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Abstract

  1. Top of page
  2. Abstract
  3. Clinical Background
  4. Radiobiology
  5. TARGIT (Targeted Intraoperative Radiotherapy)
  6. ELIOT (Intraoperative Radiotherapy With Electrons)
  7. Smaller Experiences: Data From Montpellier and North America
  8. Rationale of Proposed Fractionation Schemes in the “Overnight” APBI Trial
  9. FUNDING SOURCES
  10. REFERENCES

In accelerated partial breast irradiation (APBI), the most commonly used fractionation schemes include 340 or 385 centigrays delivered in a twice daily administration. A further progression of the APBI literature has been the recent interest in extremely short courses of adjuvant radiotherapy, usually delivered by intraoperative radiotherapy techniques. This newer area of single-fraction radiotherapy approaches remains highly contentious. In particular, the recently reported TARGIT trial has been the subject of both praise and scorn, and a critical examination of the trial data and the underlying hypotheses is warranted. Short-term outcomes of the related Italian ELIOT approach have also been reported. Although the assumptions of linear quadratic formalism are likely to hold true in the range of 2 to 8 grays, equating different schedules beyond this range is problematic. A major problem of current single-fraction approaches is that the treatment doses are chosen empirically, or are based on tolerability, or on the physical dose delivery characteristics of the chosen technology rather than radiobiological rationale. This review article summarizes the current data on ultrashort courses of adjuvant breast radiotherapy and highlights both the promise and the potential pitfalls of the abbreviated treatment. Cancer 2012. © 2011 American Cancer Society.


Clinical Background

  1. Top of page
  2. Abstract
  3. Clinical Background
  4. Radiobiology
  5. TARGIT (Targeted Intraoperative Radiotherapy)
  6. ELIOT (Intraoperative Radiotherapy With Electrons)
  7. Smaller Experiences: Data From Montpellier and North America
  8. Rationale of Proposed Fractionation Schemes in the “Overnight” APBI Trial
  9. FUNDING SOURCES
  10. REFERENCES

The therapeutic equivalence of breast-conserving therapy (BCT) and mastectomy, perhaps the most intensively studied topic in clinical oncology, has been established by multiple prospective randomized trials.1-5 However, despite the many advantages of BCT, some women may choose mastectomy or even lumpectomy alone over breast-conserving surgery and radiation therapy (BCS + RT) because of the protracted course of daily treatment involved with whole breast irradiation, which consists of daily RT to the whole breast typically over the course of 4 to 6 weeks.6, 7 Other reasons that may steer women away from BCS + RT include physician bias, patient age, fear of radiation treatments, distance from a radiation treatment facility, and socioeconomic factors.8-10

To account for this, accelerated partial breast irradiation (APBI) has been studied increasingly over the past 15 years as a more convenient alternative to whole breast irradiation.11 In general, APBI involves treating the surgical cavity with a 1- to 2-cm margin, thus reducing the volume of breast tissue by up to 50% using various radiotherapeutic methods. Technical approaches of APBI include multicatheter interstitial brachytherapy, balloon catheter brachytherapy, external 3-dimensional conformal external beam RT, and intraoperative RT (IORT). Postoperative treatment is delivered over a short period of time using larger fraction sizes. To date, the body of available literature supports the hypothesis that APBI is a safe, well-tolerated therapy that appears to be equivalent to whole breast irradiation in terms of efficacy and ultimate breast cosmesis.12-16

A further progression of the APBI literature has been the recent interest in extremely short courses of adjuvant RT, usually delivered by IORT techniques. Excellent and eminently readable literature reviews are already available for standard APBI,17 but the newer area of single-fraction RT approaches remains highly contentious and highly confusing. In this review, we will examine the potential promise and pitfalls of current methods of delivering abbreviated or ultrashort course APBI. In particular, the recently reported TARGIT trial has been the subject of both praise and scorn,18-24 and we will critically examine the underlying hypotheses and the currently reported clinical data. Also, we will review the development of and the current update of the Italian ELIOT approach.25-27 Two North American reports of ultrashort course APBI will be discussed.28-30 Finally, we will briefly present our investigational approach to delivering shorter courses of APBI based on our understanding of the shortcomings of currently reported strategies.

Radiobiology

  1. Top of page
  2. Abstract
  3. Clinical Background
  4. Radiobiology
  5. TARGIT (Targeted Intraoperative Radiotherapy)
  6. ELIOT (Intraoperative Radiotherapy With Electrons)
  7. Smaller Experiences: Data From Montpellier and North America
  8. Rationale of Proposed Fractionation Schemes in the “Overnight” APBI Trial
  9. FUNDING SOURCES
  10. REFERENCES

In whole breast irradiation, daily fraction sizes of 180 or 200 centigrays (cGy) are commonly used and are described as conventional. The rationale for conventional fractionation and the relation between fraction size and tissue response are well described by the α/β ratio in the linear quadratic model of fractionation sensitivity. In this empiric model, late-reacting normal tissues such as fibroblasts and neurons have a low α/β ratio (2-5 Gy) and are very responsive to changes in fraction size, whereas acutely reacting normal tissues such as intestinal epithelium have a high α/β ratio (>7 Gy) and are less responsive to changes in fraction size. The biological effectiveness of a given fractionation scheme size is related to the α/β ratio and may be expressed in terms of the biologically effective dose (BED):

  • equation image

where d = dose/fraction and n = the number of identical fractions.

Estimates of the α/β ratio for squamous cell carcinomas of the head, neck, and cervix uteri are >7 Gy. For this reason, the α/β ratio for tumor control probability is taken to be 10 Gy by convention, whereas the α/β ratio for normal tissue effects is taken to be 3 Gy. Different fractionation schemes can be equated using the relation:

  • equation image

where n = standard number of fractions, n1 = equivalent number of fractions in altered schedule, d = standard dose/fraction, and d1 = desired dose/fraction.

Although relatively high cumulative doses of radiation are needed for tumor control, the daily fraction size has to be respectful of the fraction sensitivity of normal tissues in the treated volume. Accounting for these assumptions, increases in fraction size have to be compensated for by reductions in cumulative radiation dose, which typically are insufficient for tumor control. As a result, daily fractions of 1.8 to 2 Gy are delivered over 4 to 8 weeks to reach a cumulative dose of 45 to 80 Gy. This understanding of radiobiological effect is referred to as the linear quadratic model.

The above discussion ignores the potential effect of cellular proliferation that may occur during a course of radiation therapy. Although commonly ignored because of the uncertainty of the relevant variables, a correction can be introduced into the above equation for this factor31:

  • equation image

where d = dose/fraction, n = number of identical fractions, T = overall treatment time after initial time lag to proliferation, and Tpot = potential tumor doubling time.

Rosenstein et al31 in their publication comparing several APBI fractionation schemes used a Tpot value of 13 days, an initial time lag of 14 days, and an α value of 0.3 Gy−1.

In contrast to the assumptions for most epithelial tumors, the α/β ratio for breast tumors may be much lower than the conventional assumption of 10 Gy. In vitro experiments in human breast carcinoma cell lines have suggested an α/β ratio of about 4 Gy. An interesting set of clinical dose-response data for inoperable and locally recurrent breast cancer was published in 1952,32 and reanalyzed to fit the linear quadratic model.33 The point estimate for the α/β ratio from this data set was 4 to 5 Gy. On the basis of this data set, clinical trialists in the United Kingdom collaborated in a series of randomized clinical trials to evaluate the relative toxicity and efficacy of different fractionation schemes.34-37 In a cumulative experience of approximately 6000 randomized women, the UK investigators demonstrated that the α/β ratio for late breast change was approximately 3.4 Gy, and the α/β ratio for tumor control was 4.6 Gy. The similarity of these 2 estimates is striking and serves to validate the hypofractionated regimens commonly being used for APBI. To summarize, although the true α/β ratio for breast cancer remains unknown, the most robust clinical data set seems to suggest an α/β ratio of 4 to 5 Gy. It should be acknowledged that the α/β ratio for different biologic subtypes of breast cancer may vary. Additional data will be needed to address this current limitation to our understanding.

In APBI, the most commonly used fractionation schemes include 340 cGy delivered in a twice daily administration, and 385 cGy delivered twice a day. Cuttino and colleagues have elegantly reported on the equivalence and appropriateness of these schedules based on the equivalent uniform biologically effective dose concept.38 The equivalent uniform biologically effective dose conversion allows for a comparison of the inhomogeneous dose delivered by brachytherapy with the more uniform delivery typical of external beam radiation therapy (EBRT) plans, and they made this comparison over a range of possible α and β values. The NSABP B-39/RTOG 0413 trial endorses both of these schedules. A significant amount of prospective data have now been accumulated and reported through a registry trial of balloon brachytherapy administered by the American Society of Breast Surgeons. The MammoSite RTS brachytherapy device (Hologic, Bedford, Mass) has been used to deliver 34 Gy in 10 fractions at a depth of 1 cm in 1449 breasts on this registry trial. This study, although not randomized, provides solid evidence supporting the efficacy and safety of APBI delivered by this mode; with a median follow-up of 59 months, the 5-year actuarial local recurrence rate is 3.56%, with good/excellent cosmesis in 89% of treated breasts (personal communication, Frank Vicini). Symptomatic seromas developed in 13%, breast infections in 9.5%, and fat necrosis in 2.2%.

In addition to these normative APBI schedules, other fractionation schemes have been used that include intraoperative techniques, which deliver a single fraction. Although the assumptions of linear quadratic formalism (briefly discussed above) are likely to hold true in the range of 2 to 7 Gy, equating different schedules beyond this range becomes an inexact science. A major problem of current single-fraction approaches is that the treatment doses are chosen empirically, or are based on tolerability, or on the physical dose delivery characteristics of the chosen technology rather than true radiobiological rationale.

TARGIT (Targeted Intraoperative Radiotherapy)

  1. Top of page
  2. Abstract
  3. Clinical Background
  4. Radiobiology
  5. TARGIT (Targeted Intraoperative Radiotherapy)
  6. ELIOT (Intraoperative Radiotherapy With Electrons)
  7. Smaller Experiences: Data From Montpellier and North America
  8. Rationale of Proposed Fractionation Schemes in the “Overnight” APBI Trial
  9. FUNDING SOURCES
  10. REFERENCES

The TARGIT approach was conceived and brought to practice by clinical trialists in the United Kingdom. TARGIT employs an intraoperative spherical applicator to deliver a single dose of 20 Gy at the applicator surface with 50-kV x-rays, resulting in a dose of 5 Gy at 1 cm.39 The TARGIT trialists have extensively advocated their treatment and the theoretical basis for the strategy. The ideas they have advanced over the past several years can be summarized as: 1) the breast harbors multicentric foci, which however remain clinically dormant and without consequence40; 2) 85% to 90% of true recurrences occur around the lumpectomy cavity41, 42; 3) local recurrences after fractionated RT occur because of microenvironmental factors that encourage proliferation43; and 4) the seemingly low dose of TARGIT is offset by the high relative biologic effectiveness (RBE) of a 50-kV x-ray beam (RBE of 1.5 at 1 cm).40 The RBE is a term that accounts for different biological effects (for a given biological endpoint) resulting from various types of radiation. Preliminary clinical data acquired by using TARGIT as a boost (at the same dose) followed by whole breast EBRT were reported in a cohort of 300 treated breasts.44 With a median follow-up of 60.5 months, 8 ipsilateral breast tumor recurrences were reported (crude failure rate of 2.7% and 5-year Kaplan-Meier estimate of 1.73%). On the basis of these results, the trialists launched the TARGIT-A trial for lower risk patients to test the efficacy of single-fraction treatment compared with fractionated whole breast EBRT, and the TARGIT-B trial to test the equivalence of TARGIT delivered as a boost in higher risk patients.

Initial findings of the TARGIT-A trial were recently published.18 A total of 2232 women were randomized to either fractionated whole breast RT (with or without a boost) or to targeted intraoperative RT at a dose of 20 Gy at the applicator surface. Patients were stratified into 2 strata: the prepathology stratum included patients who had their first definitive lumpectomy and TARGIT at the same sitting, whereas the postpathology stratum consisted of patients who were taken back to the operating room for the TARGIT treatment after final pathology had been reviewed. The investigators predefined a 2.5% absolute noninferiority margin with a background 5-year local recurrence rate of 6%. The trialists also estimated that 15% of patients assigned to TARGIT would ultimately have pathological features that would warrant additional whole breast EBRT, although these adverse features were not strictly outlined for the treating sites. The median age of patients was 63 years (interquartile range, 57-69 years), 86% of tumors were <2 cm, and 84% were grade 1 or 2; >90% of tumors were estrogen receptor-positive. Although the trial allowed lymph node-positive patients, 83% of patients were lymph node negative. Approximately 80% of patients received systemic therapy. Curiously, the median follow-up of the entire group is not reported, but appears to be approximately 24 months from the article's figures, with <20% of patients followed beyond the 4-year mark. At 4 years, there were 6 local recurrences in the intraoperative group and 5 in the EBRT group. There was no significant difference in the Kaplan-Meier estimates for local failure at 4 years (1.20% vs 0.95%, P = .41). Toxicity events were low and comparable in both arms. Although the report indicates that 14% of patients assigned to the TARGIT arm went on to also receive EBRT because of permanent pathology findings, the denominator for this percentage included patients in the postpathology stratum who already had pathological confirmation of suitability. In a letter to the editor, in response to queries, the authors subsequently acknowledged that 21% of patients in the prepathology stratum ended up requiring additional EBRT.45

That TARGIT strategy is truly novel, and is already the subject of a clinical trial involving thousands of women. Because of its prominence, a critical review of the TARGIT assumptions is warranted. The biological rationale for intraoperative single-fraction RT, as advanced by the TARGIT trialists, circumvents the potential constraints imposed by conventional radiobiology by invoking a new and currently undefined biological parameter, that of the lumpectomy cavity microenvironment. In support of their hypothesis, the authors have reported the results of translational experiments performed with wound fluid harvested from TARGIT-treated and untreated patients, and these results appear to offer tantalizing evidence that RT abrogates the proliferative cascade induced by surgical wound healing.43 However, these experiments were strictly in vitro and were performed in monolayer cell culture experiments or in 3-dimensional matrigel; clearly many exciting in vitro findings have been difficult to demonstrate or reproduce in in vivo animal models and in humans. Although interesting, we believe these data should be considered exploratory and hypothesis generating rather than definitive evidence or established fact. Even if the extrapolated conclusion is true, the time kinetics of this microenvironment effect remain unknown; a delayed 6-week course of fractionated RT may still abrogate proliferative signaling in the microenvironment with the same efficacy as TARGIT.

The authors have also attempted to draw parallels from the stereotactic radiosurgery literature,40, 46 but these comparisons are at best tenuous and unsatisfying. Radiosurgery produces a target dose at the periphery of a target volume, whereas the center of the volume receives much higher doses; in contrast, TARGIT dose is prescribed at the surface of the applicator, with no defined depth in tissue and with the entire irradiated volume receiving doses less than the prescription dose. Stereotactic radiosurgery (SRS) literature derives largely from intracranial experience. Given these differences, invoking SRS literature in support of TARGIT appears untenable.

The authors have also published mathematical models of local control as a function of different RT conditions47, 48 and have simultaneously advanced an alternate theory of why local recurrences occur, arguing that microscopic residual is less important than either 1) acquired loss of heterozygosity in adjacent morphologically normal cells leading to new tumors close to the index lesion or 2) circulating tumor cells that self-seed into the index quadrant.40, 47-49 These recent theories are interesting and may indeed be relevant to ultimate local control, but do not negate the large body of evidence that supports the microscopic residual hypothesis of local control.

First, several reports have consistently shown that margin status correlates well with local control.50-57 For example, Vicini et al have elegantly demonstrated the influence of margin status in a cohort of >600 cases treated with BCT.58 Their work is notable because they stratify patients into negative, near, and positive margins, but then also substratify the near margin group into near-least, near-intermediate, and near-most based on the number of ducts with in situ carcinoma at the margin. The 12-year rate of local recurrence correlated well with the risk of residual disease at the margin: 9%, 6%, 18%, 24%, and 30%, respectively for negative, near-least, near-intermediate, near-most, and positive margins.

Second, true ipsilateral breast tumor recurrences (IBTRs) occur over a median time interval of 3 to 5 years, whereas de novo cancers occur over a longer time interval (median, 7-9 years).59, 60 This observation supports the notion that residual disease is the primary driver of local recurrence. Finally, recent work has conclusively demonstrated that the majority of true IBTRs are clonally related to their index lesions.60-63 McGrath et al analyzed 57 IBTR specimens and their corresponding initial carcinoma specimens using a polymerase chain reaction-based allelic imbalance assay to assess clonality.60 Thirty-four of these were clonally related to the initial lesions. Clinical assignment of IBTRs to marginal miss/true recurrence versus elsewhere failure based on clinical variables such as location was not accurate.

In summary, microscopic residual disease likely accounts for most local failures. It is also probable that factors beyond our current model of microscopic residual disease contribute to the risk of local recurrence.64 Indeed, Goldstein et al have reported that a population of partially transformed monomorphic epithelial proliferations adjacent to the index cancer may represent precursor lesions that lead to IBTRs.64 The dose delivered by TARGIT is quite simply inadequate for the control of microscopic disease, even after correcting for the RBE of a 50-kV beam. Indeed, some commentators have even questioned the accuracy of this RBE correction, pointing out that RBEs are variable for different cell lines and experimental settings, and that clinical RBE comparisons between 50 kV and megavolt range radiation do not exist.24 Finally, the same dose of 20 Gy at the applicator surface is used for both boost and monotherapy treatments, which is likely an empiric selection and is confusing and inconsistent with known radiobiological principles. Perhaps because of these considerations, patient selection for TARGIT has been legally restricted in Germany to only the lowest risk patients.24

ELIOT (Intraoperative Radiotherapy With Electrons)

  1. Top of page
  2. Abstract
  3. Clinical Background
  4. Radiobiology
  5. TARGIT (Targeted Intraoperative Radiotherapy)
  6. ELIOT (Intraoperative Radiotherapy With Electrons)
  7. Smaller Experiences: Data From Montpellier and North America
  8. Rationale of Proposed Fractionation Schemes in the “Overnight” APBI Trial
  9. FUNDING SOURCES
  10. REFERENCES

The Milan group, led by Veronesi and Orecchia, has been studying the utility of intraoperative RT with electrons (ELIOT). In the ELIOT technique, an intraoperative dose of 21 Gy prescribed to the 90% isodose line is delivered with 3- to 12-MeV electrons to encompass the tumor bed.65 The appropriate electron energy is selected based on a measurement of breast thickness in the clinical target volume. The Italian group arrived at this dose after a dose escalation study demonstrated its safety.66 Of 103 treated breasts, 16 developed fibrosis (1 severe), all of which resolved by 24 months. Four patients developed fat necrosis, which was managed conservatively with aspiration and wound care, and did not impact final cosmesis. In the most recent update of the ELIOT experience, 1822 patients were treated and followed for a mean of 36 months. The cumulative rates of mild and severe fibrosis were 1.8% and 0.1%, respectively, and the cumulative rate of liponecrosis was 4.2%. The true local recurrence rate (same quadrant as the index lesion) was 2.3% (n = 42), occurring at a median of 29.2 months (annual rate of 0.77%). Another 24 patients (1.3%) developed nonquadrant failures in the treated breast (annual rate of 0.44%). In multivariate analysis, age <50 years, tumor size >2 cm, and unfavorable subtype (nonluminal A) predicted for increased risk of local recurrence. No additional therapy was offered to 6 patients with positive margins and 48 patients with close margins on final pathology; none of these patients had a local recurrence. The Italian group has completed accrual to a randomized trial of whole breast irradiation versus APBI using the ELIOT technique, and initial results from this study are expected shortly.

The ELIOT technique has several advantages over the TARGIT approach. A homogenous dose is delivered to a target volume that is generally consistent with the target volumes treated in the accumulated APBI literature. The investigators arrived at their dose using linear quadratic formalism and an α/β ratio of 10 for tumor control.66 The first of these assumptions is unlikely to be accurate at high doses, and the second (the α/β ratio for breast cancer control) is now known to be inaccurate. Furthermore, a dose prescribed to the 90% isodose line for 3-MeV electrons is different from that for 12-MeV electrons, thus creating variable prescription depths. Careful pathological analysis of >300 re-excision specimens has demonstrated that a fixed prescription depth of 1 cm from the negative-margin lumpectomy cavity is likely to treat residual disease in >90% of all patients.67 However, the ELIOT dose is probably more likely to control microscopic residual disease than the TARGIT dose. Surprisingly, the currently reported local control rates with TARGIT appear to be better than ELIOT. This can be attributed to the shorter follow-up for TARGIT, the addition of whole breast RT to unfavorable TARGIT patients, and the slightly higher risk profile of the reported ELIOT patients. In addition, in what is certainly a major departure from current standards, the ELIOT approach is agnostic to final pathology findings.

Neither the TARGIT nor the ELIOT technique allows image verification of target volume coverage or dose to organs at risk. Although unlikely, it is certainly not impossible that a deep-seated lumpectomy bed could bring an applicator in close proximity to a rib or the left ventricle without the treating physicians ever realizing it. Although the intraoperative approaches do often include an attempt to undermine the breast to introduce shielding devices, this exercise is still not image-verified and may cause more breast trauma. In any case, the very idea of treating a volume of tissue based on dose falloff characteristics of a particular photon/electron energy and a particular size applicator (lookup table-style treatment) seems to be outdated and a step in the wrong direction rather than a true advance.

Smaller Experiences: Data From Montpellier and North America

  1. Top of page
  2. Abstract
  3. Clinical Background
  4. Radiobiology
  5. TARGIT (Targeted Intraoperative Radiotherapy)
  6. ELIOT (Intraoperative Radiotherapy With Electrons)
  7. Smaller Experiences: Data From Montpellier and North America
  8. Rationale of Proposed Fractionation Schemes in the “Overnight” APBI Trial
  9. FUNDING SOURCES
  10. REFERENCES

Lemanski et al have published their experience in Montpellier of IORT as a modality of APBI using either 6- or 9-MeV electrons prescribed at a dose of 21 Gy to the 90% isodose line,68 similar to the ELIOT report. All patients were required to be pT0 or 1 and pN0 by intraoperative frozen section pathology. Forty-two patients were followed for a mean of 30 months. There were 2 local recurrences (1 true recurrence) and no grade 3 toxicities. Although an encouraging experience, the technique is unlikely to find users in institutions without the necessary resources for dedicated intraoperative pathology handling and evaluation.

Sacchini and colleagues reported their intraoperative high-dose rate (HDR) technique using a Silastic applicator (Harrison-Anderson-Mick or HAM applicator) placed in the lumpectomy cavity at the time of the operation.28, 30 A single fraction of 20 Gy was prescribed at 1 cm from the surface of the applicator. This was modified to 18 Gy at the lateral aspects of the applicator, because 5 of the first 18 patients developed significant fibrosis and retraction at the 6-month interval. Notably, a single fraction of 20 Gy delivered by HDR approximates 90 Gy delivered in 2-Gy fractions, assuming an α/β ratio of 3 for normal tissue effects. Also, the investigators do not report accounting for the steep gradient of inhomogeneity (inherent to HDR treatment) within the prescription volume. After the modest dose reduction, fewer complications were noted, although the reported follow-up is short. The Sacchini effort is an important step toward attempting to improve the convenience of APBI. However, its widespread appeal and success is likely to be limited by: 1) the lack of final pathological analysis at the time of treatment, 2) lumpectomy cavities rarely conforming to the shape of a HAM applicator, 3) lack of image-based treatment planning and target definition, 4) need for an operating room appropriately shielded for HDR treatments, and 5) uncertain radiobiology of the chosen fractionation. Nonetheless, this attempt was the first published North American effort to further compress treatment beyond the usual APBI fractionation schemes.

The William Beaumont Hospital has treated 45 patients on a phase 1/2 protocol of 7 Gy × 4 fractions using the single-lumen MammoSite RTS applicator (Hologic, Santa Clara, Calif).29 With a median follow-up of 11.4 months, there were 4 fat necrosis events (2 symptomatic), 2 rib fractures (4%), 6 cases of grade 3 breast pain (13%), and no grade 3 fibrosis. This effort was important but limited by 2 important considerations: 1) a single-lumen device was used, which limits optimization and may account for the observed rib fractures and breast pain; and 2) a formal radiobiological rationale for the selected fractionation was not provided. Formal constraints for skin and rib were not defined, except to specify that the minimum skin spacing had to be 8 mm.

A noteworthy observation of the preceding discussion is the finding that the compressed APBI schedules are highly variable with respect to treatment volume, prescription point, dose heterogeneity, and fractionation. These parameters are critical determinants of disease control and toxicity. Currently, no uniform standards exist for reporting this information.

Rationale of Proposed Fractionation Schemes in the “Overnight” APBI Trial

  1. Top of page
  2. Abstract
  3. Clinical Background
  4. Radiobiology
  5. TARGIT (Targeted Intraoperative Radiotherapy)
  6. ELIOT (Intraoperative Radiotherapy With Electrons)
  7. Smaller Experiences: Data From Montpellier and North America
  8. Rationale of Proposed Fractionation Schemes in the “Overnight” APBI Trial
  9. FUNDING SOURCES
  10. REFERENCES

The primary rationale for APBI is the enhanced convenience for patients, which may result in increased access to BCT. The fractionation schemes for APBI were devised empirically. With data now available documenting the low α/β ratio for breast cancer, the fraction sensitivity of breast cancer can be further exploited with higher fraction sizes, resulting in even more compressed treatment times. However, care must be taken not to exceed the tolerance of normal tissues. It should be stressed that with APBI, the target volume corresponds to the high-dose boost volume in a conventionally fractionated external beam RT plan. As such, the reference schedule that will serve as our standard is 60 Gy delivered in 2-Gy fractions.

Assuming tumor parameters α/β = 4 Gy, α = 0.27 Gy−1, if repopulation effects are neglected, a reference schedule of 60 Gy/30 fractions delivers a tumor BED of 90.0 Gy4. Wyatt et al69 have reviewed postoperative repopulation parameters relevant to breast cancer and used working values of effective doubling time Teff = 26 days, delay time = 0 days. This yields a K factor of 0.693/(α × Teff) = 0.693/(0.27 × 26) = 0.1 Gy/d−1. A 30-fraction treatment normally lasts around 39 days, thus the calculated BED is reduced by 39 × 0.1 = 3.9 Gy, that is, the reference tumor BED, corrected for repopulation, is 90 minus 3.9 ∼86 Gy4.

For the APBI treatment, we assume the balloon is spherical, with an average diameter of 4.5 cm. Dose is prescribed 1 cm from the balloon surface, that is, the balloon radius is 2.25 cm, and the prescription distance is 3.25 cm. Between the balloon surface and the dose prescription surface there is a large dose gradient. Assuming an inverse-square relation, the dose on the balloon surface is greater by a factor of (3.25/2.25)2 = 1.44, that is, the surface dose is 44% higher than the prescription dose.

The radiobiological influence of the dose gradient may be accounted for using the analytical method described by Dale et al.70 This approach calculates a multiplication factor (MF) with which to multiply the prescribed BED to take account of the dose gradient effect, the radiosensitivity parameters, the fractional dose, and the number of fractions. As the MF values are dependent on the specific applicator geometry under consideration, they need to be derived (as have those in the table below) for each set of circumstances. The resultant BED is that of the equivalent uniform dose that would produce the same cell kill as the reference schedule (assumed here to be 60 Gy/30 fractions).

Acknowledging the potential limitations of the linear quadratic assumptions, Table 1 summarizes those results that give the closest match to the reference BED for respective 4-, 3-, and 2-fraction balloon treatments.

Table 1. Balloon Treatments by Number of Fractions
Dose/ Fraction, GyMFBEDprescribed, Gy4BEDactual, Gy4
  1. Abbreviations: BEDactual, resultant biologically effective dose; BEDprescribed, prescribed biologically effective dose; Gy, gray; MF, multiplication factor.

4-fraction treatment
 6.751.14072.682.7
 7.01.13577.087.4
3-fraction treatment
 8.01.14272.082.2
 8.251.13775.886.2
2-fraction treatment
 10.251.14273.083.4
 10.51.13876.186.7

The methodology on which the above calculations are based assumes uniform density of tumor cells between the balloon surface and the reference surface. If the cellular density decreases with distance away from the balloon surface (as is likely) then that is an advantage, because the fractional cell kill will be greater than predicted. Although the fractional dose in the most hypofractionated schedule (2 treatments) may exceed the threshold wherein linear quadratic formalism is operant, it still does not approach the extreme doses (and uncertainty) of single-fraction intraoperative RT.

Of note, a similar fractionation scheme is found in the HDR treatment of prostate cancer, where 4 fractions of 9.5 Gy are delivered twice daily over 2 days, with an overnight stay.71 This HDR fractionation scheme has toxicities that are comparable or improved compared with low-dose radiation prostate brachytherapy. The prostate is a glandular organ with a reportedly low α/β ratio, similar to (or possibly smaller than) that for the breast.

Our multiple site, prospective, nonrandomized dose escalation study has been designed to determine the safety and feasibility of delivering APBI with the Contura MLB balloon catheter (Bard, Irvine, Calif) in a short-course, 2-day fashion. The protocol begins with treatment delivered in 4 fractions of 7 Gy delivered twice daily over 2 days. If predefined toxicities are below threshold within a 6 month follow-up period (ie, in a cohort of 30 patients ≤10 in-breast complications grade >2 and ≤1 nonbreast complication grade >2 occur), the dose prescription will be elevated to the next level; 3 fractions of 8.25 Gy delivered over 2 days. Again, in the absence of unacceptable toxicities, the dose prescription will be elevated to the final fractionation schedule, where treatment will be completed by delivering 2 fractions of 10.25 Gy, delivered over 2 days. A minimum of 6 hours must occur between dose fractions, regardless of fractionation schedule. We have defined very conservative dosimetric criteria for acceptability: maximum skin and rib dose not to exceed 100% of prescription dose, and V150 and V200 not to exceed 40 mL and 10 mL, respectively.

We believe our current work will stand up to scrutiny because it addresses the shortcomings of currently reported single-fraction strategies. Our approach allows image verification and treatment planning for every case; it allows goal-oriented optimization of dose to ensure target coverage while limiting dose to critical at-risk organs. HDR technology is widely available, and shorter courses of RT using this technology can be readily put into practice with no capital investment. Should our understanding of at-risk target volumes improve with time, the use of multilumen devices allows us the flexibility to optimize our dose to treat eccentric target volumes; thus, our approach is scalable for future imaging and pathology advancements. Our fractionation schedule is based on current radiobiological understanding and validated modeling. Logistically, the uncoupling of lumpectomy and RT affords us the opportunity to select pathology-verified patients for APBI and eases the logistical burden of coordinating sophisticated surgical, RT, and pathology services on healthcare delivery systems and personnel. The limitations of prepathology patient triage were illustrated clearly in the TARGIT-A trial, in which >20% of patients in the prepathology stratum required additional whole breast RT because of findings on final pathology, thus limiting the practicality of this approach. A balloon brachytherapy device can be placed in the office setting, thus obviating the need for a return to the operating room, as was required for the postpathology stratum of the TARGIT trial. By completing the treatment in 2 days, we significantly limit the patient's balloon time when compared with the 5-day treatment (with typical balloon times of 7-9 days when weekends are included).

It is natural for innovation to be met with skepticism and debate. The UK and Italian investigators should be commended for initiating the discussion of a treatment strategy that, should it hold up to the test of follow-up, has significant implications for both patients and payers. It is not difficult to imagine a day when stakeholders will demand shorter courses of RT. Between that day and this, it is imperative that we frame the correct questions and attempt to resolve them with well-designed clinical trials. Could our current efforts eventually prove to be a fool's errand? Perhaps, but we owe it our patients to find out.

REFERENCES

  1. Top of page
  2. Abstract
  3. Clinical Background
  4. Radiobiology
  5. TARGIT (Targeted Intraoperative Radiotherapy)
  6. ELIOT (Intraoperative Radiotherapy With Electrons)
  7. Smaller Experiences: Data From Montpellier and North America
  8. Rationale of Proposed Fractionation Schemes in the “Overnight” APBI Trial
  9. FUNDING SOURCES
  10. REFERENCES
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