Intraoperative Radiotherapy for Breast Cancer

Single-Day Targeted Intraoperative Radiotherapy is a type of breast radiotherapy in which the entire treatment is given during surgery immediately following lumpectomy. Single-Day Targeted Intraoperative Radiotherapy permits the surgery and radiotherapy to be completed in a single hospital visit instead of the usual 6 –7 week course of Conventional Postoperative Radiotherapy administered after surgery.

Single Day Treatment

Compared to

six to seven weeks

Single-Day Targeted Intraoperative Radiotherapy is designed to administer the highest dose of radiotherapy to a distance of 1 cm surrounding the lumpectomy cavity. This portion of the breast has the greatest risk of developing a breast cancer recurrence and is therefore the area targeted for radiotherapy. Like other forms of partial breast irradiation, the concept of Targeted Intraoperative Radiotherapy is based on the observation that more than 80% (See Table 1) of breast cancer recurrences occur at or near the site of the original tumor. This observation creates an opportunity to confine the radiotherapy treatment to the portion of the breast at greatest risk of a recurrence while sparing the nearby normal breast, skin, chest and shoulder the effects of radiotherapy.

Partial Breast Radiotherapy Studies
Institution	Number of Patients	Median Follow-up (Months)	Percent of Breast Recurrences
William Beaumont Hospital Royal Oak, Michigan	199	65	1.2
Oschner Clinic New Orleans, Louisiana	51	75	2.0
National Institute Oncology Budapest, Hungary	45	60	4.4
Totals	295	65	2.7%

Table 1

Proper patient selection is key. The study investigators believe that Single-Day Targeted Intraoperative Radiotherapy may be safely investigated as a treatment for women who have a low risk of breast cancer recurrence. Consequently, Single-Day Targeted Intraoperative Radiotherapy may be a viable option for women with well-defined, completely excised, early stage invasive breast cancer treatable with breast conserving surgery (lumpectomy or segmentectomy). Although the untreated parts of the breast mass still may develop a breast cancer recurrence, we know that the vast majority of breast cancer recurrences develop in the region of the breast immediately surrounding the original breast cancer. Targeted Intraoperative Radiotherapy is designed to treat that exact area.

Clinical trials have established that most women that are treated with breast conservation therapy have a low risk of local breast cancer recurrence (recurrence of breast cancer in the treated breast). The rate of local breast cancer recurrence with Conventional Postoperative Radiotherapy approaches 5% at 5 years and 14% at 20 years, with more than 2/3 of the recurrences occurring in the first 5 years after surgery. Preliminary studies investigating several forms of partial breast irradiation show very promising results, with 5-year local recurrence rates 5% or less (See Table 1). Since the majority of recurrences have been shown to occur within this initial 5-year period, we expect that the local recurrence rates associated with Single-Day Targeted Intraoperative Radiotherapy will remain comparable to Conventional Postoperative Radiotherapy.

Single-Day Targeted Intraoperative Radiotherapy has been investigated by several researchers in the United States and Europe. Initial studies show that Single-Day Targeted Intraoperative Radiotherapy may be administered safely and have recurrence rates and side effects similar to patients treated with Convention Postoperative Radiotherapy. Based on these pilot studies, the USC/Norris Comprehensive Cancer Center and Hospital is participating in an international, randomized clinical trial comparing Single-Day Targeted Intraoperative Radiotherapy to Conventional Postoperative Radiotherapy. This study is called the Targit (TARGeted Intraoperative Radiotherapy) Trial.

Under the direction of Breast Surgeon, Dennis R. Holmes, M.D. and Radiation Oncologist, Oscar Streeter, M.D., the Targit Trial will enroll women ages 40 and over undergoing lumpectomy for invasive breast cancer measuring 3 cm or less. All patients will require surgical and radiation oncological evaluation prior to enrollment in The Targit Trial.

1) Single-Day Targeted Intraoperative Radiotherapy administered as the complete dose of radiotherapy
a. Single-Day Targeted Intraoperative Radiotherapy given as the complete radiotherapy treatment can only be obtained through participation in the Targit Trial through the process of randomization. In the Targit Trial, a computer will be randomly assigned each patient to receive either Single-Day Targeted Intraoperative Radiotherapy given at the time of surgery versus Conventional Postoperative Radiotherapy given over a 6-7 week period after surgery.
2) Targeted Intraoperative Radiotherapy administered as a “Boost” to the lumpectomy cavity to be followed by Conventional Postoperative Radiotherapy.
a. Patients who do not qualify for the Targit Trial or who choose not to participate in the Targit Trial may obtain Targeted Intraoperative Radiotherapy as a “Boost” treatment of radiotherapy administered to the lumpectomy cavity at the time of surgery to be followed by a 6-week course of Conventional Postoperative Radiotherapy after surgery. Receiving Targeted Intraoperative Radiotherapy as a “boost” will replace the need for the additional 1-week “boost” radiotherapy usually given at the end of the 6-week course of Conventional Postoperative Radiotherapy.

Intraoperative Radiotherapy given as a “boost” treatment to the lumpectomy cavity followed by Conventional Postoperative Radiotherapy has been well-investigated and has been shown to be comparable to 6 week Conventional Postoperative Radiotherapy followed by a 1 week “boost”.

Single-Day Targeted Intraoperative Radiotherapy may be right for your patient if she meets the all of the following criteria:

· She is age 40 or over.
· She has an invasive breast cancer.
· Her breast cancer measures 3 centimeters or less.
· Her breast cancer is treatable with lumpectomy.
· Recent lumpectomy does not disqualify her from participation in the Targit Trial. See Frequently Asked Questions.

She will be excluded from participation in the Targit Trial if she possesses any of the following features:

· She has been diagnosed with bilateral breast cancer.
· She has a history of cancer in the same breast.
· She has multifocal or multicentric breast cancer.
· Her diagnostic breast biopsy reveals extensive non-invasive cancer (DCIS).
· She has evidence of lymph node metastasis (biopsy proven lymph node metastasis).
· She has rheumatoid arthritis, lupus, or other contraindications to breast radiotherapy.

The Targit Trial is an international randomized controlled clinical trial comparing Single-Day Targeted Intraoperative Radiotherapy to Conventional Postoperative Radiotherapy for women with early stage breast cancer treatable with lumpectomy. Currently, Single-Day Targeted Intraoperative Radiotherapy is investigational. Although small studies indicate that Single-Day Targeted Intraoperative Radiotherapy is as safe and effective as Conventional Postoperative Radiotherapy for patients with a low risk of breast cancer recurrence, a long-term, scientific, head-to-head comparison is needed to determine if the two treatments are truly equal. This is the purpose of the Targit Trial.

The Targit Trial will determine if Single-Day Targeted Intraoperative Radiotherapy is as effective as 6-7 week Conventional Postoperative Radiotherapy for the treatment of early stage invasive breast cancer. This international study will enroll 2,400 women.

In the Targit Trial, half of the participants will receive Single-Day Targeted Intraoperative Radiotherapy given at the time of surgery. The other half will receive Conventional Postoperative Radiotherapy given over a 6-7 week period after recovering from surgery. The goal of the Targit Trial will be to determine if the two treatments are equal in terms of local breast cancer recurrence, disease-free survival, and overall survival. Other outcome measures will be cosmetic outcome and patient satisfaction.

There are 4 steps to determining who receives Single-Day Targeted Intraoperative Radiotherapy or Conventional Postoperative Radiotherapy.

1. Determination of Eligibility. Each patient must meet with the surgeon and radiation oncologist at USC to determine if she is eligible for participation in the Targit Trial. This evaluation will include a physical examination, review of mammograms and ultrasounds, and review of pathology slides. Additional imaging studies (mammograms, ultrasounds, and/or breast MRI) may also be requested prior to determining eligibility.

2. Informed Consent. Upon qualifying for participation in the Targit Trial, each woman will be given an Informed Consent statement that clearly describes important aspects of the Targit Trial, including the benefits and risks of the different treatments. The trial investigators will review the Informed Consent statement with the patient, answer any questions, and request that each patient sign the Informed Consent statement confirming her willingness to participate in the Targit Trial. Signing the Informed Consent statement means that she is interested in joining the Targit Trial and that she is willing to receive whichever treatment assigned to her.

3. Randomization. After signing the Informed Consent statement, a computer that will randomly assign one of the two treatments to each participant in a process similar to flipping a coin. Half of the participants will receive Single-Day Targeted Intraoperative Radiotherapy and half will receive Conventional Postoperative Radiotherapy. To ensure the integrity of the study, neither the patient nor her doctors will be permitted to determine which treatment she will receive.

4. Scheduling of Surgery. After treatment has been determined, each woman will be scheduled for surgery. If she has been assigned to receive Single-Day Targeted Intraoperative Radiotherapy, she will receive Intraoperative Radiotherapy at the time of her breast operation while she is still under anesthesia. The radiotherapy treatment will take approximately 30-35 and will add about 45 minutes to the length of the operation. On the other hand, if she has been assigned to receive Conventional Postoperative Radiotherapy, she will receive Conventional Postoperative Radiotherapy over a 6-7 week period after she has recovered from breast surgery. She may receive Conventional Postoperative Radiotherapy at USC or at a radiation oncology treatment center near her home. Trial investigators will contact her community radiation oncology center to verify that she can obtain Conventional Postoperative Radiotherapy in a way that is required by the Targit Trial.

Intraoperative Radiotherapy is given using a device called the Intrabeam Photon Radiosurgery System (PRS System) (See Figure 1). The treatment takes approximately 30-35 minutes and adds about 45 minutes to the total length of the operation.

Photo A

Photo B

Figure 1. Photo A shows Intrabeam Photon Radiosurgery System. Phot B shows Intrabeam Photon Radiosurgery system covered by one of several different-sized applicators (arrow) designed to fit the lumpectomy cavity.

The Intrabeam PRS System is placed in the lumpectomy cavity following removal of the breast cancer (See Figure 2).

Drawing A

Drawing B

Figure 2. Drawing A shows breast and lumpectomy cavity (Star) after removal of breast cancer. Drawing B shows Intrabeam Photon Radiosurgery System and Applicator (Arrow) positioned within the lumpectomy cavity. Bright red area shows portion of breast targeted for radiotherapy

The Intrabeam PRS System is capable of delivering radiation to the inside of the breast targeting the breast tissue immediately surrounding the lumpectomy cavity. This permits the entire treatment to be given in a single dose. Also, since Targeted Intraoperative Radiotherapy can be placed directly into the lumpectomy cavity, radiotherapy can be given to the parts of the breast that need it most, while sparing the nearby normal breast, chest, and shoulder from the affects of radiation.

Single-Day Targeted Intraoperative Radiotherapy is designed to administer the highest dose of radiotherapy to a distance of 1 cm surrounding the lumpectomy cavity. This portion of the breast has the greatest risk of developing a breast cancer recurrence and it therefore the area that is targeted for radiotherapy. Although the untreated parts of the breast mass still may develop a breast cancer recurrence, we know that the vast majority of breast cancer recurrences develop in the region of the breast immediately surrounding the original breast cancer. For this reason, the study investigators believe that Single-Day Targeted Intraoperative Radiotherapy may be safely investigated as a treatment for women who have a low risk of breast cancer recurrence.

Advantages and Disadvantages of Single-Day Targeted Intraoperative Radiotherapy

The principal advantage of Single-Day Targeted Intraoperative Radiotherapy is the ability to administer the entire therapeutic dose of breast radiotherapy at the time of surgery. This allows a woman to complete her breast cancer therapy sooner, permitting a quicker return to her normal life. For women not needing chemotherapy, this means that almost the entire breast cancer therapy can be completed in a single day. Daily oral endocrine therapy would be the only treatment remaining. The end result would be greatly enhanced feasibility of breast conservation therapy for some women who otherwise might be pressed to choose mastectomy.

Another benefit of Single-Day Targeted Intraoperative Radiotherapy is the ability of the surgeon and radiation oncologist to target the radiotherapy treatment to the tissues at greatest risk of a breast cancer recurrence. This avoids the possibility of a “geographical miss” sometimes occurring with Conventional Postoperative Radiotherapy, resulting from the occasional inability to accurately identify the exact part of the breast that needs the “boost” dose of radiotherapy. Because of the potential for “geographic miss,” several pre-treatment x-rays and scans so that the radiotherapy can be properly planned. Since Single-Day Targeted Intraoperative Radiotherapy is given directed into the lumpectomy cavity, this treatment completely avoids the possibility of geographical miss. Focusing the radiotherapy treatment on the breast tissues immediately surrounding the lumpectomy cavity has the additional benefit of sparing the nearby normal breast, chest, and shoulder of the affects of radiation.

The principle disadvantage of Single-Day Targeted Intraoperative Radiotherapy is that this treatment is still under investigation as an alternative to Conventional Postoperative Radiotherapy. Although the risk of breast cancer recurrence within the first 5 years after treatment appears to be equally low for Single-Day Targeted Intraoperative Radiotherapy and Conventional Postoperative Radiotherapy, more research is needed to determine if the breast cancer recurrence rate will remain low in the Single-Day Targeted Intraoperative Radiotherapy group.

Since Single-Day Targeted Intraoperative Radiotherapy treats only a portion of the breast, a theoretical disadvantage for this treatment is the potential for an increased chance of breast cancer recurrence in the portions of the breast that are not treated with radiotherapy. To minimize the chances of a breast cancer recurrence, the Targit Trial will only enroll women who have a low risk of breast cancer recurrence.

A third disadvantage of Single-Day Targeted Intraoperative Radiotherapy is that the radiotherapy treatment is given at the time of surgery, before the final results of your pathology are known. If your pathology results indicate that you will need additional breast surgery, you will not be permitted to receive Single-Day Targeted Intraoperative Radiotherapy again. Therefore, you initial Targeted Intraoperative Radiotherapy treatment might have been wasteful. Therefore, you will have to receive Conventional Postoperative Radiotherapy after recovering from surgery. To maximize the chance that your initial surgery will be successful, the surgeon and radiation oncologist will use a range of studies to fully understand the nature and extent of your cancer prior to going into surgery. This will greatly improve the chances of successful initial surgery.

To refer your patient for consideration in the Targit Trial, please contact USC/Norris Comprehensive Cancer Center and Hospital at the following location:

New Patient Appointments:
Dennis R. Holmes, M.D.
Phone: 323-865-3933
Fax: 323-865-3105

Follow-up Patient Appointments:
Harold E. and Henrietta C. Lee Breast Center
Phone: 323-865-3371
Fax: 323-865-3517

January 2005

January 2005

February 2005