Future directions in intraoperative radiation therapy

Surg Oncol Clin N Am

12 (2003) 1099–1105

Future directions in intraoperativeradiation therapy

HollisW.Merrick III,MD,MS, FACS, FACRO (Hon)a,*,Leonard L. Gunderson, MD, MSb,

Felipe A. Calvo, MD, PhDc

aDepartment of Surgery, Medical College of Ohio, 3065 Arlington Avenue,

Toledo, OH 43614, USAbDepartment of Radiation Oncology, Mayo Clinic, Scottsdale, AZ, USA

cDepartment of Clinical Oncology, Hospital General Universitario ‘‘Gregorio Mara~nn�oon’’,

Madrid, Spain

The intent of this issue of Surgical Oncology Clinics of North America hasbeen to summarize the current knowledge of intraoperative radiationtherapy (IORT) as a component of treatment for various malignancies. Thecollated data presented herein have demonstrated that a wide variety oftreatment approaches are feasible and practical to combine external beamradiation therapy (EBRT; often delivered in conjunction with concurrentand maintenance chemotherapy), IORT, and surgical treatment. Implicit inthe use of combinations of these modalities is the close cooperation that isrequired among the operating surgeon, the treating radiation oncologist,and other involved medical specialists (eg, anesthesiologists, medicalphysicists, medical oncologists). This teamwork structure already exists inmost dedicated cancer centers; however, in the general medical community,it may not be as well established. To carry out this form of treatment,a multidisciplinary collaborative effort is essential to the success of therapy.

The data presented seem to support the concept that local control ofcancer is often enhanced with the use of multimodal therapy, which includesIORT, EBRT, and maximal resection. This approach leads to improvementin the course of the disease as manifested by increased rates of local controland enhanced patient survival and improved quality of life for the patient.These concepts have been demonstrated in the current issue for themanagement of patients who have the following cancers: gastric cancer,

* Corresponding author.

E-mail address: [email protected] (H.W. Merrick).

1055-3207/03/$ - see front matter � 2003 Elsevier Inc. All rights reserved.

doi:10.1016/S1055-3207(03)00099-1

mailto:[email protected]

1100 H.W. Merrick III et al / Surg Oncol Clin N Am 12 (2003) 1099–1105

pancreatic cancer, biliary cancers, colorectal cancers, sarcomas, gynecologicand genitourinary cancers, head and neck cancers, and breast cancer.

Although IORT has been demonstrated in numerous studies to improvelocal control, distant control and survival still remain problematic in variousmalignant conditions.Numerous treatment combinations have been designedto improve patient survival through the use of adjuvant chemotherapy asa component of either bimodality (surgery plus chemotherapy) or trimodalitytreatment (surgery plus chemoradiation). Although success, as demonstratedby a decreased risk of distant metastases, has been achieved in some malig-nancies (eg, colorectal, gastric, and breast cancers; possibly sarcomas andgynecologic cancers), the systemic component of treatment remains achallenge for the future in other disease sites (eg, pancreas, bile duct, andkidney carcinomas).

As with any therapeutic modality or combinations thereof in the treatmentofmalignant disease, careful patient selection andpretreatment evaluation arevital. The combinedmodality therapies described in this text aremost effectivefor previously untreated patients but still have a role when treating recurrentdisease. Therapies that include IORT are most effective when the tumor iscompletely excised grossly, with either tumor-free margins or microscopicallypositive margins histopathologically; yet, the patient remains at significantrisk for locally recurrent disease. In such circumstances, therapy in non-IORTinstitutions would comprise postoperative EBRT, with or without concurrentand maintenance systemic chemotherapy.

Five-year survival rates following treatment of local or regional relapsehave been demonstrated in 20% to 40% of patients when IORT is acomponent of treatment. These survival rates include recurrent colorectal(20%–30%); gynecologic, gastric, and renal cancers (20%–30%, 15%–20%,and 20%–30%, respectively); nodal relapse of colon cancer (35%–40%);and retroperitoneal sarcoma (20%–40%). For many patients who have localor regionally recurrent cancers, only palliative treatment is offered in non-IORT institutions. Several series using IORT for treatment of recurrentdisease have included significant numbers of patients who had received priorEBRT at the time of their primary disease presentation and treatment [1–3].In this select situation, the most favorable results have been achieved whenpatients receive additional low-dose preoperative EBRT (20–30 Gy in 1.8-to 2-Gy fractions) plus concurrent chemotherapy followed by gross totalresection and IORT (15–20 Gy) [4].

What may prove to be effective in select malignant conditions (preferablyregional node-negative tumors) is the use of high-dose IORT, which mayactually decrease, or even eliminate, the need for postoperative EBRT. Anexample of this type of therapy is the study, cited in the chapter on themanagement of breast cancer (chapter 12), being performed by Intra et al [5]at the European Institute of Cancer (Milan, Italy), in which breast qu-adrantectomy and high-dose IORT (21 Gy) constitute the entire local cancertreatment. Most US (eg, Medical College of Ohio, Mayo Clinic at

1101H.W. Merrick III et al / Surg Oncol Clin N Am 12 (2003) 1099–1105

Scottsdale) and some European centers prefer to use IORT to replace theEBRT boost in the treatment of patients who have early-stage breast cancer.

In Europe and the United States, IORT has been used to deliver a boostradiation dose followingpreoperative chemo-EBRT in stageT3N0 (AmericanJoint Committee on Cancer Staging Manual, Sixth Edition, Springer Verlag,New York) rectal cancers.

Administration of intraoperative radiation therapy

The logistics of administering IORThave been seen as amajor drawback toitswidespread acceptance in the generalmedical community. There are at least27 centers across the United States and at least 40 additional cancer treatmentcenters around the world where this form of therapy is being delivered [6].These are primarily academic medical centers where the emphasis may be onclinical research rather than the efficient delivery of medical care. Severalinstitutions have built an operating room in the radiation treatment area,whereas others have installed a radiation treatmentmachine near orwithin theoperating suite. These are expensive approaches, which limit the use of thevaluable space and equipment for routine therapy. Either of these systemsfacilitate the delivery of IORT; however, retrofitting an existing operatingroomwith a suitable radiotherapy machine and the requisite radiation shield-ing is rather costly, and building a fully equipped, dedicated operating roomwithin, or adjacent to, an existing radiation treatment facility is equallyexpensive. Furthermore, the transport of anesthetized patients who have opensurgical wounds from an existing surgical suite to and from an existing, andoften rather distant, radiation treatment facility carries inherent significantpotential hazards.

The development of mobile IORT technology (chapter 4) provides aneffective means of delivering IORT in a nondedicated surgical facility. MobileIORT machines can be used in conventional hospitals on a daily basis and inmultiple operating rooms. These machines are becoming more popular in theUnited States and in Europe. Such devices can facilitate delivery of IORT inlarge community hospitals, andmaymake the use of IORT feasible on a largescale. As cited by Goer et al elsewhere in this issue, several patients can betreated by a given mobile IORT device in a single day.

At present, the only mobile electron IORT device available in the UnitedStates is the Mobetron (Intraop Medical, Inc., Santa Clara, California) (Fig.1). This IORT unit comprises a built-in, self-shielding C-arm design, witha compact mobile linear accelerator capable of generating electron beams of4 to 12 MV energy. Electron beams of these energies provide the user withthe capability to deliver highly homogeneous (�10%) radiation doses fromthe surface to a depth of 4 cm (IORT dose is commonly specified at the 90%isodose line, resulting in approximately �5% dose inhomogeneity).

Another mobile IORT device, which has been used extensively in Europe,is theNOVAC 7, which is aminiature linear accelerator mounted on a robotic


arm. The electron energy range of the NOVAC 7 is somewhat more limitedthan that of the Mobetron. The highest electron energy available with theNOVAC 7 is 7 to 10 MV. There have been several studies using this device inthe treatment of breast cancer, as discussed in chapter 12.

Mobile nonelectron IORT devices available in the United States andEurope include high-dose-rate (HDR) brachytherapy and the photoelectronsuperficial x-ray machine. Mobile HDR-IORT units have been extensivelyevaluated at three US facilities (the James Cancer Center at Ohio StateUniversity, Memorial Sloan-Kettering Cancer Center, and Beth IsraelHospital in New York City). Such devices are available at other facilities,including the Mayo Clinic in Rochester and the M.D. Anderson CancerCenter in Houston.

For the mobile HDR-IORT machine, a shielded facility is necessary ineither the operating room or in the radiation treatment area. A radiation-shielded area is required for use of any high-energy HDR device.

Future studies

Attempts to complete phase 3 IORT clinical trials have been largelyunsuccessful when conducted in a single country. The same has been true of

Fig. 1. Mobetron portable IORT device.


studies attempting to test whether IORT offers an advantage when added asa component of treatment. More feasible trials may be those that involvestandard use of EBRT, IORT, and surgical resection, with subsequentrandomization of the addition of radiation sensitizers (during IORT/EBRT), protectors (before IORT), and the systemic component of treat-ment (eg, chemotherapy, immunotherapy, gene therapy).

The ability to complete large-scale phase 2 and 3 IORT trials will dependon the involvement of institutions in multiple countries (United States, Italy,Japan, and elsewhere). International trials, however, present many chal-lenges that remain to be resolved with regard to financial support and datacollection.

The International Society for Intraoperative Radiation Therapy(ISIORT) has sponsored several discussions on the development of IORTprotocols. Boxes 1 and 2 present a compilation of several of the protocolscurrently under consideration. The Retroperitoneal Sarcoma Trial is alreadyunderway in select Radiation Therapy Oncology Group institutions. A hostof ISIORT institutions have been invited to join the study. The remainingstudies will be conducted only when adequate industry support can beobtained for patient accrual, statistical support, and data management.

Summary

It is difficult to establish the degree of effectiveness of IORT asa component of treatment in some of the malignancies currently beingtreated by IORT. Locally advanced pancreatic cancer is a typical example ofa neoplasm for which it has been challenging to find effective advances intreatment. The survival time of patients who have this disease is limited to 9to 12 months (median), with a 2-year survival rate of 10% to 20% followingeven the most effective chemoradiation. It is perhaps overly optimistic toexpect that IORT will significantly enhance survival, because currentlyavailable systemic treatment options have not meaningfully affected eitheroverall patient survival times or the rate of distant metastasis in either theadjuvant setting or for metastatic disease. It is encouraging, however, thatWillett has reported five patients with 5-year survival times in theMassachusetts General Hospital IOERT series for unresectable pancreaticcancer (C.G. Willett, personal communication, 2002). Also encouraging isthe report from the Medical College of Ohio of a 5-year rate of 33% ina small group of patients with resectable pancreatic cancers treated withsingle IORT doses (without EBRT or chemotherapy) as the sole adjuvant tosurgical resection. At the same institution, during the same time period, thesame group of surgeons observed that no patient with resectable pancreaticcancer survived longer than 13 months following surgical resection alone [7].

Exciting possibilities involve the use of IORT when treating early-stagemalignant disease, as is detailed in the chapter on breast cancer. The use of


IORT as adjuvant therapy seems to be associated with an extremely lowincidence of in-breast local recurrence. Whether this is because of early stageof the disease or the adjuvant EBRT is not entirely clear at the time of thiswriting. (The results of ongoing randomized studies may not be poweredsufficiently to resolve the question.) Because the local recurrence ratecurrently is extremely low (only one reported recurrence), however, thisfinding is promising. Also exciting is the use of IORT as the sole radiation

Box 1. ISIORT disease site protocols underdiscussion*

ISIORT-01, retroperitoneal sarcoma: phase 2 studyevaluating the use of neoadjuvant chemotherapy,preop EBRT, resection and IORTUS/RTOG PIs: P. Pisters, I. Petersen, S.R. PatelEuropean PIs, Aachen/Heidelberg: M. Eble et al

ISIORT-02, phase 3 locally advanced primary or recurrentcolorectal cancer: EBRT plus concomitant andmaintenance chemotherapy, resection, IORT plus etanidazoleUS PIs: L. Gunderson, C. Willett, D. Noyes, H. Nelson,P. Burch, T. PhillipsEuropean PIs, Eindhoven: H. Martijn, H. Rutten

ISIORT-03, lung cancer: phase 2 study evaluating theuse of EBRT plus chemotherapy and IORT for NSCLCUS PIs, UCSF: D. Jablons, M. Roach, T. JahansEuropean PIs, Pamplona/Madrid: F. Calvo et al

ISIORT-04, breast cancer: phase 2 study evaluating lowerdose EBRT (40 Gy) plus boost dose IOERT (9 Gy);200 patient trialEuropean PIs, Salzburg: F. Sedelmayer et alUS PIs: pending

* Discussed at Aachen 2002 ISIORT meeting in Aachen, Germany.Abbreviations: EBRT, external beam radiation therapy; NSCLC, non-small cell

lung cancer; PI, principal investigators; RTOG, Radiation Therapy Oncology Group.

Box 2. Disease site protocols: future possibilities

RSR-13/IORT: protocol discussions with ALLOS, April 2002(colorectal, pancreas, gynecologic, lung)

C-225/IORT: Protocol discussions with Bristol/Myers/Squibb,July 2002 (colorectal, pancreas)


treatment following limited excision of breast cancer. The results of theLanciano and Milano trials (see chapter 12) are awaited with great interest.

Equally exciting is the finding of meaningful survival of 20% to 40% ofpatients who have local or regionally recurrent cancers when IORT is usedas a component of treatment together with EBRT, maximal resection, andchemotherapy, as indicated. Many of these patients still have excessive ratesof both local and distant relapse, however, necessitating the rationale forwell-controlled multi-institutional studies that involve alternate systemictherapies, radiation sensitizers, among other criteria.

References

[1] Willett CG, Shellito PC, Gunderson LL. Primary colorectal EBRT and IOEBRT.

In: Gunderson LL, Willett CG, Harrison LB, Calvo FA, editors. Current clinical

oncology: intraoperative irradiation: techniques and results. Totowa, NJ: Humana Press;

1999. p. 249–72.

[2] Gunderson LL, Willett CG, Haddock MG, Nelson H, Azinovic I, Nag S, et al. Recurrent

colorectal: EBRT with or without IOERT or HDR-IORT. In: Gunderson LL, Willett CG,

Harrison LB, Calvo FA, editors. Current clinical oncology: intraoperative irradiation:

techniques and results. Totowa, NJ: Humana Press; 1999. p. 273–306.

[3] Haddock MG, Martinez-Monge R, Petersen IA, Wilson TO. Locally advanced primary

and recurrent gynecologic malignancies: EBRT with or without IOERT or HDR-IORT.

In: Gunderson LL, Willett CG, Harrison LB, Calvo FA, editors. Current clinical

oncology: intraoperative irradiation: techniques and results. Totowa, NJ: Humana Press;

1999. p. 397–420.

[4] Haddock MG, Miller RC, Nelson H, Devine RM, Gunderson LL. Intraoperative electron

irradiation for locally recurrent rectal cancer [abstract]. Presented at the Third International

Meeting of the International Society of Intraoperative Radiation Therapy. Aachen,

Germany, September 11–14, 2002.

[5] Intra M, Gatti G, Luini A, Galimberti V, Veronesi P, Zurrida S, et al. Surgical technique of

intraoperative radiotherapy in conservative treatment of limited-stage breast cancer. Arch

Surg 2002;137:737–40.

[6] International Society of Intraoperative Radiation Therapy. Available at: http://www.

isiort.org.

[7] Dobelbower RR, Merrick HW, Khuder S, Battle JA, Herron LM, Pawlicki T. Adjuvant

radiation therapy for pancreatic cancer: a 15-year experience. Int J Radiat Oncol Biol Phys

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