		Conventionally fractionated dose escalation above 78 Gy for intact prostate cancer has been shown to improve failure- free survival. Previously occult prostatic fossa recurrences can now occasionally be visualized using advanced imaging methods such as MRI. As the disease is no longer “microscopic,” it stands to reason that dose escalation to the recurrent tumor may improve failure-free survival in the salvage setting as well.

		In the current study, the authors report on the feasibility and acute toxicity of the first 14 patients enrolled on a trial randomizing subjects to either standard 68 Gy radiotherapy to the fossa, or the same plus a simultaneous integrated boost of 76.5 Gy at 2.25 Gy/fx (EQD2= 82 Gy, alpha/ beta assumption 1.5).

		In this initial report, the authors showed the dosimetric feasibility via DVH parameters of the approach and that there was clinically no discernible acute toxicity difference between the standard arm and the dose-escalated arm. The trial continues to accrue and we await reports on late toxicity as well as impact on their primary endpoint of biochemical failure-free survival. If the authors ultimately show improved bRFS and similar late toxicity, then dose escalation to visualized fossa lesions should become a new care standard.

	MAPS is the first phase III randomized trial of MRI-mapped, dose-escalated salvage radiotherapy. In this planned feasibility analysis, we ensure dosimetric adequacy of the protocol as it relates to acute toxicity.

	Two intensity modulated radiotherapy plans were generated for each patient. In the standard fraction radiotherapy arm, 68 Gy in 34 fractions was prescribed to ≥95% of the planning target volume. In the simultaneous incorporated hypofractionated boost (SIHB) arm, an additional 2.25 Gy daily SIHB was prescribed to the gross tumor volume (GTV). The trial stipulates that ≤35% and ≤55% of the rectum should receive ≥65 Gy and ≥40 Gy, respectively, and ≤50% and ≤70% of the bladder minus the clinical target volume (B-CTV) should receive ≥65 Gy and ≥40 Gy, respectively. Acute toxicities were recorded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v4.0).

	In all plans, ≥95% of the planning target volume and GTV received the prescribed dose. Dosimetric constraints were achieved for all organs at risk except B-CTV. The highest toxicity recorded was grade 2 gastrointestinal toxicity: 1 episode per arm.

	Dose escalation is achievable with expected variations in cases with small bladders. There was no observed increase in acute toxicity.

Radical prostatectomy (RP) cures the majority of patients with localized prostate cancer. However, within 10 years of diagnosis as many as one-third will develop recurrent disease.

 In the setting of localized recurrence, salvage radiotherapy to the prostate bed is the standard treatment. However, long-term salvage rates remain suboptimal, possibly due to poor patient selection.

Ideally, only those with disease isolated to the prostate bed would receive treatment. Dynamic contrast-enhanced (DCE) MRI has been shown to reveal residual or recurrent disease with specificities of at least 80%, and sensitivities ranging from 67% to 97%.

 This is an improvement over transrectal ultrasound and conventional imaging,

 provides objective evidence for treatment, and identifies a target for dose escalation.

Compared with definitive radiotherapy, salvage doses are lower due to the assumption of only microscopic disease and toxicity limits associated with treating the bladder neck.

However, dose escalation may show benefit,

 and radiobiological modeling predicts that PSA control rates will increase along with increasing doses.

 In terms of toxicity, salvage IMRT up to 76 Gy results in <1% grade 3 GI toxicity, and 3% grade 3 GU toxicity at 5 years.

If there is a potential dose response above what is thought permissible in terms of toxicity, and we have an emerging ability to visualize foci of gross disease in the prostate bed, it follows that the addition of targeted dose escalation may improve outcomes compared with standard salvage radiotherapy alone. This is the focus of the MAPS trial— the first phase III randomized trial of MRI-mapped, doseescalated salvage radiotherapy. The primary objective is to determine the effect of an SIHB to MRI-identified foci on initial complete biochemical response (initial PSA <0.1 ng/mL at 9 months). The trial has a planned accrual of 76 evaluable patients, which would provide 80% power to detect an absolute increase of 27% in the PSA response rate, using a one-sided Fisher’s exact test with 5% significance level. This feasibility analysis details dosimetry and acute toxicity, revealing dose escalation as safely achievable.

		Figure 1. Typical DCE-MRI appearance of the non-contoured (above) and contoured GTV (below).

		DCE-MRI indicates dynamic contrast-enhanced MRI; GTV, gross tumor volume.

Between December 2010 and September 2013, 14 patients who had developed biochemical recurrence after definitive RP were enrolled in our institutional review boardapproved MAPS trial. The trial stipulates that all patients are ≥3 months post RP with the following inclusion criteria: a PSA of ≥0.1 ng/mL and ≤3.0 ng/mL within 3 months of enrollment, an MRI detectable lesion in the prostate bed, no evidence of distant metastasis, a serum total testosterone within 40% of normal assay limits within 3 months prior to enrollment, a BUN and creatinine within 40% of normal assay limits within 3 months prior to enrollment, no current active malignancy aside from nonmetastatic skin cancer or early chronic lymphocytic leukemia, Zubrod performance status <2, and age between 35 and 85 years. Any prior androgen deprivation therapy must be completed >6 months previous to enrollment and be ≤7 months in duration. Patients meeting the criteria were randomized between the SFRT arm and the SIHB arm.

		SFRT indicates standard fraction salvage radiotherapy; PTV, planning target volume; SIHB, simultaneous integrated hypo-fractionated boost; GTV, gross tumor volume; B-CTV, bladder minus clinical target volume.

All patients underwent computed tomography (CT)-based virtual simulation in the supine position with 1.5-2-mm thick slices extending from the top of the sacrum to mid femur. Per institutional protocol, all patients were instructed to eat a diet designed to reduce bowel gas for at least 24 hours prior to simulation, use a rectal enema prior to arrival, and maintain a full bladder. Tattoos were placed at the anterior, right lateral, and left lateral isocenter skin points. Under the same conditions and often during the same encounter, T2, T1 non-contrast, diffusion weighed images (DWIs), and DCE-MRI (3.0 T MRI) scans were obtained at 2.5-mm intervals. Approximately 12 DCE-MRI scans were obtained, beginning precontrast and continuing at approximately 30-second intervals postcontrast. The pelvis and prostate bed were imaged.

		Figure 2. Typical dose distributions for SFRT (left) and SIHB (right) plans.

		SFRT indicates standard fraction salvage radiotherapy; SIHB, simultaneous integrated hypo-fractionated boost.

In order to deliver the daily SIHB to the MRI-identified foci, the anatomical, diffusion, and dynamic MRI sequences were coregistered to the planning CT. Coregistration was performed within the Eclipse software using anatomical matching of the MRI and CT acquisitions in the areas of the prostate bed, penile bulb, and bladder and rectal interfaces in the region of the prostate bed. This resulted in the high quality and reproducible alignment between the two acquisitions necessary to ensure that the SIHB was delivered to the proper location.

Structures were manually contoured on the CT simulation scan using an adaptation of the recommendations of the Radiation Therapy Oncology Group.11 The clinical target volume (CTV) included the prostate bed, extending cranially from the seminal vesicle remnants and caudally to approximately 2.5 mm above the superior aspect of the penile bulb. Borders below the superior border of the pubic symphysis were the posterior aspect of the pubis anteriorly, the rectum posteriorly, and the levator ani laterally. Borders above the pubic symphysis were approximately 1 cm of the posterior bladder wall anteriorly, the mesorectal fascia posteriorly, and the sacrorectogenitopubic fascia laterally. Using CT-MRI coregistration, the MRI revealed that GTV 

 was contoured on the CT simulation scan by using the anatomical, diffusion, and dynamic MRI series. Suspicious lesions are most visible on the early and late DCE-MRI sequences (characterized by early contrast wash-in and late contrast wash-out). However, the T2 and DWI images were also used to confirm the lesion location. There was no expansion on the GTV, as the goal was to increase dose to the general area of the GTV. In addition, while the effect was greatest in the area of the GTV, the presence of a boost volume increased dose to the entire prostate bed. Therefore, adding a margin to the GTV would unnecessarily place critical organs at risk. A PTV around the CTV was defined to account for daily setup errors, and consisted of a 7 mm expansion of the CTV in all directions. The bladder was contoured in its entirety. The rectum was contoured as a whole organ from the rectosigmoid flexion to the bottom of the ischial tuberosities. The femoral heads were outlined from the top of the acetabulum to an area between the lesser and greater trochanters. For evaluation purposes, a bladder minus CTV volume was also created (B-CTV). All contours were reviewed by the principle investigator or co-investigator.

Treatment plans were generated using commercial software (Eclipse, version 11.0, Varian, Palo Alto, California) with heterogeneity correction. Two IMRT plans were generated for each patient data set: 1 for the SFRT arm and 1 for the SIHB arm (regardless of the arm under which the patient was actually treated). The prescription dose was 68 Gy in 34 fractions to ≥95% of the PTV in all plans. In the SIHB arm, a 2.25-Gy daily SIHB was prescribed to the GTV, for an absolute dose of 76.5 Gy in 34 fractions 

. The plans were quality controlled by utilizing the ArcCHECK QA device (Sun Nuclear Corporation, Melbourne, Florida) to compare the calculated and measured doses within the phantom using gamma analysis with 3% dose difference and 3-mm distance- to-agreement criterion.

A Varian Trilogy (Varian, Palo Alto, California) linear accelerator delivered volumetric- modulated arc therapy (VMAT) at either 6 MV or 18 MV energies. All patients were treated once daily, 5 times a week. Image guided radiotherapy (IGRT) was accomplished with daily cone beam CT (CBCT), using prostate bed clips and bladder and rectal filling to perform daily alignment. Patients were not treated unless aligned to any clips, with bladder and rectal filling similar to the CT simulation. Patients were instructed to express gas/stool, and urine and drink additional fluids before a repeat CBCT, as needed.

Acute toxicity was defined as during and up to 3 months after treatment. Prostate- related symptoms were assessed before treatment, weekly during treatment, and 6 weeks and 3 months after treatment completion using the NCI CTCAE v4.0. Only patients with data at all above time points were included.

The percentage of the volume of the PTV and GTV receiving the prescribed dose was recorded for the SFRT and SIHB plans. Also recorded were the maximum doses to the OARs, as well as the percentage of volume of the rectum and B-CTV receiving ≥65 Gy and ≥40 Gy. The Shapiro- Wilk normality test was used for the variables of interest. The Student’s T test was used for comparison between the SFRT and SIHB plans when the normality test was not significant. Otherwise, the Kruskal-Wallis test was used for comparing the two plans. A 2-tailed 

 value (<.05) was used to indicate statistical significance.

Fourteen patients have been enrolled on the trial to date, and data from 13 are available for acute toxicity analysis (7 randomized to SFRT and 6 to SIHB treatment). The median follow-up at this time is 15 months.

The mean CTV volume was 143.3 cc, with a range of 84.8-202.7 cc SD, 39.2 cc). The mean PTV volume was 312.8 cc, with a range of 218.3-388.9 cc (SD, 57.4). The mean GTV volume was 2.34 cc, with a range of 0.31-10.4 cc (SD, 2.8 cc). The mean volume encompassed within the 76.5 Gy isodose line was 27.6 cc, with a range of 1.02-151.3 cc (SD, 39 cc).

Dose-volume histograms (DVH) were generated for all plans (Figure 3). In every case, at least 95% of the PTV received 68 Gy, and at least 95% of the GTV received 76.5 Gy, as specified in the constraints 

, with maximum doses to the GTV kept below 115% of the prescription dose. SIHB plans demonstrated an increased integral dose to the prostate bed PTV as shown in Figure 3. While this increase occurred throughout the PTV volume, it was greatest in the region of the GTV.

		Table 2. Dosimetric results for SFRT and SIHB plans.

 P value from Kruskal-Wallis test due to non-normality. R indicates rectum; B-CTV, bladder minus clinical target volume; GTV, gross tumor volume; PTV, planning target volume; SFRT, standard fraction salvage radiotherapy; SIHB, simultaneous integrated hypofractionated boost; NA, not applicable.

Dosimetric values for target volumes and OAR are presented in

 for both SFRT and SIHB plans. We tested normality for each variable using the Shapiro- Wilk test. V76.5 (GTV)% in SIHB and V68 (PTV)% in SFRT were statistically significant (both 

 <.001), ie, not normal. All other variables were assumed to be normal. Dosimetric constraints were achieved for all OARs except for bladder. Five plans had >70% of the bladder receiving ≥40 Gy in both the SFRT and SIHB plans, and 1 plan had >50% of the bladder receiving ≥65 Gy in the SIHB plan only. Review of the plans revealed this to be due to suboptimal bladder filling. In terms of dosimetric constraints for OARs, as well as PTV and GTV coverage, there was no difference between the SFRT and SIHB plans per patient or overall, except in the case of V68 (PTV)% 

		Table 3. Number of radiotherapy-related toxicities per arm.

		SFRT indicates standard fraction salvage radiotherapy; SIHB, simultaneous integrated hypofractionated boost.

		Figure 3. Typical dose volume histogram for SFRT and SIHB plans. All SIHB DVH curves are shifted slightly to the right. The GTV for the SIHB plan is also included. SFRT

		SFRT indicates standard fraction salvage radiotherapy; SIHB, simultaneous integrated hypo-fractionated boost; DVH, dose-volume histogram, GTV, gross tumor volume.

Thirteen patients (7 treated with SFRT and 6 with SHIB) are included in the toxicity analysis. Twelve of these patients experienced toxicities (1 patient in arm 2 did not). 

 details the number of occurrences of all radiation related toxicities by treatment arm. 

 details the highest grade GU and GI toxicity per patient.

Salvage radiotherapy is the only curative treatment for patients with a localized recurrence post RP. Multiple retrospective studies have reported on the efficacy of standard dose salvage radiotherapy in achieving biochemical control, with actuarial 5-year biochemical recurrence free survival (bRFS) rates ranging from 10% to 66%.

 Advances in IMRT and IGRT have now made possible the delivery of definitive-range radiotherapy doses. Dose escalation in the salvage setting has been shown to improve biochemical control in various retrospective studies.

King et al compared 38 patients treated with 60 Gy with 84 patients treated with 70 Gy, demonstrating a significant improvement in 5-year bRFS from 25% to 58% with the higher dose. Another study reviewed 364 men who received salvage radiotherapy at 1 of 3 dose levels (low, <64.8 Gy; moderate, 64.8-66.6 Gy; high, >66.6 Gy) and found that doses greater than 66.6 Gy resulted in improved bRFS.

 A review of published reports by Ohri et al in 2012 examined the role of salvage radiotherapy dose and timing on biochemical control and found that bRFS increased with salvage radiotherapy dose by 2.5% per Gy and decreased with pre-salvage radiotherapy PSA by 18.3% per ng/mL (

 <.001). Radiobiological models predicted that an increase in the pre-salvage radiotherapy PSA from 0.4 to 1 ng/mL would increase the salvage radiotherapy dose required to achieve a 50% bRFS rate by 60 to 70 Gy.

 While randomized trial data are not yet available, these studies demonstrate the potential for improved outcomes with dose escalated salvage radiotherapy.

The benefits of dose escalation to the prostate bed are limited by the possible increase in side effects. Three-dimensional conformal radiotherapy (3D-CRT) first allowed for escalation to biologic equivalent doses of 68 Gy16 without an increase in toxicity compared with 64 Gy delivered by conventional radiotherapy (<5% late grade 3 GU toxicity and <5% late grade 3 GI toxicity).

However, escalation >68 Gy using 3D-CRT resulted in a 5-year risk of late grade 3 GU toxicity of 16%.

 The model by Ohri et al estimated that severe late toxicity rates may reach 10% at doses of approximately 70 Gy;

 however, toxicity data used for this model came from series employing 2-D or 3-D treatment techniques. In fact, it was recently reported that IMRT to a median dose of 76 Gy resulted in a 5-year risk of late grade 3 GU toxicity of 3%, and late grade 2 to 3 GI toxicity of 8%,

 which is comparable to toxicity reported with doses of 64 Gy using conventional radiotherapy.

 In our trial, with only acute toxicity available at this time, the highest reported toxicity included 1 episode of grade 2 gastrointestinal toxicity in each arm. Finally, be aware that the CTCAE grading system used in our trial may report lower grade toxicity for similar side effects compared with other scoring scales, such as that used by the Radiation Therapy Oncology Group (RTOG).

With retrospective and radiobiologic modeling evidence for improved bRFS with dose escalation,

 reservations regarding potential increases in toxicity,

 and the ability to identify gross disease in the prostate bed using DCEMRI, 

 it follows that dose escalation to the gross disease alone has the potential to improve the therapeutic ratio of salvage radiotherapy.

In this study, we have demonstrated that even though areas of gross disease in the prostate bed are close to critical structures, dose escalation to these areas results in good coverage of the PTV (range: 95%-97.9%) and GTV (range: 95%-100%) without exceeding conservative dosimetric constraints specified for the rectum in all cases and the bladder in the majority of cases. This is occasionally unavoidable, as the bladder neck must be pulled into the CTV to account for the absence of the intraprostatic urethra, and some patients are unable to achieve or maintain a full bladder (due to anatomic or physiologic limitations). In cases like this, bladder constraints were unachievable in both the SFRT and SIHB plans. Per the protocol, a primary variation will be noted if up to an additional 7.5% of the B-CTV volume exceeds the dose constraint. Beyond this constitutes a secondary protocol variation. At the least, a portion of the bladder is included in the PTV by necessity; these constitute protocol variations, not violations. Therefore, none of the plans would have resulted in a protocol violation. Regardless, the clinical acute toxicity was comparably low in both arms.

		Table 4. Highest grade GU and GI toxicity per patient according to NCI CTCAE v4.0.

Articles

Treating MRI-identified prostate lesions to definitive doses using an SIHB is possible without significantly increased dose or acute toxicity to critical structures

A Phase III Randomized Trial of MRI-Mapped, Dose-Escalated Salvage Radiotherapy Post-Prostatectomy: The MAPS Trial

		Contemporary risk-adapted local therapy for early breast cancer is a complex and evolving paradigm. Shah et al do an excellent job in summarizing the multitude of evidence-based approaches related to risk stratification, treatment options, and results. By also placing these in the context of real-world case examples, clinicians can gain valuable insight into the appropriate application of these multifaceted clinical trial data to manage the individual patient. This review highlights the enormous progress that has been achieved in recent years toward providing women with local therapy options that are safe, effective, convenient, and cost efficient.

	Breast conserving therapy (BCT) offers women the ability to preserve their breast without sacrificing local control or survival. Since its inception, a key component of BCT has been the delivery of adjuvant radiotherapy following breast-conserving surgery (BCS). However, a growing interest remains in determining if there exists a subset of women with low-risk features for whom adjuvant radiotherapy may be omitted following BCS. To date, the data are consistent in demonstrating that adjuvant radiotherapy reduces the rate of local recurrences in all risk groups. In lower-risk groups, modern trials have failed to demonstrate a survival advantage from the local control benefit derived from radiotherapy. Currently, studies are being performed to identify low-risk patients based on tumor genetics, nomograms, and other techniques. In the interim, clinicians now have alternative techniques including hypofractionated whole breast irradiation as well as accelerated partial breast irradiation which allows for a reduction in treatment duration (and possibly treatment volume) while still maintaining local control.

Over the past several decades, breast-conserving therapy (BCT) has emerged as the standard of care in the management of early-stage breast cancer. With greater than twenty-five years of follow-up, multiple randomized trials have demonstrated equivalence in outcomes between mastectomy and BCT, with BCT being shown to improve the quality of life of breast cancer survivors compared with mastectomy.

A key component in the BCT arms of the randomized trials was standard fractionation whole-breast irradiation (WBI) delivered over 5 to 6 weeks. In the decades since the initial randomized trials, adjuvant radiation therapy (RT) has continued to be a key component of the BCT technique to optimize local control. While RT has been shown to enhance local control following breast-conserving surgery (BCS), concerns exist, including acute/chronic toxicities associated with treatment, the duration of treatment, and the potential for overtreatment.

A key question being considered is the role of RT in patients who will not manifest large local control benefits with adjuvant RT compared with BCS with or without endocrine therapy. Multiple attempts have been made to omit RT following BCS, with mixed results. In spite of the lack of clarity, clinicians are facing pressure to tailor RT recommendations based on patient (age, performance status), pathologic (tumor size, margin status, grade, hormone receptor status, lymph node status), and systemic treatment (tamoxifen/aromatase inhibitor utilization) characteristics and to identify low-risk patients for whom RT may not be required. Therefore, the purpose of this clinical review is to evaluate the role of RT in low-risk patients (based on patient and pathologic features) following BCS and to provide common scenarios and recommendations based on current data and guidelines.

The role of adjuvant RT in patients undergoing BCS has been evaluated as part of the randomized trials comparing mastectomy and BCT. NSABP B-06 randomized 1861 women (stage I/II, < 4cm, 62% node negative, all underwent axillary dissection) to mastectomy, BCS, or BCS with adjuvant RT. With 20 years follow-up, the omission of RT following BCS increased the rate of local recurrence, 39% vs 14%.

 Further, the Milan III study randomized nearly 579 women (tumor size <2.5 cm, <70 years old, majority <55 years old, 32% to 44% endocrine therapy, 67% to 72% node negative, all underwent axillary dissection, nodal positivity allowed) to adjuvant RT or observation following quadrantectomy; at 10 years follow-up, adjuvant RT had reduced local recurrences (from 23% to 6%) with the greatest benefit noted in women under 45 years of age.

Similar results were seen with a trial from Sweden, which randomized 381 women (<2cm, node negative) to receive RT following BCS; at 10 years, RT had reduced the rate of local recurrence, from 24% to 8.5%.

 These findings have been replicated by other randomized trials, which have consistently demonstrated an improvement in local control with RT.

 As well, the Early Breast Cancer Trialists Group (EBCTG) meta-analysis has confirmed the improvement in local control and breast cancer mortality with adjuvant RT.

		Table 1. Trials Evaluating the Omission of Radiotherapy With Endocrine Therapy

		ALND indicates axillary lymph node dissection; DFS, disease-free survival; ER, estrogen receptor, PR, progesterone receptor; RT, radiation therapy.

It should be noted that most patients in the older randomized trials did not consistently receive endocrine therapy. With the advent of tamoxifen and aromatase inhibitors and the subsequent publication of NSABP B-14 and the EBCTG meta-analysis, trials were developed evaluating the role of RT in patients receiving endocrine therapy 

NSABP B-21 randomized 1009 women with node negative (following pathologic evaluation) tumors less than 1 cm to tamoxifen, RT, or RT and tamoxifen. At 8 years, the lowest rate of local recurrence was seen in the RT and tamoxifen arm (2.8%), with higher rates seen in the radiation alone (9.3%) and tamoxifen arms (16.5%). Compared with tamoxifen alone, RT reduced the rate of ipsilateral breast tumor recurrence (IBTR) by 49%.

 The CALGB 9343 trial randomized a potentially lower risk group of 636 women over 70 years of age with T1N0 estrogen receptor positive tumors to tamoxifen with or without adjuvant RT following BCS with negative surgical margins. At 10 years, RT further reduced the rate of local recurrence compared with tamoxifen alone (9% vs 2%), although no difference in cause-specific or overall survival (OS) was noted.

 These results were mirrored by a Canadian study that randomized 769 women 50 years or older with node negative tumors less than 5 cm to tamoxifen with or without RT following BCS with negative surgical margins. While an increase in local recurrence was noted in patients receiving tamoxifen alone (8% vs 1%), an increase in disease-free survival was noted, which may be due to the inclusion of younger patients than in the CALGB trial.

 A German 2×2 randomized trial evaluated 361 low-risk women (pT1, estrogen receptor positive, margin negative, node negative) with a randomization for adjuvant RT and tamoxifen. While underpowered, at 10 years, the rates of local recurrence were 34%, 10%, 7%, and 5% for the BCS, BCS + RT, BCS + tamoxifen, and BCS + RT + tamoxifen arms, respectively.

 A more recent Austrian study evaluated 869 women with low-risk breast cancer (tumor <3 cm, ER/PR positive, grade 1/2, node negative, margins negative) and randomized women following BCS to hormonal therapy (tamoxifen or Arimidex) with or without adjuvant RT. At 5 years, RT significantly reduced local recurrences (5.1% vs 0.4%) and overall relapses (6.1% vs 2.1%).

 Taken together, the data support the premise that even with the additional benefit of endocrine therapy, adjuvant RT provides a local control benefit even in low-risk patients.

Clinicians continue to search for a group of low-risk patients for whom RT may not be required following BCS. One method is to apply the clinical and pathologic criteria utilized in the trials themselves, such as those from the CALGB 9343 trial.

These strategies have been incorpora-â€¨ted into evidence-based guidelines, including the National Comprehensive Cancer Network (NCCN) guidelines, which provide a category 1 recommendation to omit radiation in women 70 years of age or older with T1N0 (clinically negative) estrogen receptor positive tumors should they receive adjuvant endocrine therapy. No mention is made of the role of grade or margin status.

 Similarly, nomograms have been developed using clinical and pathologic characteristics to help risk-stratify patients and provide clinicians with an estimate of the risk of local recurrence. One example is the IBTR! nomogram, which includes age, size, margins, lymphovascular invasion, tumor grade, and the utilization of chemotherapy and endocrine therapy.

A more recent technique to identify patients who may not need adjuvant RT is to use tumor genetics rather than clinical and pathologic characteristics. Panels have been developed to evaluate the benefit of systemic therapy and have been validated.

 Studies are currently looking to utilize similar gene panels to identify those patients who benefit most and least from adjuvant RT. Studies with ductal carcinoma in situ (DCIS) scoring, demonstrating an ability to stratify by risk of recurrence in some groups, have been presented recently.

 Beyond omitting RT in low-risk patients, new treatment schedules and techniques are available to shorten the duration of treatment and the volume of normal breast tissue irradiated. One alternative gaining acceptance is the use of hypofractionated whole-breast irradiation 

 A study from the Ontario Clinical Oncology Group randomized 1234 women with T1-2N0 (node dissection required) breast cancer to whole-breast irradiation with either 50 Gy in 25 fractions or 42.5 Gy in 16 fractions. Forty-one percent of women received tamoxifen and 11% received chemotherapy. At 10 years, no difference in local control (7.4% vs 7.5%) or OS was noted and toxicities and cosmesis (70% excellent/good) were comparable.

 These findings were consistent with follow-up from the START A and B trials, which demonstrated comparable local control with hypofractionated regimens compared with standard schedules.

 The START A trial randomized 2236 women (pT1-3a, 30% node positive) to 39 Gy in 13 fractions, 41.6 in 13 fractions or 50 Gy in 25 fractions with all delivered over 5 weeks; no difference in local recurrence (5.2% vs 3.5% vs 3.6%) was noted. The START B trial randomized 2215 women (pT1-3a, 21.5% node positive) to 40 Gy in 15 fractions in 3 weeks or 5 Gy in 25 fractions, with no difference in local recurrence (2.2% vs 3.3%) with reduced adverse events in the hypofractionated arm. Accelerated partial breast irradiation (APBI) is another option that shortens treatment duration and reduces the amount of normal breast tissue treated by irradiation to the lumpectomy cavity and the area surrounding it. APBI can be delivered with interstitial brachytherapy, applicator brachytherapy, or external beam techniques. Randomized data from Hungary have demonstrated equivalence in local control and survival compared with standard fractionation WBI, as has a matched-pair analysis from William Beaumont Hospital with long-term follow-up.

 More recently, applicator-based brachytherapy has emerged as the predominant brachytherapy technique, with follow-up demonstrating low rates of local recurrence and, with the development of multilumen applicators, reduced toxicities.

 Modern randomized studies comparing APBI with WBI are either under way or completed with results expected in the years to come, including the NSABP B-39 and GEC-ESTRO trials.

		Table 2: Randomized Hypofractionated Radiation Therapy Trials

When evaluating the clinical implications of modern data, it is imperative to utilize the data in conjunction with a multidisciplinary evaluation of the patient. The following examples will present common clinical scenarios and treatment recommendations.

Scenario 1: Age 70 years or greater, T1N0, estrogen receptor positive

This group currently represents the subset of patients for whom omitting RT has the greatest support based on the findings of the CALGB trial as well as the evidence-based NCCN guidelines.

 Patients should have negative margins or undergo re-excision, as trials consistently included patients with negative margins. With regard to grade, the majority of patients were grade 1/2 or grade but not evaluated while there was a subset of high-grade patients in the Canadian trial 

. It should be noted that current guidelines do not incorporate grade into the recommendations. For patients seeking an alternative to simply omitting RT, hypofractionation or APBI are reasonable alternatives to standard fractionation, though a subset analysis did find higher local recurrence with hypofractionation in high-grade tumors.

Scenario 2: Age 70 years or greater, T1N0, estrogen receptor negative

In light of estrogen receptor negativity, utilizing endocrine therapy alone following BCS is not an option for this subset of patients. While omitting RT may be an option in patients with poor performance status or significant comorbidities, RT remains the standard for patients in this group including standard fractionation WBI, hypofractionated WBI, and APBI as trials had limited numbers of receptor negative patients.

 While some concern has been raised about estrogen receptor negativity and APBI, current guidelines support the use of APBI in estrogen receptor negative patients.

With regard to margin status, negative margins should be achieved if feasible prior to initiation of RT. Limited data are available on the role of grade in this subset of patients.

Scenario 3: Age 70 years or greater, T2N0, estrogen receptor positive/negative

In patients with larger tumors (T2N0), there are limited data on omitting RT at this time. While some studies included T2 patients, most studies limited tumor size to less than 3 cm, with the exception of the Canadian trial, in which 17% of cases were >2 cm. As such, RT following BCS remains the standard with options including standard fractionation WBI, hypofractionated WBI, and APBI (<3 cm).

 For those patients requiring systemic therapy, less data are available regarding hypofractionated WBI, and subset analysis has shown higher recurrence rates with higher-grade tumors.37 In patients with positive margins, re-excision should be performed if feasible prior to RT with limited data available regarding grade and the omission of RT in this subset of patient.

Scenario 4: Age 50-70 years, T1N0, estrogen receptor positive

To date, the data do not support the omission of RT in this subset of patients. As noted in 

, subsets of patients from each trial with the exception of CALGB 9343 included women in this group, though there were small numbers, particularly less than 60 years old. The Canadian trial that included women 50 years or older not only demonstrated a local recurrence increase but a decrement in disease-free survival and as such it is not considered a standard option in evidence-based guidelines.

 For women 60 to 69 years of age, there are data evaluating the omission of RT, but this is still evolving in light of evidence-based guidelines focusing on women over age 70 years.

 Treatment options include standard fractionation WBI, hypofractionated WBI, and APBI. While the ASTRO guidelines puts patients ages 50 to 59 as a cautionary risk for APBI, the ABS and ASBS consensus statements do not.

As noted above, margin status should be considered as well as grade, particularly in high-grade patients for whom hypofractionated RT is considered.

Scenario 5: Age 50-70 years, T1N0, estrogen receptor negative

Adjuvant RT remains an essential component of BCT in this subset of patients. While standard fractionation WBI remains the standard for these patients, hypofractionated WBI represents an option for those not requiring systemic therapy.

 APBI also represents an option for appropriately selected patients though concerns regarding estrogen receptor negativity exists.

Scenario 6: Age 50-70 years, T2N0, estrogen receptor positive/negative

In this subset of patients, RT remains the standard of care following BCS. Conventional fractionation represents the standard, but hypofractionated RT can be considered in women based on national guidelines as well as dosimetric constraints.

 APBI also represents an option for appropriately selected patients in this subset with tumors less than 3 cm though there remains some debate over suitability in this subset.

 Surgical margins should be negative prior to proceeding with RT.

Trials have confirmed that adjuvant RT following BCS improves local control. However, new data allow for stratifying patients into low-risk cohorts (clinical/pathologic, molecular) who may not require RT or who may be able to receive alternatives to standard RT (eg, hypofractionated or accelerated partial breast irradiation). Future studies are required to provide long-term outcomes for patients in whom RT is omitted based on such stratification criteria.

Summa Health System and Northeast Ohio Medical University (CS, MFB), University of Nebraska Medical Center (VV), 21st Century Oncology/Michigan Healthcare Professionals (FV).

Chirag Shah, MD, Department of Radiation Oncology, Summa Health System, 161 North Forge, Suite G90, Akron, OH 44304, Phone: (330) 375-3557, Fax: (330) 375-3072. E-mail: csshah27@hotmail.com.

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Over the past several decades, breast-conserving therapy has emerged as the standard of care in the management of early-stage breast cancer.

Adjuvant Radiotherapy in Low-Risk Breast Cancer Patients: Review and Clinical Implications

Assistant Professor, Co-Chairperson Genitourinary Site Disease Group, Director of Compliance, Department of Radiation Oncology, Sylvester Comprehensive Cancer Center University of Miami

Rapid advances in the technological development of precise and conformal radiation therapy and its incorporation into the clinic have generally outpaced our ability to test these technologies in a clinical trial format. With improvements in conformity utilizing intensity modulation and set-up accuracy utilizing stereotactic techniques and tumor motion management, margins continue to shrink. We hope this will translate into improved patient outcomes by allowing higher tumor doses and decreased morbidity by improved avoidance of critical structures.

However, these advances create new questions. Respiratory motion management based upon modeling and fiducial tracking assume minimal changes in the patient’s respiratory cycle, both during a single fraction and during a course of therapy. In addition, how changes in body shape that are attributed to weight loss, bowel gas, or slight differences in patient body position that may occur inter-or intra-fraction affect the delivered dose when using these new modalities remains unclear.

This study is contemporary in how it utilizes existing resources in a massive data set to evaluate the implications of these changes measured in delivered dose to patients. With the growing integration of adaptive dose recalculation, identification and correction of these issues may now be possible.

In vivo dosimetry and verification (IVV) in conjunction with adaptive dose recalculation (ADR) is a synergistic set of processes that provides insight into actual treatment. Our intent was to test an automatic, multicenter procedure for IVV and ADR for all patients and all fractions treated on 14 helical TomoTherapy units across the United States. Additionally, our secondary goal was to create a system with metrics to flag for possible issues, establish trending, and determine possible clinical impact. Establishment of this system could both provide internal recommendations for daily IGRT and clinical improvements using IV and ADR findings. Moreover, our final goal was to evaluate deviations of the cumulative dose at the end of the treatment using Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) recommenda-tions for organs at risk.

A system for IVV and ADR that retrieves and processes machine and patient information during treatment was created. The IVV portion includes (1) checking consistency values using machine encoders and (2) using the imaging detector data and comparing a reference frac-tion with respect to daily treatment deliveries using the Gamma metric. The ADR component computes daily and cumulative doses; DVH data are compared plan data and the flagging system. Thus, a reviewer can (1) identify machine, setup, and/or anatomical issues and (2) infer possible clinical impact.

Across multi-center clinics (n=14), 153,330 IVV and 66,294 ADR fractions were analyzed. The extent of in vivo flags was independent of an individual clinic’s volume. The number of in vivo flags considerably decreases as a function of the length of time that the system is used. This was accomplished by tailoring IGRT procedures to specific anatomical sites and specific patients. With respect to disease site, 5% of all prostate treatments and more than 20% of head and neck treatments triggered some IVV action level. ADR results demonstrated that cumu-lative doses at the end of treatment for head and neck patients exceed QUANTEC limits for 9% of parotids glands and 2% larynxes. Following treatment for breast cancer, approximately 10.5% of patients exceeded QUANTEC limits for lung and 3% for heart at the end of treatment. Thus, these data suggest ADR and IV are a synergistic set of processes that allows flagging and quantifying potential clinical impact to analyze dosimetrical information on patient registries.

Radiotherapy has evolved from three-dimensional conformal radiotherapy (3D), to intensity modulated radiotherapy (IMRT)

and many forms of image-guided radiotherapy (IGRT).

 Comprehensive quality assurance (QA) procedures are evolving as the technology evolves.

 In IMRT, the typical QA procedures involve the use of phantom measurements or the delivery of a plan to a portal imager.

 IMRT QA is typically performed before clinical treatment.

Verification of what happens during the time that of actual treatment delivery may provide significant insight to evaluate the actual course of treatment. Possible issues that may go undetected with QA before treatment can be found using IVV.

Indeed, it is currently possible for the user not only to access the imaging detector information, but also gather machine sensors and monitor chambers, daily CTs from the data base or logs to create a more comprehensive IVV program. The TomoTherapy archive contains information such as couch encoders, monitor chambers, daily megavolt computed tomography (MVCT) and other sensors that provide key information during treatment. This information may be paramount to discern the cause of inaccuracies between machine, setup or anatomical changes.

Herein, an approach has been employed to combine the in-vivo dosimetry with other types of in-vivo verification (IVV). We attempted to optimize issues related to robustness and specificity of in vivo dosimetry by using information from adaptive dose recalculation (ADR). Hence, the ADR is able to compute daily doses, cumulative doses, and dose-volume histograms (DVHs) using the daily CT and machine information.

Thus, we generated a patient verification process that uses both IV and ADR as synergistic tools to analyze 153,330 IV fractions and 66,294 ADR fractions (corresponding to 3,687 ADR patients).

The verification system presented has two major components: the IVV portion and the ADR. The IVV was deployed in advance of the ADR system. Approximately 87,000 fractions over 14 clinics were generated and processed having only the IVV system. The remaining fractions (~66,000), which corresponds to approximately 3,600 patients, were processed using IV and ADR.

Information was gathered from patient archives for both processes. The TomoTherapy machine digitally records information, such as couch position, daily CT, and machine output from its imaging detectors and stores the information in the patient archive. The process begins by analyzing the patient archive information. The only human intervention to generate results consists of using the TomoTherapy patient data management system to archive treated patients two times per day. Our system automatically processes the data, generates daily and weekly reports, and sends an e-mail notification to designated personnel if a flag is out of tolerance. The reports are web based and can be accessed from any computer allowed. The flagging system is an important component to aid in the identification of possible issues and will be described later in the manuscript. Most of the processing time consists of parsing the data and generating movies used to analyze the data. The report could be generated in few minutes—per patient, per fraction&mdash;if there was a mechanism to retrieve the new information immediately after each fraction without the need to archive the patient data.

The generation of IVV and ADR systems are transparent to clinic staff and add minimal time to daily patient treatment operations. IVV provides flags related to treatment consistency using exit detectors and machine encoders. ADR computes daily and cumulative doses and DVHs to analyze possible daily and cumulative clinical impact. A more detailed description of IVV and ADR can be found in the Supplemental Materials and Methods available on the online version of the manuscript.

Gamma Flagging and Number of Patients per Day

To evaluate the impact of clinical load on differences between planned vs delivered doses, we examined between clinical volume and gamma flagging. 

 represents the number of fractions for each of the 14 participating clinics from the beginning of the implementation of the IVV program until the end of May of 2012 (10 months). In total, there were 42,866 fractions considered during this period of time that were used to answer the question of whether clinics with more patients treated per day have more in-vivo dosimetry flags or not. As shown in 

, in which each index (1 to 14) represents a clinic, there is hardly any correlation between patient load and the percentage of yellow and red flags (correlation coefficient -0.14). In fact, the busiest clinic is the one with the lowest fraction of yellow and red flags. Therefore, dose differences between planned and delivered were not correlated with patient volume in each clinic.

Flagging Trend as Function of Time of Use

The reduction of the number of flags as a function of time was analyzed for the first 10 months that the IVV system was used. 

 shows the reduction of red flags as a function of time after the clinics actively started the IVV program. The trend includes translational (Trans Red) and rotational offsets (Rot Red), kV-MV similarity metric (Sim Red), machine output related (Outp Red, Var Red) and exit dosimetry gamma (Gamma Red). A decrease in gamma flagging of 7% was observed after 10 months.

IVV Segmented by Anatomical Site and Couch Setup Verification

Several studies have reported in vivo dosimetry studies for different anatomical sites.

 shows the number of cases for each anatomical site used on this study. The total number of fractions analyzed was 153,330. The largest number corresponds to prostate, head and neck, breast, pelvis and lung. 

 is the fraction of gamma green, yellow, and red flags for each of the anatomical sites considered. Prostate and brain had the lowest yellow and red flags. For prostate, the level of red flags is under 5%, while red and yellow flags for prostate cases are on the order of 10%. Pelvis cases show similar behavior to prostate, but with a slightly higher occurrence of combined red and yellow gamma flags. Some pelvic cases involve very long fields with inguinal nodes and a large area of the femur treated at once. The gamma failures for these cases mostly relate to contralateral leg placement after the beam exits the target. In cases within the regions of head and neck, bone and connective tissue, mediastinum, lymphatic, skin, abdomen, and breast and lung, the red flags are between 10% and 20% and the combined yellow and red flag components are between 40% to 50%. The anatomical site information was determined using the ICD-9 and ICD-10 codes as reference.

Rapid advances in the technological development of precise and conformal radiation therapy and its incorporation into the clinic have generally outpaced our ability to test these technologies in a clinical trial format.

June 2015 | Contemporary Radiation Oncology

A Phase III Randomized Trial of MRI-Mapped, Dose-Escalated Salvage Radiotherapy Post-Prostatectomy: The MAPS Trial

Adjuvant Radiotherapy in Low-Risk Breast Cancer Patients: Review and Clinical Implications

Daily and Cumulative Dose Recalculation and in Vivo Verification for Helical TomoTherapy: Multicenter Validation

Declaring Our Objectives in This Inaugural Issue