Immune response and locoregional treatments for peritoneal carcinomatosis.

Peritoneal Carcinomatosis (PC) is considered as a terminal disease with short survival. It is treated with palliative therapies, consisting of repeated drainages and sometimes instillation of chemotherapy. Since the nineties, surgery has been combined with more effective systemic chemotherapy, intraperitoneal chemotherapy and hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of PC. This combination therapy significantly increases the overall survival of selected PC patients. The understanding of how intraperitoneal chemotherapy and HIPEC can cure patients is still unclear. Experts hypothesized that the efficacy is obtained by the ability of high peritoneal drug exposure and hyperthermia to directly kill cancer cells. Several studies indicate that cancer cells death directly influences the response of the immune system. For this reason, the protective effect of intraperitoneal chemotherapy and HIPEC could be mediated by its ability to kill cancer cells in an immuno-genic way, causing an efficient anticancer immune response. In this review, we investigate the role of the innate peritoneal or locoregional therapy-induced immune response in PC therapy.

A Narrative Review of Regional Hyperthermia: Updates From 2010 to 2019.

The role of hyperthermia (HT) in cancer therapy and palliative care has been discussed for years in the literature. There are plenty of articles that show good feasibility of HT and its efficacy in terms of tumor response and survival improvements. Nevertheless, HT has never gained enough interest among oncologists to become a standard therapy in clinical practice. The main advantage of HT is the enhancement of chemotherapy (CHT), radiotherapy (RT), chemoradiotherapy (CRT), and immunotherapy benefits. This effect has been confirmed in several types of tumors: esophageal, gastrointestinal, pancreas, breast, cervix, head and neck, and bladder cancers, and soft tissue sarcoma. HT effects include oxygenation and perfusion changes, DNA repair inhibition and immune system activation as a consequence of new antigen exposure. The literature shows a wide variety of randomized, nonrandomized, and observational studies and both prospective and retrospective data to confirm the advantage of HT association to CHT and RT. There are still many ongoing trials on this subject. This article summarizes the available literature on HT in order to update the current knowledge on HT use in association with RT and/or CHT from 2010 up to 2019.

Modulated Electro-Hyperthermia as Palliative Treatment for Pancreatic Cancer: A Retrospective Observational Study on 106 Patients.

Background: Pancreatic adenocarcinoma has a poor prognosis, resulting in a <10% survival rate at 5 years. Modulated electro-hyperthermia (mEHT) has been increasingly used for pancreatic cancer palliative care and therapy. Objective: To monitor the efficacy and safety of mEHT for the treatment of advanced pancreatic cancer. Methods: We collected data retrospectively on 106 patients affected by stage III-IV pancreatic adenocarcinoma. They were divided into 2 groups: patients who did not receive mEHT (no-mEHT) and patients who were treated with mEHT. We performed mEHT applying a power of 60 to 150 W for 40 to 90 minutes. The mEHT treatment was associated with chemotherapy and/or radiotherapy for 33 (84.6%) patients, whereas 6 (15.4%) patients received mEHT alone. The patients of the no-mEHT group received chemotherapy and/or radiotherapy in 55.2% of cases. Results: Median age of the sample was 65.3 years (range = 31-80 years). After 3 months of therapy, the mEHT group had partial response in 22/34 patients (64.7%), stable disease in 10/34 patients (29.4%), and progressive disease in 2/34 patients (8.3%). The no-mEHT group had partial response in 3/36 patients (8.3%), stable disease in 10/36 patients (27.8%), and progressive disease in 23/36 patients (34.3%). The median overall survival of the mEHT group was 18.0 months (range = 1.5-68.0 months) and 10.9 months (range = 0.4-55.4 months) for the non-mEHT group. Conclusions: mEHT may improve tumor response and survival of pancreatic cancer patients.

Modulated Electrohyperthermia in Integrative Cancer Treatment for Relapsed Malignant Glioblastoma and Astrocytoma: Retrospective Multicenter Controlled Study.

BACKGROUND: There are interesting studies on glioma therapy with modulated electrohyperthermia (mEHT), which combines heat therapy with an electric field. Clinical researchers not only found the mEHT method feasible for palliation but also reported evidence of therapeutic response. PURPOSE: To study the efficacy and safety of mEHT for the treatment of relapsed malignant glioma and astrocytoma versus best supportive care (BSC). METHODS: We collected data retrospectively on 149 patients affected by malignant glioma and astrocytoma. Inclusion criteria were informed consent signed; >18 years old; histological diagnosis of malignant glioma or astrocytoma; relapsed after surgery, adjuvant temozolomide-based chemotherapy, and radiotherapy; and indication for treatment with mEHT in palliative setting. mEHT was performed with capacitive coupling technique keeping the skin surface at 26°C and the tumor temperature at 40°C to 42.5°C for > 90% of treatment duration (20-60 minutes). The applied power was 40 to 150 W using a step-up heating protocol. Results from patients treated with mEHT were compared with those treated with BSC. RESULTS: A total of 149 consecutive patients were enrolled in the study, 111 (74%) had glioblastoma multiforme (GBM), and 38 (26%) had astrocytoma (AST). mEHT was performed for 28 (25%) of GBM and 24 (63%) of AST patients. Tumor response at the 3-month follow-up was observed in 29% and 48% of GBM and AST patients after mEHT, and in 4% and 10% of GBM and AST patients after BSC, respectively. The survival rate at first and second year in the mEHT group was 77.3% and 40.9% for AST, and 61% and 29% for GBM, respectively. The 5-year overall survival of AST was 83% after mEHT versus 25% after BSC and 3.5% after mEHT versus 1.2% after BSC for GBM. The median overall survival of mEHT was 14 months (range 2-108 months) for GBM and 16.5 months (range 3-156 months) for the AST group. We observed 4 long-term survivors in the AST and 2 in the GBM group. Two of the long survivors in AST and 1 in GBM group were treated by mEHT. CONCLUSIONS: mEHT in integrative therapy may have a promising role in the treatment and palliation of relapsed GBM and AST.

1st Evidence-based Italian consensus conference on cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinosis from ovarian cancer.

Ovarian cancer (OC) remains relatively rare, although it is among the top 4 causes of cancer death for women younger than 50. The aggressive nature of the disease and its often late diagnosis with peritoneal involvement have an impact on prognosis. The current scientific literature presents ambiguous or uncertain indications for management of peritoneal carcinosis (PC) from OC, both owing to the lack of sufficient scientific data and their heterogeneity or lack of consistency. Therefore, the Italian Society of Surgical Oncology (SICO), the Italian Society of Obstetrics and Gynaecology, the Italian Association of Hospital Obstetricians and Gynaecologists, and the Italian Association of Medical Oncology conducted a multidisciplinary consensus conference (CC) on management of advanced OC presenting with PC during the SICO annual meeting in Naples, Italy, on September 10-11, 2015. An expert committee developed questions on diagnosis and staging work-up, indications, and procedural aspects for peritonectomy, systemic chemotherapy, and hyperthermic intraperitoneal chemotherapy for PC from OC. These questions were provided to 6 invited speakers who answered with an evidence-based report. Each report was submitted to a jury panel, representative of Italian experts in the fields of surgical oncology, gynecology, and medical oncology. The jury panel revised the reports before and after the open discussion during the CC. This article is the final document containing the clinical evidence reports and statements, revised and approved by all the authors before submission.

Genetic modulation of the interleukin 6 (IL-6) system in patients with advanced gastric cancer: a background for an alternative target therapy.

BACKGROUND: IL-6 triggers oncogenic/angiogenic signals and the cytokine-dependent pro-cachexia cascade. The prognostic role of the functional IL-6 (promoter) rs1800795 and the IL-6R (receptor) rs8192284 single nucleotide polymorphisms (SNP) was studied in patients with advanced gastric cancer treated with palliative chemotherapy. METHODS: One-hundred-sixty-one patients were genotyped for rs1800795 and rs8192284 SNPs using polymerase chain reaction based restriction fragment length polymorphism (PCR-RFLP) analysis assay. These results were studied for association with overall survival (OS). RESULTS: In 161 assessable patients, frequencies of rs1800795 G/G, G/C and C/C genotypes were 46%, 42% and 12%, respectively. Frequencies of rs8192284 A/A, A/C and C/C genotypes were 36%, 45% and 19%, respectively. Carriers of the rs1800795 G/G and rs8192284 C/C genotypes showed the worst OS. In the multivariate model, rs1800795 G/G (1.69 hazard ratio; 95% confidence interval 1.18-2.42), and rs8192284 C/C (1.78 hazard ratio; 95% confidence interval 1.12-2.83) confirmed an adverse prognostic impact. CONCLUSIONS: In this population, genetic variants that up-regulate the IL-6 system showed impact on OS. This findings sustain the hypothesis that anti-IL-6 compounds deserve clinical studies as novel therapeutics in the palliative treatment of cancer patients.

Treatment of peritoneal carcinomatosis from colonic cancer by cytoreduction, peritonectomy and hyperthermic intraperitoneal chemotherapy (HIPEC). Experience of ten years.

INTRODUCTION: Peritoneal carcinomatosis (PC) is one of the routes of dissemination of abdominal neoplasms and is generally considered a lethal disease, with a poor prognosis by conventional chemotherapeutic treatments. While systemic chemotherapy has little impact on the treatment of peritoneal disease, some centers have reported encouraging results with cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC). This approach is based on surgical cytoreduction of the primary tumour, peritonectomy (stripping of implants on the peritoneal surface) and HIPEC. The rationale of this treatment, after macroscopic disease removal, is to obtain an elevated and persistent drug concentration in the peritoneal cavity, with limited systemic effects. Many studies have reported encouraging results on overall survival (OS) and the disease-free interval in patients affected by PC. PATIENTS AND METHODS: From October 1997 to November 2008, 411 operations for PC were performed in our institution; in 232 cases, cytoreduction plus HIPEC was carried out. Out of 72 operations for colonic cancer: 40 cytoreductions plus HIPEC, 12 cytoreductions+ EPIC (early postoperative intraperitoneal chemotherapy) and 16 debulking or explorative laparoscopies/laparotomies were performed. For the present study, the 40 patients who had undergone cytoreduction plus HIPEC for PC of colorectal cancer (CRC) were considered. RESULTS: The complication rate was 55% (22/40) and mortality rate 2.5% (1/40). The specific features of both groups were considered for the survival curves and complication rates, with special reference to the peritoneal carcinomatosis index (PCI; range 0, absence of disease to 39) and completeness of cytoreduction score (CCR; 0, no residual tumor, to CCR 3, residual nodules greater than 25 mm). In Group A, patients operated on prior to 2002, the median survival time was 16.7 months compared to 24.6 months for Group B, those operated on after 2002. The poor survival of Group A seemed to be related to higher PCI and CCR scores. CONCLUSION: Correct patient selection based on a maximum PCI of 16, associated with complete cytoreduction (CCR-0), produced encouraging results in our experience. To improve this encouraging survival outcome, it is very important to unify the surgical experience of expertise centres. Our results also suggest the need for an integrated approach to this condition to identify the correct aspect of the surgical domain and results that may be influencing the prognosis and the evolution of this patients.

Management of pseudomyxoma peritonei by cytoreduction+HIPEC (hyperthermic intraperitoneal chemotherapy): results analysis of a twelve-year experience.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare peritoneal carcinomatosis, characterized by a slowly progressive disease process with a large amount of mucus containing occasional epithelial cells. PMP is histologically classified into disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis (PMCA) and an intermediate or discordant feature group (ID). Recent studies have shown that most cases of PMP originate from ruptured appendiceal tumors with progressive dissemination in the peritoneal cavity of mucin-producing epithelial cells. Encouraging results in the treatment of PMP have been reported by surgical cytoreduction of the primitive cancer, peritonectomy (stripping of implants on the peritoneal surface) and intraperitoneal hyperthermic chemoperfusion (HIPEC). In recent trials, this combined approach has been proposed as the standard treatment for PMP. PATIENTS AND METHODS: In this study, the results of twelve years single-institution experience on 60 consecutive patients affected by PMP, treated by cytoreductive surgery and the original semi-closed HIPEC technique are reported with special reference to overall survival (OS) and progression-free survival (PFS). RESULTS: The postoperative morbidity rate was 45% (27 patients); surgical morbidity was observed in 19 patients and medical complications in 9 cases. No postoperative deaths were observed. The survival data, 53 patients were analized (the last 7 were considered only for the complications rate, postoperative mortality and cancer features, not for OS or PFS because they were too recent for evaluation). At the final follow-up of the 53 patients, five and ten years OS were respectively 94% and 84.6% . DFS was 80% and 70% at five and ten years respectively. The follow-up data indicated that the survival probability may be good in patients with hystological type appendicular adenoma optimally cytoreduced (CCR-0). Interestingly if preoperative chemotherapy was performed represented a negative prognostic factor with statistically significant impact both on OS and DFS. CONCLUSION: As in other similar studies, cytoreductive surgery plus HIPEC, even when combined with an aggressive surgical procedure, is associated with an acceptable risk of postoperative complications and mortality. This combined treatment results in DFS and OS rates that are not described in the literature for surgery associated with systemic chemotherapy and, in our opinion, may be considered the gold standard treatment for this rare tumor.

Prevalence in the use of complementary medicine among cancer patients in Tuscany, Italy.

AIMS AND BACKGROUND: A previous survey by Molassiotis et al. (Ann Oncol, 16: 655-663, 2005) on the use of complementary and alternative medicines (CAM) among cancer patients in Europe reported that 73% of the Italian cancer patients had used CAM, a number well above the European average of 36%. Some national variation in preference of CAM was reported, and Italian cancer patients were reported to have high use of homeopathy, herbal medicine, and spiritual therapies. The difference between CAM use in Italy and other European countries intrigued a further investigation of CAM use among Italian cancer patients. METHODS: A survey using the same questionnaire as Molassiotis et al. was conducted at two oncology day hospitals in Tuscany and included 132 patients (55% male, 45% female, with various forms of cancer) on chemotherapy. The response rate was 71%. RESULTS: The incidence of CAM use after cancer diagnosis among Tuscan cancer patients was 17%. The most widely used forms were herbal medicine (52%), homeopathy (30%) and acupuncture (13%). Use was higher in the urban area and among women, breast cancer patients, and persons with a higher education. These results agree with results of other studies on the use of CAM among Italians and Europeans in general, as well as among cancer patients in Italy. CONCLUSIONS: The high prevalence of CAM use among Italians reported by Molassiotis et al. cannot be regarded a national estimate on the use of CAM for cancer in Italy. Rather it may reflect a relatively high use of CAM in palliative care, in Northern Italy and in urban areas. CAM use among Italians in general as well as among Tuscan cancer patients in chemotherapy is modest compared with the overall European use and reflects a general high use of CAM among urbanites, women and those with a higher education. Most commonly used forms of CAM are herbal medicine and homeopathy.

Adjuvant intra-arterial 5-fluoruracil, leucovorin, epirubicin and carboplatin with or without systemic gemcitabine after curative resection for pancreatic adenocarcinoma.

BACKGROUND: The role of adjuvant therapy in pancreatic cancer remains controversial. Gemcitabine given systemically seems to be effective; intra-arterial chemotherapy (IAC) has a deep rationale. PATIENTS AND METHODS: The goal was to evaluate the impact of postoperative IAC followed or not by systemic gemcitabine in patients after curative resection for pancreatic adenocarcinoma. 5-fluoruracil 750 mg sq m(-1), leucovorin 75 mg sq m(-1), epirubicin 45 mg sq m(-1), carboplatin 225 mg sq m(-1) were administered every 3 weeks into celiac axis for three cycles (FLEC regimen), then gemcitabine at the dosage of 1 g sq m(-1) on days 1, 8 and 15 every 4 weeks for 3 months (FLECG regimen). RESULTS: Forty-seven patients entered the study. The first 24 received only IAC (FLEC regimen), the other 23 received the same intra-arterial regimen followed by systemic gemcitabine (FLECG regimen). After a median follow-up of 16.9 months, 29 patients recurred (61.7%). Median disease free survival (DFS) was 18 months and median overall survival (OS) was 29.7 months. One-year DFS was 59.4% and 1-year OS was 75.5%. Main grade 3 toxicity related to IAC was only nausea/vomiting in 4%; regarding gemcitabine, grade 3 toxicities were anaemia 8%, leukopenia 8%, thrombocitopenia 17%, nausea/vomiting 4%. CONCLUSIONS: FLEC regimen with or without gemcitabine is active with a very mild toxicity and results are very encouraging in an adjuvant setting.

A phase II clinical study on relapsed malignant gliomas treated with electro-hyperthermia.

The purpose of this study was to evaluate the activity and toxicity of electro-hyperthermia (ET) on relapsed malignant glioma patients. Twelve patients with histologically diagnosed malignant glioma entered the study. Eight patients had glioblastoma multiforme, two had anaplastic astrocytoma grade III and two had anaplastic oligodendroglioma. All patients were pre-treated with temozolamide-based chemotherapy and radiotherapy. Hyperthermia with short radiofrequency waves of 13.56 MHz was applied using a capacitive coupling technique keeping the skin surface at 20 degrees C. The applied power ranged between 40-150 Watts and the calculated average equivalent temperature in the tumours was above 40 degrees C for more than 90% of the treatment duration. One complete remission and 2 partial remission were achieved, with a response rate of 25%. The median duration of response was 10 months (range 4-32). The median survival of the entire patient population was 9 months, with 25% survival rate at 1 year. ET appears to have some effectiveness in adults with relapsed malignant glioma.

Hyperthermia today: electric energy, a new opportunity in cancer treatment.

Hyperthermia is an ancient, but nowadays rapidly developing treatment method in tumor-therapy. Its new paradigm applied in the electro-hyperthermia (oncothermia), which provides energy by means of electric-field and produces non-equilibrium thermal situation in the tissue. The temperature gradients formed in stationary conditions, destroy the membrane of the malignant cells and selectively eliminate the cancer tissue. The characteristic control parameter is the absorbed energy-dose, which is partly used to make the distortions, partly to increase the temperature of the target. This type of technique could be applied for some tumor sites, including brain, soft tissues, liver and abdominal masses, pancreatic cancer, head and neck tumors as well.