HIPECT4: multicentre, randomized clinical trial to evaluate safety and efficacy of Hyperthermic intra-peritoneal chemotherapy (HIPEC) with Mitomycin C used during surgery for treatment of locally advanced colorectal carcinoma.

BACKGROUND: Local relapse and peritoneal carcinomatosis (PC) for pT4 colon cancer is estimated in 15,6% and 36,7% for 12 months and 36 months from surgical resection respectively, achieving a 5 years overall survival of 6%. There are promising results using prophylactic HIPEC in this group of patients, and it is estimated that up to 26% of all T4 colon cancer could benefit from this treatment with a minimal morbidity. Adjuvant HIPEC is effective to avoid the possibility of peritoneal seeding after surgical resection. Taking into account these results and the cumulative experience in HIPEC use, we will lead a randomized controlled trial to determine the effectiveness and safety of adjuvant treatment with HIPEC vs. standard treatment in patients with colon cancer at high risk of peritoneal recurrence (pT4). METHODS/DESIGN: The aim of this study is to determine the effectiveness and safety of adjuvant HIPEC in preventing the development of PC in patients with colon cancer with a high risk of peritoneal recurrence (cT4). This study will be carried out in 15 Spanish HIPEC centres. Eligible for inclusion are patients who underwent curative resection for cT4NxM0 stage colon cancer. After resection of the primary tumour, 200 patients will be randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy in the experimental arm, or to systemic chemotherapy only in the control arm. Adjuvant HIPEC will be performed simultaneously after the primary resection. Mitomycin C will be used as chemotherapeutic agent, for 60 min at 42-43 °C. Primary endpoint is loco-regional control (LC) in months and the rate of loco-regional control (%LC) at 12 months and 36 months after resection. DISCUSSION: We assumed that adjuvant HIPEC will reduce the expected absolute risk of peritoneal recurrence from 36% to 18% at 36 months for T4 colon-rectal carcinoma. TRIAL REGISTRATION: NCT02614534 ( clinicaltrial.gov ) Nov-2015.

Survival outcomes in patients aged 75 years and over with peritoneal colorectal carcinomatosis after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC): multicenter study of the Spanish Group of Peritoneal Cancer Surgery (GECOP).

BACKGROUND: The attitude toward cytoreductive surgery with HIPEC in peritoneal carcinomatosis from colorectal cancer is unclear. The aim of this study is to report the perioperative outcomes after cytoreductive surgery with HIPEC in patients ≥ 75 years. METHODS: This retrospective multicenter study collected the data the Spanish Group of Peritoneal Cancer Surgery. Thirty-six patients with peritoneal carcinomatosis from colorectal cancer met the selection criteria for the study. Morbidity, mortality, disease-free and overall survival were analyzed. RESULTS: Morbidity (grade III-IV) was 17% and 2 patients died of complications related to the procedure (5.4%). Median disease-free survival (DFS) was 16 months. DFS at 1 and 3 years was 81% and 42%, respectively. Overall survival at 1 and 3 years was 96% and 75%. In the univariate analysis, preoperative comorbidities (p = 0.01), liver metastases (p = 0.02), blood transfusion (p = 0.001) and postoperative complications (p = 0.001); and in the multivariate analysis, perioperative blood transfusion (OR 2.56, 95% CI 1.95-6.24, p = 0.03) and postoperative complications (OR 3.25, 95% CI 2.35-7.56, p = 0.02) were associated with a lower overall survival. CONCLUSIONS: Age is not an absolute contraindication to perform cytoreduction surgery with HIPEC in highly selected elderly patients with colorectal peritoneal carcinomatosis.

Treatment of peritoneal carcinomatosis from ovarian cancer. Present, future directions and proposals.

Peritoneal carcinomatosis, considered years ago as a final stage of unresectable cancer, can now be managed with curative intention by means of a radical cytoreductive surgical procedure with associated peritonectomy and intraperitoneal chemotherapy, as described by Sugarbaker. Malignant neoplasms such as mesothelioma and pseudomyxoma peritonei, ovarian and colon cancer nowadays are experiencing some new therapeutical approaches. Higher survival rates can be reached in ovarian cancer, which is commonly diagnosed in the presence of peritoneal carcinomatosis, using an optimal cytoreductive radical surgery with intraperitoneal chemotherapy. An actualised review of the treatment of advanced ovarian cancer and a proposal of a national multicentre protocol for the treatment of peritoneal carcinomatosis from ovarian cancer has been performed by a group of Spanish surgeons and oncologists dedicated to a therapeutical approach to this pathology.

Management of peritoneal surface malignancy with cytoreductive surgery and perioperative intraperitoneal chemotherapy.

AIMS: A new treatment strategy combining maximal cytoreductive surgery for treatment of macroscopic disease and maximal perioperative intraperitoneal chemotherapy for residual microscopic disease, suggests that in a selected group of patients benefit is possible. The purpose of this study was to report our experience with this combined treatment and to identify the principal prognostic factors. METHODS: The study included 266 patients from 9 institutions operated on between July 1990 and July 2004. The median age was 55 years. RESULTS: The mortality rate was 7.8% and the morbidity rate 37.5%. The overall median survival was 13.7 months. Positive independent prognostic factors by multivariate analysis were gender, perioperative intraperitoneal chemotherapy and treatment by the second-look procedure. CONCLUSIONS: The therapeutic approach combining cytoreductive surgery with perioperative intraperitoneal chemotherapy achieved long-term survival in a selected group of patients with an acceptable morbidity and mortality.

Recommendations in the management of epithelial appendiceal neoplasms and peritoneal dissemination from mucinous tumours (pseudomyxoma peritonei).

The epithelial appendiceal neoplasms are uncommon and are usually detected as an unexpected surgical finding. The general surgeon should be aware of the diversity of its clinical manifestations and biological behaviors along with the significance of the surgical treatment on the progression of the illness and the prognosis of the patients. The operative findings and, especially, tumor histology, determine the type of surgery. Intestinal histologic subtype behaves and should be treated similarly to the right colon neoplasms; while mucinous tumors, often discordant between histology and its aggressiveness, can be treated with a simple appendectomy or require complex oncological surgeries. Mucinous tumors are often associated with the presence of mucin or tumor implants in the abdominal cavity, being the clinical syndrome known as pseudomyxoma peritonei (PMP). PMP tends to present an indolent but deadly evolution and requires a multimodal approach as a single treatment with curative potential: complete cytoreductive surgery plus hyperthermic Intra-peritoneal chemotherapy (CCRS + HIPEC) now considered the standard of care in this pathology. The general surgeon should be aware of the governing principles of the treatment of appendiceal neoplasms with or without peritoneal dissemination, know the therapeutic frontiers in every situation (avoiding unnecessary or counterproductive surgeries) and sending early these patients to specialised centres in the radical management of malignant diseases of the peritoneum in the conditions and with the necessary information to facilitate a possible radical treatment.

Morbidity and mortality outcomes after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients aged 75 years and over: Spanish group of peritoneal cancer surgery (GECOP) multicenter study.

BACKGROUND: The aim of this study is to report the perioperative outcomes of cytoreductive surgery and hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) in patients ≥75 years from a Spanish multi-institutional experience. METHODS: This multi-institutional retrospectively analyzed a prospectively collected clinical data from 10 Spanish hospitals that are part of the Spanish Group Peritoneal Cancer Surgery (GECOP). We assessed postoperative morbidity rates and performed univariate and multivariate analyses of factors associated with overall (grade I-IV) and major (grade III-IV) postoperative morbidity. RESULTS: A total of 85 patients aged ≥75 years were included. Forty six postoperative adverse events were detected in 37 patients (43.5%). Twenty five complications in 20 patients (23.5%) were mild (grade I-II) and 16 complications in 12 patients (14.1%) were moderate-severe (grade III-IV). Five patients died in the first 90 days after the procedure (5.9%). After multivariate analysis, independent factors associated with postoperative complications were: PCI> 12 (OR: 4.14, 95% CI 1.22-14.12, p = 0.043) and the need for perioperative blood transfusion (OR: 14.91, 95% CI 3.87-57.46, p < 0.001). Regarding grade III-IV complications, after multivariate analysis, the presence of preoperative albumin levels <3.5 mgr/dl (OR: 9.15, 95% CI 1.38-60.57, p = 0.017), need for diaphragmatic peritonectomy procedures (OR: 11.32, 95% CI 1.40-91.32, p = 0.023) and perioperative blood transfusion (OR: 8.58, 95% CI 1.44-51.16, p = 0.018) were independent factors. CONCLUSIONS: Cytoreductive surgery and performing HIPEC by experienced groups in selected patients aged ≥75 years can be performed with morbidity and mortality similar to that described in the literature.

NO2/NO3 and cytokine plasma profiles under different postoperative parenteral nutrition regimens.

Both nitric oxide and cytokines are considered mediators of the acute-phase response in humans, and their early postoperative period plasma levels have been found to be of prognostic value. On the other hand, it has been suggested that the fatty emulsions used in total parenteral nutrition (TPN) may induce changes in macrophage function. In the present study we investigated the postoperative evolution of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), interleukin-6 (IL-6), and nitrate/nitrite plasma levels under three different TPN regimens. Twenty-one patients diagnosed with upper digestive tract neoplasm, without preoperative TPN, and having undergone radical surgery, were randomly assigned to three groups: Group I, all nonprotein calories supplied by hypertonic glucose solution: Group II, 55% of the nonprotein calories supplied by glucose and 45% by 20% long-chain triacylglycerides emulsion (LCT) (Intralipid 20%, Kabi-Pharmacia); Group III, same as Group II, but a 20% emulsion of a mixture of medium-chain and long-chain triacylglycerides (MCT/LCT) (Lipofundina MCT/LCT 20%, B. Braun) was used instead of LCT. Blood samples were obtained on postoperative Days 1-5 and 10, 3 h after ending the lipid infusion. In all the three groups IL-1, IL-6, and TNF-alpha levels rose after surgery, peaking at Day 2, whereas NO2/NO3 levels had their peak at Day 3. Day-to-day comparison of plasma levels of cytokines and NO2/NO3 between the investigated groups did not show any statistical significance. Differences between group means were not found when the areas under the curve over the first 5 postoperative days were compared (1.72 +/- 0.25, Group I; 1.88 +/- 0.34, Group II; and 2.52 +/- 0.50, Group III, for TNF-alpha; 1.79 +/- 0.12, Group I; 1.92 +/- 0.18, Group II; and 1.50 +/- 0.12, Group III, for NO2/NO3). We conclude that the different parenteral nutrition regimens studied do not evoke alterations in cytokine and NO2 + NO3 levels in the patient groups investigated in this study.

[Surgical treatment of pulmonary aspergilloma]. / Tratamiento quirúrgico del aspergiloma pulmonar.

Pulmonary aspergilloma can now be classified as an opportunistic disease given that Aspergillus tends to colonize preexisting cavities in the lung. Aspergilloma is the usual pleuropulmonary anatomical sign, hemoptysis is the most frequent symptom and a chest film is the simplest diagnostic tool. The advisability of surgery is disputed, particularly in asymptomatic patients and/or those at high surgical risk. We describe 14 patients who underwent surgery in our department, evaluating aspects of their clinical signs, diagnosis, attitude toward treatment and the course of their disease. We believe that for patients with symptomatic pulmonary aspergilloma, the treatment of choice is surgery, preferably lung resection. All patients who do not present contraindications for general surgery can be considered operable.

[Lymphocyte subpopulations and surgery. The role of postoperative parenteral nutrition]. / Subpoblaciones linfocitarias y cirugía. Papel de la nutrición parenteral postoperatoria.

The effects of LCT-based lipid emulsions used in TPN on immune system remains controversial. In this prospective study we research the effects of three types of TPN on T-lymphocyte subsets and NK cells. 21 patients diagnosed because of upper gastrointestinal carcinoma (UGIC), and amenable of curative surgery were included in the study. TPN support was maintained 10 postoperative days at least. All patients received 35 non-proteic Kcal/KG BW/day. Group I (without lipid): received 100% of caloric intake (CI) by glucose. Group II (LCT): received 55% of CI by glucose and 45% by LCT at 20% emulsion. Group III (MCT/LCT): received 55% of CI by glucose and 45% by MCT/LCT at 20% mixture. T-lymphocyte subsets were determined by flow cytometry preoperatively and in first and tenth postoperative days. Our results suggest that patients diagnosed of UGIC present alterations of cellular immunity. These alterations are increased by the age and by surgical act. The changes found are independent of the type of TPN. LCT-based emulsions have similar effects on T-lymphocyte subsets that MCT/LCT-based emulsions.

[Major abdominal surgery and the clearance of lipid emulsions]. / Cirugía abdominal mayor y aclaramiento de emulsiones lipídicas.

The use of lipid emulsions for TPN remains controversial. Although experimental studies show that medium chain triglycerides (MCT) are beneficial over long chain triglycerides (LCT) clinical studies are contradictory. With the aim to study the clearance of two lipid emulsions a prospective study was designed. 21 patients, submitted to resective surgery because of upper gastrointestinal tract malignancy were randomized in three groups. In group I (without lipids): all caloric intake was supplied by hypertonic glucose solution. In group II (LCT group) 55% of caloric intake was supplied by glucose and 45% by a LCT 20% emulsion (Intralip[id 20%, Kabi-Pharmacia). In group III (MCT group) 55% of caloric intake was supplied by hypertonic glucose solution and 45% by a physical mixture of LCT and MCT at 20% concentration (Lipofundina MCT, B. Braun). Our results show that in postoperative period of major abdominal surgery both lipid emulsions are cleared of in a similar way. When these emulsions are administered during 12 hours per day plasmatic triglycerides are completely cleared before to start the next-day infusion of lipid emulsion. Differences in total cholesterol were not found between groups. Nevertheless LDL-cholesterol rose significatively between first and tenth postoperative day in LCT group.

[Appendiceal Crohn's disease]. / Enfermedad de Crohn apendicular.

Crohn's disease of the appendix is an uncommon process that is more frequent in young people. The most common preoperative diagnosis is acute appendicitis. At exploratory laparotomy the appendix is enlarged and malignancy may be suspected. The differential diagnosis may be difficult. Serologic tests and cultures should be performed to exclude Yersinia infections. Appendicectomy is a safe procedure when the disease is limited to the appendix. The postoperative course is usually uncomplicated with a low rate of complications and recurrence. Although it may be a different process than Crohn's disease and the recurrence rate is low, it is suggested that all the patients should be followed-up so that recurrences may be recognized and treated as early as possible. A new case is presented after two years of follow-up without recurrence.

[Colorectal cancer: has its diagnosis improved in the last decade?]. / Cáncer colorrectal: Ha mejorado su diagnóstico en la última década?

OBJECTIVE: To assess whether any shift in pathologic stage, tumor resectability and need of emergency surgery has been observed in colorectal carcinoma patients over the last ten years. EXPERIMENTAL DESIGN: Retrospective study. PATIENTS: We compare 201 patients treated in our Service from January 1981 to December 1983 (Group I) with 306 patients operated from January 1991 to December 1993 (Group II). RESULTS: No change has been noticed in any of the parameters analyzed. CONCLUSIONS: We think that the efforts in earlier detection of CCR should be increased to improve the prognosis of the disease.

[The results after extensive radical resection of locally advanced colorectal carcinoma]. / Resultados tras resección radical ampliada por carcinoma colorrectal localmente avanzado.

The results of extended resections for locally advanced colorectal cancer and the factors influencing the long term survival and recurrence rate are analyzed in 69 patients. All of them underwent radical en-bloc resection including the primary tumor and the adjacent affected structures. The existence of tumoral invasion was confirmed in 42 cases (60%). In the remaining, inflammatory adhesions were presents. Overall 5 year survival did not show significant differences between the groups of patients with benign or malignant infiltration (71% y 51% respectively). Within the same tumor stage, the results were similar for the two types of infiltration. Significant differences were found when lymph nodes metastases were considered: 65% 5 year survival in patients with negative lymph nodes versus 35% in patients with positive nodes. The probability of metastases and tumor recurrence was significantly higher in the group with malignant infiltration. Patients with positive lymph nodes showed lower disease-free interval rate. These data show that long term control of the tumor in locally advanced colorectal carcinomas can be achieved by an aggressive surgical approach. The presence of lymph mode metastases is a more useful prognostic factor influencing survival and relapse rate that the local infiltration by it-self.

[Treatment with sulindac of adenomatous polyps in familial polyposis]. / Tratamiento con Sulindac de los pólipos adenomatosos en la poliposis familiar.

BACKGROUND: The effect of sulindac, a nonsteroid antiinflammatory drug, has been reported to cause both regression and suppression of colon polyps in patients with familial adenomatous polyposis and Gardner's syndrome. We report our experience with seven patients with diffuse colonic polyposis treated with sulindac. PATIENTS AND METHODS: Seven patients with familiar adenomatous polyposis, four men and three women (mean age, 30 years; range 16 to 41 years) were included in this study. Two patients that underwent prior colectoctomy with ileorectal anastomosis and had polyps in the rectum were also included. The polyps ranged in size from 0.2 to 2.5 cm; most of them were less than 1 cm. Sulindac was given 150 mg. twice a day. Further colonoscopic examination was done at 6-month intervals during follow-up in all patients. RESULTS: A disappearance or a marked reduction in the number and size of polyps was observed in all patients after 24 months of treatment with sulindac. The drug was well tolerated and no side effects were observed during treatment. CONCLUSION: The authors conclude that sulindac is effective in inducing the regression of rectal polyps in familial, adenomatous polyposis.

[Colorectal metachronous tumors]. / Tumores metacrónicos colorrectales.

INTRODUCTION: The metachronous colorectal carcinoma is defined as a primary carcinoma which arises after surgical removal of a previous carcinoma of the large bowel. The incidence of metachronous colorectal cancer has been reported to be 1-8 per cent. THE AIM: The purpose of the present study was to determine the incidence of metachronous colorectal carcinoma and, on this basis, to propose a follow-up programme after primary resection for cure in this patient group of patients. PATIENTS AND METHODS: Twenty-eight patients with metachronous colorectal malignancies underwent surgery, 16 (57.1%) male and 12 (42.9%) female. These metachronous cancers were discovered at intervals ranging from eight months to seven years (range 28 +/- 10 months). Nine (32%) metachronous lesions were detected two years of more after the original cancer. Six of the metachronous cancers appeared in the right colon, eight were distributed throughout the transverse and descending colon, and fourteen in the rectosigmoid region. Histological examination revealed a high proportion of early stage lesions (82.1% Duke's A more B). CONCLUSION: A set of patients surviving their initial colorectal cancer should be followed for the rest of their life because of the risk of developing a second primary. In the light of our experience, a full examination of the colon in these patients is mandatory, and colonoscopy is the best diagnostic procedure.

[An adenocarcinoid tumor of the vermiform appendix]. / Tumor adenocarcinoide de apéndice vermiforme.

Goblet cell carcinoids of the vermiform appendix are uncommon. A comprehensive review of the literature revealed about 100 reported cases. Clinical presentation included: asymptomatic patients, acute appendicitis, and/or chronic intermittent lower abdominal pain with or without a palpable mass. We report the case of a 57 year-old woman with lower abdominal pain, nausea and vomiting. Normal blood tests. X-ray of the abdomen showed dilated small bowel loops with fluid levels. Initially, conservative treatment was started. After three days with no clinical improvement, the patient was operated on. An appendicocecal inflammation was found and a terminal ileum plus cecal resection with an end-to-side anastomosis was performed. The pathological diagnosis was goblet cell carcinoid. The patient shows no evidence of recurrence after 1 year follow-up.

Cytoreductive surgery and intraperitoneal chemotherapy for treatment of peritoneal carcinomatosis from colorectal origin.

Peritoneal carcinomatosis (PC) is a common form of tumour metastasis stemming from gastrointestinal and colorectal cancers. For a long time, PC has been considered a terminal clinical condition treated only with palliative systemic chemotherapy and associated with very limited results. During the last decade, the treatment of advanced colorectal disease has greatly improved with the emergence of new chemotherapy drugs and biological agents. However, the median survival rates still do not surpass 24 months, even though most of these studies correspond to groups of patients with metastatic disease to the liver and/or lung. The approach and development of cytoreductive radical surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC) are based on performing radical surgery of the entire visible tumour within the abdomen/peritoneum, followed immediately by HIPEC, which acts upon microscopic tumour that remains present after surgery and which is responsible for the persistence or relapse of peritoneal disease. Peritonectomy procedures are demanding surgical techniques that permit elimination of the tumour present in the peritoneal lining and any other organs and/or structures that are infiltrated. The synergistic effect of hyperthermia and chemotherapy has been well documented. Hyperthermia increases the cytotoxicity of some cytostatic agents and increases the penetration of certain drugs into the neoplastic cells. The prognosis for patients with PC who undergo combined treatment correlates with the volume of PC (tumour burden) measured as the Peritoneal Cancer Index (PCI) and the ability to perform a CRS, to completely eliminate the gross tumour. At least one phase III study and an important number of phase II studies have shown that CRS + HIPEC provides important survival benefits for patients with PC of colorectal origin. The combination of CRS + HIPEC is indicated for patients with good general health, a low PCI, absence of extra-abdominal metastasis and who can, technically, undergo CRS. The early identification of this group of patients, rapid referral to centres specialised in CRS + HIPEC, together with the correct application of this treatment, are key in achieving the best results.