Prophylactic surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC CO2) versus standard surgery in colorectal carcinoma at high risk of peritoneal carcinomatosis: short-term and long-term outcomes from the CHECK study - protocol for a randomised, multicentre, phase 3 trial.

INTRODUCTION: Up to one-fifth of patients with colorectal cancer will develop peritoneal metastases, frequently without other districts' involvement. Despite the recent unsuccesses of hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer peritoneal metastases treatment, the rationale in the prophylactic setting remains strong. Several clinical and pharmacokinetic data suggest that the efficacy of intraperitoneal chemotherapy is highest when the disease is microscopic. However, robust evidence demonstrating whether the addition of HIPEC for high-risk colorectal cancers offers better control of local recurrence is lacking. METHODS AND ANALYSIS: This is a multicentre randomised phase 3 trial comparing prophylactic surgery plus HIPEC CO2 with mitomycin, over standard surgical excision in patients with colorectal cancer at high risk of peritoneal carcinomatosis; 388 patients will be included in this study. The primary objective is to compare the efficacy of prophylactic surgery (radical colorectal resection, omentectomy, appendectomy, round ligament of the liver resection and bilateral adnexectomy) plus HIPEC CO2 with mitomycin and standard surgery in terms of local recurrence-free survival. The main secondary endpoints are disease-free survival (DFS), overall survival (OS) and safety. The primary endpoint will be described with a cumulative incidence function and will be analysed with Grey test to take account of the competing risks. DFS and OS will be described with the Kaplan-Meier method. ETHICS AND DISSEMINATION: This trial has been evaluated by the Italian Medicines Agency, local ethics committees and will be submitted to the Ministry of Health to notify the start of the trial according to the regulation of trials on devices with CE mark/certification.The results will be submitted for presentation at academic meetings and for publication in a peer-reviewed journal, whatever the findings. TRIAL REGISTRATION NUMBER: NCT03914820.

[Effect of astragalus injection combined with chemotherapy on quality of life in patients with advanced non-small cell lung cancer].

OBJECTIVE: To observe the effect of Astragalus injection (AI) combined with chemotherapy on quality of life (QOF) in patients with advanced non-small cell lung caner (NSCLC). METHODS: Sixty-NSCLC patients were randomly divided into the treated group (n = 30, treated with AI combined with chemotherapy) and the control group (n = 30, treated with chemotherapy alone). Chemotherapy of MVP protocol was applied to both groups. AI was supplemented to the treated group by intravenous dripping 60 ml per day. Treatment of 21-28 days as one treatment cycle, and 2-3 treatment cycles were applied. RESULTS: The effective rate in the treated group was 40.0% and in the control group was 36.7%, the mean remission rate in the treated and control group was 5.4 months and 3.3 months, the median survival period 11 months and 7 months, and the 1-year survival rate 46.75% and 30.0%, respectively, the differences of these indexes between the two groups were all significant (P < 0.05). Moreover, the clinical improving rate and QOF elevation rate in the treated group was 80.4% and 43.3%, as compared with those in the control group (50.0% and 23.3% respectively), the difference was also significant (P < 0.01). CONCLUSION: AI combined with chemotherapy can significantly improve the QOF in NSCLC patients of advanced stage.

The integrated treatment of peritoneal carcinomatosis. A preliminary experience.

Some low-grade malignant tumors arising in the abdomen, lack of infiltrative attitude and "redistribute" on the peritoneum with no extraregional spreading. In this cases the complete tumor cytoreduction followed by intra- or postoperative regional chemotherapy has curative intent. Peritonectomy is the complete removal of all the parietal peritoneum and the visceral peritoneum involved by disease. After peritonectomy hyperthermic antiblastic perfusion is carried out throughout the abdomino-pelvic cavity for 60 minutes, at a temperature of 41.5 degrees C, with mitomycin C (3.3 mg/m2/Lt of perfusate) and cisplatin (25 mg/m2/Lt) (appendicular or colorectal primary), or cisplatin alone is (ovarian primary). Alternatively the immediate postoperative regional chemotherapy is performed with 5-fluorouracil (13.5 mg/Kg) and Lederfolin (125 mg/m2) (colic or appendicular tumor) or cisplatin (25 ng/m2) (ovarian tumor), each day for 5 days. Twenty patients affected by extensive peritoneal carcinomatosis (12 ovarian, 5 colonic, 1 appendicular, 1 mesothelial and 1 gastric primary) were submitted to peritonectomy with no residual macroscopic disease in all cases except three. Six patients were treated with intraoperative intra-abdominal hyperthermic antiblastic perfusion, while immediate postoperative intra-abdominal chemotherapy was given in 4 patients and systemic chemotherapy in other 5. Hospital mortality was 20%. At a mean follow-up of 11 months 14 patients are alive, 11 without disease and the median overall survival is 10.2 months. The curative potential of the combined therapeutic approach seems high in patients with peritoneal carcinomatosis from ovarian or colorectal primary not responding to systemic chemotherapy. Selection criteria of patients can strictly affect the surgical risk and the treatment has to be reserved for controlled clinical trials.

Plasma insulin-like growth factor in primary breast cancer patients treated with adjuvant chemotherapy.

Insulin-like growth factor 1 (IGF-1) plasma level was assayed in 60 breast cancer patients undergoing six courses of adjuvant chemotherapy. The only observed variation was a slight decrease (10%) in IGF-1 concentrations, assayed before treatment, between the first and the second courses of chemotherapy. During chemotherapy courses, there were no statistically significant variations in IGF-1. These results suggest that chemotherapy, unlike the specific hormonal treatments tamoxifen and somatostatin, certainly does not act via a decrease in plasma IGF-1.

Use of antifibrosis agents and glaucoma drainage devices in the American and Japanese Glaucoma Societies.

PURPOSE: To investigate practice patterns among glaucoma subspecialists in the American Glaucoma Society (AGS) and the Japanese Glaucoma Society (JGS), regarding use of antifibrosis agents and glaucoma drainage devices. METHODS: An anonymous survey incorporating 10 clinical situations was mailed to all AGS and JGS members in December 1995. RESULTS: Half of the AGS (105 of 210), and JGS (25 of 50) members returned surveys. Most respondents (51-87%) preferred trabeculectomy with adjunctive mitomycin for all 10 clinical situations. Mitomycin concentrations varied from 0.1 to 0.8 mg/ml (range of means for 10 situations 0.31-0.39 mg/ml) and intraoperative application times ranged from 5 s to 7 min (range of means for 10 situations 2.5-4.6 min). Preferences for either no antifibrosis agent (up to 39%) or 5-fluorouracil (up to 29%) were highest in primary trabeculectomy. Thirty-seven percent to 64% of AGS members used glaucoma drainage devices, especially after complicated postsurgical glaucomas (after penetrating keratoplasty, scleral buckling, or pars plana vitrectomy) and in neovascular glaucoma, but few JGS members used them. Large differences between university- and private practice-based AGS members were found only in mitomycin use for primary trabeculectomy (33% vs. 52%, respectively; p = 0.07) and for complicated postsurgical glaucomas (46% vs. 70%, respectively; p = 0.03). CONCLUSIONS: Trabeculectomy with mitomycin was the preferred surgical procedure among AGS and JGS members in the clinical situations surveyed. Mitomycin concentration and time of application varied widely. Many respondents used 5-fluorouracil or no antimetabolite in primary trabeculectomy. Glaucoma drainage devices were widely used for complicated glaucomas in the United States.

Preoperative "chemoradiation" for stages II and III rectal carcinoma.

OBJECTIVE: To determine whether preoperative administration of combination chemotherapy and external beam irradiation ("chemoradiation") for patients with stage II or stage III rectal carcinoma had an impact on perioperative morbidity on oncologic outcome, as compared with patients not receiving preoperative chemoradiation. DESIGN: A group of patients with stage II or stage III rectal carcinoma receiving preoperative chemoradiation were followed up prospectively and compared in a nonrandomized fashion with an inception cohort group of similar patients. SETTING: Northwestern Memorial Hospital, Chicago, Ill, a tertiary care academic medical center. PATIENTS: Thirty patients with rectal carcinoma undergoing preoperative chemoradiation were compared with 56 patients not undergoing preoperative chemoradiation, and also with a subset group of 24 patients who received standard postoperative adjuvant chemoradiation. INTERVENTION: External beam radiation, 45 to 50 Gy, was delivered concurrently with fluorouracil and mitomycin 4 to 8 weeks prior to surgical resection. MAIN OUTCOME MEASURES: Patients were followed up at regular intervals for either tumor recurrence or death. In addition, the group receiving preoperative chemoradiation was evaluated for major preoperative morbidity. RESULTS: All patients agreeing to preoperative chemoradiation completed therapy. Perioperative major morbidity in this group (13%) was comparable to previously published results. Of the 56 patients with stage II or stage III rectal carcinoma not receiving preoperative chemoradiation, only 24 (43%) completed standard postoperative adjuvant chemoradiation. Patients receiving preoperative chemoradiation (n = 30), patients not receiving preoperative chemoradiation (n = 56), and the subset of the group not receiving preoperative chemoradiation who completed standard postoperative chemoradiation (n = 24) were followed up for a mean of 39 months, 31 months, and 32 months, respectively. Five-year actuarial local control rates were 96%, 83%, and 88%, respectively. Disease-free-survival rates were 80%, 57%, and 47%, respectively. Overall survival rates were 85%, 48%, and 78%, respectively. CONCLUSIONS: Preoperative chemoradiation in the treatment of stage II or stage III rectal carcinoma is well tolerated and not associated with an increase in subsequent perioperative major morbidity. In addition, local control, disease-free survival, and overall survival compare favorably with a nonrandomized inception cohort group of patients receiving standard postoperative adjuvant chemoradiation.

The role of chemotherapy in the treatment of adenocarcinoma of the pancreas.

Adenocarcinoma of the pancreas is a very disappointing disease. By the time of diagnosis, most patients have extensive metastasis, primarily to the liver, peritoneum, and the lymph system. At this point, the disease is usually too advanced to allow resection. Even if resection is performed, the recurrence rate is high. Therefore, there is an urgent need to develop non-surgical therapies. This paper reviews the current role of chemotherapy in pancreatic adenocarcinoma. Various single agent and multiple agent therapies for advanced and locally advanced pancreatic adenocarcinoma are reviewed and discussed. The role of chemotherapy as an adjuvant therapy to surgical resection is also covered in this paper.

Long-term results of single course of adjuvant intraportal chemotherapy for colorectal cancer. Swiss Group for Clinical Cancer Research (SAKK)

The efficacy of adjuvant chemotherapy after surgery for colorectal cancer remains unproven. We have investigated the efficacy of a perioperative intraportal cytotoxic regimen in a randomised trial of 533 patients with operable colorectal carcinoma. Patients were randomly assigned either a single course of portal infusion with mitomycin (10 mg/m2, one dose) plus fluorouracil (500 mg/m2 per 24 h for 7 days) starting immediately after surgery, or no adjuvant treatment. 505 (94%) were evaluable. At median follow-up of 8 years, adjuvant therapy reduced the risk of recurrence by 21% (hazard ratio 0.79 [95% CI 0.62-1.00], p = 0.051) and the risk of death by 26% (0.74 [0.57-0.97], p = 0.026). The lower risk of relapse was observed in all subgroups based on node status or localisation of the tumour; the risk reduction was greatest in patients with tumour-involved lymph nodes (Dukes' C; 0.67 [0.45-0.99], p = 0.045) and for those with colon cancer (0.78 [0.56-1.09], p = 0.151). Most of the difference in overall and disease-free survival could be attributed to a consistent reduction of all kinds of tumour recurrences (local relapses, liver metastases, and other distant metastases) in the treated group, rather than to a reduction of liver relapses only. We conclude that part of the benefit obtained with a single course of adjuvant chemotherapy via the portal vein for patients with operable colorectal carcinoma might be due to the systemic effects of the portal chemotherapy.

A new device for the treatment of pleural malignancies: intrapleural chemohyperthermia preliminary report.

The prognosis of malignant pleural tumors remains extremely unfavorable. The aim of this study is to evaluate the combination of intrathoracic intrapleural chemotherapy and intrapleural hyperthermia (ITCH) in these diseases. Under anesthesia, 5 men were studied. After pleurectomy for mesothelioma (3/5) or adenocarcinoma (2/5), ITCH is carried out for over 60 min, either with mitomycin C (4/5) or cisplatin (1/5). No pre- or postoperative death occurred. The maximal pleural temperature is 42.6 degrees C. The blood level of mitomycin C never reached the systemic toxic level. All the patients were discharged from the surgical ward, 3 are still alive 15 months later. Therefore, ITCH appears to be a safe and reliable therapy.

Mitomycin as adjunct therapy in correcting iatrogenic punctal stenosis.

A 52-year-old woman developed persistent epiphora in her left eye after undergoing occlusion of the left puncta. Two attempts to reopen the puncta with a one-snip procedure and placement of punctal silicone plugs failed. The epiphora resolved and the puncta remained patent after the patient underwent a third one-snip procedure, supplemented with topical mitomycin during and after surgery.

Quimioterapia adyuvante en cáncer gástrico: experiencia del Instituto Nacional de la Nutrición / Institutional experience with adjuvant chemotherapy in gastric cancer

Se presentan los resultados de un estudio retrospectivo de quimioterapia adyuvante en carcinoma gástrico. De 322 casos nuevos vistos en el INNSZ en un lapso de 10 años, sólo en 12.4 porciento de ellos (40 pacientes) pudo llevarse a cabo cirugía con intento curativo. De éstos, en 22 casos se administró quimioterapia adyuvante con el esquema FAM (5-FU 600 mg/m* IV días 1, 2, 3; adriamicina 30-35 mg/m* IV día 1 y mitomicina C 10 mg/m* repartido en tres días; cada seis semanas). 20 pacientes se encontraban en estadio III y dos en estadio II. Con un seguimiento promedio de 67 meses, 10 pacientes han recaído (45 porciento), de los cuales ocho han fallecido por progresión de la enfermedad, uno se encuentra vivo sin evidencia de enfermedad 24 meses después de la administración de quimioterapia con FAP (5-fluorouracilo, adriamicina y cis-platino) y uno se encuentra vivo con actividad tumoral. Nueve pacientes están vivos sin recaída (40.9 porciento); uno falleció de una enfermedad no relacionada y sin evidencia de enfermedad, y dos se encuentran perdidos. La mediana de sobrevida fue de 61 meses y la probabilidad de sobrevida estimada a cinco años de 51 porciento. De los factores pronósticos analizados (número de ganglios con metástasis, número de ciclos de quimioterapia recibida, intervalo entre cirugía e inicio de quimioterapia, y requerimiento de transfusión intraoperatoria), ninguno de ellos estuvo asociado significativamente a la recaída, aunque existió tendencia a recaer en mayor proporción en los pacientes transfundidos durante la cirugía que en los que no se transfundieron (sobrevida a cinco años sin recaída en 18 porciento versus 64 porciento respectivamente). Nuestros resultados sugieren que la quimioterapia adyuvante tipo FAM disminuye el porcentaje de recaída y aumentar la sobrevida en pacientes con cáncer gástrico operable en estadio III.

Recurrent hepatocellular carcinoma after partial hepatectomy: value of treatment with transcatheter arterial chemoembolization.

The usefulness of transcatheter arterial chemoembolization (TACE) of the hepatic artery was retrospectively evaluated in 66 patients who underwent the procedure for treatment of hepatocellular carcinoma that recurred after partial hepatectomy. The materials infused were Gelfoam sponge or Gelfoam sponge plus Lipiodol and an anticancer agent. A control group of 15 patients with recurrent tumor received oral anticancer agents alone. The cumulative survival rate for the TACE group was 88% for the first year, 57% for 2 years, 42% for 3 years, and 27% for 5 years, whereas that of the control group was 80% for the first year, 27% for 2 years, and 18% for 3 years. Thus, the prognosis of the TACE group was significantly better (p less than or equal to .01, log-rank test) than that of the control group. The survival rate was inversely correlated with the ratio of the volume of the recurrent tumor to the volume of the whole residual liver. These results suggest that TACE is more effective than oral chemotherapy for treatment of hepatocellular carcinoma that recurs after partial hepatectomy.

Mitomycin as adjunct chemotherapy with trabeculectomy.

Preliminary experience is reported in using mitomycin to improve the prognosis in trabeculectomy operations considered otherwise likely not to succeed. The medication is applied intraoperatively during an otherwise standard trabeculectomy procedure. Surgery was considered successful if the pressure was lowered to a predetermined target level, the only vision reduction was believed to be on the basis of cataract development, and there was no progression of cupping or visual field loss. With a follow-up of 6 to 42 months, the overall success rate is 84%.

Influence of local hyperthermia on the healing of small intestinal anastomoses in the rat.

Peritoneal hyperthermia may have a role in limiting serosal metastatic disease. When applied to the peritoneal cavity immediately after surgery, it is important to know the optimum temperature, and to investigate the subsequent healing of intestinal anastomoses. To study the first problem, local hyperthermia was applied to the intestinal loop of rats for 30 min. Treatment at 46.0 degrees C or 45.0 degrees C resulted in 100 per cent and 90 per cent mortality respectively, but 100 per cent survival was obtained at 44.0 degrees C. To study the second problem rats with intestinal anastomoses were studied in three groups: group A, local hyperthermia (44.0 degrees C x 30 min) applied to the intestinal loop containing the anastomosis; group B, local hyperthermia (44.0 degrees C x 30 min) applied using saline supplemented with mytomycin C (10 mg/l); group C (controls) no thermal treatment was applied. Anastomotic healing was assessed by breaking strength and histological examination. On the third day after operation, the breaking strength of anastomoses decreased to the lowest values in each group, but no statistically significant differences were noted. On the seventh and 14th day, increased resistance to breaking developed in all three groups and was greatest in the thermally treated groups. Histological findings supported these results. Local hyperthermia up to 44.0 degrees C x 30 min had no adverse effects on the healing of intestinal anastomoses.

[Hepatocellular carcinoma with a complete remission of bone metastasis achieved by arterial chemotherapy].

Reported is the case of a hepatocellular carcinoma with a complete remission of the bone metastasis by arterial chemotherapy. The patient was 60 year old male, with the chief complaint being a tumor at the right side of the chest. The diagnosis was a hepatocellular carcinoma with a bone metastasis at the right 10th rib. The bone tumor showed no decrease in size after an intra-arterial injection of adriamycin, and radiation and or hyperthermia. Therefore, intra-arterial injections of mitomycin C mixed with lipiodol were instituted through the intercostal artery, and no bone tumor was noted after start of this therapy. Although the patient subsequently died, microscopic examination of a specimen obtained at autopsy revealed no malignant cells at the right 10th rib. Intra-arterial injections of anticancer agents mixed with lipiodol therefore are thought to be useful for the treatment of a bone metastasis.

[Intra-operative pelvic hyperthermochemotherapy combined with surgery in rectal cancer].

In order to prevent local recurrence after curative surgery for rectal cancer, intra-operative pelvic hyperthermochemotherapy (IOPHC) was performed, combined with surgery. Nineteen patients with rectal cancer were given IOPHC (IOPHC group) and 25 patients who underwent curative surgery without IOPHC served as control, in the same period of time. IOPHC was done as follows: After rectal amputation or resection combined with extended lymphadenectomy, the pelvic cavity was filled with a prewarmed perfusate (physiological saline) containing 40 micrograms/ml of MMC. Then, an apparatus for IOPHC we devised was submerged in the perfusate to warm and maintain it at 45 degrees C for 90 minutes. The mean temperature of the esophagus was 37.2 degrees C, so it was not necessary to cool down the body throughout IOPHC. There was no significant postoperative morbidity between the two groups except that the total amount of exudate drained from pelvic cavity was larger in the IOPHC group. Local recurrence occurred in 3 controls, but in only one of the IOPHC group. Thus, IOPHC is a safe and reliable approach to prevent local recurrence of rectal cancer.

[Changes in the lungs and pleura following chemoembolization of liver tumors with mitomycin-lipiodol]. / Veränderungen der Lunge und Pleura nach Chemoembolisation von Lebertumoren mit Mitomycin-Lipiodol.

The authors performed 68 liver embolizations in 51 patients. As selectively as possible, Lipiodol, to block the capillary bed, and a chemotherapeutic agent were injected into the liver tumors. A CT performed 24 hours after treatment showed the distribution of the contrast medium which is also an indicator of the distribution of the chemotherapeutic agents. It was found that the contrast medium had accumulated not only in the liver but also in the lungs. Here, four different degrees of accumulation were found, according to the amount of Lipiodol used. Embolization of the liver thus involves potential hazards for the lungs, such as microembolisms, pneumonia, and toxic effects of the chemotherapeutic agents.

[Enhancing hyperthermic cytotoxicity in Walker-256 by intraarterial injection of warmed saline].

The tumor growth of Walker-256 implanted sc. on dorsum side of hindpaw of Wistar rat were suppressed by warmed (43 degrees C) water immersion. Antitumor effects of hyperthermia were increased by injection (a.i.) of saline mixed with noradrenaline (5 mcg). Although tumors in advanced stage group (D-8) are larger in size and more tumor vascularity than in early stage group (D-4), hyperthermic cytotoxicity were observed in D-8 but not observed in D-4. The hyperthermic energy injured the tumor vessels, which failed to flow the blood to the tumor cells and resulted in sever cytotoxic damage of Walker-256. Therefore, cytotoxic damage could be enhanced by injecting warmed water (43 degrees C) into tumor vessels after chemotherapy (MMC; 0.5 mg/kg) in D-8. Metastatic liver cancer was treated with thermochemotherapy. 5% of glucose warmed (43 degrees C) mixed with 0.1 mg of noradrenaline and heparin was administered into hepatic artery after chemotherapy (2 to 6 mg of MMC a.i.).