer patients with peritoneal carcinomatosis treated by cytoreductive surgery and intraperitoneal chemotherapy. Ann Surg 1995;221:124-32. 7. Beaujard AC, Glehen O, Caillot JL, Francois Y, Bienvenu J, Panteix G, et al. Intraperitoneal chemohyperthermia with mitomycin C for digestive tract cancer patients with peritoneal carcinomatosis. Cancer 2000;88:2512-9. 8. Loggie BW, Fleming RA, McQuellon RP, Russell GB, Geisinger KR. Cytoreductive surgery with intraperitoneal hyperthermic chemotherapy for disseminated peritoneal cancer of gastrointestinal origin. Am Surg 2000;66:561-8. 9. Verwaal VJ, van Ruth S, de Bree E, van Sloothen GW, van Tinteren H, Boot H. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol 2003;21:3737-43. 10. Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006; 354:34-43. 11. Markman M, Walker JL. Intraperitoneal chemotherapy in ovarian cancer: a review, with a focus on practical aspects of treatment. J Clin Oncol 2006; 24:988-94. 12. Miner TJ, Shia J, Jaques DP, Klimstra DS, Brennan MF, Coit DG. Long-term survival following treatment of pseudomyxoma peritonei: an analysis of surgical therapy. Ann Surg 2005;241:300-8. 13. Gough DB, Donohue JH, Schutt AJ, Gonchoroff N, Goellner JR, Wilson TO, et al. Pseudomyxoma peritonei. Long-term patient survival with an aggressive regional approach. Ann Surg 1994;219:112-9. Curr Probl Cancer, May/June 2009

187

14. Hinson FL, Ambrose NS. Pseudomyxoma peritonei. Br J Surg 1998;85:1332-9. 15. Cannistra SA. Intraperitoneal chemotherapy comes of age. N Engl J Med 2006;354:77-9. 16. Stewart JH, Shen P, Russell GB, Bradley RF, Hundley JC, Loggie BW, et al. Appendiceal neoplasms with peritoneal dissemination: outcomes after cytoreductive surgery and intraperitoneal hyperthermic chemotherapy. Ann Surg Oncol 2006;13:624-34. 17. Bradley RF, Stewart JH, Russell G, Levine EA, Geisinger KR. Pseudomyxoma peritonei of appendiceal origin: a clinicopathologic analysis of 101 uniformly treated patients at a single institution, with literature review. Am J Surg Pathol 2006;30:551-9. 18. Shen P, Levine EA, Hall J, Case D, Russell G, Fleming R, et al. Factors predicting survival after intraperitoneal hyperthermic chemotherapy with mitomycin C after cytoreductive surgery for patients with peritoneal carcinomatosis. Arch Surg 2003;138:26-33. 19. Shen P, Hawksworth J, Lovato J, Loggie BW, Geisinger KR, Fleming RA, et al. Cytoreductive surgery and intraperitoneal hyperthermic chemotherapy with mitomycin C for peritoneal carcinomatosis from nonappendiceal colorectal carcinoma. Ann Surg Oncol 2004;11:178-86. 20. Hall JJ, Loggie BW, Shen P, Beamer S, Case LD, McQuellon R, et al. Cytoreductive surgery with intraperitoneal hyperthermic chemotherapy for advanced gastric cancer. J Gastrointest Surg 2004;8:454-63. 21. Jacks SP, Hundley JC, Shen P, Russell GB, Levine EA. Cytoreductive surgery and intraperitoneal hyperthermic chemotherapy for peritoneal carcinomatosis from small bowel adenocarcinoma. J Surg Oncol 2005;91:112-7. 22. Loggie BW, Fleming RA, McQuellon RP, Russell GB, Geisinger KR, Levine EA. Prospective trial for the treatment of malignant peritoneal mesothelioma. Am Surg 2001;67:999-1003. 23. Levine EA. Problems of success and problems of failure: recurrent disease after cytoreductive surgery and intraperitoneal chemoperfusion. Ann Surg Oncol 2004; 11:351-3. 24. AJCC. Cancer Staging Manual, 6th edn. New York, NY: Springer-Verlag, 2002. 25. Dedrick RL, Flessner MF. Pharmacokinetic problems in peritoneal drug administration: tissue penetration and surface exposure. J Natl Cancer Inst 1997;89:480-7. 26. Dedrick RL. Interspecies scaling of regional drug delivery. J Pharmacol Sci 1986;75:1047-52. 27. Flessner MF, Dedrick RL, Schultz JS. A distributed model of peritoneal-plasma transport: analysis of experimental data in the rat. Am J Physiol 1985;248:F413-24. 28. Kuzuya T, Yamauchi M, Ito A, Hasegawa M, Hasegawa T, Nabeshima T. Pharmacokinetic characteristics of 5-fluorouracil and mitomycin C in intraperitoneal chemotherapy. J Pharm Pharmacol 1994;46:685-9. 29. Speyer JL, Collins JM, Dedrick RL, Brennan MF, Buckpitt AR, Londer H, et al. Phase I and pharmacological studies of 5-fluorouracil administered intraperitoneally. Cancer Res 1980;40:567-72. 30. Israel VK, Jiang C, Muggia FM, Tulpule A, Jeffers S, Leichman L, et al. Intraperitoneal 5-fluoro-2=-deoxyuridine (FUDR) and (S)-leucovorin for disease 188

Curr Probl Cancer, May/June 2009

predominantly confined to the peritoneal cavity: a pharmacokinetic and toxicity study. Cancer Chemother Pharmacol 1995;37:32-8. 31. Ozols RF, Young RC, Speyer JL, Sugarbaker PH, Greene R, Jenkins J, et al. Phase I and pharmacological studies of adriamycin administered intraperitoneally to patients with ovarian cancer. Cancer Res 1982;42:4265-9. 32. Bartlett DL, Buell JF, Libutti SK, Reed E, Lee KB, Figg WD, et al. A phase I trial of continuous hyperthermic peritoneal perfusion with tumor necrosis factor and cisplatin in the treatment of peritoneal carcinomatosis. Cancer 1998; 83:1251-61. 33. Markman M, Kelsen D. Efficacy of cisplatin-based intraperitoneal chemotherapy as treatment of malignant peritoneal mesothelioma. J Cancer Res Clin Oncol 1992; 118:547-50. 34. Markman M, Brady MF, Spirtos NM, Hanjani P, Rubin SC. Phase II trial of intraperitoneal paclitaxel in carcinoma of the ovary, tube, and peritoneum: a Gynecologic Oncology Group study. J Clin Oncol 1998;16:2620-4. 35. Stewart JH, Shen P, Russell G, Fenstermaker J, McWilliams L, Coldrun FM, et al. A phase I trial of intraperitoneal hyperthermic chemoperfusion for the treatment of peritoneal surface dissemination of colorectal and appendiceal cancers. Ann Surg Oncol 2008;15:2137-45. 36. Dikomey E, Franzke J. Effect of heat on induction and repair of DNA strand breaks in X-irradiated CHO cells. Int J Radiat Biol 1992;61:221-33. 37. Roti JL, Kampinga HH, Malyapa RS, Wright WD, vander Waal RP, Xu M. Nuclear matrix as a target for hyperthermic killing of cancer cells. Cell Stress Chaperones 1998;3:245-55. 38. Barlogie B, Corry PM, Drewinko B. In vitro thermochemotherapy of human colon cancer cells with cis-dichlorodiammineplatinum(II) and mitomycin C. Cancer Res 1980;40:1165-8. 39. Jacquet P, Averbach A, Stuart OA, Chang D, Sugarbaker PH. Hyperthermic intraperitoneal doxorubicin: pharmacokinetics, metabolism and tissue distribution in a rat model. Cancer Chemother Pharmacol 1998;41:147-54. 40. Los G, Smals OA, van Vugt MJ, van der Vlist M, den Englase L, McVie JG, et al. A rationale for carboplatin treatment and abdominal hyperthermia in cancers restricted to the peritoneal cavity. Cancer Res 1992;52:1252-8. 41. van Ruth S, Acherman YI, van de Vijver MJ, Hart AA, Verwaal VJ, Zoetmulder FA. Pseudomyxoma peritonei: a review of 62 cases. Eur J Surg Oncol 2003; 29:682-8. 42. Glehen O, Mohamed F, Gilly FN. Peritoneal carcinomatosis from digestive tract cancer: new management by cytoreductive surgery and intraperitoneal chemohyperthermia. Lancet Oncol 2004;5:219-28. 43. Sugarbaker PH, Chang D. Results of treatment of 385 patients with peritoneal surface spread of appendiceal malignancy. Ann Surg Oncol 1999;6:727-31. 44. Witkamp AJ, de Bree E, Kaag MM, van Slooten GW, van Coevorden F, Zoetmulder FA. Extensive surgical cytoreduction and intraoperative hyperthermic intraperitoneal chemotherapy in patients with pseudomyxoma peritonei. Br J Surg 2001;88:458-63. Curr Probl Cancer, May/June 2009

189

45. Elias D, Laurent S, Antoun S, Duvillard P, Ducreux M, Pocard M, et al. Pseudomyxoma peritonei treated with complete resection and immediate intraperitoneal chemotherapy. Gastroenterol Clin Biol 2003;27:407-12. 46. Deraco M, Baratti D, Inglese MG, Allaria B, Andreola S, Gavazzi C, et al. Peritonectomy and intraperitoneal hyperthermic perfusion (IPHP): a strategy that has confirmed its efficacy in patients with pseudomyxoma peritonei. Ann Surg Oncol 2004;11:393-8. 47. Culliford AT, Brooks AD, Sharma S, Saltz LB, Schwartz GK, O’Reilly EM, et al. Surgical debulking and intraperitoneal chemotherapy for established peritoneal metastases from colon and appendix cancer. Ann Surg Oncol 2001;8:787-95. 48. Marcus EA, Weber TK, Rodriguez-Bigas MA, Driscoll D, Meropol NJ, Petrelli NJ. Prognostic factors affecting survival in patients with colorectal carcinomatosis. Cancer Invest 1999;17:249-52. 49. Glehen O, Kwiakowski F, Sugarbaker PH, Elias D, Levine EA, de Simone M, et al. Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis from colorectal cancer: a multi-institutional study. J Clin Oncol 2004;22(16):3284-92. 50. Esquivel J, Sugarbaker P, Sticca R, Levine EA, Yan TD, Alexander R, et al. Consensus statement for cytoreductive surgery and intraperitoneal chemotherapy for colorectal carcinoma. Ann Surg Oncol 2007;14:128-33. 51. Kelly JR, Duggan JM. Gastric cancer epidemiology and risk factors. J Clin Epidemiol 2003;56:1-9. 52. Pilati P, Rossi CR, Mocellin S, Foletto M, Scagnet B, Pasetto L, et al. Multimodal treatment of peritoneal carcinomatosis and sarcomatosis. Eur J Surg Oncol 2001;27:125-34. 53. Koga S, Hamazoe R, Maeta M, Shimizu N, Murakami A, Wakatsuki T. Prophylactic therapy for peritoneal recurrence of gastric cancer by continuous hyperthermic peritoneal perfusion with mitomycin C. Cancer 1988;61:232-7. 54. Fujimoto S, Takahashi M, Mutou T, Kobayashi K, Toyosawa T. Successful intraperitoneal hyperthermic chemoperfusion for the prevention of postoperative peritoneal recurrence in patients with advanced gastric carcinoma. Cancer 1999; 85:529. 55. Yonemura Y, Fujimura T, Nishimura G, Falla R, Sawa T, Katayama K, et al. Effects of intraoperative chemohyperthermia in patients with gastric cancer with peritoneal dissemination. Surgery 1996;119:437-44. 56. Elias D, Blot F, El Otmany A, Antoun S, Lasser P, Boige V, et al. Curative treatment of peritoneal carcinomatosis arising from colorectal cancer by complete resection and intraperitoneal chemotherapy. Cancer 2001;92:71-6. 57. Sayag-Beaujard AC, Francois Y, Glehen O, Sadeghi-Looyeh B, Bienvenu J, Panteix G, et al. Intraperitoneal chemohyperthermia with mitomycin C for gastric cancer patients with peritoneal carcinomatosis. Anticancer Res 1999;19:1375-82. 58. Fujimura T, Yonemura Y, Fushida S, Urade M, Takegawa S, Kamata T, et al. Continuous hyperthermic peritoneal perfusion for the treatment of peritoneal dissemination in gastric cancers and subsequent second-look operation. Cancer 1990;65:65-71. 59. Yu W, Whang I, Chung HY, Averbach A, Sugarbaker PH. Indications for early postoperative intraperitoneal chemotherapy of advanced gastric cancer: results of a prospective randomized trial. World J Surg 2001;25:985-90. 190

Curr Probl Cancer, May/June 2009

60. Blair SL, Chu DZJ, Schwarz RE. Outcome of palliative operations for malignant bowel obstruction in patients with peritoneal carcinomatosis from nongynecological cancer. Ann Surg Oncol 2001;8:632-7. 61. Hribaschek A, Kuhn R, Pross M, Lippert H, Halangk W, Boltze C, et al. Prophylaxis of peritoneal carcinomatosis in experimental investigations. Int J Colorectal Dis 2001;16(5):340-5. 62. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:11-20. 63. MacDonald JS, Smalley R, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001;345: 725-9. 64. Kaibara N, Hamazoe R, Iitsuka Y, Maeta M, Koga S. Hyperthermic peritoneal perfusion combined with anticancer chemotherapy as prophylactic treatment of peritoneal recurrence of gastric cancer. Hepatogastroenterology 1989;36:75-8. 65. Tahara M, Ohtsu A, Boku N, Nagashima F, Muto M, Sano Y, et al. Sequential methotrexate and 5-fluorouracil therapy for gastric cancer patients with peritoneal dissemination: a retrospective study. Gastric Cancer 2001;4:212-8. 66. Yonemura Y, Ninomiya I, Kaji M, Sugiyama K, Fujimura K, Sawa T, et al. Prophylaxis with intraperitoneal chemohyperthermia against peritoneal recurrence of serosal invasion-positive gastric cancer. World J Surg 1995;19:450-5. 67. Nomura E, Niki M, Fujii K, Shinohara H, Nishiguchi K, Sonoda T, et al. Efficacy of intraperitoneal and intravenous chemotherapy and left upper abdominal evisceration for advanced gastric cancer. Gastric Cancer 2001;4:75-82. 68. Yan TD, Black D, Sugarbaker PH, Zhu J, Yoneura Y, Petrou G, et al. A systematic review and meta-analysis of the randomized controlled trials on adjuvant intraperitoneal chemotherapy for resectable gastric cancer. Ann Surg Oncol 2007;14:2702-13. 69. Farma JM, Pingpank JF, Libutti SK, Bartlett DL, Ohl S, Beresneva T, et al. Limited survival in patients with carcinomatosis from foregut malignancies after cytoreduction and continuous hyperthermic peritoneal perfusion. J Gastrointest Surg 2005;9:1346-53. 70. Glehen O, Schreiber V, Cotte E, Syag-Beaujard AC, Osinsky D, Freyer G, et al. Cytoreductive surgery and intraperitoneal chemohyperthermia for peritoneal carcinomatosis arising from gastric cancer. Arch Surg 2004;139:20-6. 71. Yonemura Y, Kawamura T, Bandou E, Takahashi S, Sawa T, Matuski N. Treatment of peritoneal dissemination from gastric cancer by peritonectomy and chemohyperthemic peritoneal perfusion. Br J Surg 2005;92:370-5. 72. Talamonti MS, Goetz LH, Rao S, Joehl RJ. Primary cancers of the small bowel: analysis of prognostic factors and results of surgical management. Arch Surg 2002;137:564-70. 73. Brucher BL, Roder JD, Fink U, Stein HJ, Busch R, Siewert JR. Prognostic factors in resected primary small bowel tumors. Digest Surg 1998;15:42-51. 74. North JH, Pack MS. Malignant tumors of the small intestine: a review of 144 cases. Am Surg 2000;66:46-51. 75. Frost DB, Mercado PD, Tyrell JS. Small bowel cancer: a 30-year review. Ann Surg Oncol 1994;1:290-5. Curr Probl Cancer, May/June 2009

191

76. Marchettini P, Sugarbaker PH. Mucinous adenocarcinoma of the small bowel with peritoneal seeding. Eur J Surg Oncol 2002;28:19-23. 77. Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 2003;21:3194-200. 78. Alberts DS, Lui PY, Hannigan EV, O’Toole R, Williams SD, Young JA, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophophamide for stage III ovarian cancer. N Engl J Med 1996;335:1950-5. 79. Markman M, Bundy BN, Alberts DS, Fowler JM, Clark-Pearson DL, Carson LF, et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, Eastern Cooperative Oncology Group. J Clin Oncol 2001;19:1001-7. 80. Armstrong DK, Bundy BN, Baergen R, et al. Randomized phase III study of intravenous (IV) paclitaxel and cisplatin versus IV paclitaxel, intraperitoneal (IP) cisplatin and IP paclitaxel in optimal stage III epithelial ovarian cancer: a Gynecologic Oncology Group Trial. Proc Am Soc Clin Oncol 2002;21:201a (abst 803). 81. Speyer JL, Beller U, Colombo N, Sorich J, Wernz JC, Hochster H, et al. Intraperitoneal carboplatin: favorable results in women with minimal residual ovarian cancer after cisplatin therapy. J Clin Oncol 1990;8:1335-41. 82. Pfeiffer P, Bennedaek O, Bertelsen K. Intraperitoneal carboplatin in the treatment of minimal residual ovarian cancer. Gynecol Oncol 1990;36:306-11. 83. Helm CW, Bristow RE, Kusamura S, Baratti D, Deraco M. Hyperthermic intraperitoneal chemotherapy with and without cytoreductive surgery for epithelial ovarian cancer. J Surg Oncol 2008;98:283-90. 84. Lentz S, Miller BE, Kucera GL, Levine EA. Intraperitoneal hyperthermic chemotherapy using carboplatin: a phase I analysis in ovarian carcinoma. Gynecol Oncol 2007;106:207-10. 85. Digiorgio A, Naticchioni E, Biacchi D, Sibio S, Accarpio F, Rocco M, et al. Cytoreductive surgery (peritonectomy procedures) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of diffuse peritoneal carcinomatosis from ovarian cancer. Cancer 2008;113:315-25. 86. Sridhar K, Doria R, Raub W, Thurer R, Saldana M. New strategies are needed in diffuse malignant mesothelioma. Cancer 1992;70:2969-79. 87. Wagner J, Sleggs C, Marchand P. Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Br J Ind Med 1960;17:260-71. 88. Robinson BW, Lake RA. Advances in malignant mesothelioma. N Engl J Med 2005;353:1591-603. 89. Chailleux E, Dabouis G, Pioche D, de Lajartre M, de Lajartre A, Rembeaus A, et al. Prognostic factors in diffuse malignant pleural mesothelioma. A study of 167 patients. Chest 1988;93:159-62. 90. Pass H, Kranda K, Temeck B, Feuerstein I, Steinberg S. Surgically debulked malignant pleural mesothelioma: results and prognostic factors. Ann Surg Oncol 1997;4:215-22. 192

Curr Probl Cancer, May/June 2009

91. Janne P. Chemotherapy for malignant pleural mesothelioma. Clin Lung Cancer 2003;5:98-106. 92. Antman K, Shemin R, Ryan L, Klegar K, Osteen R, Herman T, et al. Malignant mesothelioma: prognostic variables in a registry of 180 patients, the Dana-Farber Cancer Institute and Brigham and Women’s Hospital experience over two decades, 1965-1985. J Clin Oncol 1988;6:147-53. 93. Ribak J, Lilus R, Suzuki Y, Penner L, Selikoff I. Malignant mesothelioma in a cohort of asbestos insulation workers: clinical presentation, diagnosis, and cause of death. Br J Ind Med 1998;45:182-7. 94. Trupiano JK, Geisinger KM, Willingham MD, Manders P, Zbieranski N, Case D, et al. Diffuse malignant mesothelioma of the peritoneum and pleura, analysis of markers. Mod Pathol 2004;17:476-81. 95. Feldman AL, Libutti SK, Pingpank JF, Bartlett DL, Beresnev TH, Mavroukakis SM, et al. Analysis of factors associated with outcome in patients with malignant peritoneal mesothelioma undergoing surgical debulking and intraperitoneal chemotherapy. J Clin Oncol 2003;21:4560-7. 96. Park BJ, Alexander R, Lubutti SK, Wu P, Royalty D, Kranda KC, Bartlett DL, et al. Treatment of primary peritoneal mesothelioma by continuous hyperthermic peritoneal perfusion. Ann Surg Oncol 1999;6:582-90. 97. Cerruto CA, Brun EA, Chang D, Sugarbaker PH. Prognostic significance of histomorphologic parameters in diffuse malignant peritoneal mesothelioma. Arch Pathol Lab Med 2006;130:1654-61. 98. Yan T, Welch L, Black D, Sugarbaker P. A systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for diffuse malignancy peritoneal mesothelioma. Ann Oncol 2007;18:827-34. 99. McQuellon RP, Loggie BW, Fleming RA, Russell GB, Lehman AB, Rambo TD. Quality of life after intraperitoneal hyperthermic chemotherapy (HIPEC) for peritoneal carcinomatosis. Eur J Surg Oncol 2001;27:65-73. 100. McQuellon RP, Loggie BW, Lehman AB, Russell GB, Fleming RA, Shen P, et al. Long-term survivorship and quality of life after cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy for peritoneal carcinomatosis. Ann Surg Oncol 2003;10:155-62. 101. Alexander HR, Mavroukakis SM, Libutti SK, Pingpank JF, Beresnev TH, Marden S, et al. Impact of tumor resection and intraperitoneal chemotherapy on health related quality of life in patients with peritoneal surface malignancies. Proceedings of the 57th Annual Society of Surgical Oncology Cancer Symposium, 2004. 102. Portilla AG, Sugarbaker PH, Chang D. Second-look surgery after cytoreduction and intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal cancer: analysis of prognostic features. World J Surg 1999;23:23-9. 103. Elias D, Delperro JR, Sideris L, Benhamou E, Pocard M, Baton O, et al. Treatment of peritoneal carcinomatosis from colorectal cancer: impact of complete cytoreductive surgery and difficulties in conducting randomized trials. Ann Surg Oncol 2004;11:518-21.

Curr Probl Cancer, May/June 2009

193