Early stage prostate cancer diagnosis and staging challenges patients and clinicians, as it has proven difficult to reliably distinguish indolent and incidental disease from progressive, life-threatening disease. Standard treatment for prostate cancer generally has been directed at the entire organ or perhaps specific organ regions found generally to have a higher incidence of tumor burden, rather than at point source identification of pathologically confirmed regions of tumor. Traditionally, organ-targeted prostate cancer treatments have been accomplished either by surgical resection of the gland, or by directing multiple beams of radiation into the pelvis to encompass the entire gland in a uniform dose. In the case of prostate cancer, tumor is not partially resected surgically for treatment, as is the case in breast and other cancers. Rather, the entire prostate gland is removed during surgical intervention. Radiation treatments for prostate cancer also treat the gland and glandular areas found to have higher incidence of tumor burden, often having the impact of over-exposing normal radiosensitive tissues to unnecessary treatment, thereby increasing the likelihood of treatment related morbidities. Such poorly directed curative therapies lead to increased cost of care and decreased patient quality of life.
Alternate methods such as cryotherapy have also been explored, though again generally directed to treat, or freeze, the entire organ. While newer focal cryotherapy methods attempt to more uniquely focus the freezing process to a section of the gland in order to decrease the incidence of treatment related morbidity, appropriate targeting methods continue to rely on general assumptions about the location of areas of high tumor burden.
As computers have become better at assisting in treatment planning, it has become standard to use three dimensional (3-D) treatment planning to shape the individual field for radiation therapy to treat, for example, only the prostate itself, commonly utilizing a minimal margin of about 5 to 15 millimeters beyond the edges of the gland. Use of this planning convention allows for higher doses of radiation to be delivered while at the same time sparing the surrounding tissue and limiting morbidity. Clinical trials have confirmed that by using higher doses of radiation in a 3-D conformal approach, higher cure rates are achieved with lower toxicity.
An alternative method for achieving a high dose delivered to the entire gland is known as brachytherapy, or the placement of either temporary High Dose Rate (HDR) or permanent Low Dose Rate (LDR) radioactive sources within the prostate. These therapies allow focal radiation therapy targeting to within 10 millimeters of the glandular areas generally identified as at high risk of containing tumor. Target treatment margins for brachytherapy are typically adopted in the range of 1-10 mm. A gross target volume (GTV) of a treatment target may be defined by anatomic image studies, which may then be used to further define a clinical target volume (CTV), typically comprising the GTV plus an adequate margin to account for microscopic disease at the edge of the GTV and allowance for motion of the GTV from patient positioning variation during image study. Rarely are permanent or temporary sources placed more than 10 mm beyond either the CTV or GTV. For brachytherapy (LDR and HDR), the CTV often is equal to the GTV as there is no motion of the organ that does not include the sources, and daily set-up errors can be eliminated. A biological target volume (BTV) typically represents a region defined by a functional study that may be completely within the GTV, or may expand the GTV by showing disease extending beyond the margins defined by the GTV on the anatomic study.
More recently, again enabled in large part through improved computer software, a newer external beam radiation therapy technique, referred to as Intensity Modulated Radiation Therapy or IMRT, has become available for treating the entire organ with tighter margins of as little as 4 millimeters. IMRT provides options for targeting small volume (<1 cc) regions within a treatment planning volume (TPV) to focus higher doses than the dose delivered to the entire gland volume, comprised of the CTV, GTV and BTV. This focused IMRT treatment method, as described, is currently utilized in only a minority of select academic settings using functional images acquired with either Magnetic Resonance Spectroscopy Imaging (MRSI) or Single Photon Emission Computerized Tomography (SPECT) images to help define a region within the prostate gland believed to represent occult tumor volumes. These identified areas found to be suspicious for occult tumor on functional imaging represent findings which are indistinguishable with standard anatomic studies such as Computerized Axial Tomography (CAT or CT) scan, Magnetic Resonance Imaging (MRI) used in conjunction with Ultrasound (US) and/or US alone. While the SPECT imaging techniques rely on over expression of a specific protein identified by a radiolabeled monoclonal antibody, the MRSI technique utilizes voxel analysis of tissue composition to detect regions felt more likely to represent cancerous regions. Newer functional studies will certainly be developed in the future using similar technologies, such as Positron Emission Tomography (PET) tracers, Optical Biopsy techniques, or other similar technologies.
As discussed in more detail below, the method of the invention will enable the more effective utilization of the foregoing image modalities to localize and treat cancer within a particular target organ with tumor site localization confirmation to histopathological findings in order to more effectively target dose escalation to BTV while sparing surrounding tissues from unnecessary treatment.
Because standard image techniques (CAT, MRI, X-ray, US) are unable, in routine clinical use, to visualize specific regions containing tumor within the gland, it remains a significant problem for current therapies, resulting in increased treatment related morbidity and overall cost of care. In routine clinical practice, at the time a male patient presents with either a palpable abnormality on Digital Rectal Exam (DRE) or, more commonly, with an elevated Prostate Specific Antigen (PSA) level on a blood test, a biopsy of the gland is recommended by the physician to determine if a cancer is present. The patient's initial biopsy procedure is typically performed in the office of a urologist. Frequently, this first procedure is completed with the patient in lateral decubitus position utilizing a Trans-Rectal Ultrasound (TRUS) probe that allows biopsy sample to be taken through the TRUS probe. Sextant biopsy is regarded as the standard of reference for nonsurgical tumor localization, although limitations of sextant biopsy are increasingly recognized.
During a standard sextant biopsy procedure, typically six to twelve biopsy tissue samples will be obtained from the prostate gland with each biopsy sample involving an individual needle pass through the rectal wall and into the desired location within the gland for the biopsy. Standard sextant biopsies are directed into both the right and left general regions of the prostate gland, and may further be directed into the right and left base, mid and/or apex regions of the gland at either medial or lateral locations. Recently, it has become more common to have biopsy tissue samples recorded as to the rudimentary region within the gland from which it was obtained (medial/lateral-right/left: base, mid or apex). In addition, pathologists are more frequently in standard practice being requested to record and report the percentage of each biopsy core involved with tumor to help determine if the region of biopsy has minimal disease or bulky tumor deposits.
When a patient presents as highly suspicious for disease (e.g., rising PSA or positive DRE) and disease confirmation cannot be validated by a positive biopsy result, patients more commonly today undergo saturation biopsy procedures whereby 24-36 biopsy tissue samples are taken, making it increasingly difficult and costly to record and track the region within the gland from which the sample was obtained. Most often, only positive biopsy samples are reported for rudimentary location. Most importantly, the precise location of each biopsy sample cannot be determined even with the use of imaging studies following the biopsy procedure because the sextant localization of disease is not synonymous with volumetric localization of tumor. As such, there is no effective means of correlating the specific pathology of the biopsy site to its location in the target organ or tissue in a manner that will effectively facilitate precise localization of positive histopathology to identify tumor volumetric localization for use in treatment planning targeting. Cancer patients, such as prostate, are frequently followed for extended time periods between diagnosis, medical imaging, treatment and post-therapy follow-up. These patients are, therefore, evaluated over time by different physicians (e.g., urologists and radiation oncologists) in a number of settings (e.g., physician office, outpatient hospital imaging, surgical center) and with various imaging and image-guided treatment modalities requiring different patient positioning during imaging (supine) and treatment (lateral decubital) which, collectively, serve to obscure correlation of pathology information with in-vivo image sets.
Thus, there remains a need for the ability to refine the identification and volumetric location of disease as correlated to positive histopathology within the suspect organ or tissue, and to be able to use these refined data sets to direct therapy in a more effective and less harmful manner. It has been estimated that each year in the U.S. over one million biopsies are performed, with as many as 50% of those core samples being reported as negative. In the example of standard core biopsy sampling techniques for the prostate gland collecting 6 to 12 standard core samples per patient, millions of core tissue biopsy samples are evaluated each year. The clinical inefficiency of the biopsy procedure results in a large negative burden to patients for non-productive procedures correlating to increased risk for procedure related morbidities (e.g., fever, infection and bleeding, discomfort, and lost productivity), for the often ineffective procedure. In addition, the pathology results are routinely lost to discreet anatomic localization for use in therapy planning.