Potential of mobile intraoperative radiotherapy technology

Surg Oncol Clin N Am 12 (2003) 943–954

Potential of mobile intraoperative radiotherapy technology Donald A. Goer, PhDa, Chapple W. Musslewhite, MSa,*, David M. Jablons, MDb a

Intraop Medical, Inc., 3170 De La Cruz Boulevard, Suite 108, Santa Clara, CA 95054, USA b Division of Cardiothoracic Surgery, Department of Surgery, University of California Medical Center at San Francisco, Mt. Zion Medical Center, 1600 Divisadero Street, San Francisco, CA 94115, USA

Most centers that provide intraoperative radiotherapy (IORT) by electron beam need to transport the patient from the operating room to the radiotherapy department in the middle of a surgical procedure to deliver the radiation. An alternative approach is to install a conventional radiotherapy accelerator in a shielded bunker in the operating theater. Although this latter approach eliminates the need for patient transportation, it is costly to implement. The complex logistics of delivering IORT by patient transportation and the cost and space required to construct a shielded bunker in the operating room environment have severely restricted the number of centers that can participate in using IORT. Most centers that have accepted these challenges and have an active IORT program have focused their IORT efforts on treating patients who have advanced and recurrent disease, in which conventional therapeutic approaches offer little advantage. Recently, new technologies for electron beam IORT involving mobile linear accelerators have been developed [1–6]. These technologies allow IORT to be given in an unmodified hospital operating room [7], and the technology has the potential to be shared between hospitals (Fig. 1). This article discusses the implication of this new technology on IORT. The new mobile IORT technology will make IORT more widely available, allow sharing of the technology among hospitals, and will permit IORT use for a greater variety of cancers and in earlier stages of the disease.

* Corresponding author. E-mail address: [email protected] (C. Musslewhite). 1055-3207/03/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved. doi:10.1016/S1055-3207(03)00093-0

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Fig. 1. Mobetron (Intraop Medical, Inc., Santa Clara, California) in treatment position.

Current status of intraoperative radiotherapy IORT is the application of radiation directly to the tumor or tumor bed during surgery. In electron beam IORT, most of the tumor is removed through conventional surgical techniques. Radiation is then directly applied to the area immediately surrounding the tumor, while still exposed during surgery, with the surrounding normal tissue retracted out of the radiation beam. This direct application of radiation to the tumor site increases the effective dose to the Table 1 Intraoperative radiotherapy equivalent of fractionated external beam radiotherapy doses

IORT single dose (Gy)

Equivalent dose for tumor and acute normal tissue reactions fractionated in 2 Gya (Gy)

Equivalent dose for late normal tissue reactions fractionated in 2 Gyb; assumes no dose reduction to normal tissues (Gy)

Equivalent dose for late normal tissue reactions fractionated in 2 Gyb; assumes 50% dose reduction to normal tissues (Gy)

10 15 20 25

17 31 50 73

26 54 92 140

8 16 26 39

a

a/b = 10. a/b = 3. Data from Nag S, Gunderson L, Willett C, et al. Intraoperative irradiation with electronbeam or high-dose-rate brachytherapy. In: Gunderson L, Willett C, Harrison L, Calvo F, editors. Intraoperative irradiation: techniques and results. Totowa, NJ: Humana Press; 1999. p. 122. b

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tumor cells substantially. Table 1 shows the equivalent conventional external beam fractionated radiation dose for a single IORT dose equivalent. In principle, IORT can be used to improve the therapeutic ratio. It can be safely used to escalate the dose for advanced disease because normal tissues can be displaced from the path of the radiation beam. IORT also can be used to replace a portion of the adjuvant external beam radiotherapy (EBRT) by substituting a single dose at the time of surgery. When used as a ‘‘boost dose,’’ IORT replaces 2 to 3 weeks of conventional fractionated radiotherapy treatments, with the added benefit of avoiding radiation to normal tissues that would otherwise surround the treatment area if EBRT alone were used. Finally, because IORT is delivered at the time of surgery, when any microscopic residual tumor cells are most vulnerable, any subsequent adjuvant therapy will benefit from the fact that even a modest IORT dose is likely to result in one or two log-cell kills [8]. Although IORT is widely considered to have great potential, the limitations of previously existing equipment and facilities have severely restricted its use. Very few hospitals have operating rooms that are shielded for radiation. Most of the hospitals that conduct IORT do so by performing the surgery in the operating room and then transporting the patient, still under anesthesia and with the surgical site open, to the radiation facility for the radiation portion of the treatment. After radiation, the surgery is completed in the radiotherapy department or the patient is transported back to the operating room for the completion of the operation. Administering the IORT treatment by transportation of the patient from the operating room to the radiotherapy department adds considerable time to the surgical procedure and requires that the conventional radiotherapy accelerator and its room be specially prepared and available for the IORT patient. This method of IORT involves very complex logistics, increases patient risk, and requires a significant commitment of facilities and personnel, thus severely limiting the number of patients that can be treated. Some hospitals have constructed operating rooms in, or adjacent to, the radiotherapy department in an effort to reduce the time and complexities involved in transporting the patient. Although locating the operating room near the radiotherapy department reduces the transportation time, it is an inefficient use of operating room staff and facilities. Few hospitals have adopted this approach. Another alternative is to construct a fully shielded operating room and use modified conventional accelerator technology to provide the electron beam IORT procedure. The construction and equipment cost for such a dedicated IORT operating room can be exceedingly expensive, however. The significant weight and larger space requirements to accommodate the shielding (100 tons of shielding is required) limit the economic and practical feasibility of this approach. Fewer than a dozen hospitals have constructed dedicated, shielded IORT rooms in their operating room departments.

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Because IORT has been so difficult to integrate into cancer programs, the procedure largely has been restricted to the treatment of patients with advanced cancer who have few other chances for successful treatment. IORT has demonstrated improved treatment of patient who have advanced and recurrent cancer in many studies, showing a 20% to 50% improvement in results compared with conventional radiotherapeutic approaches [9–20].

The new technology—mobile intraoperative radiotherapy systems New technologies have been developed that permit electron beam IORT to be delivered in unshielded operating rooms. Through the use of innovative approaches, the weight of an electron beam linear accelerator for IORT has been reduced by an order of magnitude. Furthermore, in some of these new devices, special designs in the accelerator system eliminate the need to add costly shielding to the walls, ceiling, or floor of the operating room. These new IORT treatment units are mobile and can be moved from one operating room to another, or shared between hospitals. Mobile IORT technology has the potential to greatly expand IORT applications. It eliminates the time, risks, and logistical complexities of IORT connected with patient transportation and can now be implemented more easily at a larger number of institutions. The new mobile technology allows IORT to be used for shorter surgical procedures, for procedures that were deemed too risky for IORT by patient transportation, and to be seamlessly integrated into a cancer treatment program.

Potential new and expanded intraoperative radiotherapy applications Intraoperative radiotherapy for early-stage breast disease The use of IORT for early-stage breast cancer has several advantages. It allows the electron boost to be delivered at the time of surgery when the tumor bed can be visualized, thereby eliminating the possibility of a geometric miss that might occur if the boost were given by external electron beams. IORT delivers the dose subcutaneously, avoiding or reducing the potential for fibrosis or teleangiectases, which should result in improved cosmesis. IORT reduces the total radiation time by 1 to 2 weeks when used in lieu of conventional boost at the time of lumpectomy [21], or possibly can eliminate all additional radiation [22], resulting in greater convenience for the patient and lower cost of treatment. Early studies using IORT as the boost for early-stage breast cancer [23– 25] confirmed the efficacy of this approach but, until now, IORT has not been widely used to treat early-stage breast cancer. The surgical procedure for breast-conserving therapy is quite short, and it is not practical to

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administer IORT through patient transportation for this disease. The increase in the surgical time is unacceptable for most centers. Mobile IORT units that can be located in the operating room have made IORT for early-stage breast cancer practical. At the International Society of Intraoperative Radiation Therapy (ISIORT) meeting in Aachen, Germany, in September 2002, several centers that recently had obtained mobile IORT technology, announced that they had started, or were planning to start, IORT programs for early-stage breast cancer. At this meeting, four centers reported no recurrences, with a median follow-up period of at least 24 months in more than 300 patients treated with electron beam IORT as a boost for stage I and II disease [26–29]. In addition to using IORT as a boost for breast-conserving therapy, some centers are using IORT as the only adjuvant radiation treatment for earlystage breast disease in a select patient population. The European Institute of Oncology in Milan is conducting a randomized trial in node-negative women older than 48 years to determine if a single dose of IORT is equivalent to a conventional full course of EBRT [22]. It is still too early to know if IORT can replace the full course of EBRT for early-stage breast disease. However, the study was made possible because of the dedicated, mobile IORT system located in the operating room, eliminating the need to move the patient to the radiotherapy facility. Intraoperative radiotherapy for stage III non–small cell lung cancer Chemoradiation therapy has been the standard treatment for unresectable stage III non–small cell lung cancer (NSCLC). The prognosis has been poor, with 5-year survival rates of less than 10%. Furthermore, more than 40% of patients who fail die of active local or regional disease. Improved thoracic control in this disease is almost certainly dose-related. With improved chemotherapy, increasing local control may lead to long-term survival benefits. It is often difficult to escalate the dose through external beam techniques, however, because radiosensitive organs may be within the treatment volume. IORT is an ideal technique to escalate the dose while avoiding toxicity to critical structures. Table 2 shows the studies to date on the use of IORT to treat NSCLC. These IORT studies were performed using patient transportation. The largest-scale series included in these studies is a study from Pamplona, Spain [30]. In this study, a multivariate analysis showed that there was a statistically significant advantage with IORT in patients for whom a complete resection was able to be performed, for pancoasts tumors, for N0 or N1 patients, and for patients that had only microscopic residual disease after surgery (J. Aristu, MD, Paploma, Spain, personal communication 2001). Although these pilot studies demonstrated the feasibility of the technique, they were difficult to build upon given the complex logistics involving IORT through patient transportation, particularly for this site.

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Table 2 Intraoperative radiotherapy international clinical experience in non–small cell lung cancer First author (location) SmolleJeuttner [31] Aristu [30] (Pamplona, Spain) Aristu [30] (Philadelphia)

No. of patients 24

104

21

Aristu [30] (Madrid)

18

Zeng [32] (China)

33

Stage (no. patients)

Treatment protocol

Local control

I (12) II (1) IIIA (10) IIIA (48) IIIB (56)

IORT (10–20 Gy) + EBRT (46–56 Gy)

19/23 (83%)

IORT (10–20 Gy) + EBRT (46 Gy) + CT

48/92 (52%)

I (1) II (2) IIIA (15) IIIB (3)

Neoadjuvant CT with and without EBRT + S + IORT with and without postop EBRT Neoadjuvant CT with and without EBRT + S + IORT with and without postop EBRT IORT + 26 (15–25 Gy) patients with EBRT + 7 patients with CT

IIIA (11) IIIB (6) IV (1) I (5) II (5) IIIA (16) IIIB (6) IV (1)

5-y survival (%) 15

40 (IIIA) 18 (IIIB) 33

18/21 (86%)

22 16/18 (90%)

24 88%

Abbreviations: CT, chemotherapy; postop, postoperative; S, surgery.

Not many centers are comfortable transporting a patient with an open chest cavity, and missing a lung or a portion of lung, out of the operating room under portable anesthesia. A new IORT protocol, based in large part on the promising pilot study at Pamplona, will be initiated in both the United States and Europe in the near future. Several treatment centers with dedicated or mobile IORT units in the operating room are expected to participate. The US study will be coordinated by the University of California Medical Center at San Francisco (UCSF). This center has experience with an IORT program for mesothelioma [33] and also has a mobile IORT treatment system. The schema for this proposed study is shown in Fig. 2. If the results of this study are positive, as the multivariate analysis at Pamplona suggests they might be, mobile IORT systems will make the use of this technique possible at other treatment centers. Intraoperative radiotherapy for pediatric disease In pediatric disease, local control, when combined with adjuvant systemic therapy, often results in long-term survival. IORT has proved to be an important factor in the enhancement of local control. EBRT in this patient population is often limited by the toxicities of the radiation treatment. Even

Fig. 2. Proposed IORT treatment of NSCLC. Abbreviation: AUC, area under curve.

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if doses sufficient to achieve local control with EBRT can be delivered, the resulting morbidity to normal tissues can be significant. Adequate local control, with acceptable morbidity, is the challenge in this patient population. With IORT, radiation sufficient to achieve local control can be delivered at the time of the surgical resection, when normal, sensitive tissues can be displaced away from the radiation beam. Despite the potential advantages of IORT for pediatric patients, fewer than 200 pediatric patients treated with IORT have been reported in the literature (Table 3). Almost all of these patients required transporting from the operating room to the radiotherapy department to receive the IORT portion of their treatment. This method of IORT delivery significantly increased the anesthesia time for these pediatric patients and subjected them to increased risks. Despite these impressive results in the few patients treated, the risk associated with patient transport for the IORT procedure must be balanced against the potential gain. With a mobile, self-shielded IORT treatment system in the operating room, the IORT procedure can be given safely, with a minimal increase in anesthesia time and the elimination of transportation risks. In 1998, the UCSF obtained a mobile, self-shielded IORT treatment system. Before that time, IORT was given after the patient was transported to the radiotherapy department. Approximately 10% of all IORT treatments at UCSF are currently being given for pediatric patients, since the patient transport requirement has been discontinued. Recently, UCSF updated their results for pediatric neuroblastoma at the ISIORT meeting in Aachen, Germany [34]. Reporting on 34 patients, with a median follow-up period for surviving patients of 31.5 months (range, 6.2–163.4 mo), the reported 2-year Kaplan-Meier estimates of local control and overall survival were 87% and 69%, respectively. All high-risk and intermediate-risk patients with gross total resection (GTR) had 100% local control with IORT treatment alone. Eliminating 2 to 3 weeks of EBRT in these very young patients, including eliminating the total body irradiation treatment in

Table 3 Intraoperative radiotherapy for pediatric disease

First author (institution)

No. patients

Local control (%)

Survival (%)

Follow-up (mo)

Haase [35] (Denver Children’s) Benign Malignant Schomberg [36] (Mayo Clinic) Haas-Kogan [37] (UCSF) Neuroblastoma

11 48 11 18 (GTR) 5 (STR)

91 75 91 89 0

100 63 73 89 0

51 51 99 36 21

(mean) (mean) (median) (median) (median)

Abbreviations: GTR, surgery achieved gross total resection; STR, patients had a subtotal resection.

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most cases, is a real benefit in this patient group. Mobile IORT units make pediatric IORT safer to implement and will allow more pediatric patients to benefit from the advantages of IORT in controlling local disease with minimum morbidity. Intraoperative radiotherapy for stage II/III rectal cancer In rectal cancer, IORT generally has been reserved for patients with advanced and recurrent disease where conventional approaches have not resulted in satisfactory local control or survival. In earlier-stage rectal cancer, doses of adjuvant EBRT of 50 Gy or more, delivered over 5 weeks, generally provide adequate local control. Dose levels greater than 45 Gy in the abdomen, however, often result in clinical complications, such as late severe colitis, diarrhea, bowel obstruction, and bleeding, in as many as 25% of patients. Although modern radiotherapy delivery techniques can reduce these complications somewhat, they still remain higher than desired. A small pilot study (63 patients) at the University of Heidelberg [38] was initiated to test the possibility of treating primary rectal cancer (clinically staged as T3) and achieve good local control by combining moderate doses of EBRT with moderate doses of IORT. In this pilot study, the EBRT (mean dose, 41.4 Gy) was delivered either before or after IORT (mean dose, 11.3 Gy). Table 1 shows that the mean IORT dose of 11.3 Gy is equivalent to about 20 Gy delivered through fractionated EBRT treatments. Because the small bowel and other critical structures can be excluded from the radiation field during IORT, this dose intensification can be given without incurring significant side effects. By limiting the IORT dose to less than 15 Gy, complications from IORT are also greatly reduced. In the Heidelberg study, the complication rates were very low and the local control was as good or better than historical comparisons. This method of dose intensification can be applied to any anatomic site in which the dose to control the disease through EBRT alone is high enough to cause undesirable complications. Newer EBRT delivery techniques, such as intensity-modulated radiotherapy (IMRT), might also theoretically result in lower complications. IMRT is more time-consuming to deliver than conventional EBRT treatments, however, and generally prolongs the treatment by several weeks. It is therefore not practical to provide IMRT for every patient. Dose intensification with IORT, however, shortens the overall time to deliver the adjuvant therapy by at least a week while providing adequate tumor dose for control. The reduced EBRT dose that is now possible because of the IORT dose intensification should result in lower complications. Mobile IORT systems, because they require no shielding in the operating room, will make IORT more widely available and allow hospitals to use IORT dose intensification to control earlier-stage disease while reducing the

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EBRT that may be required. The reduction of a week or more in EBRT is not only more convenient for the patient (treatment is completed in less time with fewer complications) but is more cost-effective to deliver. The reduction in the per-patient EBRT workload that could result from IORT dose intensification will allow more patients to be treated with EBRT in the radiotherapy department or permit more patients to receive IMRT.

Summary Mobile IORT units have the potential to change the way patients who have cancer are treated. The integration of IORT into cancer treatment programs, made possible by the new technologies of mobile linear accelerators that can be used in unshielded operating rooms, makes IORT significantly less time-consuming, less costly, and less risky to administer. It is now practical for IORT to be used in early-stage disease, in addition to advanced disease, and in sites for which patient transportation in the middle of surgery is considered too risky. Preliminary results of trials for early-stage breast and rectal cancer indicate benefits of IORT. Pediatric patients and patients who have lung cancer, previously underserved by IORT therapies, can be offered potential gains when patient transport issues do not limit IORT. Furthermore, because many of these mobile systems require no shielding, it is now practical for mobile units to be shared between hospitals, making this new mobile technology much more widely available.

References [1] Mills M, Fajardo L, Wilson D, et al. Commissioning of a mobile electron accelerator for intraoperative radiotherapy. J Appl Clin Med Phys 2001;2:121. [2] Beddar S, Domanovic M, et al. Mobile linear accelerators for intraoperative radiation therapy. AORN J 2001;74(5):700–5. [3] Beddar S, Domanovic M, et al. A new approach to intraoperative radiation therapy. AORN J 2001;74(4):500–5. [4] Meurk ML, Goer DA, Spalek G, Cook T. The Mobetron: a new concept for IORT. Front Radiat Ther Oncol 1997;31:65–70. [5] Zonca G, Fossati V, Basso S, et al. Preliminary studies for clinical applications of Novac 7, a robotic mobile intraoperative electron beam unit. Front Radiat Ther Oncol 1997;31:60–4. [6] Ronsivalle C, Picardi L, Vignati A, Tata A, Benassi, M. Accelerators development for intraoperative radiation therapy [paper WPPH022]. In: Peter Lucas, editor. Proceedings of the Institute of Electrical and Electronics Engineers (IEEE) 2001 Particle Accelerator Conference, Chicago: 2001. Piscataway NJ: IEEE Press. [7] Daves J, Mills M. Shielding assessment of a mobile electron accelerator for intraoperative radiotherapy. J Appl Clin Med Phys 2001;2:165. [8] Okunieff P, Sundararaman S, Chen Y. Biology of large dose per fraction radiation therapy. In: Gunderson L, Willett C, Harrison L, Calvo F, editors. Intraoperative irradiation: techniques and results. Totowa, NJ: Humana Press; 1999. p. 25–46.

D. Goer et al / Surg Oncol Clin N Am 12 (2003) 943–954

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[9] Willett C, Shellito P, Gunderson L. Primary colorectal EBRT and IOERT. In: Gunderson L, Willett C, Harrison L, Calvo F, editors. Intraoperative irradiation: techniques and results. Totowa, NJ: Humana Press; 1999. p. 273–305. [10] Mannaerts G, Martijn H, Crommelin M, Dries W, Repalaer van Driel O, Rutten H. Feasibility and first results of multimodality treatment, combining EBRT, extensive surgery, and IORT in locally advanced primary rectal cancer. Int J Radiat Oncol Biol Phys 2000;47(2):425–33. [11] Gunderson L, Willett C, Haddock M, et al. Recurrent colorectal: EBRT with or without IOERT or HDR-IORT. In: Gunderson L, Willett C, Harrison L, Calvo F, editors. Intraoperative irradiation: techniques and results. Totowa, NJ: Humana Press; 1999. p. 273–305. [12] Rutten H, Mannaerts G, Martijn H, Wiggers T. Intraoperative radiotherapy for locally recurrent rectal cancer in The Netherlands. Eur J Surg Oncol 2000;26(Suppl A):S16–20. [13] Haddock M, Martinez-Monge R, Petersen I, Wilson T. Locally advanced primary and recurrent gynecological malignancies. In: Gunderson L, Willett C, Harrison L, Calvo F, editors. Intraoperative irradiation: techniques and results. Totowa, NJ: Humana Press; 1999. p. 397–419. [14] Martinez-Monge R, Jurado M, Aristu J, et al. Intraoperative electron beam radiotherapy during radical surgery for locally advanced and recurrent cervical cancer. Gynecol Oncol 2001;82:538–43. [15] Foote R, Garrett P, Rate W, et al. IORT for head and neck cancer. In: Gunderson L, Willett C, Harrison L, Calvo F, editors. Intraoperative irradiation: techniques and results. Totowa, NJ: Humana Press; 1999. p. 471–97. [16] Petersen I, Calvo F, Gunderson L, et al. Extremity and trunk soft tissue sarcomas. In: Gunderson L, Willett C, Harrison L, Calvo F, editors. Intraoperative irradiation: techniques and results. Totowa, NJ: Humana Press; 1999. p. 359–78. [17] Gieschen H, Willett C, Donohue J, et al. Electron or orthovoltage IORT for retroperitoneal sarcomas. In: Gunderson L, Willett C, Harrison L, Calvo F, editors. Intraoperative irradiation: techniques and results. Totowa, NJ: Humana Press; 1999. p. 329–58. [18] Martinez-Monge R, Gerard J, Kramling H, Guillemin F, Calvo F. Gastric IORT with or without EBRT. In: Gunderson L, Willett C, Harrison L, Calvo F, editors. Intraoperative irradiation: techniques and results. Totowa, NJ: Humana Press; 1999. p. 175–200. [19] Glehen O, Beaujard A, Romestaing P, et al. Intraoperative radiotherapy and external beam radiation therapy in gastric adenocarcinoma with R0–R1 surgical resection. Eur J Surg Oncol 2000;26(Suppl A):S10–2. [20] Calvo F, Zincke H, Gunderson L, Aristu J, Gerard J, Berian J. Genitourinary IORT. In: Gunderson L, Willett C, Harrison L, Calvo F, editors. Intraoperative irradiation: techniques and results. Totowa, NJ: Humana Press; 1999. p. 421–36. [21] Dobelbower RR, Merrick HW, Eltaki A, Bronn DG. Intraoperative electron beam therapy and external photon beam therapy with lumpectomy as primary treatment for early stage breast cancer. Ann Radiol 1989;6:497–501. [22] Veronesi U, Orecchia R, et al. A preliminary report of intraoperative radiotherapy (IORT) in limited-stage breast cancers that are conservatively treated. Eur J Cancer 2001;37: 2178–83. [23] Dubois JB, Hay M, et al. IORT in breast carcinomas. Front Radiat Ther Oncol 1997;31:131–7. [24] Merrick HW, Battle JA, et al. IORT for early breast cancer: a report on long-term results. Front Radiat Ther Oncol 1997;31:126–30. [25] Reitsamer R, Peintinger F, Sedlmayer F, et al. Intraoperative radiotherapy given as a boost after breast conserving surgery in breast cancer patients. Eur J Cancer 2002;38:1607–10. [26] Sedlmeyer F, Menzel C, Reitsamer R, et al. IORT with electrons as boost strategy during breast conserving therapy in limited-stage cancer [abstract 11.2]. In: Abstracts of the Third

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[27]

[28]

[29]

[30]

[31]

[32] [33]

[34]

[35] [36] [37] [38]

D. Goer et al / Surg Oncol Clin N Am 12 (2003) 943–954 International Meeting of the International Society of Intraoperative Radiation Therapy, Aachen, Germany. 2002. Ciccone V, Ciabattoni A, Fortuna G. A pilot randomized study on use of intraoperative radiotherapy for stage I and II breast cancer [abstract 11.3]. In: Abstracts of the Third International Meeting of the International Society of Intraoperative Radiation Therapy, Aachen, Germany. 2002. Odantini R, Al Sayyad S, Bellia SR, et al. Three years of follow-up in patients with breast cancer treated with IOERT (intraoperative electron radiation therapy) as boost [abstract 11.5]. In: Abstracts of the Third International Meeting of the International Society of Intraoperative Radiation Therapy, Aachen, Germany. 2002. Hager E, Forsthuber E, Primik F, Sabitzer H, Szalay S. Intraoperative radiotherapy in breast cancer. How we did it [abstract 11.6]. In: Abstracts of the Third International Meeting of the International Society of Intraoperative Radiation Therapy, Aachen, Germany. 2002. Aristu J, Calvo F, Martinez R, et al. Lung cancer. In: Gunderson L, Willett C, Harrison L, Calvo F, editors. Intraoperative irradiation: techniques and results. Totowa, NJ: Humana Press; 1999. p. 437–53. Smolle-Juttner, Geyer E, Kapp KS, et al. Evaluating intraoperative radiation therapy (IORT) and external beam radiation therapy (EBRT) in non-small cell lung cancer (NSCLC). Five years experience. Eur J Cardiothorac Surg 1994;8:511–6. Zeng DW, et al. IORT for non-small cell lung cancer: preliminary report of 33 cases. Front Radiat Ther Oncol 1997;31:138–9. Jablons D, Roach M, et al. Resection and IORT Followed by three-dimensional conformal radiotherapy with or without adjuvant chemotherapy for malignant mesothelioma. Front Radiat Ther Oncol 1997;31:140–5. Doyle K, Matthay K, Weinberg V, et al. Intraoperative radiation therapy for intermediate and high risk pediatric neuroblastoma [abstract 9.2]. In: Abstracts of the Third International Meeting of the International Society of Intraoperative Radiation Therapy, Aachen, Germany. 2002. Haase GM, Meagher DP, McNeely LK, et al. IOERT. Cancer 1994;73:740–7. Schomberg P, Gunderson L, Moir C, Gilcrest G, Smithson W. Intraoperative electron irradiation in the management of pediatric malignancies. Cancer 1997;79:2251–6. Haas-Kogan D, Fisch B, Wara W, et al. Intraoperative radiation therapy for high-risk pediatric neuroblastoma. Int J Radiat Oncol Biol Phys 2000;47(4):985–92. Eble M, Lehnert T, et al. Intraoperative radiotherapy as adjuvant treatment for stage II/III rectal cancer. Cancer Res 1998;146:152–60.