Surgeon-Level Variation in Utilization of Local Staging and Neoadjuvant Therapy for Stage II-III Rectal Adenocarcinoma.

INTRODUCTION: Neoadjuvant therapy (NT) is the standard of care for clinical stage II-III rectal adenocarcinoma, but utilization remains suboptimal. We aimed to determine the underlying reasons for omission of local staging and NT. METHODS: We conducted a retrospective study of patients with clinical stage II-III or undocumented clinical stage/pathologic stage II-III rectal adenocarcinoma who were treated in 2010-2016 in one of nine Intermountain Healthcare hospitals. The outcomes of omission of local staging and NT were examined with multivariable models. Risk- and reliability-adjusted rates of local staging and NT were calculated for surgeons who treated ≥ 3 patients. Pathologic and long-term outcomes were examined after excluding patients who were not resected or who underwent local excision (N = 11). RESULTS: Local staging was omitted in 43/240 (17.9%) patients and NT was omitted in 41/240 (17.1%). The strongest risk factors for local staging and NT omission were upper rectal tumors and surgeons who treated ≤ 3 cases/year. Thirty-six of 41 (87.8%) cases of omitted NT had local staging omitted. Adjusted surgeon-specific local staging rates varied 1.6-fold (56.3-92.4%) and NT rates varied 2.8-fold (34.1-97.1%). Surgeon local staging and NT rates were strongly correlated (r = 0.92). NT was associated with lower rates of positive circumferential radial margins (7.9 vs. 20.0%; P = 0.02), node positivity (33.3 vs. 55.0%; P = 0.01), and local recurrences (7.6 vs. 14.9% at 5 years; P = 0.0176). CONCLUSIONS: NT omission should be understood as a consequence of surgeon failure to perform local staging in most cases. Quality improvement efforts should focus on improving utilization of local staging.

Value of surgical resection and timing of therapy in patients with pancreatic cancer at high risk for positive margins.

BACKGROUND: Surgical resection remains the best chance at long-term survival in pancreatic cancer, though margin-positive resections are associated with diminished survival. We examined the effect of margin-positive resection on survival, as well as the role and timing of additional therapies through the National Cancer Database (NCDB). PATIENTS AND METHODS: Patients with stage IIA-III pancreatic adenocarcinoma diagnosed from 2004 to 2013 were identified in NCDB. Survival was compared using univariate and multivariate Cox proportional hazards modelling for patients who underwent surgery with negative (R0), microscopically positive (R1) and macroscopically positive (R2) margins or non-surgical treatment. We further analysed patients by margin status, timing of additional therapy (neoadjuvant therapy (NAT) vs adjuvant therapy (AT) vs none) and clinical stage. RESULTS: We analysed 44 852 patients. Median survival (MS) for patients who did not undergo surgery was 10.3 months, compared with 19.7 months for R0 (P<0.001), 14.3 months for R1 (P<0.001) and 9.8 months (P=0.07) for R2 resections. NAT (MS 23.2 months) was associated with improved survival compared with AT (MS 21.5 months) in negative-margin patients and equivalent (MS 17.6 months) to AT (MS 16.8 months) in positive-margin patients. Survival for stage III NAT positive-margin patients (MS 19.8 months) was equivalent to AT after negative margins (MS 18.4 months, P=1.00). Improved R0 rates were seen with NAT (88% vs 81%, P<0.001), especially in stage III patients (85% vs 59%, P<0.001). CONCLUSION: R1 resections portend poorer survival than R0 but do not negate the benefit of surgery when additional therapy is given. NAT was associated with improved R0 rates and improved survival for stage III positive-margin patients.

Vulvar Recurrences After Intensity-modulated Radiation Therapy for Squamous Cell Carcinoma of the Anus.

OBJECTIVES: The objective is to determine localregional control (LRC), distant metastasis free survival, disease-free survival, overall survival (OS), and toxicity for patients with squamous cell carcinoma of the anus treated with definitive chemotherapy and intensity-modulated radiation therapy (IMRT). MATERIALS AND METHODS: We conducted a retrospective review of patients treated using IMRT for squamous cell carcinoma of the anus at our institution since 2005. Patients with local recurrences were identified and reviewed. The Kaplan-Meier curves were used for LRC and OS. RESULTS: From 2005 to 2014, 52 patients were treated with IMRT-based chemoradiation for squamous cell carcinoma of the anus. Median dose to the primary tumor was 54 Gy. LRC, distant metastasis free survival, OS, and disease-free survival were 92.3%, 88.5%, 86.5%, and 84.6%, respectively, with a median follow-up of 20 months. Two local failures occurred at the anal primary site and 2 in the vulva. Despite subsequent palliative radiotherapy and chemotherapy, neither patient with a vulvar recurrence achieved disease control. CONCLUSIONS: In a cohort of patients treated with IMRT-based chemoradiation, 2 vulvar recurrences were identified within the avoided external genitalia despite limited recurrence rates within the cohort overall. This experience suggests that for patients with a locally advanced primary tumor and bulky bilateral inguinal or pelvic disease, the in-transit vulvar dermal lymphatics may be at risk for subclinical involvement and subsequent recurrence. If substantiated by a similar pattern of recurrence at other institutions, the external genitalia may need to be reclassified from an avoidance structure to a clinical treatment volume in patients with locally advanced anal cancer.

Multiagent induction chemotherapy followed by chemoradiation is associated with improved survival in locally advanced pancreatic cancer.

BACKGROUND: The role of chemoradiotherapy (CRT) in locally advanced pancreatic cancer (LAPC) is uncertain after multiple randomized clinical trials have yielded mixed results. The authors used the National Cancer Data Base (NCDB) to determine whether CRT yields a survival benefit compared with chemotherapy alone (CT). METHODS: Patients with nonmetastatic LAPC diagnosed during 2004 through 2014 were identified in the NCDB. Patients who received CT were compared with those who received CRT using chi-square analysis. Univariate and multivariate Cox regression analyses were used to compare demographic, clinical, and treatment characteristics that were predictive of survival. Propensity score matching and shared frailty analysis were done. Subgroup analyses were undertaken to examine patients who underwent pancreatectomy and cohorts of patients who received different CT or CRT regimens. RESULTS: In total, 8689 patients with LAPC were identified. CRT was associated with improved survival (median survival [MS], 13.5 months) compared with CT (MS, 10.6 months) on multivariate analysis (hazard ratio [HR], 0.80; P < .001). Induction chemotherapy before CRT (HR, 0.67; P < .001) and multiagent chemotherapy (HR, 0.72; P < .001) were also identified as independent predictors of survival compared with concurrent CRT and single-agent CT, respectively. Patients in the CRT group who received multiagent induction chemotherapy had superior MS and pancreatectomy rates (MS, 17.5 months; HR, 0.70; P < .001; pancreatectomy rate, 10%) compared with those who received multiagent CT alone (MS, 12.4 months; pancreatectomy rate, 3.3%). Patients who underwent pancreatectomy experienced improved survival (MS, 22 vs 10.6 months; HR, 0.39; P < .001). CONCLUSIONS: In this NCDB analysis, maximizing systemic chemotherapy before CRT improved survival compared with CT alone in patients with LAPC. Continued analysis of CRT in properly selected patients after maximized systemic therapy is needed. Cancer 2017;123:3816-24. © 2017 American Cancer Society.

Reirradiation for locoregionally recurrent lung cancer: outcomes in small cell and non-small cell lung carcinoma.

OBJECTIVES: To our knowledge this is the largest report analyzing outcomes for re-irradiation (reRT) for locoregionally recurrent lung cancer, and the first to assess thoracic reRT outcomes in patients with small cell lung cancer (SCLC). METHODS: Forty-eight patients (11 SCLC, 37 non-small cell lung cancer [NSCLC]) receiving reRT to the thorax were identified; 44 (92%) received reRT by intensity-modulated radiotherapy. Palliative responses, survival outcomes, and prognostic factors were analyzed. RESULTS: NSCLC patients received a median of 30 Gy in a median of 10 fractions, whereas SCLC patients received a median of 37.5 Gy in a median of 15 fractions. Median survival for the entire cohort from reRT was 4.2 months. Median survival for NSCLC patients was 5.1 months, versus 3.1 months for the SCLC patients (P=0.15). In NSCLC patients, multivariate analysis demonstrated that Karnofsky performance status≥80 and higher radiation dose were associated with improved survival following reRT, and 75% of patients with symptoms experienced palliative benefit. In SCLC, 4 patients treated with the intent of life prolongation for radiographic recurrence had a median survival of 11.7 months. However, acute toxicities and new disease symptoms limited the duration of palliative benefit in the 7 symptomatic SCLC patients to 0.5 months. CONCLUSIONS: ReRT to the thorax for locoregionally recurrent NSCLC can provide palliative benefit, and a small subset of patients may experience long-term survival. Select SCLC patients may experience meaningful survival prolongation after reRT, but reRT for patients with symptomatic recurrence and/or extrathoracic disease did not offer meaningful survival or durable symptom benefit.

Dose-limiting toxicity after hypofractionated dose-escalated radiotherapy in non-small-cell lung cancer.

PURPOSE: Local failure rates after radiation therapy (RT) for locally advanced non-small-cell lung cancer (NSCLC) remain high. Consequently, RT dose intensification strategies continue to be explored, including hypofractionation, which allows for RT acceleration that could potentially improve outcomes. The maximum-tolerated dose (MTD) with dose-escalated hypofractionation has not been adequately defined. PATIENTS AND METHODS: Seventy-nine patients with NSCLC were enrolled on a prospective single-institution phase I trial of dose-escalated hypofractionated RT without concurrent chemotherapy. Escalation of dose per fraction was performed according to patients' stratified risk for radiation pneumonitis with total RT doses ranging from 57 to 85.5 Gy in 25 daily fractions over 5 weeks using intensity-modulated radiotherapy. The MTD was defined as the maximum dose with ≤ 20% risk of severe toxicity. RESULTS: No grade 3 pneumonitis was observed and an MTD for acute toxicity was not identified during patient accrual. However, with a longer follow-up period, grade 4 to 5 toxicity occurred in six patients and was correlated with total dose (P = .004). An MTD was identified at 63.25 Gy in 25 fractions. Late grade 4 to 5 toxicities were attributable to damage to central and perihilar structures and correlated with dose to the proximal bronchial tree. CONCLUSION: Although this dose-escalation model limited the rates of clinically significant pneumonitis, dose-limiting toxicity occurred and was dominated by late radiation toxicity involving central and perihilar structures. The identified dose-response for damage to the proximal bronchial tree warrants caution in future dose-intensification protocols, especially when using hypofractionation.

Locoregional recurrence following accelerated partial breast irradiation for early-stage invasive breast cancer: significance of estrogen receptor status and other pathological variables.

BACKGROUND: Understanding risk factors for locoregional recurrence (LRR) after accelerated partial breast irradiation (APBI) can help to guide patient selection for treatment with APBI. Published findings to date have not been consistent. More data are needed as these risk factors continue to be defined. METHODS: A total of 277 women with early-stage invasive breast cancer underwent lumpectomy and were treated adjuvantly at our institution with APBI using high-dose rate brachytherapy. APBI was delivered using multicatheter interstitial brachytherapy (91 %) or single-entry catheter brachytherapy (9 %) to a dose of 32-34 Gy in 8-10 twice daily fractions. Failure patterns and risk factors for recurrence were analyzed. RESULTS: With a median follow-up of 61 months, the 5-year locoregional control rate was 94.4 %. Negative estrogen receptor (ER) status was strongly associated with LRR on multivariate analysis (p < 0.005). Lobular histology, the presence of an extensive intraductal component, and lymphovascular invasion also were significant but to a lesser degree than ER-negative status. Patients with multiple risk factors were at highest risk for LRR. Age was not significantly associated with increased risk for LRR. CONCLUSIONS: The presence of specific pathological features, particularly ER negative status, was associated with increased risk of LRR in this cohort of women treated with APBI. Further investigation is warranted to determine whether patients with adverse pathological risk factors are at higher risk of LRR after APBI than after conventional whole breast irradiation (WBI), as these same features also may place women at risk for LRR after WBI.

Estimated radiation pneumonitis risk after photon versus proton therapy alone or combined with chemotherapy for lung cancer.

BACKGROUND: Traditionally, radiation therapy plans are optimized without consideration of chemotherapy. Here, we model the risk of radiation pneumonitis (RP) in the presence of a possible interaction between chemotherapy and radiation dose distribution. MATERIAL AND METHODS: Three alternative treatment plans are compared in 18 non-small cell lung cancer patients previously treated with helical tomotherapy; the tomotherapy plan, an intensity modulated proton therapy plan (IMPT) and a three dimensional conformal radiotherapy (3D-CRT) plan. All plans are optimized without consideration of the chemotherapy effect. The effect of chemotherapy is modeled as an independent cell killing process using a uniform chemotherapy equivalent radiation dose (CERD) added to the entire organ at risk. We estimate the risk of grade 3 or higher RP (G3RP) using the critical volume model. RESULTS: The mean risk of clinical G3RP at zero CERD is 5% for tomotherapy (range: 1-18 %) and 14% for 3D-CRT (range 2-49%). When the CERD exceeds 9 Gy, however, the risk of RP with the tomotherapy plans become higher than the 3D-CRT plans. The IMPT plans are less toxic both at zero CERD (mean 2%, range 1-5%) and at CERD = 10 Gy (mean 7%, range 1-28%). Tomotherapy yields a lower risk of RP than 3D-CRT for 17/18 patients at zero CERD, but only for 7/18 patients at CERD = 10 Gy. IMPT gives the lowest risk of all plans for 17/18 patients at zero CERD and for all patients with CERD = 10 Gy. CONCLUSIONS: The low dose bath from highly conformal photon techniques may become relevant for lung toxicity when radiation is combined with cytotoxic chemotherapy as shown here. Proton therapy allows highly conformal delivery while minimizing the low dose bath potentially interacting with chemotherapy. Thus, intensive drug-radiation combinations could be an interesting indication for selecting patients for proton therapy. It is likely that the IMRT plans would perform better if the CERD was accounted for during optimization, but more clinical data is required to facilitate evidence-based plan optimization in the multi-modality setting.

Intensity-modulated radiotherapy might increase pneumonitis risk relative to three-dimensional conformal radiotherapy in patients receiving combined chemotherapy and radiotherapy: a modeling study of dose dumping.

PURPOSE: To model the possible interaction between cytotoxic chemotherapy and the radiation dose distribution with respect to the risk of radiation pneumonitis. METHODS AND MATERIALS: A total of 18 non-small-cell lung cancer patients previously treated with helical tomotherapy at the University of Wisconsin were selected for the present modeling study. Three treatment plans were considered: the delivered tomotherapy plans; a three-dimensional conformal radiotherapy (3D-CRT) plan; and a fixed-field intensity-modulated radiotherapy (IMRT) plan. The IMRT and 3D-CRT plans were generated specifically for the present study. The plans were optimized without adjusting for the chemotherapy effect. The effect of chemotherapy was modeled as an independent cell killing process by considering a uniform chemotherapy equivalent radiation dose added to all voxels of the organ at risk. The risk of radiation pneumonitis was estimated for all plans using the Lyman and the critical volume models. RESULTS: For radiotherapy alone, the critical volume model predicts that the two IMRT plans are associated with a lower risk of radiation pneumonitis than the 3D-CRT plan. However, when the chemotherapy equivalent radiation dose exceeds a certain threshold, the radiation pneumonitis risk after IMRT is greater than after 3D-CRT. This threshold dose is in the range estimated from clinical chemoradiotherapy data sets. CONCLUSIONS: Cytotoxic chemotherapy might affect the relative merit of competing radiotherapy plans. More work is needed to improve our understanding of the interaction between chemotherapy and the radiation dose distribution in clinical settings.

Dosimetric comparison of left-sided whole breast irradiation with 3DCRT, forward-planned IMRT, inverse-planned IMRT, helical tomotherapy, and topotherapy.

BACKGROUND AND PURPOSE: To compare left-sided whole breast conventional and intensity-modulated radiotherapy (IMRT) treatment planning techniques. MATERIALS AND METHODS: Treatment plans were created for 10 consecutive patients. Three-dimensional conformal radiotherapy (3DCRT), forward-planned IMRT (for-IMRT), and inverse-planned IMRT (inv-IMRT) used two tangent beams. For-IMRT utilized up to four segments per beam. For helical tomotherapy (HT) plans, beamlet entrance and/or exit to critical structures was blocked. Topotherapy plans, which used static gantry angles with simultaneous couch translation and inverse-planned intensity modulation, used two tangent beams. Plans were normalized to 50Gy to 95% of the retracted PTV. RESULTS: Target max doses were reduced with for-IMRT compared to 3DCRT, which were further reduced with HT, topotherapy, and inv-IMRT. HT resulted in lowest heart and ipsilateral lung max doses, but had higher mean doses. Inv-IMRT and topotherapy reduced ipsilateral lung mean and max doses compared to 3DCRT and for-IMRT. CONCLUSIONS: All modalities evaluated provide adequate coverage of the intact breast. HT, topotherapy, and inv-IMRT can reduce high doses to the target and normal tissues, although HT results in increased low doses to large volume of normal tissue. For-IMRT improves target homogeneity compared with 3DCRT, but to a lesser degree than the inverse-planned modalities.

Outcomes after accelerated partial breast irradiation in patients with ASTRO consensus statement cautionary features.

PURPOSE: To evaluate outcomes among women with American Society for Radiation Oncology (ASTRO) consensus statement cautionary features treated with brachytherapy-based accelerated partial breast irradiation (APBI). METHODS AND MATERIALS: Between March 2001 and June 2006, 322 consecutive patients were treated with high-dose-rate (HDR) APBI at the University of Wisconsin. A total of 136 patients were identified who met the ASTRO cautionary criteria. Thirty-eight (27.9%) patients possessed multiple cautionary factors. All patients received 32 to 34 Gy in 8 to 10 twice-daily fractions using multicatheter (93.4%) or Mammosite balloon (6.6%) brachytherapy. RESULTS: With a median follow-up of 60 months, there were 5 ipsilateral breast tumor recurrences (IBTR), three local, and two loco-regional. The 5-year actuarial rate of IBTR was 4.8%±4.1%. The 5-year disease-free survival was 89.6%, with a cause-specific survival and overall survival of 97.6% and 95.3%, respectively. There were no IBTRs among 32 patients with ductal carcinoma in situ (DCIS) vs. 6.1% for patients with invasive carcinoma (p=0.24). Among 104 patients with Stage I or II invasive carcinoma, the IBTR rate for patients considered cautionary because of age alone was 0% vs. 12.7% in those deemed cautionary due to histopathologic factors (p=0.018). CONCLUSIONS: Overall, we observed few local recurrences among patients with cautionary features. Women with DCIS and patients 50 to 59 years of age with Stage I/II disease who otherwise meet the criteria for suitability appear to be at a low risk of IBTR. Patients with tumor-related cautionary features will benefit from careful patient selection.

Hypofractionation does not increase radiation pneumonitis risk with modern conformal radiation delivery techniques.

PURPOSE: To study the interaction between radiation dose distribution and hypofractionated radiotherapy with respect to the risk of radiation pneumonitis (RP) estimated from normal tissue complication probability (NTCP) models. MATERIAL AND METHODS: Eighteen non-small cell lung cancer patients previously treated with helical tomotherapy were selected. For each patient a 3D-conformal plan (3D-CRT) plan was produced in addition to the delivered plan. The standard fractionation schedule was set to 60 Gy in 30 fractions. Iso-efficacy comparisons with hypofractionation were performed by changing the fractionation and the physical prescription dose while keeping the equivalent tumor dose in 2 Gy fractions constant. The risk of developing RP after radiotherapy was estimated using the Mean Equivalent Lung Dose in 2-Gy fractions (MELD(2)) NTCP model with α/ß=4 Gy for the residual lung. Overall treatment time was kept constant. RESULTS: The mean risk of clinical RP after standard fractionation was 7.6% for Tomotherapy (range: 2.8-15.9%) and 9.2% for 3D-CRT (range 3.2-20.2%). Changing to 20 fractions, the Tomotherapy plans became slightly less toxic if the tumor α/ß ratio, (α/ß)(T), was 7 Gy (mean RP risk 7.5%, range 2.8-16%) while the 3D-CRT plans became marginally more toxic (mean RP risk 9.8%, range 3.2-21%). If (α/ß)(T) was 13 Gy, the mean estimated risk of RP is 7.9% for Tomotherapy (range: 2.8-17%) and 10% for 3D-CRT (range 3.2-22%). CONCLUSION: Modern highly conformal dose distributions are radiobiologically more forgiving with respect to hypofractionation, even for a normal tissue endpoint where α/ß is lower than for the tumor in question.

Pulsed reduced dose-rate radiotherapy: case report : a novel re-treatment strategy in the management of recurrent glioblastoma multiforme.

The initial management of malignant gliomas is multimodality in nature, consisting of surgery, radiation therapy and chemotherapy. However, once progression has occurred, treatment options are limited both in terms of selection and efficacy. We report a case of a 37 year-old male diagnosed with a Grade II astrocytoma initially treated with surgery and external beam radiation therapy consisting of 54 Gy delivered in 1.8 Gy fractions that subsequently progressed to a Grade IV astrocytoma. This was managed with temozolomide chemotherapy until the patient exhibited further progression. Although the patient had received prior full dose radiotherapy, he was re-treated with external beam radiotherapy delivered at a substantially reduced dose-rate. This reduction in dose-rate is obtained by delivering treatment in a series of 0.2 Gy pulses separated by 3 min time intervals, creating an apparent dose rate of 0.0667 Gy/min. The region of recurrence was treated to a dose of 50 Gy delivered using 25 daily fractions of 2.0 Gy. The patient had both a radiographic response and clinical improvement following re-irradiation using pulsed reduced dose-rate radiotherapy with no apparent acute or late neurologic toxicities at a time when other treatment options were not available. Despite delivering 104 Gy to the tumor bed and the surrounding brain parenchyma, at no time was there radiographic evidence of radiation-induced normal tissue necrosis. The radiobiologic basis for the use of pulsed reduced dose-rate external beam radiotherapy in the management of recurrent glioma patients is discussed.