Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Symptoms and General Pathology

Wounds and Injuries

Breast Neoplasms

Hyperthermia

Fever

Breast Diseases

Skin Diseases

Anti-Infective Agents

All Drugs and Chemicals

Antineoplastic Agents

Antirheumatic Agents

Anti-Bacterial Agents

Doxorubicin

Liposomal doxorubicin

Epirubicin

Antibiotics, Antitubercular

Immunologic Factors

Alkylating Agents

Antineoplastic Agents, Alkylating

Enzyme Inhibitors

Preoperative Anthracycline Doxorubicin 60mg/m2 (or Epirubicin 100 mg/m2) + Standard of Care chemotherapy and drugs + Thermotherapy. Thermotherapy at first 3 chemotherapy treatments for Anthracycline chemotherapy nominally every 21±7 days plus Standard of Care chemotherapy.

Preoperative Anthracycline Doxorubicin 60mg/m2 (or Epirubicin 100 mg/m2) + Standard of Care chemotherapy and drugs

Anthracycline Doxorubicin 60mg/m2 (or Epirubicin 100 mg/m2) + Standard of Care chemotherapy and drugs + Thermotherapy. Thermotherapy at first 3 chemotherapy treatments for Anthracycline chemotherapy nominally every 21±7 days plus Standard of Care chemotherapy. (A targeted tumor temperature of 44ºC (plus or minus 1.5ºC) and a targeted thermal dose of 80 equivalent treatment minutes (plus or minus 20 treatment minutes)). In the event that the targeted minimum cumulative thermal dose of 180 equivalent treatment minutes is not achieved in the first three treatments, an optional fourth thermotherapy treatment may be administered in combination with the fourth course of Anthracycline and standard of care chemotherapy. Standard of care (including breast imaging, drugs, and radiation) will be provided to all eligible subjects during and following the above study treatments.

Focused Microwave Thermotherapy

Anthracycline Doxorubicin 60mg/m2 (or Epirubicin 100 mg/m2) + Standard of Care chemotherapy and drugs. Anthracycline chemotherapy nominally every 21±7 days. Standard of care (including breast imaging, drugs, and radiation) will be provided to all eligible subjects during and following the above study treatments.

Chemotherapy (control)

Deborah Moorad-Watts

William C Dooley, MD

John R Keyserlingk, MD

William C. Dooley, MD

John Keyserlingk, MD

The purpose of this randomized Phase III study is to determine whether preoperative focused microwave heat treatment and chemotherapy combined are more effective than preoperative chemotherapy alone in the treatment of large breast cancer tumors in the intact breast. Combining heat with chemotherapy before surgery might shrink the tumor so that it can be removed in a breast conserving surgery (lumpectomy) instead of a mastectomy.

This randomized multicenter Phase III clinical trial is intended to provide histopathological and clinical information on an innovative, minimally-invasive approach (focused microwave thermotherapy) to the preoperative treatment of breast cancer, using a minimally invasive focused microwave phased array device, the Medifocus, Inc. APA 1000 Breast Thermotherapy Treatment System (heat treatment). Subjects with large primary operable breast cancer, in the intact breast, with clinical tumor size greater than or equal to 3.5 cm (including tumor classification T2 or T3), clinically node negative N0 or node positive (N1 or N2) with distant metastasis (M1) or without distant metastasis (M0) will be randomized (ratio 1:1) to receive (1) preoperative thermotherapy combined with preoperative anthracycline-based combination chemotherapy and standard of care versus (2) preoperative anthracycline-based combination chemotherapy and standard of care alone. The anthracycline-based regimen will be limited to those of the current National Comprehensive Cancer Network (NCCN) guidelines for dose/drug/schedule at the time of patient enrollment. In both arms of the study, standard of care including breast imaging, drugs, and radiation therapy will be provided to all eligible subjects during and following the preoperative regimen. At the clinical discretion of the treating physician, subjects that are estrogen-receptor positive may receive Tamoxifen therapy the day following the completion of chemotherapy. Radiation therapy to the breast tissues and lymph nodes will be given as part of the standard of care for eligible subjects. Treatment Arm I (new arm) regimen includes three preoperative thermotherapy treatments at intervals corresponding to the first three cycles of anthracycline-based combination chemotherapy plus standard of care. The addition of preoperative thermotherapy to preoperative anthracycline-based combination chemotherapy may improve the tumor response rate in terms of shrinkage (the primary endpoint) and may increase the option to perform breast conservation (a secondary endpoint) compared to that achieved with preoperative anthracycline-based combination chemotherapy and standard of care alone. Note: Since there is no consensus combination drug regimen for neoadjuvant treatment of large breast cancer tumors, each study site will use its own standard of care which will include other chemotherapy/drug agents commonly used in combination with an anthracycline (Doxorubicin (trade name Adriamycin) or Epirubicin (trade name Ellence)), which is the study base drug type.

The rationale for including patients that have distant metastasis (M1) at enrollment in this study is as follows. Traditionally, patients with stage IV (metastatic) breast cancer and an intact primary breast tumor have been treated with chemotherapy and radiation for palliation of symptoms, because this metastatic condition is considered to be an incurable disease. In some cases, surgery has been considered for stage IV patients with large, symptomatic breast lesions to control local wound complications and to improve quality of life. However, four recent retrospective peer-reviewed studies have suggested that removing the primary tumor may lead to an improvement in overall survival.

The investigator or designee will fully explain the nature of the study to the subject, along with the aims, methods, anticipated benefits, potential hazards and discomfort that participation might entail. After the nature of the study has been explained and all the subject's questions have been answered, and if the subject agrees to participate in the study, the informed consent will be reviewed and signed by the subject.

Each subject will be treated by thermochemotherapy (new arm) or chemotherapy alone (control arm) and followed for 90 days after surgery during the study. Patients will be followed annually as practiced as standard of care by each participating institution - patients will be followed for tumor recurrence and future medical intervention related to the patient's breast cancer.

Thermotherapy is administered in an out-patient setting. During thermotherapy which is completed in approximately 60 minutes or less, the patient is treated in the prone position on a treatment bed. After administering a local anesthetic, to guide the treatment a minimally invasive combination microwave/temperature probe is placed in the tumor under ultrasound guidance. The thermotherapy treatment is adjusted in accordance with patient comfort.

Anthracycline-based chemotherapy will be administered in accordance with standard preoperative chemotherapy delivery at each study center - the number of chemotherapy cycles and cycle timing may vary in this study. Each study center will be using anthracycline (Doxorubicin or Epidoxorubicin) as the base chemotherapy agent and the other chemotherapy agents and drugs will vary depending on the study center and subject specific needs. Each cycle of Doxorubicin at 60 mg/m2 for four cycles or Epidoxorubicin at 100 mg/m2 for 6 cycles and combination Standard of Care chemotherapy will be administered nominally every 21 (plus or minues 7) days. The timing between cycles of anthracycline can be subject specific at the physician's discretion, but in no case will anthracycline be administered with a cycle timing of less than seven (7) days between anthracycline cycles. A thermotherapy session will be administered on the same day as the administration of the first, second, and third cycle of preoperative Doxorubicin or Epidoxorubicin chemotherapy. Chemotherapy will be administered and then the subject will receive thermotherapy. (If the thermotherapy session cannot be administered on the same day as Doxorubicin or Epidoxorubicin chemotherapy it will be administered as soon as possible the following day but no later than 36 hours post Doxorubicin or Epidoxorubicin chemotherapy. The remaining cycle(s) of chemotherapy will then be administered without thermotherapy. If the desired cumulative minimum thermal dose is achieved in the first three thermotherapy treatments, the remaining cycle(s) of chemotherapy will then be administered without thermotherapy. If the desired cumulative minimum thermal dose is not achieved during the first three preoperative Doxorubicin or Epidoxorubicin chemotherapy cycles, thermotherapy will be administered with the fourth cycle of preoperative chemotherapy. If the subject cannot tolerate more than one or two thermotherapy treatments, the subject will continue in the study on the remaining cycles of chemotherapy. If the subject has clinically progressive disease, the thermo-chemotherapy treatment will be discontinued and the subject will receive the remaining cycles of chemotherapy preoperatively or postoperatively (as standard care).

At the end of the course of thermo-chemotherapy or chemotherapy alone, and following all pre-surgery evaluations, the surgeon and subject will make decisions on the extent of surgery to be performed. These decisions will be made on the basis of surgical and institutional standards, and those of the National Comprehensive Cancer Network (NCCN) Breast Cancer Treatment Guidelines. Subjects will undergo mastectomy or breast-conserving surgery. It is understood that some subjects will select mastectomy for treatment even when the surgeon recommends breast conservation. The surgeon shall document the reasons why either mastectomy or breast conservation was selected.

The subject will undergo clinical exam and imaging of the breast to measure tumor size, the day prior to or the day of the lumpectomy or mastectomy. Any additional imaging will be at the discretion of the physician. At the discretion of the physician, an optional core biopsy of the tumor will be taken the day prior or the day of the surgery.

Following surgery, pathology will be performed on the excised breast tumor tissue to determine tumor cell death. For breast conservation, the breast must be of sufficient size to allow adequate tumor removal with a satisfactory cosmetic result. The objective of surgery is to obtain local control of the breast cancer with the best cosmetic result possible. A breast conservation surgery procedure requires excision of the tumor and margins without removal of more normal breast tissue than is required to achieve negative margins. Pathologic evaluation of the excised tissue will determine whether the margins are negative or positive. For subjects with involved margins following breast conservation surgery, if the breast will tolerate it, the subject may undergo one or more further segmental resections in order to achieve clear margins.

Randomized Study of Combination Chemotherapy With or Without Focused Microwave Thermotherapy Before Surgery in Treating Women With Large Breast Cancer Tumors

Randomized Pivotal Trial to Assess the Safety and Efficacy of Preoperative Focused Microwave Thermotherapy Plus Preoperative Chemotherapy Versus Preoperative Chemotherapy Alone for Cytoreduction of Large Breast Cancer in Female Patients With Intact Breast

Evaluate the efficiency of preoperative focused microwave thermotherapy as an adjunct to chemotherapy to increase the ultrasound-measured absolute mean tumor percent shrinkage by volume over that achieved by SOC preoperative chemotherapy.

Evaluate the potential benefits of this combination treatment to increase the absolute rate for which the surgeon can recommend breast conservation (lumpectomy or partial mastectomy) over that achieved using standard of care preoperative chemotherapy alone.

Evaluate the potential benefits of this combination treatment to increase the clinical (caliper-measured) absolute mean tumor shrinkage by area over that achieved by SOC preoperative chemotherapy

Evaluate the potential benefits of the combination treatment to increase the absolute mean tumor shrinkage by area on mammography over the achieved by SOC preoperative chemotherapy

Evaluate the potential benefits of this combination treatment to increase the absolute mean tumor shrinkage by volume based on magnetic resonance imaging (MRI) over that achieved by SOC preoperative chemotherapy.

Evaluate the potential benefits of this combination treatment to increase the absolute mean percent localized pathologic tumor cell kill by volume over that achieved by SOC preoperative chemotherapy.

Medifocus, Inc.

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Neuroendocrine Tumor

Neuroepithelioma

Immunostimulating Interstitial Laser Thermotherapy (imILT)

Immunostimulating Interstitial Laser Thermotherpy (imILT) is a specific form of thermotherapy, which, in addition to destroying tumor tissue, has been optimized to cause a tumor specific immunologic response.

Immunostimulating Interstitial Laser Thermotherapy

Johan Hansson, MD PhD

Thermotherapy is a technology aiming at destroying tissue, for example tumor tissue. Immunostimulating Interstitial Laser Thermotherpy (imILT) is a specific form of thermotherapy, which, in addition to destroying tumor tissue, has been optimized to cause a tumor specific immunologic response. In laboratory animals the imILT method has also been shown to induce a so called abscopal effect. This means that when one tumor is treated with imILT other, untreated, tumors also decrease in size. The immunologic response has previously been characterized in breast cancer patients after receiving imILT treatment , and presumed abscopal effects induced by imILT have also been described in a malignant melanoma patient.

The purpose of this trial is to investigate the functionality and safety of the imILT treatment method in patients diagnosed with malignant melanoma. The inflammatory process, following on the treatment, will also be described in order to provide a more in depth knowledge of the treatment for this indication. The purpose is also to evaluate efficiency when it comes to local tumor destruction as well as understanding of the subsequent immunological effects. Since immunologically based treatment of malignant melanoma is under intense review with so called "immune checkpoint inhibitors" this trial will also provide valuable information on how imILT, in the future, could be combined with these new and, for some patients, very effective treatment regimens.

The treatment method has successfully been used for treatment of patients with breast cancer and malignant melanoma . Treatment of breast cancer patients caused an increase of cytotoxic T lymphocytes in the treated tumor, as well as activated dendritic cells at the tumor border. Regulatory T lymphocytes decreased in the regional lymph nodes.

This trial is explorative, prospective, open and non-randomized. Five malignant melanoma patients stage III - IV will be treated in this trial, which is estimated to be carried out during a time period of 12 months.

Immunostimulating Interstitial Laser Thermotherapy in Malignant Melanoma

Exploratory Study on Immunostimulating Interstitial Laser Thermotherapy in Malignant Melanoma

Evaluation of the laser system by analysis of treatment logs of the device.

Evaluation of the laser system by analysis of user questionnaire.

Measurement of tumor burden by irRC criteria.

Quantification of cellular infiltrate and activation markers by immunohistochemistry and flow cytometry.

Clinical Laserthermia Systems AB

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Digestive System Diseases

Recurrence

Carcinoma

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Peritoneal Neoplasms

Neoplasms, Glandular and Epithelial

Endocrine Gland Neoplasms

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

Endocrine System Diseases

Gonadal Disorders

Ovarian Cancer

Ovarian Epithelial Cancer

Fallopian Tube Cancer

Pharmaceutical Solutions

Cisplatin

Cytoreduction

Hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) with cisplatin

Perfusion of the peritoneum with 42°C warm 25 mg/l cisplatin solution. Perfusion volume depends on body size (3 - 6 l).

If cisplatin amount exceeds the equivalent of 62.5 mg/m² body surface, cisplatin is dosed by body surface (62.5 mg/m²)(safety margin).

Perfusion is performed with the open or Coliseum technique for 90 min.

Perfusion of the peritoneum with 42°C warm 25 mg/l cisplatin solution.

Hyperthermic intraoperative intraperitoneal chemotherapy

Surgical removal of tumor nodules

including resection of organs infested with tumor

Cytoreduction

Cisplatin is applied as chemotherapy during surgery

Markus Lüdin, MD

Most studies performing hyperthermic intraoperative intraperitoneal chemotherapy dose the cytotoxic drugs according to the body surface (like 50 mg/m² cisplatin) in analogy to systemic, intravenous chemotherapy (usually using the same dose). Although there seems to be a correlation between body surface and blood volume, the pharmacodynamics of drugs dosed by the body surface is still highly variable and thus dosing on the body surface is increasingly considered controversial for systemic administration.

For hyperthermic intraoperative intraperitoneal chemotherapy dosing by the body surface makes even less sense, since the aim is the highest possible drug concentration in the peritoneum without undue local and systemic toxicity. Furthermore, most studies using intraoperative chemotherapy vary the volume of the perfusate according to the size of the patient. Since the amount of cytotoxic drug is already fixed by the dosing on the body surface (amount \[mg\] = dose \[mg/m²\] x body surface \[m²\]) the effective concentration (mg/l) in the perfusate can vary considerably between patients. On the other hand pharmacokinetic analyses have shown that reducing the concentration of the cytotoxic drug in the perfusate reduces the efficacy even if the amount of the drug remains the same.

In this study the safety of a new dosing regime will be evaluated. The concentration of cisplatin in the perfusate will be held constant independent of body weight or size to achieve the highest effectiveness of the chemotherapy. The primary endpoint is the safety of the treatment. All patients should be able to receive full dose systemic carboplatin chemotherapy after completion the trial treatment.

Disease Background:

Between 1997 and 2001 the incidence of ovarian cancer in Switzerland was 15.8 per 100'000 women and ranks fifth among the cancer incidence in women. Nearly half of the patients die of the disease leading to a mortality rate of 7.7 per 100'000. Together with pancreatic cancer, ovarian cancer ranks fifth among cancer related deaths in women. The most common form of ovarian cancer is the epithelial ovarian cancer with an incidence of 91.1%. Thus, in the following the term ovarian cancer will refer solely to malignant epithelial ovarian cancer (78.6% of all ovarian cancers) excluding borderline or low malignancy epithelial ovarian tumors (12.5%).

Early stages of the disease (FIGO I - IIA) show practically no symptoms, thus 80% of ovarian cancers are diagnosed at later stages (FIGO IIB - IV), a main reason for the high mortality. Treatment for all stages are surgical removal of visible and resectable tumor nodules, ovaries, uterus, omentum, pelvic and paraaortic lymph nodes, in advanced stages tumor infested organs or organ parts have to be removed (=cytoreduction or debulking). Survival time strongly depends on the completeness of the cytoreduction. Surgery is followed by a chemotherapy of carboplatin and paclitaxel or carboplatin alone (except for the low risk FIGO stage IA, G1).

Published survival rates after therapy vary considerably and are mainly dependent on the stage of the tumor and the remaining tumor size (some tumor masses cannot be resected due to the proximity to vital organs like major blood vessels).

_____Stage______survival after 5 years

* FIGO I........76% - 93%
* FIGO II.......60% - 74%
* FIGO III......23% - 41%
* FIGO IV..........11%

(from J. S. Berek \& N. F. Hacker, Practical Gynecologic Oncology 3ed. Philadelphia: Lippincott Williams \& Wilkins, 2000, 504.)

Even with optimal debulking and adjuvant chemotherapy about 55% of all patients suffer from recurrent ovarian cancer which is considered essentially an incurable disease, since the response rate of a secondary treatment is 30% and the median survival is about 60 weeks.

Therapy background:

Hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC)

Unless the tumor has already metastasized (FIGO IV) ovarian cancer tumor nodules are restricted to the peritoneal cavity. Since standard chemotherapy is applied intravenously the cytotoxic drugs can reach the cancer cells only by diffusion into the peritoneum or via the blood stream by the sometimes poor vascularisation of the tumor nodules. To improve the exposure of the tumor to the cytotoxic drugs clinical trials were performed to deliver the chemotherapy directly into the peritoneum (intraperitoneal chemotherapy). While this type of therapy shows very promising results, it also has some serious drawbacks: permanent catheters have to be implanted, even distribution of the instillate is difficult and sometimes linked with considerable discomfort for the patient.

Alternatively the intraperitoneal chemotherapy can be applied directly after the cytoreductive surgery (intraoperative intraperitoneal chemotherapy). Since the peritoneum is completely opened, the perfusate can easily reach all surfaces and the surgeon can facilitate the distribution by gentle agitation with his hands. Since the whole procedure is performed during the surgery under full anesthesia the patient does not have to suffer additional discomfort. While intraperitoneal chemotherapy can be applied repeatedly like conventional chemotherapy, the intraoperative chemotherapy can only be performed once. Thus, the effectiveness of the treatment should be as high as possible. This can be achieved by using the highest possible drug concentration and by increasing the temperature of the perfusate to approximately 42°C (hyperthermic intraoperative intraperitoneal chemotherapy). The rational for the hyperthermic treatment is several fold. First, it has been shown that some tumors can be killed by elevated temperatures alone. Second, the elevated temperatures increase the diffusion rate of the drugs into the tumor and thus the drug can penetrate deeper into the tumor nodules. Furthermore, elevated temperatures increase the cell membrane permeability and thus the uptake of the cytotoxic drugs by the tumor cells. Finally, with some cytotoxic drugs, like cisplatin, the cytotoxicity can be increased about 50 fold by a temperature increase from 37°C to 42°C in tissue culture models.

Rationale for performing the trial:

Most studies performing hyperthermic intraoperative intraperitoneal chemotherapy dose the cytotoxic drugs according to the body surface (like 50 mg/m² cisplatin) in analogy to systemic, intravenous chemotherapy (usually using the same dose). Although there seems to be a correlation between body surface and blood volume, the pharmacodynamics of drugs dosed by the body surface is still highly variable and thus dosing on the body surface is increasingly considered controversial for systemic administration. However, only very few drugs are dosed differently, e.g. carboplatin.

For hyperthermic intraoperative intraperitoneal chemotherapy dosing by the body surface makes even less sense, since the aim is the highest possible drug concentration in the peritoneum without undue local and systemic toxicity. Furthermore, most studies using intraoperative chemotherapy vary the volume of the perfusate according to the size of the patient. Since the amount of cytotoxic drug is already fixed by the dosing on the body surface (amount \[mg\] = dose \[mg/m²\] x body surface \[m²\]) the effective concentration (mg/l) in the perfusate can vary considerably between patients. On the other hand pharmacokinetic analyses have shown that reducing the concentration of the cytotoxic drug in the perfusate reduces the efficacy even if the amount of the drug remains the same.

In this study the safety of a new dosing regime will be evaluated. The concentration of cisplatin in the perfusate will be held constant independent of body weight or size to achieve the highest effectiveness of the chemotherapy. However, if the amount of cisplatin would exceed the equivalent of 62.5 mg/m² body surface, dosing would be again based on the body surface (62.5 mg/m²) for safety reasons.

The primary endpoint is the safety of the treatment. All patients should be able to receive full dose systemic carboplatin chemotherapy after completion the trial treatment.

Treatment plan:

Patients undergo cytoreductive surgery to remove all visible tumor nodules.

After the cytoreduction the hyperthermic intraoperative intraperitoneal chemotherapy is performed. For 90 min 42°C warm cisplatin solution (25 mg/l) is perfused through the peritoneum. Afterwards cisplatin will be removed by repeatedly rinsing the peritoneum with Ringer lactate solution. During the whole procedure the patient will receive a strong hydration according to a predefined protocol.

Cisplatin pharmacokinetics:

The concentration of platinum will be determined in perfusate, plasma and urine at various time points.

Various published pharmacokinetic models of cisplatin clearance will be tested with the data obtained. Furthermore, we want to test whether pharmacokinetic parameters might correlate with nephrotoxicity to allow a prediction of nephrotoxic events.

Translational research:

Tumor tissue removed during the cytoreduction will be used for various in vitro experiments:

* Histological examination for infiltrating lymphocytes and determination of the lymphocytes
* Determine the depth of platinum infiltration after treatment of the tumor nodules under various conditions with cisplatin (in vitro)
* Analysis of tumor cell biology after chemotherapy and heat treatment in vitro (protein phosphorylation, release of second messengers)

Hyperthermic Intraoperative Intraperitoneal Chemotherapy of Recurrent Ovarian Cancer - A Feasibility Study

Are patients fit to receive six courses of systemic carboplatin chemotherapy after completion of trial.

If chemotherapy starts within 3 months after surgery and at least 4 courses could be administered, patient is considered fit.

If chemotherapy is stopped early for reasons clearly unrelated to study treatment (e.g. platinum resistance), patient is also considered fit.

any serious surgical event (Dindo scale \>= III (reoperation required) or CTCAE grade \>=3)

Cantonal Hospital of St. Gallen

Oberarzt

Hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC)

HIPEC

Age, Categorical

Age, Continuous

Sex: Female, Male

Switzerland

Region of Enrollment

Sascha Müller, MD

Fitness for Systemic Chemotherapy

no nephrotoxicity (normal GFR)

CTCAE grade 1 nephrotoxicity (by GFR)

Nephrotoxicity

Surgical Complications

Overall Survival

Pharmacokinetics

Hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC)

Tumor nodules are removed surgically. If necessary infested organs like colon are resected (=cytoreduction).

To destroy remaining tumor cells or invisible nodules the peritoneum is prefused with 42°C warm 25 mg/l cisplatin solution. Perfusion volume depends on body size (3 - 6 l).

If cisplatin amount exceeds the equivalent of 62.5 mg/m² body surface, cisplatin is dosed by body surface (62.5 mg/m²)(safety margin).

Perfusion is performed with the open or Coliseum technique for 90 min.

Overall Study

Immunostimulating Interstitial Laser Thermotherapy (imILT) is a specific form of thermotherapy, which, in addition to destroying tumor tissue, has been optimized to cause a tumor specific immunologic response.

Thermotherapy is a technology aiming at destroying tissue, for example tumor tissue. Immunostimulating Interstitial Laser Thermotherapy (imILT) is a specific form of thermotherapy, which, in addition to destroying tumor tissue, has been optimized to cause a tumor specific immunologic response. In laboratory animals the imILT method has also been shown to induce a so called abscopal effect. This means that when one tumor is treated with imILT other, untreated, tumors also decrease in size. The immunologic response has previously been characterized in breast cancer patients after receiving imILT treatment , and presumed abscopal effects induced by imILT have also been described in a malignant melanoma patient.

The purpose of this trial is to evaluate efficiency when it comes to local tumor destruction of the imILT treatment method in patients diagnosed with solid tumors. The purpose is also to investigate the functionality and safety as well as understanding of the subsequent immunological effects. Since immunologically based treatment of various solid tumors is under intense review with so called "immune checkpoint inhibitors" this trial will also provide valuable information on how imILT, in the future, could be combined with these new and, for some patients, very effective treatment regimens.

The treatment method has successfully been used for treatment of patients with breast cancer and malignant melanoma. Treatment of breast cancer patients caused an increase of cytotoxic T lymphocytes in the treated tumor, as well as activated dendritic cells at the tumor border. Regulatory T lymphocytes decreased in the regional lymph nodes.

This trial is explorative, prospective, open and non-randomized. Thirty patients diagnosed with solid tumors will be treated in this trial, which is estimated to be carried out during a time period of 18 months.

Immunostimulating Interstitial Laser Thermotherapy in Solid Cancers

To Evaluate the Safety & Palliative Treatment Effect on Patients With Solid Cancers by Immunostimulating Interstitial Laser Thermotherapy (imILT)

Quantification of cellular infiltrate and activation markers by immunohistochemistry.

Quantification of cellular infiltrate and activation markers by flow cytometry.

Evaluation of pain is performed using the visual analog scale (VAS).

Evaluation of Quality of Life is evaluated using a standardized questionnaire (EORTC, general).

Colorectal Neoplasms

Adenocarcinoma

Neoplasm Metastasis

Disease Progression

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Neoplastic Processes

Abdominal Neoplasms

Peritoneal Diseases

Micronutrients

Oxaliplatin

Bevacizumab

Leucovorin

Fluorouracil

Irinotecan

Capecitabine

Mitomycins

Mitomycin

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

At the discretion of the treating physician, perioperative systemic therapy consists of either four 3-weekly neoadjuvant and adjuvant cycles of capecitabine with oxaliplatin (CAPOX), six 2-weekly neoadjuvant and adjuvant cycles of 5-fluorouracil/leucovorin with oxaliplatin (FOLFOX), or six 2-weekly neoadjuvant cycles of 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) followed by either four 3-weekly (capecitabine) or six 2-weekly (5-fluorouracil/leucovorin) adjuvant cycles of fluoropyrimidine monotherapy. Bevacizumab is added to the first three (CAPOX) or four (FOLFOX/FOLFIRI) neoadjuvant cycles.

CRS-HIPEC is performed according to the Dutch protocol in all study centres.

CRS-HIPEC is performed according to the Dutch protocol in all study centres.

Neoadjuvant systemic therapy should start within four weeks after randomisation. Adjuvant systemic therapy should start within twelve weeks after CRS-HIPEC. In case of unacceptable toxicity or contraindications to oxaliplatin or irinotecan in the neoadjuvant setting, CAPOX or FOLFOX may be switched to FOLFIRI and vice versa. In case of unacceptable toxicity or contraindications to oxaliplatin in the adjuvant setting, CAPOX of FOLFOX may be switched to fluoropyrimidine monotherapy. Dose reduction, prohibited concomitant care, permitted concomitant care, and strategies to improve adherence are not specified a priori, but left to the discretion of the treating medical oncologist. Perioperative systemic therapy can be prematurely discontinued due to radiological or clinical disease progression, unacceptable toxicity, physicians decision, or at patients request.

Perioperative systemic therapy

Four three-weekly neoadjuvant and adjuvant cycles of CAPOX (130 mg/m2 body-surface area \[BSA\] of oxaliplatin, intravenously \[IV\] on day 1; 1000 mg/m2 BSA of capecitabine, orally twice daily on days 1-14), with bevacizumab (7.5 mg/kg body weight, IV on day 1) added to the first three neoadjuvant cycles.

Perioperative CAPOX-bevacizumab

Six two-weekly neoadjuvant and adjuvant cycles of FOLFOX (85 mg/m2 body-surface area \[BSA\] of oxaliplatin, intravenously \[IV\] on day 1; 400 mg/m2 BSA of leucovorin, IV on day 1; 400/2400 mg/m2 BSA of bolus/continuous 5-fluorouracil, IV on day 1-2), with bevacizumab (5 mg/kg body weight, IV on day 1) added to the first four neoadjuvant cycles.

Perioperative FOLFOX-bevacizumab

Six two-weekly neoadjuvant cycles of FOLFIRI (180 mg/m2 body-surface area \[BSA\] of irinotecan, intravenously \[IV\] on day 1; 400 mg/m2 BSA of leucovorin, IV on day 1; 400/2400 mg/m2 BSA of bolus/continuous 5-fluorouracil, IV on day 1-2) and either four three-weekly (capecitabine (1000 mg/m2 BSA, orally twice daily on days 1-14) or six two-weekly (400 mg/m2 BSA of leucovorin, IV on day 1; 400/2400 mg/m2 BSA of bolus/continuous 5-fluorouracil, IV on day 1-2) adjuvant cycles of fluoropyrimidine monotherapy, with bevacizumab (5 mg/kg body weight, IV on day 1) added to the first four neoadjuvant cycles.

Perioperative FOLFIRI-bevacizumab

CRS-HIPEC is performed according to the Dutch protocol in all study centres. The choice of HIPEC medication (oxaliplatin or mitomycin C) is left to the discretion of the treating physician, since neither one has a favourable safety or efficacy. CRS-HIPEC should be performed within six weeks after completion of neoadjuvant systemic therapy, and at least six weeks after the last administration of bevacizumab in order to minimise the risk of bevacizumab-related postoperative complications.

CRS-HIPEC, experimental arm

CRS-HIPEC is performed according to the Dutch protocol in all study centres. The choice of HIPEC medication (oxaliplatin or mitomycin C) is left to the discretion of the treating physician, since neither one has a favourable safety or efficacy. CRS-HIPEC should be performed within six weeks after randomisation.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Randomized Study of Combination Chemotherapy With or Without Focused Microwave Thermotherapy Before Surgery in Treating Women With Large Breast Cancer Tumors	NCT01204801	Breast Cancer	Focused Microwa... Chemotherapy (c...	18 Years -	Medifocus, Inc.
Immunostimulating Interstitial Laser Thermotherapy in Malignant Melanoma	NCT02650492	Melanoma Malignant Melan...	Immunostimulati...	18 Years -	Clinical Laserthermia Systems AB
Hyperthermic Intraoperative Intraperitoneal Chemotherapy of Recurrent Ovarian Cancer - A Feasibility Study	NCT00968799	Epithelial Ovar... Fallopian Tube ...	Hyperthermic in... Cytoreduction Cisplatin	18 Years - 70 Years	Cantonal Hospital of St. Gallen
Randomized Study of Combination Chemotherapy With or Without Focused Microwave Thermotherapy Before Surgery in Treating Women With Large Breast Cancer Tumors	NCT01204801	Breast Cancer	Focused Microwa... Chemotherapy (c...	18 Years -	Medifocus, Inc.
Immunostimulating Interstitial Laser Thermotherapy in Solid Cancers	NCT02690428	Neoplasms	Immunostimulati...	18 Years -	Clinical Laserthermia Systems AB
Perioperative Systemic Therapy for Isolated Resectable Colorectal Peritoneal Metastases	NCT02758951	Colorectal Neop... Colorectal Canc... Colorectal Neop... Colorectal Carc... Colorectal Aden... Peritoneal Neop... Peritoneal Carc... Peritoneal Canc... Peritoneal Meta... Peritoneal Neop... Peritoneal Neop...	Perioperative s... Perioperative C... Perioperative F... Perioperative F... CRS-HIPEC, expe... CRS-HIPEC, cont...	18 Years -	Catharina Ziekenhuis Eindhoven
Immunostimulating Interstitial Laser Thermotherapy in Pancreatic Cancer	NCT02973217	Neoplasms Pancr...	Immunostimulati...	18 Years - 80 Years	Clinical Laserthermia Systems AB

Spots Global Cancer Trial Database for hyperthermia, induced