Intraoperative Irradiation

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Chapter 16 Intraoperative Irradiation

Intraoperative irradiation (IORT) is the delivery of radiation at the time of surgery. The rationale is straightforward: increasing doses of radiation enhance local tumor control. In many clinical situations the dose delivered by external beam radiation therapy (EBRT) techniques is limited by tolerance of surrounding normal tissues. To overcome this, intraoperative irradiation has been employed as a technique facilitating tumor dose escalation.

In this chapter the rationale and treatment strategies of intraoperative electron radiation therapy (IOERT), high-dose-rate intraoperative brachytherapy (HDR-IORT), as well as orthovoltage techniques with surgery are reviewed. These strategies usually integrate EBRT and chemotherapy.

History

The use of IORT was first employed almost 100 years ago.¹ The contemporary approach to IORT was initiated in the 1960s by Abe and colleagues in Japan. These investigators advocated resection (where possible) with large single-dose radiation therapy (25 to 40 Gy using cobalt-60).² By the mid-to-late 1970s, many institutions in the United States (e.g., Howard University, Massachusetts General Hospital, the Mayo Clinic, and the National Cancer Institute [NCI]) had adopted IORT as a treatment approach using linear accelerator–based electron treatment in the operating room. Presently there are about 90 centers in at least 16 countries worldwide with active IORT programs.

Rationale

IORT has the potential to improve local control and the therapeutic ratio in many tumor sites by (1) reducing the volume of the irradiation “boost” field by direct tumor/tumor bed visualization and conformal treatment; (2) exclusion of part or all of dose-limiting normal structures by operative mobilization, direct shielding, or varying electron beam energy; and (3) allowing the delivery of high-dose irradiation by the just-mentioned methods.

Although early investigators studied this modality separately in the treatment of resected and unresectable malignancies, current approaches frequently employ this technique in combination with fractionated EBRT (with or without concomitant chemotherapy) and resection. The rationale is that EBRT fields encompass the primary tumor and surrounding tissues harboring potential microscopic disease. In contrast to a large single fraction of irradiation, fractionated EBRT is radiobiologically advantageous in promoting tumor control while minimizing late normal tissue injury.

Shrinking-field techniques permit dose escalation. This approach is used in the treatment of many malignancies, including head and neck cancer, breast cancer, and cervical cancer, with excellent local control and acceptable morbidity to dose-limiting normal tissues. These “boost” fields can be delivered in a multitude of ways, including interstitial and intracavitary techniques as well as superficial electrons. For selected intra-abdominal, pelvic, thoracic, and other malignancies, IORT is a technique for localized dose escalation.

Biology

When EBRT is fractionated there is a preferential therapeutic advantage for normal tissues relative to tumor as defined by the “4Rs” of classical radiobiology (normal tissue repair, tumor reoxygenation, tumor redistribution, and normal tissue repopulation). With a single large fraction of radiation therapy, these advantages are lost. In addition, large doses per fraction may result in increased risk of late effects. There is evidence that small vessel injury caused by large doses per fraction may contribute to late effects, and ischemic complications are dose dependent.³ Furthermore, tumor response to single and fractionated radiation therapy depends on the percentage of hypoxic cells within a tumor. This differential sensitivity between hypoxic and well-oxygenated cells increases with increasing dose.

Using alpha/beta (α/β) calculations, biologically equivalent doses to a fractionated EBRT course using 2 Gy per fraction for varying IORT doses have been estimated (Table 16-1). There are disadvantages from a late effects standpoint with IORT, but many of these disadvantages are mitigated by exclusion of nontarget tissues from the radiation field by direct inspection, mobilization, and shielding.⁴ When combined with EBRT and resection, IORT doses of 10 to 20 Gy provide local control for most solid tumors, especially in the setting of microscopic residual tumor tissue. When combined with EBRT and surgery there is little reason to exceed IORT doses of 10 to 20 Gy. Late normal tissue complications are often the limiting sequelae of IORT administration, and careful planning and administration with techniques designed to reduce the dose to nontarget tissues are of paramount importance.

TABLE 16-1 Estimated Biologically Equivalent EBRT Doses (2 Gy/day) of Varying IORT Doses

Local Control: An Important Endpoint

For any treatment a patient’s disease is considered incurable if local control of the tumor is not achieved. If conventional treatment methods of EBRT, chemotherapy, and surgery provided high local control rates, IORT as a component of treatment would be unnecessary. Although local control rates are satisfactory in many tumor sites using conventional techniques, local failure is problematic in other sites, including abdominal and pelvic malignancies. Treatment of these areas employing standard EBRT techniques is limited by normal tissue tolerance.

Pancreatic Cancer

EBRT with 5-FU–based chemotherapy employed in the treatment of unresectable pancreatic cancer results in a doubling of median survival compared with surgical bypass/stenting alone (3 to 6 months vs. 9 to 13 months) and an increase in 2-year survival from 0% to 5% to 10% to 20%.⁵ Unfortunately, these techniques result in poor local control rates. Series from the Mayo Clinic, Thomas Jefferson University Hospital, and other institutions report local failure rates exceeding 70% to 80%^6,7,8,9,10 (Table 16-2).

TABLE 16-2 Pancreas: EBRT ± IOERT or Brachytherapy for Unresectable/Borderline Resectable Cancers

Retroperitoneal Sarcoma

When surgery is used as the primary treatment modality for retroperitoneal sarcomas, local failure has been reported to range from 40% to 90%. Despite the addition of EBRT to surgery, local failure rates are 40% to 80%. This is in contrast to extremity sarcomas in which local control rates approach 90%. Because of the limited tolerance of surrounding normal tissue (small intestine, stomach, liver, kidney, spinal cord), EBRT doses are limited. A randomized NCI trial evaluating IORT in retroperitoneal sarcomas demonstrated that patients receiving IORT + EBRT experienced significantly improved local control and less small bowel toxicity versus patients treated with EBRT alone (80% in-field relapse; see later discussion).¹¹

Colon and Rectal Cancer

In patients with locally advanced (T4) or locally recurrent colon and rectal cancer, local control is difficult to achieve, despite multimodality therapy. Studies from Princess Margaret Hospital and the Mayo Clinic report local failure rates of 90% or greater in evaluable patients treated with EBRT with or without systemic therapy.^12,¹³ In radiation-naive patients, the optimal approach in patients with locally advanced disease is preoperative EBRT combined with 5-FU–based chemotherapy followed by resection. Despite this, local recurrence occurs in 30% to 70% of patients.¹⁴

Cervical Cancer

For patients with cervical cancer, para-aortic nodal metastases are common. Despite the presence of these “distant” metastases, 15% to 20% of patients are cured by radical radiotherapy techniques, employing EBRT doses of 55 to 60 Gy. However, high complication rates have been reported with these doses and techniques.^15,¹⁶ As in rectal cancer, patients with recurrent cervical cancer in the pelvis or para-aortic region have a poor long-term prognosis with 5-year overall survival (OS) rates ranging from 5% to 30%. These patients have often been previously irradiated, and re-treatment with meaningful doses of EBRT is usually not feasible given normal tissue tolerance. When patients have para-aortic or locally recurrent disease, administration of IORT is a feasible method to escalate dose and enhance local control.

Local Control: Radiation Dose, Complications, Shrinking-Field Techniques, Distant Metastases

Influence of Dose

In both animal and human models the probability of local control of a tumor by radiation is proportional to the total dose administered. The dose of radiation to control a tumor locally depends on several factors, including tumor type, clonogen number, and tumor microenvironment. Thus a given radiation dose may be able to control a small tumor with high probability and acceptable morbidity but that same dose may be insufficient against disease of larger volume. Clinical experience has generated a body of data correlating local control by tumor type and radiation dose. In vivo data for a variety of irradiated human tumors of varying sizes and types are summarized in Figure 16-1.

Figure 16-1 Local control versus dose of irradiation.

From Gunderson LL, Tepper JE, Biggs DJ, et al: Intraoperative ± external beam irradiation. Curr Probl Cancer 7:8, 1983.

The studies of Fletcher examined local control probability as a function of radiation dose for patients undergoing treatment for breast carcinoma and squamous cell carcinoma of the upper aerodigestive tract (see web-only Table 16-1 on the Expert Consult website). For breast cancer patients, control of subclinical disease was 60% to 70% with 30 to 35 Gy, 85% with 40 Gy, and 95% with 45 to 50 Gy. For larger/palpable tumors, EBRT doses of 46 Gy, 59 Gy, and 76 to 90 Gy result in a local control probability of 20%, 35% to 50%, and 70% to 80%, respectively.^17,18,19,20 These data suggest that marked improvements in local control can be achieved by escalating radiation doses.

WEB-ONLY TABLE 16-1 Tumor Control Probability Correlated with Irradiation Dose and Volume of Cancer

Dose (Gy)	Tumor Control Probability
Squamous Cell Carcinoma: Upper Aerodigestive Tract
50*	>90% subclinical
	~60% T1 lesions of nasopharynx
	~50% 1- to 3-cm neck nodes
60*	~90% T1 lesions of pharynx and larynx
	~50% T3 and T4 lesions of tonsillar fossa
	~90% 1- to 3-cm neck nodes
	~70% 3- to 5-cm neck nodes
70*	~90% T2 lesions of tonsillar fossa and supraglottic larynx
70*	~80% T3 and T4 lesions of tonsillar fossa
Adenocarcinoma of the Breast
50*	>90% subclinical
60*	90% clinically positive axillary nodes, 2.5-3.0 cm
70*	65% 2-3 cm primary
70-80 (8-9 wk)	30% >5 cm primary
80-90 (8-10 wk)	56% >5 cm primary
80-100 (10-12 wk)	75% 5-15 cm primary

* 10 Gy in five fractions each week.

Modified from Fletcher GH, Shukovsky LJ: The interplay of radiocurability and tolerance in the irradiation of human cancers. J Radiol Electrol 56:383-400 1975.

Dose Versus Complications

The chief limitation of EBRT to control macroscopic disease in the abdomen and pelvis is normal tissue tolerance. Normal organs such as stomach, small bowel, and kidney have tolerance levels well below the radiation doses required to eradicate most abdominal and pelvic malignancies. Exceeding these EBRT doses results in a prohibitive risk of late normal tissue damage (see web-only Table 16-2 on the Expert Consult website). Because of this, “conventional” tolerable doses of EBRT from 45 to 55 Gy using 1.8 to 2.0 Gy per fraction are not curative in most abdominal and pelvic malignancies, with resultant local persistence/local recurrence of disease common in patients treated with radiation therapy alone. This often results in tumor-related morbidity and mortality such as bowel obstruction and perforation, ureteral obstruction, and neuropathy.

WEB-ONLY TABLE 16-2 Gastrointestinal Radiation Tolerance

Although local control is enhanced with increasing doses of radiation, tumor dose-response curves with EBRT closely resemble normal tissue complication curves. Therefore, efforts to improve local control through escalating EBRT doses may also result in treatment-related complications (Fig. 16-2). In an R1 (microscopic residual) resection, EBRT doses of 60 Gy or higher using conventional fractionation schemes are necessary to achieve a high probability of local control. In an R2 (gross residual) resection, even higher doses are usually required. Such doses exceed normal tissue tolerance (see web-only Table 16-2 on the Expert Consult website).

Figure 16-2 Radiation dose versus incidence of tumor control or complications.

From Gunderson LL, Tepper JE, Biggs DJ, et al: Intraoperative ± external beam irradiation. Curr Probl Cancer 7:8, 1983.

Because of the risks associated with dose escalation beyond normal tissue tolerance, an attractive alternative in patients with locally advanced malignancies is to deliver moderate doses of EBRT (i.e., at or below accepted tolerance of surrounding normal tissue). A typical course would range from 45 to 50 Gy at 1.8 to 2.0 Gy per fraction, followed by surgical exploration. After resection, IORT would be performed, avoiding or minimizing irradiation of surrounding organs by shielding or mobilization. With this approach, an increase in local control with decreased risk of normal tissue complications (relative to an EBRT-only approach) can be achieved (see Fig. 16-2: local control curve shifts to left with IORT; complication curve shifts to right with increasing EBRT doses).

Shrinking-Field (Boost) Techniques

The concept of shrinking-field irradiation, otherwise known as administering “boost” treatments, has been used for decades by radiation oncologists. This strategy entails treating larger fields encompassing the primary/recurrent tumor along with locoregional lymph node basins and other tissues at risk for subclinical disease. These larger fields receive a dose sufficient to control microscopic disease yet respect normal organ tolerance (often 45 to 50 Gy using 1.8 to 2.0 Gy per fraction). Fields are then reduced to encompass gross disease with smaller margins, excluding dose-limiting normal tissues. An additional 20 to 35 Gy may then be administered to these fields using either EBRT or brachytherapy techniques, bringing the cumulative dose to 65 to 80 Gy. These approaches are employed in many tumor sites, including gynecologic and head and neck cancers, with excellent long-term outcomes and local control with relatively low and acceptable morbidity levels. The concept of administering IORT in conjunction with EBRT is a logical application of this approach.

Development of Distant Metastases

Preclinical data suggest that the incidence of distant metastases is related to both tumor size as well as the development of locally recurrent disease in multiple spontaneous tumor systems.²¹^–²³ In fibrosarcoma and squamous cell carcinoma cell lines in rodent models, Ramsay and associates²¹ reported increased rates of distant metastases in tumors measuring 6 versus 12 mm, as well as primary versus recurrent tumors. Additionally, Suit and colleagues²³ showed that in mouse mammary tumors treated with single-dose irradiation, increasing rates of local failure were associated with increasing rates of distant metastases. Specifically, the incidence of metastatic disease was 31% (16 of 52) of mice with local control, 50% (9 of 18) in those with local relapse salvaged by resection, and 80% (12 of 15) in mice with local relapse in whom salvage was not attempted. Similar high rates of metastases associated with local failure have been observed in human malignancies, including cervical,²⁴ prostate,²⁵ head and neck,²⁶ and breast²⁷ cancers. These and other data suggest that metastases may arise from locally recurrent disease.

Patient Selection and Evaluation

Candidates for IORT should be evaluated by the treating surgeon and radiation oncologist in the multidisciplinary setting. This allows for joint decisions regarding the appropriateness of IORT and whether further studies that may influence IORT and EBRT planning are appropriate. Additionally, joint decisions can be made defining the optimal sequencing of surgery/IORT and EBRT. Informed consent should be obtained from both specialties, specifically with regard to potential risks, benefits, and side effects of proposed treatments. Criteria for the appropriate selection of patients for IORT include the following:

1 Surgery alone will result in a high probability of incomplete resection (microscopic or gross residual disease) and resultant high probability of failure within the tumor bed. Potential candidates must be appropriate for surgical attempts at gross total resection. IORT administration should be performed at the time of a planned operation.

2 There is no evidence of distant metastases. Rare exceptions include resectable single-organ metastasis, slow progression of systemic disease, excellent chemotherapy options, and patients with oligometastatic disease with slow systemic progression and high probability of symptomatic local failure.

3 EBRT doses required for high probability of local control after subtotal or no resection exceed normal tissue tolerance. (Total doses required for eradication in this setting are 60 to 70 Gy for microscopic disease and 70 to 90 Gy for gross disease at 1.8 to 2.0 Gy per fraction.)

4 Surgical displacement or shielding of dose-limiting structures or organs can be accomplished during IORT administration, allowing for acceptable risks of immediate and late effects. Theoretically, EBRT in conjunction with IORT should result in an improved therapeutic ratio between disease eradication and normal tissue complications.

Pretreatment patient evaluation in patients eligible for IORT should include a thorough history and physical examination, with attention to palpable disease and its relationship to anatomically immobile normal structures. Examples include pelvic disease and its relationship to the pelvic sidewall, presacral space, prostate, or vagina. Computed tomography (CT), magnetic resonance imaging (MRI), and endoscopic ultrasonography may aid in identifying adherence to structures (e.g., bony pelvis, large vessels) that may be surgically unresectable for cure. Examination under anesthesia may be helpful in some situations, including locally advanced gynecologic and rectal cancers. Routine blood chemistries including a complete blood cell count, liver function tests, renal function tests, and tumor-specific serum tests (e.g., carcinoembryonic antigen, CA19-9) should be obtained when appropriate. Patients should be evaluated clinically and radiographically for evidence of distant spread. Positron emission tomography (PET), preferably in conjunction with CT, may facilitate defining local disease extent as well as unsuspected distant metastases. Evaluation of distant metastases is particularly important in the recurrent setting where concurrent distant failure is common. Biopsy confirmation of disease should usually be obtained before proceeding with resection.

Sequencing and Dose: EBRT, IORT

Sequencing with Surgery

For patients with localized malignancy, the goal of curative oncologic surgery is an R0 (margin-negative) resection. Because of the locally advanced and infiltrative nature of many primary tumors (including colorectal, gynecologic, and upper gastrointestinal malignancies, sarcomas, etc.) and locally recurrent malignancies, surgery may be compromised with close margins or microscopic/gross residual tissue. For patients with locally advanced tumors, preoperative EBRT to doses of 45 to 50 Gy using 1.8- to 2.0-Gy fractions (with or without chemotherapy) followed by laparotomy, resection, and IORT offers theoretical and clinical advantages over resection and IORT followed by EBRT. These are listed as follows:

1 By postponing surgical resection until after preoperative therapy is completed, patients with disease that is rapidly progressive may avoid an unnecessary surgical procedure with associated morbidity.

2 Preoperative therapy may allow for tumor downstaging and facilitate resection with curative intent.

3 Preoperative therapy may reduce the risk of tumor seeding/dissemination at resection.

4 Preoperative therapy allows delivery of treatment to disease with an intact vasculature, potentially improving the delivery of chemotherapy and improving oxygen delivery for EBRT.

5 The morbidity and delayed recovery time associated with extensive surgical procedures may prevent the timely delivery of postoperative therapy in a high percentage of patients.^28,²⁹

The role of preoperative versus postoperative therapy has been evaluated in rectal cancer. A large German randomized trial demonstrated that patients undergoing neoadjuvant irradiation and chemotherapy experienced significantly improved local control and less toxicity than patients receiving postoperative irradiation and chemotherapy.³⁰

Radiation Dose and Technique

Techniques combining EBRT and IORT have been fairly uniform in the United States and Europe. In previously untreated patients, EBRT doses of 45 to 54 Gy have been employed, delivering 1.8 to 2.0 Gy per fraction, 5 days per week, over 5 to 6 weeks. Because of the anatomic location of pelvic and abdominal malignancies, high-energy (>10 MV) photons delivered via linear accelerators using multifield, shaped techniques are required. CT-, PET-, and/or MRI-based treatment planning permits accurate definition of the target volume. For extrapelvic, unresected, or residual disease after resection, radiation doses of 40 to 45 Gy delivered at 1.8 to 2.0 Gy per fraction with a 3- to 5-cm margin accounting for microscopic extension and target mobility are sometimes utilized. Treatments are generally delivered through multifield techniques aided by three-dimensional–based treatment planning. Reduced-field or “boost” techniques are often used to bring the total dose to 45 to 54 Gy as dictated by tolerance of surrounding normal tissue (see earlier discussion). Concurrent administration of chemotherapy during EBRT varies by tumor site: for patients with gastrointestinal malignancies, concurrent 5-FU–based regimens (plus cisplatin, oxaliplatin, or mitomycin C) are frequently implemented; and for patients with gynecologic cancers, concurrent cisplatin is frequently given. In carefully selected patients who have received prior irradiation, preoperative EBRT doses of 20 to 30 Gy at 1.5 to 1.8 Gy per fraction (often with concurrent chemotherapy) may be employed.

The IORT dose should be based on extent of residual disease at resection, the amount of EBRT delivered previously, and the type and volume of normal tissue irradiated. For patients who have received preoperative doses of 45 to 54 Gy (1.8 to 2.0 Gy per fraction, 5 days per week), IORT doses usually range from 10 to 20 Gy. For patients with microscopic residual tissue or close margins, doses of 10 to 12.5 Gy are often administered. Patients with gross residual disease require higher doses, and 15 to 20 Gy is usually administered. In previously irradiated patients, in whom additional EBRT is feasible (20 to 30 Gy), the dose of IORT generally ranges between 15 and 20 Gy. In patients in whom no or very limited EBRT is planned, IORT doses from 25 to 30 Gy have been administered; however, doses in this range should be judiciously employed given the risk of normal tissue damage, specifically peripheral nerve injury.

The biologic effectiveness of single-dose IORT in early responding tissues (tumor) relative to an equivalent total dose of fractionated EBRT has been estimated to be 1.5 to 2.5 times the IORT dose delivered 4,31,32 (see Table 16-1). Therefore the effective tumor doses (when “normalized” to fractionated EBRT doses) of IORT treatment added to 45 to 50 Gy given by EBRT are as follows: 10-Gy IORT dose, 60 to 80 Gy; 15-Gy IORT dose, 75 to 87.5 Gy; and 20 Gy IORT dose, 85 to 100 Gy. These figures are not intended to be exact but represent educated estimates.

A discussion of the technical aspects of IORT administration is beyond the scope of this chapter. In brief, the implementation of IORT-based treatment is a multidisciplinary effort including one or multiple surgeons, radiation oncologist, anesthesiologist, operating room nurse, radiation physicist/dosimetrist, and therapist. In its broadest sense, IORT may be administered with either electrons (IOERT) or high-dose-rate photon afterloading techniques (HDR-IORT). Each method has potential advantages and disadvantages (see later and web-only Tables 16-6 and 16-7).

Dose-Limiting Structures and Tolerance

The development of normal tissue late effects increases with increasing radiation dose as well as dose delivered per fraction. Therefore, the incidence of late normal tissue effects in patients receiving IORT plus EBRT would be higher than those receiving EBRT alone. However, in this context the severe morbidity and mortality associated with locally recurrent tumor is often overlooked. As an example, when EBRT alone is used as the primary treatment modality for locally advanced rectal cancer, more than 90% of patients experience local persistence or local recurrence of disease with associated symptomatology. These symptoms include severe pelvic pain and neuropathy, which are difficult to manage clinically; the vast majority of patients experience disease-related death within 2 to 3 years. An argument can be made that the tumor-related morbidity/mortality approaches 100% in these patients.³³

IORT tolerance for intact or surgically manipulated organs or structures in animals (primarily canines) is seen in Table 16-3. Much of this information has been derived from studies from the NCI^{34,35,36–38,39} and Colorado State University.⁴⁰^–⁴²

TABLE 16-3 Normal Tissue Tolerance to Intraoperative Electron Irradiation in Animals (Usually Dogs)

Several dose-sensitive structures have been studied in humans receiving IORT, including the ureter and peripheral nerve.

Ureter

Clinical studies of the effect of IOERT on the ureters of human cancer patients have been undertaken at the Mayo Clinic.⁴³ Doses of 10 Gy administered intraoperatively resulted in a 50% incidence of ureteral obstruction, increasing to 70% with doses from 15 to 25 Gy. This high complication rate relative to canine models may be due to age-related factors, surgical manipulation, EBRT, and/or tumor bed effects.

In an update of this experience, Mayo Clinic investigators reported on 146 patients with locally advanced malignancies receiving IORT to one or both ureters with doses between 7.5 and 30 Gy.⁴⁴ They reported the risk of obstruction after IOERT is significant and increases with time and IORT dose. However, obstruction risk for ureters not receiving IOERT was also high, which suggests an underlying risk of ureteral injury from other causes (EBRT, surgical manipulation of ureters). (A more detailed discussion of ureteral tolerance with IORT can be found on the Expert Consult website.)

The rates of clinically apparent type 1 obstruction (obstruction from any cause) after IOERT at 2, 5, and 10 years were 47%, 63%, and 79%, respectively. The rates of clinically apparent type 2 obstruction (obstruction occurring at least 1 month after IOERT, excluding obstruction caused by tumor or abscess and patients with stents) at 2, 5, and 10 years were 27%, 47%, and 70%, respectively. Multivariate analysis revealed that the presence of obstruction before IOERT was associated with an increased risk of clinically apparent type 1 obstruction (p <.001). Increasing IOERT dose was associated with an increased risk of clinically apparent type 2 obstruction (p <.04). Obstruction rates in ureters not receiving IOERT at 2, 5, and 10 years were 19%, 19%, and 51%, respectively.

Peripheral Nerve

Peripheral nerve tissue is the principal dose-limiting normal tissue for IORT in the pelvis and retroperitoneum. Data regarding peripheral nerve tolerance and neuropathy comes from canine models as well as clinical analyses from patients treated intraoperatively.* Peripheral nerve tissue is often situated adjacent to or directly involved by tumor in the abdomen and pelvis. Because of this, the relative surgical “immobility” of the peripheral nerve, and the inability to shield the nerve from the IORT field, nerve tissue will often receive full-dose EBRT and IORT.

The mechanism of neuropathy after IORT is poorly understood. Peripheral nerve tolerance depends on the volume of nerve irradiated and total dose delivered. In animal models, histomorphologic findings after IORT have demonstrated decreased central nerve fiber density, particularly in large nerve fibers receiving more than 20 Gy. Electron microscopy analysis has demonstrated increased microtubule density and neurofilament accumulation within axons without associated myelin changes, suggesting possible hypoxic injury related to vascular changes.⁵⁴

A Spanish study evaluated 45 patients with primary or locally recurrent extremity soft tissue sarcoma undergoing resection with IOERT (10 to 20 Gy).⁵⁵ Nine patients received IOERT alone secondary to prior EBRT or patient refusal. Five patients developed neurotoxicity at a median of 13 months; 4 of the 5 showed objective weakness and/or sensory loss. Most patients developing neuropathy received IOERT doses greater than 15 Gy.

An analysis from the Mayo Clinic evaluated peripheral nerve tolerance in 51 patients undergoing IOERT for primary or recurrent pelvic malignancies.⁴³ Patients received EBRT (median dose 50.4 Gy), maximal resection where possible, and IOERT boost from 10 to 25 Gy using 9- to 18-MeV electrons. Sixteen (32%) of patients experienced grade I to III peripheral neuropathy as manifested by pelvic/extremity pain, leg weakness, numbness, or tingling. Pain was severe (grade III) in 3 of 51 patients (6%) (see web-only Table 16-3 on the Expert Consult website).