Data from the targeted intraoperative radiation therapy clinical trial, known as TARGIT-A, are showing that patients who received a single dose of radiation at the time of breast conservation surgery have comparable outcomes to patients who received multiple radiation doses administered during a conventional radiotherapy treatment program of five to six weeks in duration.
Four-year outcomes from this international clinical trial were presented at the American Society of Clinical Oncology (ASCO) annual meeting held in Chicago earlier this month, and they also were published online in the Lancet (June 4, 2010). Almost 40% of participants have reached the four-year milestone.
If the outcomes of breast cancer patients enrolled and randomized in each arm of the TARGIT-A trial continue to be comparable, this clinical trial may ultimately change longstanding radiation therapy protocols for treating many patients with early-stage breast cancer, as well as provide a formidable challenge to the assumption that currently administered levels of radiation dose to the breast are essential for effective tumor control.
The pilot study
The TARGIT-A trial originated from a premise by Jayant Vaidya, MD, PhD, senior lecturer and consultant surgeon at Whittington, Royal Free, and University College London Hospitals in London, that breast conservation treatment with surgery and radiation therapy needs to be focused and targeted to the immediate vicinity of the primary tumor.
Vaidya began laboratory work on intraoperative radiation therapy (IORT) in 1994. Working with his professor, Michael Baum MD, currently professor emeritus of surgery at University College London, he developed the concept, tools, and a surgical operative procedure to give targeted IORT to tissues immediately surrounding a breast cancer tumor.
Starting in July 1998, Vaidya, Baum, and Jeffrey Tobias MD, professor of cancer medicine and consultant in clinical oncology at University College London Hospitals, began clinical use of IORT. They initiated a pilot study of 25 women who were given a radiation boost to the tumor bed immediately following tumor removal. None of the patients experienced any major complications. Two to three years after treatment, no patient had developed local recurrences, according to an article published by the authors in the Annals of Oncology (2001, Vol. 12:8, pp. 1075-1080).
For the pilot procedure, radiation dose was delivered using a photon radiosurgery system (Photoelectron, North Billerica, MA). This device employed a miniature electron-beam-driven x-ray source that provided a point source of low-energy x-rays. Electrons traveled through an electron-beam drift tube to a thin conical sheath with a sphere at its tip. The sphere produced a uniform dose of radiation to a prescribed depth. Because the radiation consisted of soft x-rays, the beam was rapidly attenuated to reduce radiation dose to more distant tissue. This characteristic also enabled the procedure to be performed in unmodified operating room suites.
Several sphere sizes were available for use with differently sized surgical cavities. The radiation delivered was proportional to the time the device was activated. Delivery of 5 Gy, for example, took approximately 20 minutes at 1 cm from the margins of a 3.5-cm tumor cavity.
The success of this pilot, which shortened radiation therapy treatment by one week, convinced these physicians to develop a randomized clinical trial to compare conventional radiation therapy to radiation therapy delivered to the index quadrant alone. The first patient was randomized to the TARGIT trial on March 24, 2000, and the trial reached its accrual goal in April 2010.
The TARGIT trial
Thirty-one healthcare treatment facilities in 10 countries located in the U.K., Europe, North America, and Australia, including two U.S. surgery centers, enrolled 2,232 women diagnosed with early-stage breast cancer. Patients were eligible for enrollment if they were 45 years old or older and were suitable for wide local excision for invasive ductal carcinoma that was diagnosed as unifocal. Exclusion of patients with a tumor size greater than 3.5 cm was recommended but not mandated. No exclusion limitations were placed on grade and nodal status.
The trial allowed each center to restrict patient inclusion criteria beyond the core protocol. Participating centers recruited conservatively. The patient mix is evenly balanced between the two groups with respect to ages and age range representation. The median age was 63 at the time of enrollment. Forty percent of the patients were ages 55 to 64, 33% were ages 65 to 74, and only 17% were ages 45 to 64. For reasons that were unexplained, 17% were under the recommended enrollment cutoff age of 45.
Tumor sizes were small: 36% of the total were smaller than 1 cm and 86% were smaller than 2 cm. Fourteen percent of the women had tumors larger than 2 cm, and 15% had grade 3 tumors. Only 16% had nodal involvement, with 4% of the IORT group and 2% of the conventional treatment group having involvement in more than three lymph nodes.
Of 1,119 patients enrolled, 1,025 (92%) completed conventional external-beam radiation therapy (EBRT), while 996 (89.5%) of 1,113 patients enrolled received targeted IORT. Fourteen percent of this latter group subsequently received EBRT after histopathology showed involved margins, invasive lobular carcinoma, nodal involvement, or lymphovascular invasion.
Patients who received EBRT to the whole breast, whether in the randomized group or the subset of patients in the IORT group, received a radiation dose of 40 to 56 Gy in 15 to 25 fractions, with or without a boost of 10 to 16 Gy in five to eight fractions.
Treatment for the targeted IORT was delivered with an updated device (Intrabeam, Carl Zeiss Meditec, Dublin, CA) that provided a point source of up to 50 kV maximum low-energy rays at the tip of a tube 3.2-mm in diameter. Radiation was activated for 20 to 35 minutes, delivering approximately 20 Gy that attenuated to 5 to 7 Gy at 1-cm depth. The dose of 20 Gy at the applicator surface is estimated as equal to a fractionated dose of 70 Gy, according to the authors.
Patients are scheduled for follow-up at three and six months after treatment, then every six months up to the five year mark, and annually thereafter for an additional five years.
The primary objective of the trial is to compare local recurrence rates in the conserved breast. The researchers reported that six patients in the IORT group and five in the EBRT group had local recurrence. Four patients in the IORT group and three in the EBRT group had axillary recurrences, and one patient in each group had uncontrolled local recurrence and died. None of these represented statistically significant differences based on Kaplan-Meier analysis.
Due to increased survival, the authors have revised their original estimate made in 1999 of a five-year local recurrence rate of 6% to an estimate of 1.5%. Because the current rates are 1.2% and 0.96% for the IORT and EBRT groups, respectively, the research team believes that its results are robust. Only 739 patients are at risk based on the assumption the authors make that peak hazard of local recurrence passes by the fourth year after treatment.
Frequencies of complications and major toxicity were similar in both groups, Baum reported to ASCO attendees. IORT patients had slightly lower levels of clinically significant toxicity, at 3.3% and 3.9%, respectively. A total of 81 patients experienced these.
Seromas needing more than three aspirations, wound infections needing intravenous antibiotics, any complication needing surgical intervention, skin breakdowns, and delayed wound healing were classified as major toxicities. Six patients (0.54%) in the IORT group had Radiation Therapy Oncology Group (RTOG) grade 3 toxicities, compared with 21 patients (2.1%) in the EBRT group. IORT group patients had more wound breakdowns and incidents of delayed healing, at 2.8%, compared with 1.9% of the EBRT group.
In total, 17% of the patients experienced complications, with 24 patients (16 IORT versus eight EBRT) having three to six recorded complications each.
The research team also emphasized that irradiation of intrathoracic structures was almost completely avoided with IORT treatment. The researchers will monitor and compare cardiac toxicity in both groups
The research team acknowledged that the results reported from the TARGIT-A trial are still early, and longer-term follow-up is needed to monitor delayed recurrences at the location of the tumor and new primary tumors outside the quadrant. However, the group believes that the four-year results represent a major milestone.
"For selected patients with early breast cancer, a single dose of radiation therapy delivered at the time of surgery by use of targeted intraoperative radiotherapy should be considered as an alternative to external-beam radiation therapy delivered over several weeks," Baum told ASCO attendees. "It is the sincere hope of the TARGIT group that these results influence a paradigm shift."
In addition to patient convenience and a potentially lower risk of toxicities, the TARGIT technique represents the potential for huge cost savings and the ability for cancer treatment centers operating at capacity to treat many more patients. In 2004, Vaidya and colleagues estimated that use of this technique for qualified breast cancer patients could annually save an estimated a $23 million in the U.K.
At facilities with treatment backlogs, these patients will receive radiation therapy immediately, without delays of up to many weeks. Patients who are unable to undergo radiation therapy due to frailty or geographical constraints may be able to choose this treatment option rather than forego treatment altogether.
Will the TARGIT trial results stimulate adoption? One hospital has stepped up to the plate. Hoag Cancer Center of Hoag Memorial Hospital Presbyterian in Newport Beach, CA, announced on June 24 that it would begin to offer IORT to selected patients.
"The beauty of IORT for breast cancer patients is that within minutes they have completed their radiation treatment without realizing it. It's the difference between 30 minutes or 30 days of treatment," said Melvin Silverstein MD, clinical professor of surgery at the University of Southern California in Los Angeles and medical director of the Hoag Breast Care Center.
The University of Southern California is a participating institution in the TARGIT-A trial.
By Cynthia E. Keen
AuntMinnie.com staff writer
June 29, 2010
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