Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Symptoms and General Pathology

Digestive System Diseases

Gland and Hormone Related Diseases

Wounds and Injuries

Behaviors and Mental Disorders

Rare Diseases

Uterine Cervical Neoplasms

Recurrence

Esophageal Neoplasms

Carcinoma

Pancreatic Neoplasms

Prostatic Neoplasms

Carcinoma, Squamous Cell

Sarcoma

Hyperthermia

Neuroendocrine Tumors

Fever

Anus Neoplasms

Disease Attributes

Neoplasms by Histologic Type

Rectal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Rectal Diseases

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Endocrine Gland Neoplasms

Pancreatic Diseases

Endocrine System Diseases

Anus Diseases

Body Temperature Changes

Stress Disorders, Traumatic

Heat Stress Disorders

Esophageal Cancer

Pancreatic Cancer

Soft Tissue Sarcoma

Neuroendocrine Tumor

Anal Cancer

Neuroepithelioma

Patients will receive 6-8 treatments additional loco-regional hyperthermia concurrent to re-irradiation. Hyperthermia will start on the third day of fractionated radiotherapy and will be given twice per week. According to site of recurrent disease either deep-regional, capacitive or superficial hyperthermia devices may be used.

loco-regional hyperthermia by the use of microwave, capacitive, or superficial hyperthermia devices.

loco-regional hyperthermia

Sebastian Zschaeck, MD

Sebastian Zschaeck, M.D.

This study investiagates deep-regional or superficial hyperthermia to enhance radiotherapy or chemoradiation in patients that suffer recurrent disease after previous radiotherapy.

patients that present a relapse within the previously irradiated volume can be included in this trial. These patients will receive re-irradiation according to clinical guidelines and hyperthermia as study intervention. According to tumor location hyperthermia can either be performed by microwave or by capacitive devices.

The primary endpoint of this study is non-inferiority of re-irradiation compared to the initial course of radiotherapy (calculated as time to local failure).

Patients will receive additional hyperthermia according to physicians´choice as a radiosensitizer to standard of care re-irradiation or re-chemoradiation.

Hyperthermia Enhanced Re-irradiation of Loco-regional Recurrent Tumors

Local tumor recurrence of re-irradiated lesions, calculated with the Kaplan-Meier estimates. Local recurrence after hyperthermic re-irradiation will be compared to time-to recurrence after initial treatment.

Overall survival after start of re-irradiation

Progression-free survival after start of re-irradiation

Freedom from distant metastases after start of re-irradiation

patient reported quality of life measured by the EORTC qlq-c30 questionnaire.

Charite University, Berlin, Germany

MD, PI

Immune System Diseases

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Hypersensitivity

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Gonadal Disorders

Neoplasms, Glandular and Epithelial

Ovarian Cancer

Ovarian Epithelial Cancer

Central Nervous System Depressants

All Drugs and Chemicals

Pharmaceutical Solutions

Antineoplastic Agents

Anesthetics

Cisplatin

The eligible patients, after anesthesia preparation will be submitted to a surgical complete cytoreduction.

If the patient is randomized to make chemo-hyperthermia, surgery will be followed by HIPEC with the closed technique.

The eligible patients, after anesthesia preparation will be submitted to a surgical complete cytoreduction attempt that consist in the removal of all macroscopically visible tumor nodules from the visceral and parietal peritoneum. To obtain a complete cytoreduction, different procedures are required, as described by Sugarbaker (30), which may include omentectomy, splenectomy, diaphragmatic, pelvic,parietal peritonectomy and / or visceral, bowel resection, hepatic resection and cholecystectomy.

Secondary citoreduction

If the patient is randomized to make chemo-hyperthermia, surgery will be followed by HIPEC with the closed technique, that consist in the perfusion of the abdominal cavity with a solution containing cisplatin (CDDP) 75 mg/m2 in 2L/m2 heated saline. The solution is heated and perfused with two special pumps (Hyperex, Korea or Stoeckert munich). The temperature of inflow and outflow of the solution, will be maintained, respectively, between 41 ° and 42.5 ° C. The intraperitoneal temperature will be maintained at 41.5 ° C and monitored by thermometers inserted into the subphrenic space and into the pelvis. After 60 minutes of perfusion the surgical incision will be open after removal of the entire solution. The global temperature will be measured by thermometer inserted into the esophagus and rectum. A Swan-Ganz catheter will be kept in place during the HIPEC for monitoring cardiovascular function.

Hyperthermic intra-peritoneal chemotherapy (HIPEC)

Catholic University of Sacred the Hearth

Fagotti Anna, MD, PhD

Fanfani Francesco, MD

Costantini Barbara, MD

Perelli Federica, MD

The purpose of this study is to determine the role of surgery followed by hyperthermic intra-peritoneal chemotherapy (HIPEC) versus surgery alone in patients with platinum-sensitive first recurrence of ovarian cancer. Moreover it is a prospective randomized multicenter trial, aimed to investigate the prognostic role of surgery plus HIPEC versus surgery alone in terms of progression free interval, overall survival, morbidity and mortality, second recurrence pattern, quality of life with EORTC QLQ-C30 and QLQ OV28 questionnaires.

Among the malignancies of the female genital tract, ovarian cancer is the second most common cancer after the endometrial tumor, but the more lethal, representing the fifth leading cause of death among women in industrialized countries. For the most part, these are epithelial tumors (\>70%), who begin with vague gastrointestinal symptoms, general malaise, abdominal bloating, weight loss and fatigue. Because of the non-specificity oh the symptoms and the often late presentation, about 70% of the diagnosis is made at an advanced stage of disease (IIIC). In the last two decades only a modest improvement in survival was achieved. Moreover, even after optimal cytoreduction followed by adjuvant chemotherapy based on platinum and taxane, which is currently the standard for this type of disease, most patients with stage III disease developed a recurrence.

Rational of HIPEC in recurrent ovarian cancer: the cytoreduction. Contrary to what happens in the primary disease is not yet clear what is the standard treatment in recurrent epithelial ovarian cancer (EOC).

Patients who experience a recurrence within 6 months from the end of the first-line chemotherapy are considered platinum-resistant and have applied for a salvage treatment with second line drugs with low response rates and poor survival. Patients who recur after 6 months are considered platinum-sensitive and, therefore, subject to a new chemotherapy treatment with a platinum compound possibly in combination with paclitaxel (re-challenge). In these patients it is possible to achieve a clinical response rate similar to the primary treatment, with median survival reported between 12 and 24 months. Recently surgery affirmed a major role not only in the primary treatment but also in recurrent chemo-sensitive ovarian cancer. A meta-analysis of 2019 patients has shown that obtain an optimal secondary cytoreduction independently correlates with survival (OS) after recurrence. However, a recent Cochrane, showed that, from the studies available nowadays, is not possible to substantiate a difference in prognosis between the exclusive chemotherapy treatment and the association of surgery with adjuvant chemotherapy.

The results of the multicenter trial DESKTOP I show that, even in the presence of peritoneal carcinomatosis, the 2-year survival improves if an optimal cytoreduction is obtained.

Rational of HIPEC in recurrent ovarian cancer: intraperitoneal chemotherapy Many patients who undergo optimal cytoreduction may benefit from adjuvant chemotherapy administered intraperitoneally (IP). Several randomized trials have demonstrated improved survival associated with IP platinum-based chemotherapy as first-line adjuvant therapy after optimal cytoreduction, although it is still unclear which patients might benefit most, or what would be the best drug , its dose or the right number of cycles. The adjuvant IP therapy, however, seems to have more side effects than intravenous therapy (IV) and consequently a worsening of the quality of life (QOL).

Rational use of HIPEC in recurrent ovarian cancer: hyperthermia The association of hyperthermia plus chemotherapy to the surgery based its rational on the cytotoxic effect of hyperthermia, which not only cause a rupture of cell membranes due to protein denaturation (direct effect), but also an increase in the permeability of new vessels and an impairment of receptor protein complexes (indirect effect). The sensitivity of the solid tumors to hyperthermia is probably linked to the creation of a microenvironment with a low pH, low oxygen tension, low glucose levels in response to high temperature. Inactivation of tumor cells is time and temperature dependent, and starts at 40-41 ° C. Experimental data show that human tumor cell lines are more sensitive to a moderate hyperthermia (41-42 ° C).

Furthermore, the ability of its cytotoxic chemotherapeutic agents, including mitomycin C, doxorubicin, cisplatin and oxaliplatin, is enhanced by hyperthermia itself.

Secondary cytoreduction (CRS), HIPEC and ovarian cancer Since its first appearance in 1980, the HIPEC associated with surgery has had an increasingly important role in the treatment of several types of cancer with peritoneal dissemination.

The rational for this therapeutic approach is based on the achievement of higher drug concentrations in contact with the peritoneal surface with a lower systemic concentrations, resulting in a decrease in the systemic toxicity of treatment. The addition of hyperthermia proved to be able to have a cytotoxic effect on tumor cells directly and indirectly, and a synergistic effect with several cytotoxic agents.

Two recent trials including heterogeneous populations of patients with EOC have demonstrated that the use of the HIPEC in association with CRS is followed by an overall survival (OS) of three years after the recurrence that vary between 20-63%. Data from a trial which took place at this Institution and was recently published about the use of HIPEC platinum-sensitive recurrent EOC patients, showed a median disease-free interval (PFS) and OS of 24 and 38 months respectively, with an estimated PFS and OS at 3 years of 44% and 92% respectively. These data not only confirm those previously reported in the literature, but are more significant, probably because of the highly selected population, a characteristic that contrasts with the wide heterogeneity of most of the other trials made until now.

In fact, as demonstrated by the meta-analysis by Bristow et al, the median survival after recurrence in the same group of patients treated with CRS and standard adjuvant chemotherapy alone was 30.3 months. This difference in survival compared with that of our trial could be justified by the increased rate of optimal cytoreduction obtained in our Institution (95.3% vs. 52.2%).

In addition, on the basis of the criteria developed by Markman, that any second-line treatment after recurrence which reaches a PFS similar or comparable to that after the primary disease is considered to be effective, our data show an additional benefit obtained by HIPEC. In the series of patients underwent CRS + HIPEC at this Institution, in fact, the median PFS after primary disease was substantially equal to that after recurrence with values of 25 and 24 months respectively (p = ns). Therefore treatment with CRS associated with HIPEC in with platinum-sensitive recurrent EOC patients would seem to offer the same opportunities in terms of prognosis than primary treatment.

Regarding the complications linked to this procedure, the trials completed at our Institution, showed morbidity and mortality rates about of 35% and 0%, consistent with the data presented by recent review (12 - 52% and 0,9-5,8% respectively), which are however more heterogeneous due to differences between the considered studies. In addition, the analysis divided into two blocks per year of execution of the procedure, has demonstrated a significant reduction in the percentage of complications (up to 26.7%) with a statistically significant difference.

Currently, despite the presence of a strong biological and pharmacological rational and the over 10 years application in EOC, the use of HIPEC in the clinical practice continues to receive mixed reviews. The limit to the confidence in this procedure is the lack of randomized clinical trials and the heterogeneity of the different phase II studies conducted, which resulted in a lack of scientific evidence level I-II. Moreover, the finding of high rates of the related morbidity and mortality, has precluded the use of this procedure to many patients with peritoneal disease.

The primary objective of this trial is therefore to assess whether the use of CRS in combination with HIPEC is able to offer an effectively advantage in terms of survival compared to the exclusive optimal CRS, in platinum-sensitive recurrent EOC patients, whom potentially could undergo complete cytoreduction on the basis of the pre-and intraoperative evaluation.

Hyperthermic Intra-peritoneal Chemotherapy (HIPEC) in Ovarian Cancer Recurrence

Surgery Plus Hyperthermic Intra-peritoneal Chemotherapy (HIPEC) Versus Surgery Alone in Patients With Platinum-sensitive First Recurrence of Ovarian Cancer: a Prospective Randomized Multicenter Trial.

The progression-free interval (PFI) will be evaluated from the time of secondary cytoreduction (± HIPEC) to the evidence of a second recurrence of disease.

The overall survival (OS) will be evaluated from the time of secondary cytoreduction ± HIPEC to death or last FU.

Surgical complications and morbidity will be monitored and recorded in special forms both during surgery and during the period of hospital stay. The following complications should be reported to the coordinating center UCSC within 24 hours Events recorded during surgery and up to 60 days of the latter: transfusion of more than 10 units of blood in 24 hours, re-laparotomy for complications, pulmonary embolism, sepsis, death (regardless of cause), new hospitalization for surgical complication.

Events between 60 days and the end of follow-up period: death (regardless of cause).

Catholic University of the Sacred Heart

Direttore del Dipartimento per la Tutela della salute della Donna e della Vita Nascente Università Cattolica del Sacro Cuore-Roma

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Hyperthermia Enhanced Re-irradiation of Loco-regional Recurrent Tumors	NCT04889742	Recurrent Cance... Prostate Cancer Cervical Cancer Anal Cancer Sarcoma Rectal Cancer Neuroendocrine ... Esophageal Canc... Pancreas Cancer Squamous Cell C...	loco-regional h...	18 Years -	Charite University, Berlin, Germany
Hyperthermic Intra-peritoneal Chemotherapy (HIPEC) in Ovarian Cancer Recurrence	NCT01539785	First Recurrenc...	Secondary citor... Hyperthermic in...	18 Years - 70 Years	Catholic University of the Sacred Heart

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