R E G I O N A L

A Publication of the Evansville Cancer Center, A Vantage Oncology Facility Spring/Summer 2006

Oncology UpdateEvansville Cancer Center

700 N. Burkhardt Road, Evansville, Indiana 47715

PRESORTEDSTANDARDU.S.POSTAGEPAID

PermitNo.2054Evansville,IN

Evansville Cancer Center is the only only ACRO accredited only ACRO accredited onlycancer facility in the entire Tri-State area!

International Prostate Brachytherapy Symposium:Poster Presentation by Aly Razek, MD

The outcomes from the prostate cancer treatment program at Evansville Cancer Center were accepted for presentation and presented by Aly Razek, M.D. at the International Prostate Brachytherapy Symposium in New York City, New York held June 22-23, 2006.

Is Brachytherapy Is Brachytherapy for a Very Large Prostate Feasible?for a Very Large Prostate Feasible?for a Very Large Prostate Feasible?for a Very Large Prostate Feasible?for a Very Large Prostate Feasible?for a Very Large Prostate Feasible?

Aly Razek, M.D., FACROAly Razek, M.D., FACRO, A. Korba, M.D., FACRO, P. Siami, M.D., S. Shah, Ph.D., W. Fisher, M.D., D. Foertsch, M.D., T. Gadient, M.D., P. Gilson, M.D., B. Romick, MD., B. Samm, M.D., A. Sorensen, B.S., B. Smith, R.N., B.S.N., OCN.

I NTRODUCT ION Radiation treatment of prostate cancer includes external beam radiation therapy (EBRT), Low Dose Rate brachytherapy (LDR) using I-124 or PD-103 radioactive seeds, or High Dose Rate brachytherapy (HDR) using an Ir-192 source in combination or as monotherapy. In general, adequate coverage in large volume prostates may not be achieved using LDR brachytherapy. There is also an inherent risk of urethral and rectal morbidity due to the need of placing a rela-tively greater number of seeds in order to approach a dose/volume appropriate to the enlarged gland. In 1999 the American Brachytherapy Society (1) in the selection criteria for permanent brachytherapy of prostate cancer has suggested that a prostate volume of greater than 60 cc is a contraindication for permanent seed brachytherapy.

HDR brachytherapy utilizing transrectal ultrasound (TRUS) and Ir-192 based HDR remote afterloader was fi rst introduced at Kiel University (2), Kiel, Germany in 1986 with a protocol consisting of conventional external beam radiation therapy (EBRT) and two HDR Ir-192 fractions delivered two weeks apart. Since then, a number of institutions including Seattle, Washing-ton (3) and Royal Oak, Michigan (4) have used HDR brachytherapy for the treatment of prostate cancer in combination with EBRT or as monotherapy. The HDR brachytherapy is delivered in multiple fractions with a single insertion requiring hospitalization of the patient. At Evansville Cancer Center/Tri-State Prostate Cancer Center, prostate HDR brachytherapy is performed on an outpatient basis with two procedures two weeks apart in combination with EBRT using IMRT. Prior to initiation of IMRT program in September 2003, EBRT was delivered using 3D-conformal treatment planning.

METHODS AND MATER IALS HDR brachytherapy at Evansville Cancer Center/Tri-State Prostate Cancer Center is performed by a team consisting of a radiation oncologist, urologist, physicist, nursing and anesthesia staff. A total of 250 patients with early prostate cancer stage T1,2NO have been treated with a protocol of combined EBRT and HDR brachytherapy with tumor dose of 45 or 50.4 Gy. EBRT was followed after a period of four weeks by two fractions of TRUS guided HDR brachytherapy two

weeks apart as an outpatient procedure. Flexible interstitial afterloading catheters are placed in the prostate gland through the perineum using transrectal ultrasound. A template with 0.5 cm. grid is used to direct the needles. The patient is placed in the lithotomy position under spinal anesthesia. The ultrasound probe is inserted in the rectum. The probe is attached to a stabilizer along with the template. Stabilization devise is then moved to a midglandular region of the prostate and adjusted to

Aly Razek, M.D., FACRO Dr. Razek graduated from Cairo University. He completed his residency at Washington University in St. Louis, Mo. He is board certifi ed in both radiation oncology and pediatrics. He co-authored four text books in radiation oncology and contributed to more than 20 publications in oncology journals. He served on the national committee of the Southwest Oncology group, Intergroup Ewings sarcoma and National Wilms Tumor Committee. Dr. Razek is a fellow of the American College of Radiation Oncology.

RADIAT ION ONCOLOGISTSAl Korba, M.D., FACRO, Aly Razek, M.D., FACRO, Shannon Lamb, M.D. & Crystal Reed, M.D.

MEDICAL ONCOLOGISTS RADIATION PHYSICISTS Rick Ballou, M.D., Ph.D. & Lotfi Hadad, M.D. Saiyid Masroor Shah, Ph.D. & Arnold Sorensen, B.S.

The Evansville Cancer Center, a Vantage Oncology facility, is expanding to continue the delivery of state-of-the-art cancer treatments to the Tri-State commu-nity. The Evansville Cancer Center is the region’s onlyonlyfacility accredited by the American College of Radia-tion Oncology.

Evansville Cancer Center is Growing... Again!

Metastatic Colon Cancer: Many Options & Better Survival Colorectal cancer remains the third most common cancer in males and females in the U.S. and the second most common cause of death from cancer. Approximately 60%-80% of all cases of colorectal cancer can be detected early by doing routine colonoscopies. Colonoscopy also enables the identifi cation and removal of adenomatous polyps which are the precursor lesions for colorectal cancer. In spite of the known benefi ts of colonoscopy, many persons do not adhere to the screening guidelines of the American Cancer Society. Unfortunately, many persons do not have a colonoscopy until symptoms of disease have appeared. It is well known that there’s no miracle cure for the advanced stages of colon cancer, but there are a lot of drugs that can improve the quality of life for those patients, in addition to extending meaningful survival. In the last few years, research has resulted in new discoveries that have dramatically improved the prognosis for persons living with the colorectal cancer. For the past three decades, the drug treatment for colorectal cancer was limited to S-FU and Leucovorin. Patients who were able to tolerate the protocol gained about 6 months of extra survival time using the combination. But beginning in 2000, new drugs began to appear on the horizon. In that year, the FDA approved Camptosar (Irinotecan) for fi rst-line use. A protocol called IFL, which also is known as the Saltz regimen, became the standard of care. This drug belongs to the class of drugs called topoisomerase I inhibitors. The drugs bind to DNA-topoisomerase complexes resulting in DNA damage which in turn interferes with the growth of cancer cells. Survival times for patients increased to 14 months with the addition of this drug to standard protocols. Next down the drug pipeline was Eloxatin which is a platinum based anticancer agent. It demonstrated a better effi cacy in relation to the drugs that were presently being used for the treatment of colorectal cancer. Thus studies were initiated that evaluated protocols that included Eloxatin such as: FOLFOX ( continuous SFU/Leucovorin and Oxaliplatin) and XELOX (in combination with Xeloda, which is an oral SFU). FOLFOX became the standard of care by the end of 2003. Oncologists started telling their patients: you have “a couple of years” to enjoy your family. Then two more new colorectal cancer drugs (Avastin and Erbitux) were approved by the FDA. Erbitux is approved by the FDA as a second line treatment for metastatic colorectal cancer. It is a monoclonal antibody that blocks the effects of Epidermal Growth Factor (EGF) which encourages the development of cancer cells. Unlike traditional chemotherapy, in which toxic drugs don’t discriminate between the tumor and healthy cells, Erbitux targets the tumor cells which result in fewer side effects. It can be used in combination with Irinotecan or alone. Erbitux does not lengthen the lives of patients, but delays the progression of disease and shrinks the size of tumor lesions. So the results may seem modest at best, and you may wonder at the benefi t of shrinking a tumor if it doesn’t help someone live longer. This is the conundrum of oncology.

Avastin is the fi rst of a long-awaited anticancer agent class called angiogenesis inhibitors. They starve tumors by inhibiting capillary growth to and within the tumor. It is a monoclonal antibody that blocks the effects of the vascular endothelial growth factor (VEGF). Because of its specifi c target, Avastin also has few side effects, especially when compared with the toxic effects of traditional chemotherapy. The following are protocols which can be utilized for the treatment of colorectal cancer:For fi rst line treatment:For fi rst line treatment: - FOLFOX with or without Avastin - FOLFIRI (Irinotecan with continuous SFU/Leucovorin) with or without Avastin- SFU/Leucovorin with Avastin For second line treatment:- Erbitux with or without lrinotecan- Avastin with any combination not used in the fi rst line, or we can consider Xeloda.

What are the outcomes of the above regimens? It’s diffi cult to access because survival length is impacted by stage of illness at diagnosis, presence of metastases, nodal involvement and the impact of the individual. What we do know is persons with metastatic colorectal disease are experiencing an average survival time of more than 2 years.

ensure that the prostate is covered by the grid positions with the row 2 (Siemens type grid nomenclature) a little above the inferior (rectal) border of the gland and prostate centered to the midline of the template. Plastic catheters (with stainless steel inserters in the catheters to provide rigidity) are placed under ultrasound guidance. Before inserting the catheter, a guide channel is made using a sharp stainless steel pathfi nder (trocar). The catheters are placed following a preplan in a modifi ed peripheral loading pat-tern to control the dose to the urethra and rectum. The tips of all the catheters are adjusted so that they are just beyond the base plant (0.0 plane). On average, 12-14 catheters inserted. However, with large volume prostates, 16-18 catheters are usually used. After the placement of catheters, the template is removed from the stepper unit and sutured to the perineum. The catheters are secured via a template locking mechanism to ensure that they do not slide. After suturing the template, the patient’s legs are placed on a MICK leg support ramp. Velcro straps are used to avoid any motion of the legs during the rest of the procedure. Cystos-copy is performed to ensure that no needles are too close or passing through the bladder wall or urethra. Dye is then injected into the bladder and the patient is transferred to the CT scanner room.

An initial scout CT scan (pictured at left) is performed to verify that the tips of the catheters are passing just beyond the base (0.0) plane. If needed, the catheters are pushed further to the desired depth and relocked. Dye in the bladder is utilized to visualize the bladder. Once the urologist and radiation oncologist are satisfi ed with the placement, the metallic inserters are re-moved from the catheters, secured to the template, and marked to check for any possible sliding of the catheters during the patient transfer from the CT table. CT scan is performed with 5 mm slice thickness. The scan usually includes a few slices before the base plan (showing part of the bladder) and similar slices beyond the apex.

CT scans are transferred to the ABACUS treatment planning computer via Diacom. The isodose plan is generated using an optimization program. The optimization plan, invariably, does not provide a satisfactory isodose plan and dwell times. The calculated dwell times are edited and manipulated manually to obtain a satisfactory plan. The fi nal plan is developed so that the dose about the periph-ery (0-2 mm around the prostate gland) of the prostate is 10 Gy. Rectal dose is maintained to be less than 10 Gy. The dose to the urethra is restricted as not to exceed 12 Gy (usually between 10 and 12 Gy). The dose to the lateral regions of the prostate is 12 Gy with the inside non-contiguous areas to receive up to 15 Gy dose.

After approval of the isodose plan the patient is brought to the HDR remote afterloader treatment room and treated as per isodose plan. After completion of the treatment, the catheters are removed and the patient is brought to the recovery area. Once the patient has urinated and there are no observable after effects of anesthesia, he is allowed to go home.

RESULTS Fifty-fi ve patients out of 250 treated with HDR brachytherapy had greater than 60 cc prostate volume as determined by the ultra-sound volume studies. The details about these patients are provided in the following table.

Prostate Volume (cm) Prostate Volume (cm)3 No. of Patients Lupron 60 - 79.9 11 33 80 - 111 9 22

55 20

As shown by the isodose distributions, adequate coverage was attained with rectal and bladder doses not to exceed desired levels. In only one case adequate coverage was not achieved due to pelvic anatomical limitations and an additional EBRT dose was deliv-ered as a substitute. No severe acute morbidity was noted within this group of 55 patients. Two patients died due to other medial conditions. One patient died of metastatic disease and one patient is alive with metastatic disease.

CONCLUS ION Our experience demonstrates that HDR brachytherapy in general can be performed as an outpatient procedure and patients toler-ate two applications very well. It also demonstrates that large volume prostates can be effectively treated using HDR brachythera-py. Adequate conformal dose distributions is achieved. Rectal and bladder dose can be limited as desired to minimize genitourinary toxicity. Long term observation will be required to observe late complications and biochemical control.

REFERENCES(1) Nag S, Beyer D, et al. American Brachytherapy Society (ABS) recommendations for transperieneal permanent brachytherapy of prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 1999;44:789-799.(2) Kovacs G, Wirth B, Bertermann R, et al. Prostate preservation by combined external beam and HDR brachytherapy at node negative prostate cancer patients in an intermediate analysis after 10 years experience. Int. J. Radiat. Oncol. Biol. Phys. 1996;36:198.(3) Mate TP, Gottesman JE, Hatton J, et al. High Dose Rate Afterloading Iridium-192 Prostate Brachytherapy: Feasibility report. Int. J. Radiat. Oncol. Biol. Phys. 1998;41:525-533(4) Stromberg J, Martinez A, Gonzalez J, et. al. Ultrasound-guided high does rate conformal brachytherapy boost in prostate cancer: Treatment description and preliminary results of a Phase I/II clinical trial. Int. J. Radiat. Oncol. Biol. Phys. 1995;33:161-171

Isodose distribution on CT slice using ABACUS planning system.

Lotfi Hadad, MD Dr. Hadad received his Medical Degree with hon-ors in 1993 from Aleppo University, Syria. He completed his residency program in Internal Medi-cine at Cook County Hos-pital in Chicago, Illinois. His fellowship in Medical Oncology was completed at John H. Stroger, Jr. Hospital of Cook County and RUSH Medical Center in Chicago, Illinois. Dr. Hadad is board certifi ed in Internal Medicine and in Medical Oncology.