Login| Sign Up| Help| Contact|

Patent Searching and Data

Document Type and Number:
WIPO Patent Application WO/2014/174395
Kind Code:
This invention addresses the most prevalent and deadly cancers, lung cancer. Treatment today for lung cancer is limited and prognosis is poor. In this invention, a new approach to meeting the goal improving the treatment of lung cancer is provided.

Application Number:
Publication Date:
October 30, 2014
Filing Date:
April 07, 2014
Export Citation:
Click for automatic bibliography generation   Help
International Classes:
A61N7/02; A61K9/00; A61M16/00
Foreign References:
Other References:
"Merck Manual Professional Edition", 15 August 2007, article "Lung Carcinoma: Tumours of the Lungs"
COLLINS, LG; HAINES C; PERKEL R; ENCK RE: "Lung cancer: diagnosis and management", AMERICAN FAMILY PHYSICIAN (AMERICAN ACADEMY OF FAMILY PHYSICIANS, vol. 75, no. 1, January 2007 (2007-01-01), pages 56 - 63
FERLAY, J; SHIN HR; BRAY F ET AL.: "Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008", INTERNATIONAL JOURNAL OF CANCER, vol. 127, no. 12, December 2010 (2010-12-01), pages 2893 - 2917
VAN DER ZEE J: "Heating the patient: a promising approach?", ANNALS OF ONCOLOGY, vol. 13, no. 8, 2002, pages 1173 - 1184
WUST P; HILDEBRANDT B; SREENIVASA G: "Hyperthermia in combined treatment of cancer", THE LANCET ONCOLOGY, vol. 3, no. 8, 2002, pages 487 - 497
CHANG E; ALEXANDER HR; LIBUTTI SK ET AL.: "Laparoscopic continuous hyperthermic peritoneal perfusion", JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS, vol. 193, no. 2, 2001, pages 225 - 229
FALK MH; ISSELS RD.: "Hyperthermia in oncology", INTERNATIONAL JOURNAL OF HYPERTHERMIA, vol. 17, no. 1, 2001, pages 1 - 18
CLINE HE ET AL.: "MR-guided focused ultrasound surgery", JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY, vol. 16, no. 6, 1992, pages 956 - 65
CLARK LC; GOLLAN F.: "Survival of mammals breathing organic liquids equilibrated with oxygen at atmospheric pressure", SCIENCE, vol. 152, 1966, pages 1755 - 6
GREENSPAN JS; WOLFSON MR; RUBINSTEIN S. D.; SHAFFER TH.: "Liquid ventilation of human pre-term neonates", J PEDIATR, vol. 117, 1990, pages 106 - 11
GAUGER PG; PRANIKOFF T; SCHREINER RJ; MOLER FW; HIRSCHL RB.: "Initial experience with partial liquid ventilation in pediatric patients with acute respiratory distress syndrome", CRIT CARE MED, vol. 24, 1996, pages 16 - 22
HIRSCHL RB; PRANIKOFF T; GAUGER P.: "Liquid ventilation in adults, children and full term neonates", LANCET, vol. 346, 1995, pages 1201 - 2
LI C ET AL.: "Breast cancer", 28 May 2010, WILEY INTERSCIENCE, article "Noninvasive Treatment of Malignant Bone Tumors Using High-Intensity Focused Ultrasound"
SUNG H. K. ET AL.: "The potential role of dynamic MRI in assessing the effectiveness of high-intensity focused ultrasound ablation of breast cancer", INT. J. HYPERTHERMIA, vol. 26, no. 6, September 2010 (2010-09-01), pages 594 - 603
ORGERA G ET AL.: "High-Intensity Focused Ultrasound Effect in Breast Cancer Nodal Metastasis", RADIOL MED, vol. 116, 2011, pages 734 - 748
LESLIE T. ET AL.: "High-Intensity Focused Ultrasound for Hepatocellular Carcinoma: A Single-Center Experience", THE BRITISH JOURNAL OF RADIOLOGY, vol. 85, 2012, pages 1363 - 1370
NG K.K. ET AL.: "High Intensity Focused Ultrasound for Hepatocellular Carcinoma", ANN SURG., vol. 253, no. 5, May 2011 (2011-05-01), pages 981 - 7
G ORGERA ET AL.: "Ultrasound-Guided High-Intensity Focused Ultrasound (USgHIFU) Ablation in Pancreatic Metastasis from Renal Cell Carcinoma", CARDIOVASC INTERVENT RADIOL., 20 October 2011 (2011-10-20)
ORGERA G. ET AL.: "High Intensity Focused Ultrasound Ablation of Pancreatic Neuroendocrine Tumours: Report of Two Cases", CARDIOVASC INTERVENT RADIOL, 2010
PANCREAS, vol. 40, 2011, pages 1080Y1086
WANG Y. ET AL.: "Ultrasound-guided high intensity focused ultrasound treatment for extra-abdominal desmoid tumours: Preliminary results", INT. J. HYPERTHERMIA, vol. 27, no. 7, November 2011 (2011-11-01), pages 648 - 653
RITCHIE, R. W ET AL.: "Extracorporeal high intensity focused ultrasound for renal tumours: a 3-year follow-up", JOURNAL COMPILATION 2010 BJU INTERNATIONAL, vol. 106, 2010, pages 1004 - 1009
SHEHATA I. A.: "Treatment with high intensity focused ultrasound: Secrets revealed", EUROPEAN JOURNAL OF RADIOLOGY, vol. 81, 2012, pages 534 - 541
ORGERA, G ET AL.: "High-intensity focused ultrasound (HIFU) in patients with solid malignancies: evaluation of feasibility, local tumour response and clinical results", RADIOL MED, vol. 116, 2011, pages 734 - 748
ORSI, F. ET AL.: "High-Intensity Focused Ultrasound Ablation: Effective and Safe Therapy for Solid Tumors in Difficult Locations", AJR 2010, vol. 195, 2010, pages W245 - W252
ILLING, R.O. ET AL.: "The safety and feasibility of extra-corporeal high-intensity focused ultrasound (HIFU) for the treatment of liver and kidney tumours in a Western population", BRITISH JOURNAL OF CANCER, vol. 93, 2005, pages 890 - 895
ZHANG Y ET AL.: "Enhancement of anti-tumor vaccine in ablated hepatocellular carcinoma by high-intensity focused ultrasound", WORLD J GASTROENTEROL, vol. 16, no. 28, 28 July 2010 (2010-07-28), pages 3584 - 3591
HANCOCK, J.B. ET AL.: "Using liquid ventilation to improve lung function in patients with respiratory distress syndrome: A comprehensive review of the literature", AANA JOURNAL, vol. 72, no. 3, June 2004 (2004-06-01)
Attorney, Agent or Firm:
ROLAND, André (P.O. Box 5107, Lausanne, CH)
Download PDF:

1. A method for treating tumours of the lung in a warm blooded creature comprising:

a) replacing the air in the lung(s) in a transient manner, with a liquid;

b) employing high energy, focused ultrasound to eliminate visible carcinomas of the lung, and c) employing whole or partial-lung hyperthermia at between 42 and 45 degrees C for a period of time;

d) removing liquid from the lung(s) and replacing it with air.

2. The method of Claim 1 where the warm blooded creature is a human being.

3. The method of Claim 1 combining the use of a High Intensity Focused Ultrasound machine with a machine for the transient replacement of air in a lung(s), with an appropriate life support system.

4. The method of Claim 1 where the air replacement liquid introduced in the lung(s) is a fluorinated hydrocarbon, such as (but not limited to) FX-80, FC-75, FC-43, FC-77, FC-75, FC- 3280, Rimar 101, Perfluorodecalin, Perflubron, LiquiVent.

5. The method of Claim 1 employing high energy, focused ultrasound to remove visible carcinomas of the lung employing ultrasound visual surveillance.

6. The method of Claim 1 employing high energy, focused ultrasound to remove visible carcinomas of the lung employing MRI visual surveillance.

7. The method of Claim 1 where one is employing lung hyperthermia at between 42 and 50 degrees C for a period of one hour.

8. The method of Claim 1 where part of, or the entire procedure, is repeated.

9. The method of Claim 3 where the lung hyperthermia is performed at between 42 and 50 degrees C for a period between 30 minutes and two hours.

10. The method of Claim 3 where the treatment protocol is performed without prior employment of high energy, focused ultrasound to remove visible carcinomas of the lung.

11. The method of Claim 3 where the treatment protocol is followed up with radiotherapy.

12. The method of Claim 3 where the treatment protocol is followed up with chemotherapy.

13. The method of Claim 3 where the treatment protocol is followed up with radiotherapy and chemotherapy.

14. Medical device comprising all the elements which are required to carry out the method of anyone of the previous claims.

Lung cancer treatment


The invention relates to the treatment of lung cancer. It more precisely relates on the use of high ultrasound energy in such a treatment.


Lung cancer is a disease characterized by uncontrolled cancerous cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung, in a process called metastasis, into nearby tissue and eventually, to other parts of the body. Most cancers that start in the lung, known as primary lung cancers, are carcinomas that derive from epithelial cells. The main types of lung cancer are small-cell lung carcinoma (SCLC), also called oat cell cancer, and non-small-cell lung carcinoma (NSCLC). The most common cause of lung cancer is long-term exposure to tobacco smoke [Lung Carcinoma: Tumours of the Lungs". Merck Manual Professional Edition, Online edition. Retrieved 2007-08-15], and which causes 80-90% of lung cancers. Non-smokers account for 10-15% of lung cancer cases, and these cases are often attributed to a combination of genetic factors, radon gas, asbestos, and air pollution including second-hand smoke.

The most common symptoms are coughing (including coughing up blood), weight loss and shortness of breath. Lung cancer may be seen on chest radiography and by computed tomography (CT) scan. The diagnosis is confirmed with a biopsy. This is usually performed by using bronchoscopy or CT-guided biopsy. Treatment and prognosis depend on the histological type of cancer, the stage (degree of spread), and the patient's general well-being, measured by performance status. Common treatments include surgery, chemotherapy, and radiotherapy. NSCLC is sometimes treated with surgery, whereas SCLC usually responds better to chemotherapy and radiotherapy.

Survival depends on stage, overall health, and other factors. Overall, 15% of people in the United States diagnosed with lung cancer survive five years after the diagnosis [Collins, LG; Haines C, Perkel R, Enck RE (January 2007). "Lung cancer: diagnosis and management". American Family Physician (American Academy of Family Physicians) 75 (1): 56-63]. Worldwide, lung cancer is the most common cause of cancer-related deaths in men and women, and is responsible for 1.38 million deaths annually, as of 2008 [Ferlay, J; Shin HR, Bray F et al. (December 2010). "Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008". International Journal of Cancer 127 (12): 2893-2917]. In the early eighties, it became clear that SCLC was an extremely sensitive tumour to radiation and to chemotherapeutic agents. With cisplatinum etyoposide combinations or cyclophosphamide, anthracycline and vincristine/etyoposide regimens responses were observed in 50-70%, with 20-30% complete remissions in extensive disease. For limited stage patients chemotherapy associated with thoracic radiation was able to produce a cure rate of 10-20%. But despite these early good results no breakthrough came later on, and in the last decade or so, we are still facing this plateau. New agents have recently been included in the therapeutic armament, such as gemcitabine, irinotecan, paclitaxel. This fact has allowed many patients to receive a relatively active second line therapy, but the overall survival remains unchanged. Targeted therapies are undergoing some evaluations, but the data are too premature and so far quite discouraging. At the present time there is an urgent need to improve clinical research in this somehow forgotten, and for a lack of treatment, disease.

Lung cancer is the most common cause of death from cancer in both men and women in the United States. Despite new treatments, survival from non-small cell types of lung cancer— the most common form of the disease— averages less than one year. [The Lung Association].

In the United States there has been a steady rise in the age-adjusted national death rate from pulmonary related diseases. The overwhelmingly predominant contributor to this trend is lung cancer. Currently about 8% of all deaths in the industrialized world are attributed to lung cancer. In the United States, an estimated 155,000 new cases of lung cancer are currently diagnosed each year, and about 142,000 will die of the disease, about 1 death every 4 minutes! Only about 10% of the patients currently diagnosed with lung cancer will survive beyond 5 years.

Targeted therapies are a newer treatment for certain kinds of non-small cell lung carcinoma (NSCLC). They come as a pill you take once a day.

In Canada, two targeted therapies have been approved for non-small cell lung cancer treatment, gefitinib (Iressa©) and erlotinib (Tarceva©).

Gefitinib (Iressa) and erlotinib (Tarceva) belong to a group of medicines called "growth factor receptor tyrosine kinase inhibitors". They prevent the activation of a protein called epidermal growth factor receptor (EGFR) that spans the outer wall of cells. Normally, activation of EGFR protein sends signals to the inside of cells to make them divide. Gefitinib and erlotinib interfere with this protein. This helps stop the cancer cells from growing and spreading.

Gefitinib and erlotinib will work best in people whose cancer cells have a specific genetic mutation, called "activating mutations of the epidermal growth factor receptor tyrosine kinase" ("EGFR-TK" for short). However, these targeted medicines are used in cancer patients who have the mutation and those whose mutational status is unknown (i.e. those who have not been tested for the mutation).

Erlotinib hydrochloride (Tarceva) has been employed for adults with non-small cell lung cancer at an advanced stage who have tried chemotherapy, but where the chemotherapy did not help stop the cancer. Gefitinib (Iressa) was first approved for adult patients with advanced non-small cell lung cancer who were not helped by other treatments. It has also recently been approved in Canada for the initial (first- line) treatment of adult patients who are non-smokers or previous light smokers who have the adenocarcinoma type of non-small cell lung cancer and whose cancer has spread around the lungs or to other parts of the body (metastasized)

Currently, provincial health plans and private plans do not cover the cost of gefitinib (Iressa) as first- line treatment, and hospitals do not usually test patients to see if they have the Epidermal Growth Factor Receptor tyrosine kinase (EGFR-TK) mutations.

Doctors are discovering new ways to diagnose and treat lung cancer, giving people a better chance of recovery than before. But lung cancer is still one of the deadliest of cancers. Canadian women with lung cancer have an average five-year survival rate of 18%. In other words, 18% of women diagnosed with lung cancer are likely to be still alive five years after their diagnosis. Canadian men with lung cancer have an average five-year survival rate of 13%.


This invention is based on combining three technologies, namely hyperthermia, focused ultrasound therapy and the transitory replacement of air in the patient's lung((s) by an oxygen providing and carbon dioxide removing liquid.Hyperthermia.

Hyperthermia (also called thermal therapy or thermo-therapy) is a type of cancer treatment in which body tissue is exposed to high temperatures (up to 113°F) (National Cancer Institute Fact Sheet). Research has shown that high temperatures can damage and kill cancer cells, usually with minimal injury to normal tissues. By killing cancer cells and damaging proteins and structures within cells, hyperthermia may shrink tumours.

Hyperthermia is under study in clinical trials but is not widely available.

Hyperthermia is almost always used with other forms of cancer therapy, such as radiation therapy and chemotherapy [van der Zee J. Heating the patient: a promising approach? Annals of Oncology 2002; 13(8): 1173— 1184] [Wust P, Hildebrandt B, Sreenivasa G Hyperthermia in combined treatment of cancer. The Lancet Oncology 2002; 3(8):487-497]. Hyperthermia may make some cancer cells more sensitive to radiation or harm other cancer cells that radiation cannot damage. When hyperthermia and radiation therapy are combined, they are often given within an hour of each other. Hyperthermia can also enhance the effects of certain anticancer drugs.

Numerous clinical trials have studied hyperthermia in combination with radiation therapy and/or chemotherapy. These studies have focused on the treatment of many types of cancer, including sarcoma, melanoma, and cancers of the head and neck, brain, lung, esophagus, breast, bladder, rectum, liver, appendix, cervix, and peritoneal lining (mesothelioma). Many of these studies, but not all, have shown a significant reduction in tumour size when hyperthermia is combined with other treatments. However, not all of these studies have shown increased survival in patients receiving the combined treatments.

Several methods of hyperthermia are currently under study, including local, regional, and whole-body hyperthermia [Chang E, Alexander HR, Libutti SK, et al. Laparoscopic continuous hyperthermic peritoneal perfusion. Journal of the American College of Surgeons 2001 ; 193 (2): 225-229].

In local hyperthermia, heat is applied to a small area, such as a tumour, using various techniques that deliver energy to heat the tumour. Different types of energy may be used to apply heat, including microwave, radiofrequency, and ultrasound. Depending on the tumour location, there are several approaches to local hyperthermia: External approaches are used to treat tumours that are in or just below the skin. External applicators are positioned around or near the appropriate region, and energy is focused on the tumour to raise its temperature. Intraluminal or endocavitary methods may be used to treat tumours within or near body cavities, such as the esophagus or rectum. Probes are placed inside the cavity and inserted into the tumour to deliver energy and heat the area directly.

Interstitial techniques are used to treat tumours deep within the body, such as brain tumours. This technique allows the tumour to be heated to higher temperatures than external techniques. Under anaesthesia, probes or needles are inserted into the tumour. Imaging techniques, such as ultrasound, may be used to make sure the probe is properly positioned within the tumour. The heat source is then inserted into the probe. Radio frequency ablation (RFA) is a type of interstitial hyperthermia that uses radio waves to heat and kill cancer cells.

In regional hyperthermia, various approaches may be used to heat large areas of tissue, such as a body cavity, organ, or limb. Deep tissue approaches may be used to treat cancers within the body, such as cervical or bladder cancer. External applicators are positioned around the body cavity or organ to be treated, and microwave or radio frequency energy is focused on the area to raise its temperature. Regional perfusion techniques can be used to treat cancers in the arms and legs, such as melanoma, or cancer in some organs, such as the liver or lung. In this procedure, some of the patient's blood is removed, heated, and then pumped (perfused) back into the limb or organ. Anticancer drugs are commonly given during this treatment (National Cancer Institute Fact Sheet).

Continuous hyperthermic peritoneal perfusion (CHPP) is a technique used to treat cancers within the peritoneal cavity, including primary peritoneal mesothelioma and stomach cancer. During surgery, heated anticancer drugs flow from a warming device through the peritoneal cavity. The peritoneal cavity temperature reaches 106-108°F

Whole-body hyperthermia is used to treat metastatic cancer that has spread throughout the body. This can be accomplished by several techniques that raise the body temperature to 107-108°F, including the use of thermal chambers or hot water blankets (National Cancer Institute Fact Sheet).

The effectiveness of hyperthermia treatment is related to the temperature achieved during the treatment, as well as the length of treatment and cell and tissue characteristics. To ensure that the desired temperature is reached, but not exceeded, the temperature of the tumour and surrounding tissue is monitored throughout hyperthermia treatment [Falk MH, Issels RD. Hyperthermia in oncology.

International Journal of Hyperthermia 2001; 17(1): 1—18]. Using local anaesthesia, the doctor inserts small needles or tubes with tiny thermometers into the treatment area to monitor the temperature.

Imaging techniques, such as CT (computed tomography), may be used to make sure the probes are properly positioned.Focused Ultrasound Cancer Therapy.

Various groups have been involved in Focused ultrasound cancer therapy developments over a number of years. This technology is also referred to as non-invasive surgery.

The first investigations of HJFU for non-invasive ablation were reported by Lynn et al. in the early 1940s. Extensive important early work was performed in the 1950s and 1960s by William Fry and Francis Fry at the University of Illinois and Carl Townsend, Howard White and George Gardner at the Interscience Research Institute of Champaign, 111., culminating in clinical treatments of neurological disorders. In particular High Intensity ultrasound and ultrasound visualization was accomplished stereotaxically with a Cincinnati Milacron precision milling machine to perform accurate ablation of brain tumours. Until recently, clinical trials of HIFU for ablation were few (although significant work in hyperthermia was performed with ultrasonic heating), perhaps due to the complexity of the treatments and the difficulty of targeting the beam noninvasively. With recent advances in medical imaging and ultrasound technology, interest in HIFU ablation of tumours has increased.

The first commercial HIFU machine, called the Sonablate 200, was developed by the American company Focus Surgery, Inc. (Milipitas, CA) and launched in Europe in 1994 after receiving CE approval, bringing a first medical validation of the technology for benign prostatic hyperplasia (BPH). Comprehensive studies by practitioners at more than one site using the device demonstrated clinical efficacy for the destruction of prostatic tissue without blood loss or long term side effects. Later studies on localized prostate cancer by Murat and colleagues at the Edouard Herriot Hospital in Lyon in 2006 showed that after treatment with the Ablatherm (EDAP TMS, Lyon, France), progression-free survival rates are very high for low- and intermediate- risk patients with recurrent prostate cancer (70% and 50% respectively) [F-J Murat, L Poissonier and A Gelet (2006). "Recurrent Prostate Cancer After Radiotherapy - Salvage Treatment by High Intensity Focused Ultrasound]. HIFU treatment of prostate cancer is currently an approved therapy in Europe, Canada, South Korea, Australia, and elsewhere. A Multicenter Clinical Study of the Sonablate® 500 (SB-500) for the Treatment of Localized (Tlc/T2a) Prostate Cancer With HIFU is ongoing.

Magnetic Resonance Guided Focused Ultrasound MRgFUS was first cited in the article "On-line MRI monitored non-invasive ultrasound" by Hynynen et al., in Proceedings of the annual international conference of the IEEE engineering in medicine and biology society, October 1992. "MR-guided focused ultrasound surgery"], [Cline HE et al., Journal of Computer Assisted Tomography. 1992, 16(6): 956-65] was published at nearly the same time. U.S. Patent #5247935 had been previously filed on March 19, 1992. The technology was later transferred to InsighTec in Haifa Israel in 1998. The InsighTec ExAblate 2000 was the first MR Guided focused ultrasound system to obtain FDA market approval in the United States.

Haifu Model JC and JC200 by Chongqing Haifu Ltd. are complete ultrasound guided tumour treatment systems, and they were CE approved in 2005 for benign and malignant tumours.

HJFU-2001(Sumo Corporation Ltd) is an enhanced technology treatment system that does not require anaesthesia. Since 2001 it has been used in Asian countries to treat Liver/Pancreas/Bladder/Uterus/Kidney. This instrument is CFDA/CE/ISO 13845 Approved. The transitory replacement of air in the patient's lung(s) by an oxygen-providing and carbon dioxide removing liquid.

PFCs are synthetic "oils" made up of carbon and fluorine atoms only. They were developed as inert insulating materials in the Manhattan Project during World War II. PFCs are stable and do not react with living tissues but have a large carrying capacity for gases including oxygen, carbon dioxide and nitrogen.

Uses of PFCs in humans were investigated for many years before they were considered for treating decompression sickness or DCS. Compounds with their characteristics had long been sought by pursuers of two major quests in medicine: the quest for liquid breathing and the quest for a blood substitute.

It's important as a blood substitute to think of PFCs as a temporizing measure. You can't give PFCs over a long period because the body needs time to get rid of them. Breakdown products of the PFCs build up in the system because the body can't excrete them fast enough, and that can cause problems. You can't keep somebody alive for months with just PFCs in their bloodstream.

Today there are three or four compounds being investigated in the medical communities of the United States and other Western countries: Oxycyte (Oxygen Biotherapeutics Inc., North Carolina), Oxygent (New Alliance Pharmaceuticals/Sanguine Corporation, Georgia) and Perftoran (HemoTek Inc., Texas). Perftoran is available in Russia and perhaps other parts of the world, and Oxygent is being manufactured not only in the U.S. but in China, too, where it may already be available. In the U.S. There are groups working to respond to some final questions as concerns the FDA regarding side effects (possible toxicity related to platelet counts) of all PFC infusions. Once that side effect is better understood several human trials can move forward to the next round of research. It has been proposed that a human trial in DCS (during transport and prior to recompression) would make great sense.

Respiratory diseases are one of the commonest cause of morbidity and mortality in newborn babies. During the past few years several new modalities of treatment like using surfactants have been introduced. One of them, and probably the most fascinating, is of liquid ventilation. Partial liquid ventilation of the lung(s), on which much of the existing research has concentrated, requires partial filling of lungs with perfluorocarbons (PFCs) and ventilation with gas tidal volumes using conventional mechanical ventilators. Various physico-chemical properties of PFCs make them the ideal media. It results in a dramatic improvement in lung compliance and oxygenation and decline in mean airway pressure and oxygen requirements. It shows further promise for lung washing procedures, pulmonary image enhancement, and pulmonary administration of drugs and as a technique to increase functional residual capacity in lung hypoplasia syndromes. With the transitory replacement of air in the patient's lungs by an oxygen providing and carbon dioxide removing liquid no long-term side effects were reported. [Arvind Sehgal and Robert Guaran Indian J Chest Dis Allied Sci 2005; 47: 187-192].

The use of fluids such as saline, silicone oils and PFCs for breathing has been under investigation for many decades. In 1966, Clark and Gollan first reported the ability of PFC liquid breathing to sustain life [Clark LC and Gollan F. Survival of mammals breathing organic liquids equilibrated with oxygen at atmospheric pressure. In Science 1966; 152: 1755-6] these investigators observed that mouse, rats and other animals could survive in complete immersion in oxygen-saturated silicon oils for prolonged periods of time and recover uneventfully. The first trial of liquid ventilation in pre-term neonates in 1989 showed the feasibility and potential of liquid ventilation in humans [Greenspan JS, Wolfson MR, Rubinstein S. D. Shaffer TH. Liquid ventilation of human pre-term neonates. J Pediatr 1990; 117: 106- 11]. Much of the work in the 1990's has focused on fine tuning the technique to complement clinical trials and elaborately exploring potential toxicity and interactions with other organ systems.

US ******* teaches an early approach of combining ultrasound heating and liquid ventilation as a treatment for a lung cancer. This teaching is however limited by the approach employed and in no way precludes this invention.

Several studies of PLV utilising the PFC sterile perflubron (C8F17Brl, LiquiVent; Alliance Pharmaceutical Corporation, San Diego, California) have been completed or are ongoing in humans [Gauger PQ Pranikoff T, Schreiner RJ, Moler FW, Hirschl RB. Initial experience with partial liquid ventilation in pediatric patients with acute respiratory distress syndrome. Crit Care Med 1996; 24: 16- 22], and [Hirschl RB, Pranikoff T, Gauger P. Liquid ventilation in adults, children and full term neonates. Lancet 1995; 346: 1201-2]. The LiquiVent dose packaging is designed for hanging on a IV pole at the bedside of the mechanically ventilated patient, where it is drip-infused through the Liqui Vent administration set, a sterile-wrapped infusion set that connects to the standard side port adapter fitting on the patient's endotracheal tube and provides the physician with drip-rate and dose-volume control. Other PFC's which have been studied include FX-80, FC-75, FC-43 (perfluorotributylamine) and perfluoroctane.


The problem of present treatments of lung cancer is that the prognosis is poor and that no effective new treatments have come to light over recent years. This creates a clear "Unmet Need" necessitating a new approach to treating cancer of the lung. In this invention we describe such an advantageous procedure which is based on multiple existing technologies that have been advantageously combined in this invention.

Whole body hyperthermia, as described earlier, is a promising new treatment approach. Its use is however limited by the medical care required to treat a patient whose body temperature needs to be raised to around 42 to 43 degrees C for a period of around one hour. Further this temperature is not optimally high enough to effectively eliminate all tumour cells, and higher, more effective temperatures cannot be achieved without considerable health risks to the patient. Whole-body hyperthermia, which is at this time one of the riskiest treatments, usually results in diarrhoea, nausea, vomiting, fatigue, and other symptoms of sunstroke; it may also cause cardiovascular problems. [Information from the U.S. National Cancer Institute].

98 % of lung tumours are carcinomas, which are often quite visible using MRI or Ultrasound procedures. There has been considerable progress in the treatment of non-lung tumours using focused ultrasound or HIFU ablation technology. A summary of these results is given below:

Bone cancer

Li C, et al. 2010. Noninvasive Treatment of Malignant Bone Tumors Using High-Intensity Focused Ultrasound. Published online May 28, 2010 in Wiley InterScience: www.interscience.wiley.com Breast cancer

Sung H. K., et al. 2010. The potential role of dynamic MRI in assessing the effectiveness of high- intensity focused ultrasound ablation of breast cancer. Int. J. Hyperthermia, September 2010; 26(6): 594-603.

Orgera Q et al. 2011. High-Intensity Focused Ultrasound Effect in Breast Cancer Nodal Metastasis. Radiol med (2011) 116:734-748 DOI 10.1007/sl l547-011-0634-04.

Liver cancer

High-intensity focused ultrasound treatment of liver tumours: post-treatment MRI correlates well with intra-operative estimates of treatment volume:

Leslie T, et al. 2012. High-Intensity Focused Ultrasound for Hepatocellular Carcinoma: A Single- Center Experience. The British Journal of Radiology, 85 (2012), 1363-1370.

HIFU cannot transmit through alveoli in the lungs, and can only be applied to localized lung tumours on the outside of the lung itself.

Pancreatic cancer

Ng K.K.et al. 2011 High Intensity Focused Ultrasound for Hepatocellular Carcinoma. 5. Ann Surg. 2011 May;253(5):981-7. DOI: 10.1097/SLA.0b013e3182128a8b.

G Orgera et al. 2011. Ultrasound-Guided High-Intensity Focused Ultrasound (USgHJFU) Ablation in Pancreatic Metastasis from Renal Cell Carcinoma. Cardiovasc Intervent Radiol. DOI 10.1007/s00270-011-0291-y. Published online: 20 October 2011

Orgera g., et al. 2010. High Intensity Focused Ultrasound Ablation of Pancreatic Neuroendocrine Tumours: Report of Two Cases. Cardiovasc Intervent Radiol (2010)DOI 10.1007/s00270 010 98840. Sung H.Y., et al. 2011. Long-Term Outcome of High-Intensity Focused Ultrasound in Advanced Pancreatic Cancer. Pancreas 2011;40: 1080Y1086.

Desmoid tumours

Wang Y,. et al. 2011. Ultrasound-guided high intensity focused ultrasound treatment for extra- abdominal desmoid tumours: Preliminary results. Int. J. Hyperthermia, November 2011 ; 27(7):


Kidney cancer

Ritchie, R. W, et al., 2010. Extracorporeal high intensity focused ultrasound for renal tumours: a 3- year follow-up. JOURNAL COMPILATION 2010 BJU INTERNATIONAL 106, 1004 - 1009 General Oncology

Shehata I. A. 2012. Treatment with high intensity focused ultrasound: Secrets revealed. European Journal of Radiology 81 (2012) 534- 541.

Orgera, G, et al. 2011. High-intensity focused ultrasound (HIFU) in patients with solid malignancies: evaluation of feasibility, local tumour response and clinical results. Radiol med (2011) 116:734-748. DOI 10.1007/sll547-011-0634-04.

Orsi, E, et al. 2010. High-Intensity Focused Ultrasound Ablation: Effective and Safe Therapy for Solid Tumors in Difficult Locations. This is a Web exclusive article. AJR 2010; 195:W245-W252. 0361-803X/10/1953-W245. © American Roentgen Ray Society.

Illing, R.O., et al. 2005. The safety and feasibility of extra-corporeal high- intensity focused ultrasound (HIFU) for the treatment of liver and kidney tumours in a Western population. British

Journal of Cancer (2005) 93, 890 - 895.

Immune response

Zhang Y, et al, 2010. Enhancement of anti-tumor vaccine in ablated hepatocellular carcinoma by high-intensity focused ultrasound. World J Gastroenterol 2010 July 28; 16(28): 3584-3591 ISSN 1007-9327.

Lung cancer

Despite the remarkable progress made in HIFU treatment of multiple cancers, HIFU is not, in its present form, applicable to the treatment of lung cancer. This is essentially due to the presence of air in the lungs which precludes the use of HIFU.

The importance of these non-invasive approaches to cancer treatment is that they replace surgical interventions. With the present lack of new antibiotic development and the increase in nosocomial diseases in hospitals, surgical interventions are increasingly likely to lead to nosocomial infections that can no longer be treated.

In this invention we employ the transient replacement of air in a lung cancer patient's lung(s) with a liquid based on PFC's, thus providing for the use of HIFU ablation of visible sarcomas in the lung, followed by local lung hyperthermia to eliminate metastases.

US 158,536 teaches an early attempt to apply ultrasound heating to the treatment of lung cancer employing liquid ventilation. We have extended this early work very significantly in this invention. The replacement of air in the lungs by a PFC based liquid during the treatment protocol is based on work described by:

Hancock, J.B. et al. 2004. Using liquid ventilation to improve lung function in patients with respiratory distress syndrome: A comprehensive review of the literature. AANA Journal/June 2004/Vol. 72, No. 3

This article is a review of the research findings on the subject of liquid ventilation and how it has shown to improve lung function in patients with respiratory distress syndrome. An overview of the physiology behind the success of liquid ventilation, including current research outcomes, is presented. The literature documenting research data was obtained through an Internet search of articles published from 1962 to 2002. This and previous research articles are incorporated into this patent.

Atypical treatment may be illustrated by the following sequence of actions.

Firstly, the patient is imaged to determine the precise location and volume of the tumour(s) to be treated. This imaging may be associated with the placement of markers permitting the calculation of the localisation of the tumour(s) during the HIFU treatment, by any appropriate means.

Once the images have been treated by appropriate software and/or practitioner expertise, and the position of the patient within the machinery determined, the actual treatment can begin.

The patient is first mildly sedated, to ease the application of the ventilator intra-tracheal tube, and to avoid any panic attacks or other psychological disorders induced by the treatment conditions, and to avoid reflexive movement. The patient is also at that time instrumented with life-sign monitors as required, and the sensors required by the ventilator.

The patient (under normal gas ventilation at this point) is then positioned so that the HIFU generator is correctly positioned to apply heat to the treatment volume, immobilized, and the lung(s) slowly infused with the liquid at core-body temperature. At this point, the HIFU heating of the tumour(s) takes place. The preferred treatment protocol is to employ HIFU to destroy all visible traces of lung sarcomas. A subsequent hyperthermia approach may also be applied. The objective here is to destroy any remaining cancer cells in the patient's lung(s) that could result in metastatic tumours subsequently.

To do this the ventilating liquid is heated so as to produce a constant temperature in the lung(s) of degrees centigrade for any time that experience may dictate. Current knowledge would indicate that ί period of one hour would be effective. Once this hyperthermia treatment is complete, the liquid in ttu lungs is exchanged for air by progressive reduction in the volume of liquid being transported at first then by any other means including gravitational (repositioning of the patient), whereupon the treatmen is complete. It has been shown that the lung residue of the liquids proposed here evaporate over ί period of weeks, and have no adverse effect on the subject.

There is no reason that this entire treatment protocol cannot be repeated at any time, should this become necessary or be deemed useful. Indeed, it may be found to be beneficial (in terms of patien comfort or treatment efficacy or a detailed protocol) to apply treatment to the lungs separately maintaining one lung in normal gas ventilation whilst treating the other. Gravity might be used tc circumscribe the lung volume being infused.

The references cited in the specifications are incorporated herein by reference, to the extent that thej supplement, explain, provide a background for, or teach methodology techniques and/or compositions employed herein.

It will be understood that the various details of the invention can be changed without departing fron the scope of the invention. Furthermore, the foregoing description is for the purpose of illustration only and not for the purpose of limitation, the invention being defined by the claims appended hereto.