Blogs Expert Journal Opening the Therapeutic Window in Cancer Treatment: Increasing Cure, Decreasing Toxicity



Opening the Therapeutic Window in Cancer Treatment: Increasing Cure, Decreasing Toxicity



Written by  Facing Cancer Together
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THE CONCEPT OF THE ‘THERAPEUTIC WINDOW’


The core goal of physicians and medical researchers in advancing medical intervention can be defined as ‘opening the therapeutic window’.  

Conceptually, a medical intervention with an ‘open’ therapeutic window is one that is effective in providing cure and, at the same time, doing so with no side effects or with side effects that are minimal or tolerable.



Refining medical interventions, therefore, means widening the therapeutic window by increasing the chance of cure and also decreasing the risk for harm.

 Cancer treatment is a prime example of these core principles of medical advancement. Particular examples include prostate and breast cancer, which affect hundreds of thousands of patients in the United States each year.




radiation-for-cancer-patientsREFINING RADIATION TREATMENT FOR PROSTATE AND BREAST CANCER



Radiation for prostate cancer uses X-ray beams aimed at giving radiation dose to the prostate and, at the same time, optimally avoiding radiation dose to the bowel and bladder.  Better delivery of radiation dose to the prostate increases cure and minimizing dose to the bowel and bladder minimizes side effects.  

Both targeting accuracy and treatment delivery have seen revolutionary advances in the past decade.

  Older techniques of radiation delivery, as late as 5-10 years ago, involved aiming radiation beams using skin marks and films of the bony anatomy of the pelvis.  Since skin marks and bony landmarks provide only modest accuracy in terms of locating the prostate, the aperature of the radiation beams was always widened significantly beyond the shape of just the prostate itself.  Doing so increased radiation dose to bowel and bladder, organs which are adjacent to the prostate, resulting in side effects and limiting the dose that can be delivered to the prostate cancer cells.  In the past decade, evolution in CAT scan technology has permitted CAT scanners to be permanently integrated into radiation delivery machines.  Instead of skin marks and bony anatomy, the radiation beams can be aimed by scanning a patient during each treatment, with targeting accuracy to a 16th of an inch.  

In addition to tremendously improved radiation targeting, radiation delivery itself has been revolutionized.

cancer-cell-divisionComputerized radiation delivery systems, termed IMRT (intensity-modulated radiation therapy), now permit us to irradiate the prostate gland using hundreds of dynamic beam angles around the patient, controlling the dose to bowel and bladder and preferentially delivering radiation to the prostate cancer cells -- quite far from older techniques of radiation delivery ten years ago, which used 4-6 static beams with little control in terms of radiation dose to bowel and bladder.

Together, these advancements have permitted the use of smaller aperatures of radiation and decreased dose to bowel and bladder and thus fewer side effects.  And, as a consequence, we have been able to give higher and higher radiation doses to the prostate itself, translating into higher rates of cure.

In breast cancer, which affects more than one in ten women in the United States, preventing local recurrence has been successful for decades, but early one this was at the cost of having a mastectomy which removes the breast entirely.  Later surgical techniques, termed partial mastectomy or lumpectomy, removed the breast mass and preserved the breast itself, but these were associated with high rates of recurrence in the breast.  These rates could be decreased by radiation given following surgery.  Radiation was typically given to the entirety of the breast, and here there was concern about radiation dose to the heart and lung tissue. However, in the past 10-15 years, radiation techniques have evolved to irradiate the tumor bed alone, with little dose reaching heart and lung tissue.  Multiple reports, including a report from the York Cancer Center, have demonstrated that patients who are well-selected for tumor bed radiation have successful prevention of cancer recurrence in the breast.  The breast cancer experience thus shows an evolution of treatment which has permitted the ability to achieve very low rates of cancer recurrence simultaneously with the ability to preserve the breast itself and minimize the portion of the body that requires radiation following surgery.




dna-cancer-genetic-mappingTHE MOLECULAR BIOLOGY REVOLUTION



One of the goals of the field of medical oncology is using ‘systemic therapy’ to decrease the risk that a localized cancer will spread.  The mainstay of systemic therapy during the past half century has been chemotherapy, which principally kills rapidly multiply cells.  As cancer cells typically do rapidly multiply, they are preferentially killed, whereas most of our bodies’ normal cells multiply slower and are affected by chemotherapy to a lesser degree.  However, there are certain types of normal cells (for example, those that line the gut) that do multiply rapidly, resulting in the potential for chemotherapy side effects.  

The past decade has seen a revolution in systemic therapy, with the integration of drugs that kill cells not by whether those cells multiply rapidly, but rather by whether those cells carry genetic signatures.  With the genetic mapping of cancer, researchers have been able to develop drugs belonging to two primary classes -- ‘small molecules’ and ‘antibodies’ -- which have the ability to target tumor cells with selectivity that is higher by orders of magnitude relative to conventional chemotherapy.  In many breast cancers, for example, a ‘tyrosine kinase’ protein has been found to be abnormally activated and drive cancer growth.  Trastuzumab, an antibody against this protein, was developed and rapidly shown to decrease breast cancer recurrence when added to conventional chemotherapy, and this well-tolerated therapy is now integrated into the standard-of-care for breast cancers with this genetic signature.




THE THIRD COMPONENT OF THE ‘OPEN THERAPEUTIC WINDOW’



Widening the therapeutic window -- increasing the chance of cure, decreasing the risk of harm -- has come at increasing financial cost.  Prostate cancer radiation using CAT scan-guided targeting and computerized treatment delivery costs perhaps twice as much as the older radiation techniques, as the new techniques involve more technology, more equipment, and more work to implement.  Genetically targeted treatments likewise have increased costs, primarily stemming from research and development as well as shokek_ori_md_wellspanproduction.  Therefore, as we have been able to widen the therapeutic window, we have come to face the question of whether, on a national level, we will be able to afford the continually increasing price of “better” medicine. 

Physicians and medical researchers today find themselves motivated to provide the highest level of care -- the best care -- on an individual level to their patients, but, as they do so, they have to realize that implementing state-of-the-art treatments has financial implications on a national level.  As we continue to widen therapeutic windows in the coming decade and beyond, physicians and researchers will have to realize that medical interventions with truly “open” therapeutic windows are ones that are more effective and less potentially harmful -- but also financially available to all of us.



written by


Ori Shokek, M.D.

Radiation Oncologist
WellSpan Radiation Oncology



Since 2008, Dr. Ori Shokek has been part of the York Cancer Center as staff radiation oncologist.  He was previously on the faculty of the Johns Hopkins Oncology Center in Baltimore, Maryland.  In addition to his clinical work at the York Cancer Center, Dr. Shokek’s academic responsibilities include involvement in the teaching program for radiation oncology resident physicians at Johns Hopkins.  He is also on the reviewer staff of the International Journal of Radiation, Biology, & Physics, the premiere scientific journal in the field of radiation oncology, and has written multiple articles in the field of cancer therapy.

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