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Posts Tagged ‘cancer therapy’


GE Healthcare has acquired Biosafe Group SA, a supplier of Integrated Cell Bioprocessing Systems for Cell Therapy and Regenerative Medicine Industry

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Researchers of University of Texas at San Antonio, USA, have developed a new, non-invasive method which can kill cancer cells in two hours, an advance that may significantly help people with inoperable or hard-to-reach tumours, as well as young children stricken with the deadly disease.

 

The method involves injecting a chemical compound, nitrobenzaldehyde, into the tumour and allowing it to diffuse into the tissue. A beam of light is then aimed at the tissue, causing the cells to become very acidic inside and, essentially, commit suicide. Within two hours, up to 95 per cent of the targeted cancer cells are estimated to be dead.

 

The method was tested against triple negative breast cancer, one of the most aggressive types of cancer and one of the hardest to treat. The prognosis for triple negative breast cancer is usually very poor. One treatment in the laboratory was able to stop the tumour from growing and doubled the chances of survival in the mice.

 

According to the researchers all forms of cancer attempt to make cells acidic on the outside and attract the attention of blood vessels as an attempt to get rid of the acid. But, instead, the cancer cells latches onto the blood vessel and uses it to make the tumour grow bigger.

 

Chemotherapy treatments target all cells in the body, and certain chemotherapeutics try to keep cancer cells acidic as a way to kill the cancer. This is what causes many cancer patients to lose their hair and become weak. This method however, is more precise and can target just the tumour.

 

This research is presently extended on drug-resistant cancer cells to make this therapy as strong as possible. The researchers also started to develop a nanoparticle that can be injected into the body to target metastasised cancer cells. The nanoparticle is activated with a wavelength of light which can pass harmlessly through skin, flesh and bone and still activate the nanoparticle.

 

This non-invasive method will help cancer patients with tumours in areas that have proven problematic for surgeons, such as the brain stem, aorta or spine. It could also help people who have received the maximum amount of radiation treatment and can no longer cope with the scarring and pain that goes along with it, or children who are at risk of developing mutations from radiation as they grow older.

 

References:

 

http://www.ndtv.com/health/researchers-develop-new-method-to-kill-cancer-cells-in-2-hours-1424509

 

https://www.consumeraffairs.com/news/new-non-invasive-cancer-therapy-shows-promise-062916.html

 

http://www.mirror.co.uk/science/new-cancer-treatment-can-kill-8341452

 

https://www.sciencedaily.com/releases/2016/06/160627214423.htm

 

http://reliawire.com/photodynamic-acidification-therapy/

 

http://www.gizmag.com/making-cancer-cells-acidic/44070/

 

 

http://www.oncologynurseadvisor.com/general-oncology/initial-photodynamic-therapy-tests-promising/article/508292/

 

https://www.sciencedaily.com/releases/2016/06/160627214423.htm

 

http://www.thehindu.com/sci-tech/health/new-method-can-kill-cancer-cells-in-two-hours-shows-study/article8785315.ece

 

http://www.aol.com/article/2016/07/06/new-cancer-treatment-method-causes-cells-to-commit-suicide/21424984/

 

http://zeenews.india.com/news/health/diseases-conditions/new-method-that-can-kill-cancer-cells-in-2-hours-developed_1901377.html

 

http://www.digitaltrends.com/health-fitness/ultraviolet-light-kills-cancer-cells/

 

https://www.thesun.co.uk/news/1385404/light-can-kill-cancer-in-just-two-hours/

 

http://www.techtimes.com/articles/168268/20160704/new-cancer-therapy-method-ultraviolet-light-may-soon-replace-chemotherapy.htm

 

https://www.engadget.com/2016/07/01/scientists-use-light-to-nuke-cancer-cells-in-mice/

 

Nuha Buchanan Kadri, Matthew Gdovin, Nizar Alyassin, Justin Avila, Aryana Cruz, Louis Cruz, Steve Holliday, Zachary Jordan, Cameron Ruiz and Jennifer Watts. Photodynamic acidification therapy to reduce triple negative breast cancer growth in vivo. Journal of Clinical Oncology, Vol 34, No 15_suppl (May 20 Supplement), 2016: e12574.

 

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Nanoscale photodynamic therapy

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Researchers from the Centre for Nanoscale BioPhotonics (CNBP), an Australian Research Centre of Excellence, have shown that nanoparticles used in combination with X-rays, are a viable method for killing cancer cells deep within the living body.

The research, published in the journal Scientific Reports is based on the successful quantification of singlet oxygen produced during photodynamic therapy for cancer. Singlet oxygen molecules (a highly reactive form of oxygen) are able to kill or inhibit growth of cancer cells in the body due to their toxicity.

Co-lead author on the paper, Ewa Goldys, Deputy Director of the CNBP and Professor at Macquarie University explained, “Photodynamic therapy is where light sensitive compounds are placed near diseased cells, then activated by light, producing short lived molecular by-products that can destroy or damage the cells being targeted.”

“In this case, X-rays (a form of light) were used to stimulate cerium fluoride (CeF3) nanoparticles which had been placed near a group of cells. Singlet oxygen was produced as a by-product of the X-ray and CeF3 interaction, which was then successfully measured.”

Goldys believes the research is significant, as this is the first time that anyone has been able to quantify accurately, the number of singlet oxygen molecules produced in this type of procedure.

“Singlet oxygen molecules are a far more reactive form of oxygen but they can only kill cancer cells if generated in sufficient quantity”, said Goldys.

“In our testing we established that therapeutic radiation dose X-rays, produce enough singlet oxygen molecules to be effective in photodynamic therapy.”

According to Goldys, photodynamic therapy has traditionally utilised near-infrared or visible light which has been unable to penetrate far into the body, limiting its use to cancer treatment, on or near the surface of the skin.

“We’re looking to target cancer cells deeper in the body hence the use of X-rays, which can really penetrate into deeper levels of tissue, and are already used in medical diagnostic and therapy.’

Concluded Goldys, “What we’ve shown through our measurements is the applicability of the photodynamic therapy approach to effectively treat tumours within.”

“The beauty of this type of treatment is that it uses different biological pathways to kill cells as compared to chemotherapy, radiotherapy and other current cancer practices.

“Deep tissue photodynamic therapy will potentially provide new treatment options for the cancer patients of the future.”

Next steps with this research will see differing nanoparticles tested and measured, for effectiveness in singlet oxygen production.

ernstein, MD, FCAP, Curator

LPBI

 

Counting Cancer-busting Oxygen Molecules

Macquarie University   http://www.rdmag.com/news/2016/02/counting-cancer-busting-oxygen-molecules

 

 

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Targeted immunotherapy

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Fighting cancer with targeted drugs “Cancer” is a collective term that describes numerous different and malignant new tissue formations. Malignant tumors emerge from changes in DNA fragments when the body can no longer counteract these mutations, which is often associated with increased age. Yet the risk of developing cancer also depends on genetic factors, lifestyle habits and different environmental influences. Chemotherapy – an optimized base The classic triad of medical treatment, radiation therapy and surgery is a proven procedure.

While radiation therapy uses ionizing radiation to completely inactivate or at least push back the tumor, cytostatic drugs are applied in chemotherapy to inhibit cell growth. The treatment planning depends on specific tumor characteristics, the patient’s overall health condition, as well as the stage of the disease. New, individual therapeutic approaches promise more effective cancer treatment.

Chemotherapy is almost always applied – mainly by infusion, while certain cytostatic drugs are also suited for oral administration. Since researchers have tested and re-combined proven active ingredients in different doses, as well as introduced new substances, good results are now often achieved at higher tolerance. While emerging countries focus on chemotherapy, the standard treatment in the industrial world is more and more often combined with new, targeted therapeutic approaches.

Revolution in cancer treatment The cell division of healthy people is strictly regulated. A cell is only reproduced when it receives an according signal. If this procedure is thrown out of balance, the result is uncontrolled cell growth. Unlike cytostatic drugs, which act as cellular toxin, modern therapies draw on the molecular bases of tumor development. A type of enzymes known as kinases plays an important role in transmitting the signals. Kinase inhibitors act as low-molecular agents and block their function. For instance, the treatment of chronic myeloid leukemia with the active ingredient Imatinib1 has proven successful and spurred research. Most kinase inhibitors are administered orally and are partly based on highly complex formulations. Angiogenesis inhibitors are another example of targeted therapeutics. They block the development of blood vessels, which are indispensable for the growth of tumor cells. Immunotherapy against cancer In immunotherapy, the patient’s own immune system is stimulated to take independent action against tumor cells. This way, monoclonal antibodies can be developed, which attach themselves to the characteristic structures of the tumor surface. They inhibit cell proliferation (uncontrolled cell growth) or induce cell death. The targeted effect of monoclonal antibodies can also be combined with cell poison such as cytostatic agents or toxins.

Like in a Trojan Optimal operator protection at the highest product quality – sterile filling lines combined with barrier systems 1

Vasella, Daniel (2003): Magic Cancer Bullet: How a Tiny Orange Pill May Rewrite Medical History 6

 

Checkpoint inhibitors block the control points and are thus able to direct the immune system against the cancer. Since antibodies are complex protein structures that are “digested” by the gastrointestinal tract, this therapy is administered via infusion.

Therapeutic differentiation The trend is toward individually tailored therapies. Companion diagnostics are consequently becoming the focus of active ingredient development to verify the effectiveness for each patient before treatment initiation. Conversely, this implies an even closer cooperation between pharmaceutical companies and manufacturers of laboratory diagnostics as well as medical devices. Ever more specific therapies reduce the number of patients available for clinical studies, increasingly blurring the line between drug development and treatment. This medicine, which is described as “translational”, offers great opportunities to fight tumors formerly known as difficult to treat. More targeted tumor therapies will hence change the image of cancer – from death sentence to a severe, yet manageable chronic condition.

For further information, please contact: Dr Johannes Rauschnabel Phone: +49 7951 402 452 E-mail: johannes.rauschnabel@bosch.com

So-called antibody-drug conjugates transport the cell poison directly into the cancer cells. In the context of “checkpoint inhibition”, particular attention has recently been paid to monoclonal antibodies. The immune system is equipped with control points that protect the organism against autoimmune reactions. Tumors use these mechanisms to thwart a counter-reaction of the immune system.

Fighting cancer with Bosch technologies

The portfolio from Bosch Packaging Technology is suited for nearly all forms of oncological drug development, production and filling. For instance, sterile filling lines can be combined with barrier systems to protect operators from highly potent active agents such as cytostatic drugs, while ensuring the highest possible quality. Oral cytostatic drugs such as the active ingredient Imatinib can be processed on capsule filling machines and tablet presses from Bosch, which in conjunction with containment systems protect the operators from product dust. Bosch also offers machines for all laboratory process steps for both liquid and solid pharmaceuticals. Devices for the biopharmaceutical production of monoclonal antibodies and antibody-drug conjugates are among the core process competencies of the Bosch subsidiary Pharmatec. The production of antibodies requires a multi-stage process. First, the cells are cultivated in increasing scaling steps and harvested (upstream process). The active ingredients are then separated and purified using different technologies, followed by the formulation of the final injection solution (downstream process).

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Examples of Surgical Procedures [4.4]

Writer and Curator: Larry H. Bernstein, MD, FCAP 

It is not possible to discuss surgical procedures without a firsthand knowledge of the principles of surgical, radiation and medical oncology and the current interdisciplinary approach to the care of the patient with cancer with respect to the type of cancer, the stage, the patient health status, the preoperative preparation, the assessment of treatment for cure or of palliation, and the postoperative plan for management of the patient.

Cancer surgery has evolved over the decades from a radical ‘one size fits all’ approach to a patient-specific, cancer-specific direction, which means that surgeons rely on their multidisciplinary partners in the assessment of patients. As surgeons are frequently the first specialists involved with most solid tumors, familiarity with pre-operative imaging, pathological biopsy and patient-selection, careful surgical technique and staging are fundamental to the surgeon’s armamentarium.

Surgical resection of cancers remains the cornerstone of treatment for many types of cancers. Historically, surgery was the only effective form of cancer treatment, but developments in radiation therapy and chemotherapy have demanded that surgeons work with the other disciplines of medicine in order to achieve best results for the patient with cancer.

This type of interaction between the medical disciplines together with the supportive care groups required by cancer patients is defined as multidisciplinary care. It is now widely recognized that for optimal treatment of cancer a multidisciplinary team with the surgeon as part of this team is essential.

Surgery is effective treatment for cancer if the disease is localized. Defining the extent of the cancer before surgery has become much more accurate with modern imaging methods including computed tomography (CT), positron emission tomography (PET) scanning and high resolution ultrasound. The exploratory operation to determine the extent of disease, or attempting a ‘curative’ resection when the disease has already spread beyond the bounds of a ‘surgical’ cure, is not part of the modern surgical treatment of cancer. Oncological trained surgeons are now distinguished from more general surgeons because of the particular needs of the cancer patients.

Clinical trials are required to evaluate new treatments and treatment combinations. The struggle against the scourge of cancer has seen an explosion in basic research directed towards cancer. This academic element to cancer care is a constant feature as all those involved in cancer care endeavor to advance the understanding of the management of cancer patients.

Three main questions to consider are implied from the preceding:

What is the type of cancer?

In most cases, this requires a tissue diagnosis. In modern oncology, it is unusual or inappropriate to start treatment based on clinical diagnosis alone without tissue diagnosis. Tissue diagnosis is also important to perform molecular studies to select appropriate targeted therapies.

What is the extent of the spread of the cancer?

This is answered by staging scans including CT scans, bone scans and PET scans.

Is it curable or not curable?

This depends on the type of cancer and the presence or absence of and the extent of metastasis.

For curable cancers, rate of cure is determined by prognostic factors (for example: tumor size and nodal status in breast cancer).

For incurable cancers, duration of survival is expressed in median survival rather than in absolute time frame.

Most solid tumors require adequate and site-specific imaging. This facilitates diagnosis and staging of the primary tumor and staging for distal metastases. Not all modalities are appropriate for all sites. For example mammography using the BIRADS system and ultrasound are used in breast cancers to assess a primary breast cancer. Meanwhile, an esophageal cancer requires a CT and a low rectal cancer will be best assessed with MRI or endorectal ultrasound, while a thyroid cancer is best evaluated with neck ultrasound.

One of the biggest challenges for the surgeon is to choose the correct surgery for the correct patient and with the tumor type and biology in mind. Although surgery removes a tumor and provides further pathological information to estimate prognosis and influence adjuvant therapies, the surgery cannot cause more morbidity than the cancer and must achieve surgical goals without compromising tumor biology.

The TNM staging system (American Joint Commission on Cancer AJCC) is devised for cancers to allow an assessment of T- tumor, N- nodal metastases and M- distal metastases. The goal of having a site-specific staging system is to estimate prognosis, facilitate treatment planning including the sequence of treatments and allow comparisons of treatment for different stages. Generally, a combination of different ‘T’, ‘N’, and ‘M’ allows the cancer to be grouped into stages. Stages I-IV usually depict a tumor in the following state: Stage 1- early and superficial cancer, Stage 2- locally advanced, Stage 3- regionally advanced with lymph node metastases and Stage 4- distant metastatic disease.

Despite suggestive imaging, a cancer is not diagnosed until histopathological biopsy. Biopsies where tissue (as opposed to cells) are provided to the pathologist increase the accuracy of the pre-operative diagnosis but may not always be feasible. Biopsies may be undertaken percutaneously — for example, a core biopsy of the breast, fine needle aspiration of thyroid or endoscopically such as in gastric cancer or colon cancer.

A biopsy should confirm the tumor type, grade, may show lymphovascular invasion and in some cases, special immunohistochemical stains may be performed to assess hormone receptor status such as in breast cancer or flow cytometry may be performed to assess subtypes such as in lymphoma. Staging may also require a biopsy of draining lymph nodes.

The aims of any cancer surgery are to remove the cancer with an adequate margin of normal tissue with minimal morbidity. Clear margins have an impact on local control.  Many solid tumors require removal of the draining lymph nodes for the purpose of staging and/or to achieve local control. Surgery has become more conservative with the advent of sentinel node biopsy, and is frequently used in breast cancer and melanoma. The sentinel node biopsy is a  staging tool to predict prognosis and influence use of adjuvant therapies. Surgery is performed for cure by removing the primary cancer and lymph nodes.

When tumors are locally advanced, a neoadjuvant approach with chemotherapy, radiotherapy or targeted therapies may be important to ‘control’ the growth of a tumor, down-stage a tumor to render it operable, or because the impact of systemic disease risk may outweigh those of local control. Similarly, patients with metastatic disease may still require surgery to prevent complications of the primary tumor, such as bowel obstruction from a colon cancer.

The preceding paragraphs define the discipline of surgical oncology. In summary, surgical oncology is the involvement of a specialty trained surgeon as part of a multidisciplinary team program, the use of appropriate surgery in an adequately staged patient and the involvement of the surgeon in academic programs particularly involved with clinical trials.

The use of effective techniques in the operating theater, the careful management of the patient undergoing surgery and supportive post-operative care are similar requirements to those of all other disciplines of surgery.

Communication with the patient and family, the obtaining of informed consent and the careful honest, realistic but where possible optimistic explanation of the results of surgery, are all matters of high importance to all surgical practice. However, the ability to talk sympathetically to cancer patients and their family is particularly important in the field of surgical oncology.

Multidisciplinary care

Surgeons need to understand the principles and practical consequences of the treatment offered by radiation oncologists, medical oncologists and the paramedical disciplines in order to be able to work in a team to treat cancer patients.

Principles of cancer surgery
Dr. Anita Skandarajah MBBS MD FRACS — Author
Cancer Council Australia Oncology Education Committee — Co-author
http://wiki.cancer.org.au/oncologyformedicalstudents/Principles_of_cancer_surgery

http://www.surgwiki.com/wiki/Principles_of_surgical_oncology

Principles of surgery for malignant disease
http://www.surgwiki.com/wiki/Principles_of_surgical_oncology#Principles_of_surgery_for_malignant_disease

Screening

Surgical resection has the potential to cure early or localized cancers which have not metastasized. In general early cancers equate with curability. For example, a malignant polyp in the colon is usually curable by surgery. However, this does not always hold true. Small breast cancers may metastasize early with cure not inevitable from surgical excision alone. Screening for cancer to detect early asymptomatic cancers is now commonplace.

For screening to be effective, the test must be able to detect a common cancer at a stage when it can be cured by treatment. For screening to be effective it must be introduced on a population basis. The most effective screening program has been cervical screening where, since its introduction, there has been a substantial fall in mortality from cervical cancer in all age groups. Similar less dramatic effect is seen with breast cancer screening by mammography.

Surgeons are involved in screening programs performing endoscopies and biopsies (e.g. abnormal Barrett’s mucosa), excising polyps from the colons at colonoscopy and biopsying mammographically detected breast lesions.

Diagnosis

A tissue diagnosis is essential prior to the creation of any management plan for a cancer patient. The consequences of many cancer treatments are so severe that only rarely can treatment be commenced without a pathological diagnosis. Tissue is obtained by fine needle aspiration, core biopsy or by excisional biopsy.

Assessment of the patient

An important early part of the assessment of a patient with cancer is to determine the psychological and physical fitness of the patient. An idea of the ‘health’ of the patient can be gained from a simple clinical assessment, the Eastern Cooperative Oncology Group (ECOG) status. Patients who are ECOG 3 or lower will usually have a poor outcome from any treatment including major surgery.

All patients undergoing major surgery need assessment of the clinical status including, where appropriate, tests of cardiac function, for example scans and angiography if indicated, respiratory status by lung function tests and renal function tests including creatinine clearance.

Staging of malignant disease

Accurate staging of the extent of disease is of great importance in formulating a treatment plan. Clinical stage is that defined by clinical examination and imaging of the patient. It is often not accurate but with the use of high quality CT and PET scanning the accuracy is improved. Pathological staging is that defined after excisional surgery by the anatomical pathologist. It is accurate in defining the extent of disease associated with a primary tumor. The staging system is varied according to the primary site of the tumor.

Rectal cancers have a long-standing clinical and pathological staging system known as the Cuthbert-Dukes staging system. Dukes A is local disease in the rectum not invading muscularis propria; Dukes B, the tumour has extended through the wall of the bowel; and Dukes C, where there is lymph node involvement. Dukes D is when distant metastases are present. The Dukes system is commonly used alongside the TNM system.

Methods of clinical staging include radiological methods such as CT, MRI and ultrasound. Within the area of nuclear medicine are PET scanning and nuclear scanning generally (e.g. bone scanning). Laparoscopy is an added staging method which detects intra-abdominal tumors.

Decision about treatment at the multidisciplinary conference

Armed with information about the diagnosis of the cancer, the extent of the disease, that is the clinical stage of the disease and the fitness of the patient, decisions can be made about the most appropriate treatment program. Ideally consultation with a multidisciplinary team occurs at this stage, however if the decision regarding surgery is straightforward, the multidisciplinary conference usually occurs after the surgery when a pathological stage has been determined. However many cancers require down-staging with radiotherapy or chemotherapy prior to surgery, and multidisciplinary consultations early are important to facilitate this process.

The provision of written information to the patient and family, with careful and repeated discussions, is necessary to ensure that the patient can give informed consent to any treatment plan offered. Patients have the right to refuse all or some of the treatment plan and they are encouraged to be part of the decision making process.

At this stage discussions regarding involvement in research projects, use of resected tissues and involvement in clinical trials need to be commenced.

Principles of operative surgical oncology

The technical issues in surgical oncology are not different from other surgical intervention. Open surgery, laparoscopic surgery, robotic surgery, ablative interventions and other technical interventions all have a place in modern surgical oncology. However some important oncological principles exist which must be followed by the surgeon for a satisfactory outcome.

Definition of curative surgery

Despite modern staging methods, occult tumor spread is still discovered by the surgeon, for example small-volume peritoneal disease or unsuspected nodal disease. Frozen section examination of the disease is necessary to confirm the diagnosis. So-called curative surgery is only performed when a total excision of the tumor is possible. The primary tumor and the associated lymph node drainage fields are excised in continuity. A measure of the adequacy of the oncological surgical operation is demonstrated by the findings on pathological examination of the specimen. The operative specimens need to be correctly orientated by the surgeon to allow the pathologist to carefully examine and interpret the specimen given to him. The key issues are:

  • whether the margins of the specimen removed are clear of tumor
  • the total number of lymph nodes excised together with the number of involved lymph nodes.
  • Standards exist for the adequacy of the surgical excision to be assessed in many tumors.

Palliative surgery

Here the operation is performed to overcome some symptom-producing consequence of the tumor either by resection or bypass. This is to remove a potentially symptomatic lesion even though a cure is known to be impossible.
Examples include the following:

In case of pyloric obstruction from an advanced cancer of the stomach, a gastrojejunostomy will provide good palliation of vomiting.

Resection of a bleeding cancer of the colon is justified even in the presence of metastases.

Many other examples exist. ‘Tailoring’ this type of surgery to the needs of the patient without undue morbidity or loss of quality of life is an important role for an oncological surgeon.

Margins of surgical excision

The degree to which normal tissues should be removed with the primary tumor is a subject constantly being researched. A universal rule is not possible to formulate. In general a margin of 2-5 cm is suggested. Particular examples follow:

For excision of melanomas the depth of excision is more important than the extent of surrounding skin. A margin of 2 cm usually suffices in contrast to the 5 cm previously practiced.

However for esophageal resection the majority of the esophagus needs to be resected because the tumor does spread up and down in the submucosal plane.

Soft tissue sarcomas may spread along aponeurotic planes so that complete excision requires the resection of the entire muscle group and fascial compartment to encompass this type of spread.

The recognition that spread of rectal cancer occurs into perirectal tissues has led to the use of the total mesorectal excision of the rectum to improve the completeness of resection.

The principle of complete local excision with an adequate margin is paramount in surgical oncology and it needs to be achieved in different ways depending on the type of tumor being resected.

Lymph node resection

Traditionally the draining lymph nodes from a primary tumor are excised with the local lesion. The main benefit of this removal is increased staging information, which will affect the decisions regarding post-operative adjuvant therapy. In some situations there may be a survival benefit from removal of early-involved lymph nodes. However prophylactic excision of uninvolved nodes does not provide a survival advantage to the patient and exposes the patient to increased morbidity from the node removal. An example is the prophylactic removal of groin lymph nodes (radical groin dissection), when these glands are not involved. This operation is nowadays not performed when the glands are clinically not involved as randomized controlled trials have shown that survival rates have not improved but the morbidity from the operation is significant. Poor skin healing and swelling of the affected leg are two such complications.

Rehabilitation

It is necessary to undertake rehabilitation of the cancer patient who has undergone major a resection. This usually involves the allied health disciplines, part of the oncology team. The type and duration of the process will vary according to the type of tumor and surgery performed.

Follow-up of patient after initial treatment

A program of follow-up is required for cancer patients after their initial treatment. This is for two main reasons. This is to observe the patient and investigate when appropriate to detect recurrent disease, which can then be treated effectively. By definition this is only likely to be useful to the patient when strong effective postoperative therapies are available which will have a real impact on the control of cancer.

Conclusion

The principles of surgical oncology can be applied to many of the systemic practices of surgery. In simple terms the surgeon operating on cancer patients in the 21st century must have some understanding of the malignant process, be prepared to work as part of a team and offer multidisciplinary care, communicate well with a very concerned sometimes desperate group of patients, operate with a high level of skill and perform an adequate cancer operation, help the patient rehabilitate from the treatment and finally be prepared to be involved in the advancing area of surgical science as applied to cancer patients. As God knows, surgeons cannot cure all cancers on their own.

Principles of Surgical Oncology    (Apr 08, 2009)
http://www.cancernetwork.com/articles/principles-surgical-oncology-2 Lawrence D. Wagman, MD, FACS

Surgical oncology, as its name suggests, is the specific application of surgical principles to the oncologic setting. These principles adapt standard surgical approaches to the unique situations that arise when treating cancer patients.

The surgical oncologist must be knowledgeable about all of the available surgical and adjuvant therapies, both standard and experimental, for a particular cancer. This enables the surgeon not only to explain the various treatment options to the patient but also to facilitate and avoid interfering with future therapeutic options.

Invasive diagnostic modalities

As the surgeon approaches the patient with a solid malignancy or abnormal nodal disease or the rare individual with a tissue-based manifestation of a leukemia, selection of a diagnostic approach that will have a high likelihood of a specific, accurate diagnosis is paramount. The advent of high-quality invasive diagnostic approaches guided by radiologic imaging modalities has limited the open surgical approach to those situations where the disease is inaccessible, a significant amount of tissue is required for diagnosis, or a percutaneous approach is too dangerous (due, for example, to a bleeding diathesis, critical intervening structures, or the potential for unacceptable complications, such as pneumothorax).

Lymph node biopsy

The usual indication for biopsy of the lymph node is to establish the diagnosis of lymphoma or metastatic carcinoma. Each situation should be approached in a different manner.

Lymphoma The initial diagnosis of lymphoma should be made on a completely excised node that has been minimally manipulated to ensure that there is little crush damage. When primary lymphoma is suspected, the use of needle aspiration does not consistently allow for the complete analyses described above and can lead to incomplete or inaccurate diagnosis and treatment delays.

Carcinoma The diagnosis of metastatic carcinoma often requires less tissue than is needed for lymphoma. Fine-needle aspiration (FNA), core biopsy, or subtotal removal of a single node will be adequate in this situation. The use of immunocytochemical analyses can be successful in defining the primary site, even on small amounts of tissue.

Head and neck adenopathy The head and neck region is a common site of palpable adenopathy that poses a significant diagnostic dilemma. Nodal zones in this area serve as the harbinger of lymphoma (particularly Hodgkin lymphoma) and as sites of metastasis from the mucosal surfaces of the upper digestive tract; nasopharynx; thyroid; lungs; and, occasionally, intra-abdominal sites, such as the stomach, liver, and pancreas. The surgical oncologist must consider the most likely source of the disease prior to performing the biopsy. FNA or core biopsy becomes a valuable tool in this situation, as the tissue sample is usually adequate for basic analysis (cytologic or histologic), and special studies (eg, immunocytochemical analyses) can be performed as needed.

Biopsy of a tissue-based mass

Several principles must be considered when approaching the seemingly simple task of taking a tissue biopsy. As each of the biopsy methods has unique risks, yields, and costs, the initial choice can be a critical factor in the timeliness and expense of the diagnostic process.

Mass in the digestive tract In the digestive tract, biopsy of a lesion should include a representative amount of tissue taken preferably from the periphery of the lesion, where the maximum amount of viable malignant cells will be present. The biopsy must be of adequate depth to determine penetration of the tumors. This is particularly true for carcinomas of the oral cavity, pharynx, and larynx.

Breast mass Although previously a common procedure, an open surgical biopsy of the breast is rarely indicated today. Palpable breast masses that are highly suspicious (as indicated by physical findings and mammography) can be diagnosed as malignant with close to 100% accuracy with FNA. However, because the distinction between invasive and noninvasive diseases is often required prior to the initiation of treatment, a core biopsy, performed either under image guidance (ultrasonography or mammography) or directly for palpable lesions, is the method of choice.

An excellent example of the interdependence of the method of tissue diagnosis and therapeutic options is the patient with a moderate-sized breast tumor considering breast conservation who chooses preoperative chemotherapy for downsizing of the breast lesion. The core biopsy method establishes the histologic diagnosis, provides adequate tissue for analyses of hormone-receptor levels and other risk factors, causes little or no cosmetic damage, does not perturb sentinel node analyses, and does not require extended healing prior to the initiation of therapy. In addition, a small radio-opaque clip can be placed in the tumor to guide the surgical extirpation. This step is important because excellent treatment responses can make it difficult for the surgeon to localize the original tumor site.

Mass in the trunk or extremities For soft-tissue or bony masses of the trunk or extremities, the biopsy technique should be selected on the basis of the planned subsequent tumor resection. The incision should be made along anatomic lines in the trunk or along the long axis of the extremity. When a sarcoma is suspected, FNA can establish the diagnosis of malignancy, but a core biopsy will likely be required to determine the histologic type and plan neoadjuvant therapy.

Specific Surgical References

Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data
AJ Breugom, M Swets, Jean-François Bosset, L Collette, ..CJH van de Velde
Lancet (Oncology) 2015; 16: 200-207.
http://dx.doi.org/10.1016/S1470-2045(14)71199-4

Background The role of adjuvant chemotherapy for patients with rectal cancer after preoperative (chemo)radiotherapy and surgery is uncertain. We did a meta-analysis of individual patient data to compare adjuvant chemotherapy with observation for patients with rectal cancer. Methods We searched PubMed, Medline, Embase, Web of Science, the Cochrane Library, CENTRAL, and conference abstracts to identify European randomized, controlled, phase 3 trials comparing observation with adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with non-metastatic rectal cancer. The primary endpoint of interest was overall survival. Findings We analyzed data from four eligible trials, including data from 1196 patients with TNM stage II or III disease, who had an R0 resection, had a low anterior resection or an abdominoperineal resection, and had a tumor located within 15 cm of the anal verge. We found no significant differences in overall survival between patients who received adjuvant chemotherapy and those who underwent observation (hazard ratio [HR] 0·97, 95% CI 0·81–1·17; p=0·775); there were no significant differences in overall survival in subgroup analyses. Overall, adjuvant chemotherapy did not significantly improve disease-free survival (HR 0·91, 95% CI 0·77–1·07; p=0·230) or distant recurrences (0·94, 0·78–1·14; p=0·523) compared with observation. However, in subgroup analyses, patients with a tumor 10–15 cm from the anal verge had improved disease-free survival (0·59, 0·40–0·85; p=0·005, p interaction=0·107) and fewer distant recurrences (0·61, 0·40–0·94; p=0·025, p interaction=0·126) when treated with adjuvant chemotherapy compared with patients undergoing observation. Interpretation Overall, adjuvant fluorouracil-based chemotherapy did not improve overall survival, disease-free survival, or distant recurrences. However, adjuvant chemotherapy might benefit patients with a tumor 10–15 cm from the anal verge in terms of disease-free survival and distant recurrence. Further studies of preoperative and postoperative treatment for this subgroup of patients are warranted.

Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial
IH Kunkler, LJ Williams, WJL Jack, DA Cameron, JM Dixon, et al.
Lancet Oncol 2015; 16: 266–73
http://dx.doi.org/10.1016/S1470-2045(14)71221-5

Background For most older women with early breast cancer, standard treatment after breast-conserving surgery is adjuvant whole-breast radiotherapy and adjuvant endocrine treatment. We aimed to assess the effect omission of whole-breast radiotherapy would have on local control in older women at low risk of local recurrence at 5 years. Methods Between April 16, 2003, and Dec 22, 2009, 1326 women aged 65 years or older with early breast cancer judged low-risk (ie, hormone receptor-positive, axillary node-negative, T1–T2 up to 3 cm at the longest dimension, and clear margins; grade 3 tumor histology or lympho-vascular invasion, but not both, were permitted), who had had breast conserving surgery and were receiving adjuvant endocrine treatment, were recruited into a phase 3 randomized controlled trial at 76 centers in four countries. Eligible patients were randomly assigned to either whole-breast radiotherapy (40–50 Gy in 15–25 fractions) or no radiotherapy by computer-generated permuted block randomization, stratified by center, with a block size of four. The primary endpoint was ipsilateral breast tumor recurrence. Follow-up continues and will end at the 10-year anniversary of the last randomized patient. Analyses were done by intention to treat. The trial is registered on ISRCTN.com, number ISRCTN95889329.n Findings 658 women who had undergone breast-conserving surgery and who were receiving adjuvant endocrine treatment were randomly assigned to receive whole-breast irradiation and 668 were allocated to no further treatment. After median follow-up of 5 years (IQR 3·84–6·05), ipsilateral breast tumor recurrence was 1·3% (95% CI 0·2–2·3; n=5) in women assigned to whole-breast radiotherapy and 4·1% (2·4–5·7; n=26) in those assigned no radiotherapy (p=0·0002). Compared with women allocated to whole-breast radiotherapy, the univariate hazard ratio for ipsilateral breast tumor recurrence in women assigned to no radiotherapy was 5·19 (95% CI 1·99–13·52; p=0·0007). No differences in regional recurrence, distant metastases, contralateral breast cancers, or new breast cancers were noted between groups. 5-year overall survival was 93·9% (95% CI 91·8–96·0) in both groups (p=0·34). 89 women died; eight of 49 patients allocated to no radiotherapy and four of 40 assigned to radiotherapy died from breast cancer. Interpretation Postoperative whole-breast radiotherapy after breast-conserving surgery and adjuvant endocrine treatment resulted in a significant but modest reduction in local recurrence for women aged 65 years or older with early breast cancer 5 years after randomization. However, the 5-year rate of ipsilateral breast tumor recurrence is probably low enough for omission of radiotherapy to be considered for some patients.
Disease-free survival after complete mesocolic excision compared with conventional colon cancer surgery: a retrospective, population-based study   CA Bertelsen, AU Neuenschwander, JE Jansen, M Wilhelmsen, et al.
Lancet Oncol 2015; 16: 161–68
http://dx.doi.org/10.1016/S1470-2045(14)71168-4

Background Application of the principles of total mesorectal excision to colon cancer by undertaking complete mesocolic excision (CME) has been proposed to improve oncological outcomes. We aimed to investigate whether implementation of CME improved disease-free survival compared with conventional colon resection. Methods Data for all patients who underwent elective resection for Union for International Cancer Control (UICC) stage I–III colon adenocarcinomas in the Capital Region of Denmark between June 1, 2008, and Dec 31, 2011, were retrieved for this population-based study. The CME group consisted of patients who underwent CME surgery in a centre validated to perform such surgery; the control group consisted of patients undergoing conventional colon resection in three other hospitals. Data were collected from the Danish Colorectal Cancer Group (DCCG) database and medical charts. Patients were excluded if they had stage IV disease, metachronous colorectal cancer, rectal cancer (≤15 cm from anal verge) in the absence of synchronous colon adenocarcinoma, tumor of the appendix, or R2 resections. Survival data were collected on Nov 13, 2014, from the DCCG database, which is continuously updated by the National Central Office of Civil Registration. Findings The CME group consisted of 364 patients and the non-CME group consisted of 1031 patients. For all patients, 4-year disease-free survival was 85·8% (95% CI 81·4–90·1) after CME and 75·9% (72·2–79·7) after non-CME surgery (log-rank p=0·0010). 4-year disease-free survival for patients with UICC stage I disease in the CME group was 100% compared with 89·8% (83·1–96·6) in the non-CME group (log-rank p=0·046). For patients with UICC stage II disease, 4-year disease-free survival was 91·9% (95% CI 87·2–96·6) in the CME group compared with 77·9% (71·6–84·1) in the non-CME group (log-rank p=0·0033), and for patients with UICC stage III disease, it was 73·5% (63·6–83·5) in the CME group compared with 67·5% (61·8–73·2) in the non-CME group (log-rank p=0·13). Multivariable Cox regression showed that CME surgery was a significant, independent predictive factor for higher disease-free survival for all patients (hazard ratio 0·59, 95% CI 0·42–0·83), and also for patients with UICC stage II (0·44, 0·23–0·86) and stage III disease (0·64, 0·42–1·00). After propensity score matching, disease-free survival was signifi cantly higher after CME, irrespective of UICC stage, with 4-year disease-free survival of 85·8% (95% CI 81·4–90·1) after CME and 73·4% (66·2–80·6) after non-CME (log-rank p=0·0014). Interpretation Our data indicate that CME surgery is associated with better disease-free survival than is conventional colon cancer resection for patients with stage I–III colon adenocarcinoma. Implementation of CME surgery might improve outcomes for patients with colon cancer.

Biomolecular and clinical practice in malignant pleural mesothelioma and lung cancer: what thoracic surgeons should know
I Opitza, R Bueno, E Lim, H Pass, U Pastorino, M Boeri, G Rocco, et al.
European J Cardio-Thor Surg 46(2014):602–606
http://dx.doi.org:/10.1093/ejcts/ezu048

Today, molecular-profile-directed therapy is a guiding principle of modern thoracic oncology. The knowledge of new biomolecular technology applied to the diagnosis, prognosis, and treatment of lung cancer and mesothelioma should be part of the 21st century thoracic surgeons’ professional competence. The European Society of Thoracic Surgeons (ESTS) Biology Club aims at providing a comprehensive insight into the basic biology of the diseases we are treating. During the 2013 ESTS Annual Meeting, different experts of the field presented the current knowledge about diagnostic and prognostic biomarkers in malignant pleural mesothelioma including new perspectives as well as the role and potential application of microRNA and genomic sequencing for lung cancer, which are summarized in the present article.

 

Principles of Surgical Therapy in Oncology
Michael S. Sabel, Kathleen M. Diehl, and Alfred E. Chang
With the expansion of the multidisciplinary approach to cancer, the role of the surgeon has changed significantly. In addition to the well-established curative role, surgeons are often asked to obtain tissue for diagnosis and staging, debulk tumors as part of multimodality therapy, palliate incurable patients, or prevent cancer by the surgical removal of nonessential organs. As the management of cancer is altered by new discoveries in genetics, molecular biology, immunology, and improved therapeutics, so too will the functions of the surgical oncologist change. With our increased understanding of the genetic predisposition to cancer, the surgeon is increasingly being asked to remove healthy organs to prevent malignancy. However, as other effective methods of prevention are developed, such as chemoprevention or gene therapy, this role will certainly diminish. Improving imaging technologies may have diminished the need for surgical intervention for staging (such as in Hodgkin’s lymphoma), but the expanded use of neoadjuvant therapies often requires interventions to accurately assess response to therapy. In addition, harvesting tumors may become increasingly important for molecular staging as well as identifying molecular targets for specific therapies. It is therefore imperative for surgical oncologists to remain up-to-date on the newest approaches to cancer therapy, both multidisciplinary and experimental, and be prepared to adapt to the changing requirements for surgery.

The major objective for surgery of the primary cancer is to achieve optimal local control of the lesion. Local control is defined as the elimination of the neoplastic process and establishing a milieu in which local tumor recurrence is minimized. Historically, this was achieved with radical extirpative surgeries that shaped the surgical oncologists’ major objective, namely, avoiding a local recurrence. Before William Halsted’s description of the radical mastectomy, surgical

treatment of breast cancer resulted in a dismal local control rate of less than 30%. The reason why Halsted’s procedure was adopted as a standard approach was because he achieved greater than 90% local control, despite the fact that the overall survival of his patients was not improved.4 The latter was due to the locally advanced stage of the patients who were treated in those days. This consideration ushered in the concept of en bloc removal of adjacent tissue when removing a primary cancer. Halsted’s mastectomy involved the removal of adjacent skin (often necessitating a skin graft), underlying pectoral muscles, and axillary lymph nodes (Figure 4.1). One of the major principles of surgical therapy of the primary tumor is to obtain adequate negative margins around the primary tumor, which could mean different operative approaches depending on the tumor type and its local involvement with adjacent structures. For example, the removal of a primary colon cancer that involves an adjacent loop of small bowel or bladder requires the en bloc resection of the primary tumor along with removal of the involved segment of small bowel and bladder wall. This approach avoids violation of the primary tumor margins that could lead to tumor spillage and possible implantation of malignant cells in the surrounding normal tissues. Aside from biopsies of the primary tumor, the lesion should not be entered during a definitive resection. In fact, any biopsy tract or incision that was performed before the tumor resection should be included in the procedure to reduce the risk of local recurrence (Figure 4.2). The risk of local recurrence for all solid malignancies is clearly increased if negative margins are not achieved. The adequacy of the negative margin has been defined for most tumor types either from retrospective clinical experience or prospective clinical trials. For example, a 5-cm margin is an adequate bowel margin for primary colon cancers that has been established from clinical experience. Likewise, it is accepted that a 2-cm distal margin for rectal cancers results in adequate local control. Through several prospective, randomized clinical trials, the margins of excision for primary cutaneous melanomas differ according to the thickness of the primary (see Chapter 60). It was a commonly held notion that the development of a local recurrence would in itself result in metastatic disease with decreased overall survival. However, this has not been borne out in the context of prospective trials as described here. The emergence of multimodal therapy has dramatically affected the surgical approach to many primary cancers, especially when surgical resection of the tumor is combined with radiotherapy. Local control is significantly improved after surgical resection of breast, rectal, sarcoma, head and neck, and pancreatic primary cancers. In fact, the addition of radiation therapy as an adjunctive therapy has allowed for less-radical procedures to be performed with an improvement in the quality of life of patients. A prime example of this is in breast cancer. Several clinical trials have demonstrated that the overall survival of patients with invasive breast cancer was comparable if treated by mastectomy versus lumpectomy plus adjuvant radiotherapy.

The regional lymph nodes represent the most prevalent site of metastasis for solid tumors. Because of this, the involvement of the regional lymph nodes represents an important prognostic factor in the staging of the cancer patient. For this reason, the removal of the regional lymph nodes is often performed at the time of resection of the primary cancer. Besides staging information, a regional lymphadenectomy provides regional control of the cancer. Examples of this are patients with melanoma who have tumor metastatic to lymph nodes. It is well documented that the removal of these regional lymph nodes can result in long-term survival benefit in approximately 20% to 40% of individuals depending upon the extent of nodal involvement. Hence, the removal of regional lymph nodes can be therapeutic. The controversies regarding regional lymphadenectomy for solid malignancies have related to the timing of the procedure as well as the extent of the procedure. For some visceral solid tumors such as gastric and pancreatic cancers, the extent of lymphadenectomy at the time of primary tumor resection has been hypothesized to be important in optimizing local and regional control and has an impact on improving overall survival. This concept has not been borne out in prospective randomized trials of gastric cancer in which the extent of lymphadenectomy has been examined.

Based on these trials, the more-extended lymphadenectomy appears to result in more accurate staging of patients at a cost of increased morbidity. For nonvisceral solid tumors such as melanoma, breast cancers, and head and neck squamous cancers, the elective removal of regional lymph nodes at the time of primary tumor resection has been postulated to result in better survival outcomes compared to taking the wait-and-watch approach. The latter involves performing a lymphadenectomy only when the patient relapses in a nodal basin that would then necessitate a therapeutic lymph node dissection. In prospective randomized clinical studies evaluating elective versus therapeutic lymph node dissection in various tumor types, there was no survival advantage for performing elective lymph node dissections (Table 4.2). It is apparent from these controversies that the initial removal of regional lymph nodes is most important for its staging impact, rather than its therapeutic effect. The introduction of selective lymphadenectomy based upon the concept of the sentinel lymph node has dramatically improved our ability to stage the regional lymph nodes of certain cancers. This is reviewed in more detail in the Diagnosis and Staging section of this chapter.

One of the earliest examples of surgical prophylaxis is the recommendation for total proctocolectomy for subsets of patients with chronic ulcerative colitis. Patients with pancolitis, onset of disease at a young age, and a long duration of colitis are at high risk of developing colorectal cancer.36 Other clinical diseases of the large intestine also illustrate the role of proctocolectomy in cancer prevention. Familial adenomatous polyposis coli (FAP) syndrome, defined by the diffuse involvement of the colon and rectum with adenomatous polyps often in the second or third decade of life, almost always predisposes to colorectal cancer if the large intestine is left in place. However, the role of screening and prophylactic proctocolectomy changed dramatically with the identification of the gene responsible for FAP, the adenomatous polyposis coli (APC) gene, located on the long arm of chromosome 5 (5q21).37 Now, children of families in which an APC mutation has been identified can have genetic testing before polyps become evident. Carriers can have screening and surgical resection once polyps appear, usually in the late teens or early twenties. Although not ideal, the palatability of proctocolectomy in this population was furthered with the description of the total abdominal colectomy, mucosal proctectomy, and ileoanal pouch anastomosis.38

Another example of prophylactic surgery is the bilateral mastectomy for women at high risk of developing breast cancer. Before the identification of the BRCA genes, prophylactic mastectomies were typically reserved as an option for women with lobular carcinoma in situ (LCIS). However, with the identification of BRCA1 and BRCA2, the role of prophylactic mastectomies has been greatly expanded. For women with BRCA1 or BRCA2 mutations, the lifetime probability of breast cancer is between 40% and 85%.41–43 Because mastectomy cannot remove all breast tissue, women can expect a 90% to 94% risk reduction with prophylactic surgery.44 Schrag et al. calculated the estimated gain in life expectancy after prophylactic surgery versus no operation in women with either a BRCA1 or BRCA2 mutation and found a 30-year-old woman would be expected to gain 2.9 to 5.3 years of life, depending on her family history.45 However, potential benefits of prophylactic mastectomy must be weighed against quality of life issues and the morbidity of the surgery.46 In addition, other methods for prophylaxis, such as tamoxifen chemoprevention or bilateral oophorectomy, must be considered. Along with the increased risk of breast cancer with BRCA1/2 mutations, the risk of ovarian cancer is also increased. Bilateral oophorectomy after childbearing is complete not only reduces the risk of ovarian cancer47 but may also decrease the risk of breast cancer.48 A detailed discussion must be held with each patient considering bilateral mastectomies regarding the risks and benefits, the knowns and unknowns. It is becoming increasingly important that today’s surgical oncologist have a clear understanding of genetics and inherited risk.

Increased genetic knowledge has also changed our approach to thyroid cancer. Medullary thyroid cancer (MTC) is a wellestablished component of multiple endocrine neoplasia syndrome type 2a (MEN 2a) or type 2b (MEN 2b). Previously, family members at risk for MEN 2 underwent annual screening for elevated calcitonin levels; however, this only detected MTC after it developed. In 1993 it was identified that mutations in the RET proto-oncogene were present in almost all cases of MEN 2a and 2b. Now family members of MEN patients can be screened for the presence of a RET mutation. Those without the mutation need not undergo additional screening, whereas those with the mutation should undergo total thyroidectomy at a young age (6 years for MEN 2a, infancy for MEN 2b).49

The readers are reminded that older or elderly patients will increasingly make up the population of patients with cancer. Currently 60% of all malignancies, and 70% of all cancer deaths, occur in people over the age of 65.58 In addition to the previously mentioned considerations, assessment of the older patient should include evaluation of activities of daily living, depression, cognitive function, current medications and potential medication interactions, and available social support.59–62

  1. Lewison EF. Breast Cancer and Its Diagnosis and Treatment. Baltimore: Williams & Wilkins, 1955.
  2. Rutledge RH. Theodore Billroth: a century later. Surgery (St. Louis) 1995;118:36–43.
  3. Weir R. Resection of the large intestine for carcinoma. Ann Surg 1886;1886(3):469–489.
  4. Halsted WS. The results of operations for the cure of cancer of the breast performed at the Johns Hopkins Hospital from June 1889 to January 1894. Ann Surg 1894;320(13):497–555.
  5. Clark JG. A more radical method for performing hysterectomy for cancer of the cervix. Johns Hopkins Bull 1895;6:121.
  6. Crile G. Excision of cancer of the head and neck. JAMA 1906; XLVII:1780.
  7. Miles WE. A method for performing abdominoperineal excision for carcinoma of the rectum and terminal portion of the pelvic colon. Lancet 1908;2:1812–1813.
  8. Krakoff IH. Progress and prospects in cancer treatment: the Karnofsky legacy. J Clin Oncol 1994;12:432–438.
  9. Farber S, Diamond LK, Mercer RD, et al. Temporary regressions in acute leukemia in children produced by folic acid antagonist, aminopteroyl-glutamic acid. N Engl J Med 1948;238: 693.
  10. Huggins CB, Hodges CV. Studies on prostatic cancer: the effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941;1:293–297.
  11. Lawrence W Jr, Wilson RE, Shingleton WW, et al. Surgical oncology in university departments of surgery in the United States. Arch Surg 1986;121:1088–1093.
  12. Fisher B, Remond C, Poisson R, et al. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1989;320:822–828.

Quality of surgery: has the time come for colon cancer?
Lancet (Oncology)   Feb 2015; 16  
http://dx.doi.org/10.1016/S1470-2045(14)71223-9

Major improvements in outcomes for rectal cancer have occurred in the 30 years since the introduction of total mesorectal excision and multidisciplinary treatment.1 This situation should continue to improve with more radical surgery for low rectal cancer. Pioneering work by leaders of rectal cancer surgery was initially ignored and it took the independent reproduction of the improved outcomes in single hospital and small regional studies before large-scale regional and national training programs led to major reductions in local recurrence, significant improvements in survival, and major financial savings occurred around the world. Colon cancer accounts for around 70% of bowel cancer and although survival has improved, it has not been to the same extent as that for rectal cancer, with substantial variation remaining between hospitals for operative cases. Historical reports have shown significantly improved survival in colon cancer following surgical standardization,2–4 and excellent results from Japan have largely been ignored.5 The rectal cancer story is repeating itself. Colonic cancer resection in western countries is unfortunately still viewed as a routine procedure with little concern surrounding these major variations in outcome. Indeed the focus has been on laparoscopic surgery rather than optimisation of the surgery. In The Lancet Oncology, a paper by Claus Anders Bertelsen and colleagues,6 and the debate it should generate, is a key step to reproduce the benefits of optimum rectal cancer surgery in colonic cancer, and hints at what could be achievable by the routine adoption of high-quality surgery. In this detailed report, the researchers show that implementation of complete mesocolic excision (CME) with central vascular ligation (CVL) results in a major improvement in survival. By simply visiting and adopting the methods of expert surgeons in Erlangen, led by Werner Hohenberger,4 and by quality controlling their surgery through mesocolic grading, routine specimen photography, and internal and external pathology audit,7 the researchers have independently reproduced results from Erlangen and Japan. The improvement in outcome described could be attributable to two specific variables; first, CME, which comprises the intact removal of the mesocolon and its lymphatic drainage within embryological planes. This procedure should be routine; it does not increase risks to the patient and might seem obvious since careful dissection following anatomical planes is a basic principle of surgery and such planes were described in the early 20th century, but on close scrutiny surgical planes are very variable and must be improved.8,9 Second, but more controversially, is the role of CVL. This procedure entails more radical central dissection, with potential risk to major vessels, nerves, and organs such as the pancreas. In Erlangen, Japan, and now in Hillerød, such surgery seems to be safe, but several important questions remain. How much benefit does it convey in addition to mesocolic surgery? What is the learning curve and is this achievable for all surgeons? Can it be safely achieved laparoscopically? Is the same benefi t derived for all stages of disease?

Radiation therapy in the locoregional treatment of triple-negative breast cancer
Meena S Moran
Lancet Oncol 2015; 16: e113–22

This Review assesses the relevant data and controversies regarding the use of radiotherapy for, and locoregional management of, women with triple-negative breast cancer (TNBC). In view of the strong association between BRCA1 and TNBC, knowledge of baseline mutation status can be useful to guide locoregional treatment decisions. TNBC is not a contraindication for breast conservation therapy because data suggest increased locoregional recurrence risks (relative to luminal subtypes) with breast conservation therapy or mastectomy. Although a boost to the tumour bed should routinely be considered after whole breast radiation therapy, TNBC should not be the sole indication for postmastectomy radiation, and accelerated delivery methods for TNBC should be off ered on clinical trials. Preliminary data implying a relative radioresistance for TNBC do not imply radiation omission because radiation provides an absolute locoregional risk reduction. At present, the integration of subtypes in locoregional management decisions is still in its infancy. Until level 1 data supporting treatment decisions based on subtypes are available, standard locoregional management principles should be adhered to.

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Leaders in Pharmaceutical Business Intelligence announce their latest addition to the BioMed e-Series ebooks: Cancer Biology and Genomics for Disease Diagnosis, Volume One.

This ebook is a compendium of recent breakthroughs, articles, and commentary on cancer research, cancer detection and diagnosis and treatment, written and curated by a team of PhD, MD, MD/PhD, PharmD clinicians, scientists, and writers having expertise in oncology.

Leaders in Pharmaceutical Business Intelligence will demonstrate this e-book at  The Sachs Cancer Bio Partnering and Investment Forum, held March 19, 2014 at the New York Academy of Sciences in New York, USA.

A post on this site entitled The 2nd ANNUAL Sachs Cancer Bio Partnering & Investment Forum Promoting Public & Private Sector Collaboration & Investment in Drug Development, 19th March 2014 • New York Academy of Sciences • USA explains the program, agenda, a description of this investment conference.

A flyer of the demonstration by Leaders in Pharmaceutical Intelligence is included below (please click on picture):

SACHS FLYER 2014 CANCER EBOOKjpeg-page1

SACHS FLYER 2014 CANCER EBOOKjpeg-page2

 

The flyer can be downloaded as a .pdf here: SACHS FLYER 2014 CANCER EBOOK

April 2014 will see LAUNCH of next VOLUME in Series C: e-Books on Cancer & Oncology Radiation Oncology & Immunotherapy in Cancer

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Author: Ziv Raviv PhD

 

Part A: Introduction to the PI3K/Akt pathway

Background

Akt/Protein kinase B (PKB) is a cytosolic serine/threonine kinase that promotes cell survival by inactivation of targets of the apoptotic pathways [1], and is implicated in the execution of many other cellular processes including:  cell proliferation, angiogenesis, glucose metabolism [2], protein translation, and gene transcription, all are mediated by extracellular and intracellular signals. In many cancers Akt is overexpressed and has central role in cancer progression and cancer cell survival [3,4], what makes it an attractive target for cancer therapy.

The Akt signaling pathway

Upstream signaling:

The Akt signaling pathway is initiated by growth factors leading to the recruiting and activation of phosphoinositol-3-kinase (PI3K) on receptor tyrosine kinases (RTKs). PI3K is then translocated to the cell membrane where it phosphorylates inositol ring at the D3 position of phosphatidylinositol  to form phosphatidylinositol (3,4,5)-triphosphate (PIP3). PIP3 serves to anchor Akt to the plasma membrane where it is phosphorylated at Thr308 by PDK1 and is further completely activated by mTOR by phosphorylation of Ser473. In certain circumstances activated Ras can also activate PI3K.

Downstream signaling:

Upon activation Akt is transducing its signals to downstream substrates to induce various intracellular processes, among them are: Activation of mTOR and its downstream effector S6K – to facilitate activation of translation; Phosphorylation of Bad – that inhibits apoptosis ; Phosphorylation of the tumor suppressor gene FOXO1 – inducing its ubiquitination and subsequent degradation by the proteasome;  Inhibition by phosphorylation of glycogen synthase kinase 3 (GSK-3) – which results in increase of glycogen synthesis.   Regulation of cell growth and survival is executed also by blocking apoptosis by Akt-associated survivin (BRC5) upregulation and via the NF-κB pathway by activation of IκB kinase (IKK).

  • Watch a Video on Akt Signaling Pathway

Figure 1: The Akt signaling pathway

AKT_cClick on image to enlarge

Taken from: Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. Workman P et al. Curr Opin Pharmacol. 2008 Aug;8(4):393-412

Negative regulation:

PI3K-dependent Akt activation is negatively regulated by the tumor suppressor protein PTEN, which works essentially opposite to PI3K, namely,  PTEN acts as a phosphatase and dephosphorylates PIP3 back to PIP2. This step removes Akt from its membrane anchoring through PIP3 resulting in substantial decreased rate of Akt activation and consequently inactivation of Akt-depended downstream pathways. In addition, PIP3 can also be dephosphorylated by the SHIP family of inositol phosphatases form PIP2.

Involvement of Akt  in cancer

The PI3K/Akt pathway is frequently altered and deregulated in many human malignancies. Hyper-activation of AKT kinases is one of the most common molecular findings in human malignancies and account for malignant transformation. Mechanisms for Akt pathway activation include loss of tumor suppressor PTEN function, amplification or mutation of PI3K, amplification or mutation of Akt, activation of growth factor receptors, inactivation of the translation repressor protein 4E-BP1 [5], and exposure to carcinogens [3 ,4]. For instance, heterozygous deletion of PTEN in mice elicits spontaneous tumors attributed mainly to activation of Akt. In addition, the production PIP3 by PI3K is over-activated in a wide range of tumor types. On the other hand, Akt knockout mice demonstrate that Akt is required for both cancer cell survival and oncogenic transformation. That activation of Akt is oncogenic, could be explained by preventing normal apoptosis of cells, thereby enabling accumulation of more oncogenic mutations in these cells. In addition, activation of Akt can also abrogate cell cycle checkpoints and can overcome G2/M cell-cycle arrest mediated by DNA mismatch repair. Thus, cells in which Akt is activated can accumulate mutations because the G2 cell-cycle point is abrogated and survive and continue to divide because of the anti-apoptotic activity of Akt. It is, therefore, proposed that this dual activity of Akt activation may explain the frequent activation of Akt in human malignancies [6].

Taken together, Akt activation has an effective role in cancer and through its downstream substrates Akt controls many cancer related cellular processes such as cell metabolism, growth and survival, proliferation, and motility, all of which contribute to tumor initiation and progression. Therefore, this pathway is an attractive therapeutic target for cancer treatment because it serves as a convergence point for many growth stimuli. Moreover, activation of the PI3/Akt pathway confers resistance to many chemotherapeutic drags [6], and is a poor prognostic factor for many types of cancers. Therefore, small molecule agents that block PI3K/Akt signaling might block many aspects of the tumor-cell phenotype [7,8]. Indeed, the Akt pathway is a major target for anticancer drug development by pharmaceutical companies.

  • The below Part B review the efforts to develop targeted Akt therapies for cancer.

 

Part B: Clinically available/in clinical development PI3K/Akt/mTOR inhibitors 

As described in Part Athe PI3/Akt cascade is a major intracellular signaling route conferring pro-survival signals to the cell. In cancer, there are many conditions where the PI3K/Akt pathway is deregulated, an attribute that is contributing to cancer formation and propagation. Given that Akt servers as convergence point to many pro-survival signals together with it being deregulated frequently in cancers, make Akt as a valuable target for developing anti-cancer therapy.

In addition, Akt shortens patient survival by allowing cancer cells to escape the cytotoxic effects of standard chemotherapy drugs. The importance of the Akt pathway in cancer thus is also evident from its significant role in the resistance of tumors to chemotherapies. A considerable route in developing anti- Akt based therapies is thus combining Akt inhibitors with standard chemotherapy rather than the using of Akt inhibitors as single agents.

Even in targeted therapies for cancer, such those that target receptor tyrosine kinases (RTKs) and other signaling pathways, it has been demonstrated that when applying a targeted agent such as trastuzumab  (Herceptin) a compensation reaction of increasing of downstream and parallel signaling pathways components, among them Akt, occurs in response, which enables cancer cells to be spared the effects of these targeted drugs. Therefore a multi-targeting approach with selective inhibitors would be useful, and inhibiting Akt directly will restore sensitivity to agents such as trastuzumab.

(i) Inhibitors that are in clinical use

Temsirolimus (CCI-779; marked as Torisel by Pfizer), an analog of sirolimus (rapamycin), is an immunophilin-binding antibiotic that blocks the initiation of the translation of mRNA by inhibiting mammalian target of rapamycin (mTOR) in a highly specific manner. Rapamycin itself is toxic and found in the clinic however as an immunosuppressant to prevent rejection in organ transplantation. Temsirolimus acts by interacting with mTOR, preventing the phosphorylation of eIF4E-BP1 and p70S6K, and thereby inhibiting the initiation of the translation of mRNA. The main mechanism of temsirolimus is inhibition of proliferation by G1 phase arrest induction, yet without inducing apoptosis. Temsirolimus was introduced only recently to treat renal cell carcinoma (RCC). In this cancer type HIF-1a levels are accumulated since its degradation is reduced significantly due to mutations of von Hippel Lindau tumor-suppressor gene and the activation of mTOR only worsen that accumulation of HIF1-a, which is its downstream effector. Therefore by blocking mTOR function temsirolimus is reducing the accumulation of HIF-1a. Temsirolimus has been generally well tolerated by advanced RCC patients that could be attributed to its high specificity toward mTOR. However, temsirolimus is associated with a small, but significant increased risk of developing a fatal adverse event. Nevertheless, temsirolimus benefit the overall patient population with the approved indications, including RCC. In the pivotal phase III study, temsirolimus demonstrated median overall survival (OS) in previously untreated patients of 10.9 months in patients with advanced RCC with poor prognostic risk, compared with 7.3 months for interferon-alpha. Temsirolimus remains the only treatment that shows a significant improvement in OSin treatment-naive, poor-risk patients with advanced RCC. Temsirolimus approved cancer indications are RCC and mantle cell lymphoma (MCL), and many other cancer conditions are found in advanced clinical development processes, including various solid tumors, diffused tumors (leukemias and lymphomas), and even in soft tissue sarcomas (STS).

Everolimus (RAD001; marketed by Novartis  as Afinitor) is an ester derivative of rapamycin and is also an inhibitor mTOR.  The drug inhibits oncogenic signaling in tumor cells and angiogenic signaling in vascular endothelial cells. Key features of everolimus include good tolerability, unique mechanism of action, G1 arrest, and induction of apoptosis. In vitro studies have demonstrated a cooperative effect between everolimus and gefitinib in various cancer cell lines. Treatment of human cancer cell lines with everolimus results in a decrease in p-4E-BP1, p-p70S6K, and p-S6 levels while increasing p-AKT levels. The rise of p-AKT is accompanied with a parallel increase in downstream p-GSK-3a/ß, suggesting feedback activation of the AKT pathway. Thus AKT activation could revert the antitumor activity of everolimus. Gefitinib completely prevents everolimus-induced p-AKT increase and markedly enhances the everolimus mediated decrease in p-4E-BP1 and p-p70S6K.

Everolimus is approved for the treatment of RCC, progressive pancreatic neuroendocrine tumors, breast cancer in post-menopausal women with advanced hormone receptor (HR)-positive/HER2-negative. In addition the drug is used as a preventive drug of organ rejection after renal transplantation. As with the case of temsirolimus, everolimus has also a slight increase of mortality risk over other drugs.

Cancer indications that are now in clinical development for treatment by everolimus, some of which are in advanced clinical studies, include various forms of leukemias and lymphomas such as AML, ALL CML, T-cell leukemia, diffuse large B-cell lymphoma (DLBCL), non-Hodgkin’s lymphoma (NHL), and MCL. Everolimus is particularly applicable to the treatment of leukemia because mTOR-related messengers, particularly PI3K, AKT, p70S6K kinase and 4E-BP1, are known to be both constitutively activated in hematologic malignancies and interfere with the activity of current anti-leukemia therapy. Solid tumors such as lung, breast, prostate, and colorectal at various stages, as well as brain cancers and STS are also in developmental stages for everolimus treatment.

(ii) Inhibitors that are in advanced clinical development (phase II/III)

Perifosine (KRX-0401) by AEterna Zentaris – among Akt inhibitors under development for cancer therapy, perifosine is found in advanced stages of clinical development and is moving toward phase III clinical trials. It belongs to alkylphosphocholines (ALP) – phospholipid-like molecules – which disrupt lipid-mediated signal transduction pathways that are necessary for tumor cell growth and survival. ALP induce apoptotic cell death in a variety of tumor cell lines. Perifosine primarily acts on the cell membrane where it inhibits signaling that could explain its capability to inhibit Akt, as Akt interaction with PIP3 in the cytosolic face of the plasma cell membrane is essential to its activation. In addition to Akt, perifosine inhibits also JNK and NF-kB, both are also associated with apoptosis, cell growth, differentiation, and survival. In addition to its potential efficacy as a single agent, perifosine may provide synergistic effects when combined with established cancer treatments such as radiotherapy, chemotherapy, tyrosine kinase inhibitors such as commercially available EGFR inhibitors, and endocrine therapies.

Many clinical trials were/are conducted with perifosine in various cancer conditions and settings. Especially successive phase II studies engaged perifosine were with colorectal cancer (CRC), where patients with metastatic disease treated with the combination of capecitabine and perifosine had more than doubled the median time to progression (TTP) of the disease, which led to an ongoing phase III study. Other solid cancer indications phase II studies employing perifosine that had encouraging results include metastatic RCC (mRCC) and non-small lung cancer (NSLC). Perifosine is also exmined in clinical trials with hematological cancers. Advanced stages clinical studies were conducted in multiple myeloma (MM), where patients treated with the combination of perifosine + bortezomib (proteasome inhibitor) and dexamethasone, in which after, a phase III study was conducted on that basis. However, that phase III study was terminated in March 2013 upon recommendation by data safety monitoring board to discontinue the experiment since it was highly unlikely that the trial would achieve a significant difference in progression-free survival (PFS).  Another potential benefit for perifosine has been documented in Waldenström’s macroglobulinemia (WM).  In addition, perifosine is examined in other hematologic cancers such as in AML, CLL and lymphomas.

MK-2206 – MK-2206 by Merck is an allosteric inhibitor of Akt that is currently widely examined in tens of clinical experimentation where some of them are in phase II status.  In preclinical experiments, MK-2206, demonstrated synergistic activity when combined with other targeted therapies, such as erlotinib in NSCLC cell lines, and lapatinib in breast cancer cell lines and in xenograft mice bearing ovarian cancer, MK-2206 treatment led to substantial growth inhibition and sustained inhibition of Akt.

Several phase II research studies employing MK-2206 are in progress, among them found a multicenter study with advanced ovarian cancer resistant to platinum therapy, and another multicenter study with breast cancer patients. Phase I/II study is conducted also for CLL patients. Many others phase I studies are in progress, among them trails testing the combinations of MK-2206 with other targeted drugs as well as chemotherapy. For instance an ongoing phase I study is evaluating the addition of MK-2206 to trastuzumab in patients with solid tumors HER2 positive, or another study is conducted to evaluate MK-2206 in combination with trastuzumab and lapatinib for the treatment of HER2 positive, advanced solid tumors. MK-2206 is testing also in advanced NSCLC with the combination of gefitinib in one study and with erlotinib in another. In another relatively large phase I study, patients with advanced solid tumors were randomized to MK-2206 either given with carboplatin and paclitaxel, docetaxel, or erlotinib. Another study with patients bearing locally advanced or metastatic solid tumors or metastatic breast cancer examined MK-2206 given with and paclitaxel (Taxol). Finally MK-2206 and selumetinib administration was tested in phase I studies in patients with advanced CRC. Other cancer indications that are investigated MK-2206 as single agent or in combination with chemotherapy in phase I studies include prostate cancer,  head and neck cancer, large B cell lymphoma, leukemias such as AML, and melanoma.

Ridaforolimus (AP23573/MK-8669,; Taltorvic by Merck) – Ridaforolimus is an oral mTOR inhibitor found in several clinical trials. A compressive phase III experiment was conducted with ridaforolimus in metastatic STS and metastatic bone sarcomas (SUCCEED – Sarcoma Multi-Center Clinical Evaluation of the Efficacy of Ridaforolimus) by Merck and Ariad Pharmaceuticals that had presented positive data at the beginning showing that patients that have received ridaforolimus had a median progression-free survival (PFC) – the primary endpoint of the study – of 17.7 weeks compared with 14.6 weeks for those received placebo. However, FDA’s oncologic drugs advisory committee (ODAC) panel (March 2012) did not approved the use of ridaforolimus as maintenance therapy for patients with metastatic soft-tissue sarcoma or bone sarcoma. The committee did not think that a significant difference was observed between the groups in terms of OS and although patients did experience a longer disease-free period before their cancer returned when receiving ridaforolimus, the delay was not significant. There was also a concern regarding side effects. In a complete response letter, (June 2012) the FDA did not approve the SUCCEED application in its present form, therefore, Merck formally withdrawn the marketing authorization application for ridaforolimus for sarcoma. However, Merck still continue experimenting ridaforolimus in other cancer indications. A phase II study is conducted in breast cancer patients examining ridaforolimus alone, ridaforolimus + dalotuzumab, or ridaforolimus + Exemestane. Another phase II study is conducted in female adult patients harboring recurrent or persistent endometrial cancer. A third Phase II study is examining ridaforolimus in patients with taxane-resistant androgen-independent prostate cancer. Many phase I experiments are conducted with ridaforolimus among them: experiment in pediatric patients with solid tumors treated with dalotuzumab given alone or in combination with ridaforolimus; Bicalutamide and ridaforolimus in men with prostate cancer; Combinations of carboplatin/paclitaxel/ridaforolimus in endometrial and ovarian tumors; Safety study examining ridaforolimus  in patients with progressive or recurrent glioma, and others. Given the consequences as with the SUCCEED experiment; it remains to see whether ridaforolimus alone or in combinations would be approved and be valid in the clinical arena.

RX-0201 (Archexin) by Rexahn Pharmaceuticals is an antisense oligonucleotide directed toward Akt1 mRNA. RX-0201 was demonstrated to significantly downregulated the expression of AKT1 at both the mRNA and protein levels. In addition combined treatment of RX-0201with several cytotoxic drugs resulted in an additive growth inhibition of Caki-1 clear cell carcinoma cells. In addition, preclinical experiments demonstrated that RX-0201 given at nano-molars as a single agent induced substantial growth inhibition in various types of human cancer cells. Furthermore, in vivo studies using nude mice xenografts have resulted in significant inhibition of tumor growth and tumor formation treated with RX-0201. Therefore RX-0201 was further tested in phase I studies in patients with solid tumors. The only dose limiting toxicity (DLT) observed was Grade 3 fatigue. Phase II studies of RX-0201 were approved thus in advanced RCC. Furthermore, another phase II study was completed last year with encouraging results.  This phase II trial was conducted in metastatic pancreatic cancer, assessing the combination of RX-0201 and gemcitabine. The study enrolled 31 patients and the primary endpoint was overall survival following 4 cycles of therapy with a 6-month follow-up. The study demonstrated that treatment with RX-0201 in combination with gemcitabine resulted in a median survival of 9.1 months compared to the published survival data of 5.65 months for gemcitabine given alone. The most frequently side effects were constipation, nausea, abdominal pain, and pyrexia, regardless of relatedness.

BKM120 – by Novartis is an oral selective class-I PI3K inhibitor, induces its inhibition in an ATP-competitive manner, thereby inhibiting the production of the secondary messenger PIP3 and activation of downstream signaling pathway. BKM120 was shown to induce pro-apoptotic effects in vitro and anti-tumor activity in vivo. BKM120 is enrolled in many clinical trials at all levels for several cancer indications. Phase I experiments are performed with the following cancers: CRC in combination with panitumumab; RCC; breast cancer (HR+/HER2+); breast cancer (triple negative, recurrent); ovarian cancer; and leukemias.  Phase II trials include: endometrial cancer; metastatic NSCLC; malignant melanoma (Braf V600 mutated); prostate; and glioblastoma multiforme (GBM).

A phase III study is currently enrolled with postmenopausal breast cancer patients with HR+/HER2- (local, advanced or metastatic), examining BKM120 in combination with fulvestrant. In preliminary clinical experiments activity was observed with BKM120 in patients with breast cancer, as a single agent or in combination with letrozole, or trastuzumab. In this phase III study, postmenopausal women with HR+/HER2- breast cancer whom were treated with aromatase inhibitor (AI), and are refractory to endocrine and mTOR inhibition (mTORi) combination therapy, are randomized to receive continuous BKM120 or placebo daily, with fulvestrant. The rational for this experiment is that the use of PI3K inhibition may overcome resistance to mTORi in breast cancer by targeting the PI3K pathway upstream.  The primary endpoint of the trail is PFS and the secondary endpoint is OS. Other secondary endpoints are overall response rate and clinical benefit rate, safety, pharmacokinetics of BKM120, and patient-reported quality of life.

CAL-101 (Idelalisib) – by Gilead Sciences is an orally bio-available, small molecule inhibitor of PI3K delta proposed for the treatment hematologic malignancies. In preclinical efficacy studies, CAL-101 inhibited the PI3K pathway and decreased cellular proliferation in primary CLL and AML cells, and in a range of NHL cell lines. The delta form of PI3K is expressed primarily in blood-cell lineages, including cells that cause or mediate hematologic malignancies, inflammation, autoimmune diseases and allergies. Therefore, CAL-101 as specific inhibitor of the PI3K-delta is expected to have therapeutic effects in these diseases without inhibiting PI3K signaling that is critical to the normal function of healthy cells. A variety of studies have shown that inhibition of other PI3K forms can cause significant toxicities, particularly with respect to glucose metabolism, which is essential for normal cell activity. CAL-101 was shown to block constitutive PI3K signaling, resulting in decreased phosphorylation of Akt and other downstream effectors, an increase in PARP and caspase cleavage, and an induction of apoptosis across a broad range of immature and mature B-cell malignancies. Importantly, CAL-101 does not promote apoptosis in normal T cells or NK cells, nor does it diminish antibody-dependent cellular cytotoxicity (ADCC) but decreased activated T-cell production of various inflammatory and anti-apoptotic cytokines. These findings provide rationale for the clinical development of CAL-101 as a first-in-class targeted therapy for CLL and related B-cell proliferative disorders. Indeed several clinical trials are currently enrolled for Hodgkin’s lymphoma, NHL, and CLL. Phase III clinical trials for CLL are now recruiting patients aimed to examine CAL-101 in combination with Bendamustine and Rituximab in one study;  CAL-101 + Rituximab;  and the combinations of CAL-101 with Ofatumumab in third phase III study. Both Rituximab and Ofatumumab are monoclonal Abs for CD20, which is primarily found on the surface of B cells. In addition, another phase III study of CAL-101 in combination with Bendamustine and Rituximab for indolent NHLs is also now recruiting patients.

(iii) Other Akt pathway inhibitors in clinical development.

There are dozens of agents targeting Akt pathway that are found at preclinical and clinical development. The various inhibitors are targeting various elements of the Akt pathway including: Akt itself, PI3K, mTOR, and PDK1. Most of these agents are small molecules inhibitors, some are extracts while others are synthetic, but also include an antisense oligonucleotide (RX-0201 to Akt).

The list below describes shortly agents which currently reached phase II stage and their relevant indications:

XL-147 – sponsored by Sanofi, small molecule-pan PI3K inhibitor for breast cancer and endometrial cancer.

XL-765 – also of Sanofi, inhibitor of the activity of PI3K and mTOR, for HR+/HER2- breast cancer patients.

BN108 – by Bionovo, an aqueous extract of Anemarrhena asphodeloides, is an orally available dual inhibitor, that induces apoptotic cancer cell death by rapid inactivation of both Akt and mTOR pathways, for breast cancer.

GDC-0068 – by Genentech, is an orally available small molecule pan-Akt inhibitor, for prostate cancer.

BEZ235 – by Novartis is a dual ATP-competitive PI3K and mTOR inhibitor, prevents PI3K signaling and inhibits growth of cancer cells with activating PI3K mutations. Phase II study is recruiting patients with metastatic or unresectable malignant PEComa (perivascular epithelioid cell tumors), other phase II include endometrial cancer indications and metastatic HR+/HER2-breast cancer patients.

BAY 80-6946 – is a pan class I PI3K inhibitor by BayerPhase II for NHL, currently recruiting.

Nelfinavir  – by ViiV Healthcare is an HIV protease inhibitor found to downregulate Akt phosphorylation by inhibiting proteasomal activity and inducing the unfolded protein response (UPR). HIV-1 protease inhibitor was found induces growth arrest and apoptosis of human prostate cancer cells in vitro and in vivo in conjunction with blockade of androgen receptor, STAT3 and AKT signaling. A phase I/II trial is enrolled for patients with locally advanced CRC to test Nelfinavir in combination with chemo/radiotherapy.

Triciribine  Triciribine phosphate monohydrate (TCN-PM) is a specific AKT inhibitor used also in the basic research arena but undergo also several clinical studies. Currently a phase II sponsored by Cahaba Pharmaceuticals is recruiting, to examine triciribine with paclitaxel in patients with locally advanced breast cancer. And a phase I/II experiment of combination with carboplatin in ovarian patients is planned.

GSK2110183 – by GlaxoSmithKline  is an oral panAkt inhibitor. Phase II is recruiting subjects with solid tumors and hematologic malignancies.

(iv) Conclusive remarks

Given the broaden arsenal of agents targeting Akt that are in pre-clinical and clinical development, it is extremely important to figure out how to use them optimally and to elucidate carefully which of them have the greatest potential to proceed into advanced stages of clinical trials and to clinical approval.  One of the various considerations in developing valid Akt inhibitors for the clinic use should be choosing a relevant cancer in which Akt has a central role in its development/propagation (e.g. mRCC). Since there is cross-talk between the Akt pathway to other pathways especially by involvement of RTKs (e.g. VEGFR), there is a rational to apply Akt inhibitions in cancer indications that had good results with inhibition of RTKs where combinations of Akt with agents such as sunitinib, could results in a synergistic anti-cancer effect. The combinations of Akt inhibitors with RTKs inhibitors could also overcome the compensate reaction to agents such as Herceptin that confer resistance. It is important to introduce efficient Akt inhibitor on the background of existing anti-cancer chemotherapies where Akt inhibitors can complement these therapies by circumvent frequent resistance to these drugs. Finally, the developing of biomarkers for a validation of the efficacy of candidate Akt inhibitor to be developed in further advance clinical studies for specific cancer indications is essentially needed, to ensure that accurate efforts would be invested at the most validate Akt inhibitors. Such biomarkers could be levels of phosphorylated Akt in blood or mRNA levels to be monitored upon treatment with Akt inhibitors and the correlation to the efficacy of these inhibitors, and that is besides of their prognostic value. The status of mutations of PI3K and PTEN could also serve as a marker for the efficiency of Akt inhibitors and how to use them optimally.

 

References

1. Song G, Ouyang G, Bao S (2005) The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 9 (1):59-71

2. Gonzalez E, McGraw TE (2009) The Akt kinases: isoform specificity in metabolism and cancer. Cell Cycle 8 (16):2502-2508

3. Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2 (7):489-501

4. Altomare DA, Testa JR (2005) Perturbations of the AKT signaling pathway in human cancer. Oncogene 24 (50):7455-7464

5. She QB, Halilovic E, Ye Q, Zhen W, Shirasawa S, Sasazuki T, Solit DB, Rosen N (2010) 4E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling pathways that integrates their function in tumors. Cancer Cell 18 (1):39-51

6. Kim D, Dan HC, Park S, Yang L, Liu Q, Kaneko S, Ning J, He L, Yang H, Sun M, Nicosia SV, Cheng JQ (2005) AKT/PKB signaling mechanisms in cancer and chemoresistance. Front Biosci 10:975-987

7. Pal SK, Reckamp K, Yu H, Figlin RA (2010) Akt inhibitors in clinical development for the treatment of cancer. Expert Opin Investig Drugs 19 (11):1355-1366

8. Hsieh AC, Truitt ML, Ruggero D (2011) Oncogenic AKTivation of translation as a therapeutic target. Br J Cancer 105 (3):329-336

9. Alexander W (2011) Inhibiting the Akt pathway in cancer treatment. P T.  April; 36(4): 225–227

10. LoPiccolo J, Blumenthal GM, Bernstein WB, Dennis PA.(2008) Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat.  Feb-Apr;11(1-2):32-50

11. Weigelt B and Downward J (2012) Genomic Determinants of PI3K Pathway Inhibitor Response in Cancer. Front Oncol. 2012;2:109

12. Janna Elizabeth Hutz. Genetic analysis of the PI3k/AKT/mTOR signaling pathway. udini.proquest.com

Resources

New medicine Oncology KnowledgeBASE (nmOK)

ClinicalTrials.gov

Related articles on this Open Access Online Scientific Journal

AKT signaling variable effects. Reporter: Larry H Bernstein, MD

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Author: Ziv Raviv, PhD

Introduction

Sarcoma is a general class of cancers of mesenchymal cells that form connective tissues. Sarcoma can start in any part of the body and can be formed in the bones or in soft tissues. Sarcomas are rare cancers as compared to the more common epithelial cancers (carcinomas). Around 15,000 new cases of sarcomas diagnosed in the United States every year. Both children and adults can develop a sarcoma, however, while in adults it accounts for only about 1% of all cancers, sarcoma represents around 15% of all cancers in children.

There are tens of different types of sarcomas. This fact makes a particular type of sarcoma to be even rarer. Being sarcoma an uncommon cancer, it is strongly recommended for patients diagnosed with sarcoma to get consultant and treatment for the disease in sarcoma centers, or at list be treated by an oncologist physician that had experienced with sarcomas.

As stated, sarcomas are cancers of connective tissues, namely tissues that connect the body, holding it together. These tissues include: bones, cartilage, muscle, nerve, blood and lymph vessels, and fat. Therefore, sarcomas nomenclature is based according to the normal tissue type they most closely resemble (as opposed to carcinomas where the nomenclature is based upon the organ or part of the body where cancer is originated). Few examples: Osteosarcoma (OS) – cancer of bones origin; Chondrosarcoma – cancer of cells that produce cartilage; Fibrosarcoma – cancer derived from fibrous connective tissues cells; Rhabdomyosarcoma (RMS) –  cancer from skeletal muscle progenitors; Liposarcoma – cancer that arises in fat cells, etc.

  • Watch a Dana-Farber Cancer Institute – About Sarcoma Video

Soft tissues sarcoma (STS)

Among sarcomas, the group of soft tissues sarcoma (STS) is the largest one, consists of many different types of cancers that origin in soft connective tissues that support and connect overall body parts. STSs account for less than 1% of all new cancer cases where about 11,000 new cases are diagnosed each year in the US, and about 4,000 people are dying from it each year.  STS can occur almost anywhere in the body: about 60% of STSs occur in an arm or leg, 30% in the trunk (torso) or abdomen, and 10% in the head or neck. Because there are many different types of STS, it is more of a family of related cancer diseases then a single one. The specific types of STS are often named according to the normal tissue cells they most closely resemble (see introduction), however, some STSs do not look like any type of normal tissue and are thought to arise from stem cells.  In addition to their tissue resemblance name, STS are characterized with grades and stages (Table I) where low-grade STSs are often local tumors that grow more slowly and are treated surgically (although radiation therapy or chemotherapy may be used occasionally), and intermediate – and high-grade STSs are tumors that are more likely to metastasize and are treated with a combination of surgery, chemotherapy and/or radiation therapy.

Figure 1. STS of the thigh muscle just above the knee.

soft_tissue_sarcoma_leg

Taken from the Mayo Clinic webpage.

Table I: Sarcoma Staging System according to AJCC

Stage

Grade

Size

Location 

Metastasis

IA

Low

< 5cm

Superficial or Deep

No

IB

Low

≥ 5cm

Superficial

No

IIA

Low

≥ 5cm

Deep

No

IIB

High

< 5cm

Superficial or Deep

No

IIC

High

≥ 5cm

Superficial

No

III

High

≥ 5cm

Deep

No

IV

Any

Any

Any

Yes

Adapted from sarcomahelp.org

Diagnosis

In their early stages, STSs usually do not stimulate any symptoms and can grow unnoticed. This is because STSs are grown within soft connective tissues which are elastic and flexible, thus the tumor can develop quite large before being felt and cause any symptoms. The first noticeable symptom is usually a painless lump or swelling, however, since most lumps are not sarcoma they are often misdiagnosed. Eventually, the tumor interferes with normal body activities and cause pain by pressing against nerves and muscles, or if the sarcoma is located at the abdomen the tumor can induce abdominal pains or constipation. Therefore, when STS is suspected it should be examined for any unusual lumps growing to define whether they are malignant even if symptoms are not present, preferred by a sarcoma specialist. There are no standard screening tests for sarcoma. Usually a biopsy of the suspected tumor is taken to evaluate if indeed it is malignant and to define its type and grade. In addition, molecular testing of the tumor could be performed to identify specific genes unique to the tumor. Finally, imaging tests may be used to find out whether the cancer has metastasized.

Prognosis and current treatment

The five-year survival rate for localized-low grade sarcomas is 83%; 54% for intermediate sarcomas (spread to regional lymph nodes); and 16% for high grade STSs that have spread to distant parts of the body to form metastasis. Survival is depended also on tumor size, location, type, mitotic rate, and whether it is superficial or deep.

Surgery

Treatment options depend on the type and stage of cancer, possible side effects, and the patient’s preferences and overall health. Treatment can be a long and arduous process for many patients. Usually STSs are treated with surgery whenever it is possible. Should the tumor is not removable by surgery it may be possible to control its growth with radiation therapy. For a sarcoma that can be surgically removed, radiation therapy and/or chemotherapy may be given before or after surgery to reduce tumor recurrence. Small STSs can usually be effectively eliminated by surgery alone. However, sarcomas larger than 5 cm are often treated with a combination of surgery and radiation therapy or chemotherapy before surgery – to shrink the tumor and make its removal easier, or during and after surgery – to eradicate any remaining microscopic tumor cells. In addition, radiation and chemotherapy pre-surgical treatment might facilitate less surgery, preserving the limbs if the tumor is located in the arms or legs (limb-sparing surgery). Historically, STSs were treated with amputation; however, nowadays at least 90% of tumors are removed using limb-sparing surgery. In intermediate-high stages, chemotherapy and radiation therapy may also be used to reduce the size of the sarcoma or relieve pain and other symptoms.

Radiotherapy

The most commonly used radiation form is external beam radiation. Another mean of post surgically radiation is brachytherapy. This technique allows for high doses of radiation over a short period of time. The decision to use radiation before and/or after surgery is not standardized and may be changed on an individual case basis; Table II describes the choices of using radiation with surgery.

Table II: The advantages and disadvantages of the timing of radiotherapy

T2_aClick on table to enlarge

Adapted from sarcomahelp.org

Proton therapy (also called proton beam therapy), a type of radiation treatment that uses protons rather than x-rays is also being adapted to treat sarcoma. This mode of radiotherapy allows target the radiation much more focused at the tumor site and thus is much protective to surrounding healthy tissue. This procedure however, is currently only available in a few specialized cancer centers in the US. In addition, particle therapy treatment with heavier charged particles such as carbon ions is being used and studied for the treatment of sarcomas in Japan and Germany.

Chemotherapy

Chemotherapy is often used when a sarcoma has already spread and can be given before surgery or, after surgery as adjuvant chemotherapy to destroy any microscopic tumor cells remained after surgery.  In addition, when a tumor is considered non-operable, cycles of chemotherapy could be performed in order to shrink the tumor and make it necrotic to enable its removal by operation.

  • Watch a STS chemo + surgery Video

Different drugs are used to treat different subtypes of sarcoma. The types of chemotherapy that are used alone or in combination for most STSs include doxorubicin and ifosfamide that are the most common chemotherapy drugs employed for STS, as well as other ordinary chemotherapy drugs. The drug trabectedin, approved for use in Europe, is given for patients with advanced STS when conventional chemotherapy fails. Trabectedin has been shown to have high activity levels in the treatment of a specific subtype of liposarcoma (myxoid/round cell liposarcoma). Other chemotherapy drugs that are only used for certain subtypes of STS include: paclitaxel, docetaxel for Angiosarcoma; as well as vincristine, etoposide, actinomycin, and cyclophosphamide for Rhabdomyosarcoma and Ewing sarcoma.

Experimental chemotherapy drugs include Eribulin, a drug approved for treatment of breast cancer that has shown promising results in early clinical trials. In addition, new versions of sarcoma standard chemotherapy that cause fewer side effects are being studied in ongoing clinical trials. For instance, the three new versions of ifosfamide: palifosfamide, glufosfamide, and TH-302.

Targeted therapy

As genetic and molecular cancer research has evolved, targeted treatment to sarcoma became available. Targeted treatment to sarcoma intends to inhibit the growth and spread of cancer cells by hitting specific proteins, mainly by blocking the action of protein kinases.

Imatinib, a tyrosine-kinase inhibitor was approved in 2002 by the FDA for the treatment of gastrointestinal stromal tumor (GIST) in advanced stages and it is now the standard first-line treatment for GIST. In 2006, sunitinib multi-target receptor tyrosine kinase (RTK) inhibitor was also approved for the treatment of GIST when imatinib fails. Imatinib has been approved recently for use for patients with GIST after initial surgery, to try to prevent recurrence of the tumor. Imatinib is approved also for the treatment of advanced stage dermatofibrosarcoma protuberans (DFSP). Pazopanib, another multi-targeted inhibitor of receptor tyrosine kinase, has also been approved for patients with advanced STS as well as for use in sarcomas other than liposarcoma and GIST in conditions where standard chemotherapy is not working. Regorafenib is a new kinase inhibitor with significant activity in patients with advanced GIST who have already been treated with imatinib and suntinib. The FDA is currently reviewing a phase III clinical trial of this drug.

Closing remarks

Research efforts are made in order to elucidate new sarcoma-specific molecular targets. Studying sarcomas unique genetic fingerprints and understanding their value to sarcoma, not only can assist developing new drugs, but also may help better prediction of patients’ prognosis. To find the most effective treatment, tests to identify the genes, proteins, and other sarcoma-associated factors need to be developed and performed to give a better matched treatment for each patient.  However, being sarcoma a highly diverse group of cancers make these efforts a hard task. These issues will be discussed further in future post(s) to be published in Pharmaceutical Intelligence.

Resources

  1. http://www.cancer.net
  2. http://www.sarcomahelp.org
  3. http://www.cancer.gov
  4. http://sarcomaalliance.org
  5. http://www.sarcoma.org.uk
  6. http://www.mayoclinic.com

Additional related references

  1. Soft tissue sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Casali, PG & Blay, JY. Ann Oncol. 2010 May;21 Suppl 5:v198-203.
  2. Chemotherapy in adult soft tissue sarcoma. Jain A, Sajeevan KV, Babu KG, Lakshmaiah KC. Indian J. Cancer. 2009 Oct-Dec;46(4):274-87.
  3. State-of-the-art approach in selective curable tumours: soft tissue sarcoma. Judson I. Ann Oncol. 2008 Sep;19 Suppl 7:vii166-9.
  4. Soft tissue sarcomas of adults: state of the translational science. Borden EC, et al. Clin Cancer Res. 2003 Jun;9(6):1941-56.
  5. Management of soft-tissue sarcomas: an overview and update. Singer S, Demetri GD, Baldini EH, Fletcher CD. Lancet Oncol. 2000 Oct;1:75-85.

Videos

  1. http://www.youtube.com/watch?v=J35GBjTxzIE
  2. http://www.youtube.com/watch?v=f97oWMANXDw

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