Recurrent/Metastatic Nasopharyngeal Carcinoma Treatment from Present to Future: Where Are We and Where Are We Heading?

OPINION STATEMENT: Nasopharyngeal carcinoma (NPC) is distinct in its anatomic location and biology from other epithelial head and neck cancer (HNC). There are 3 WHO subtypes, which considers the presence of Epstein-Barr virus (EBV) and other histopathology features. Despite the survival benefit obtained from modern treatment modalities and techniques specifically in the local and locally advanced setting, a number of patients with this disease will recur and subsequently die of distant metastasis, locoregional relapse, or both. In the recurrent setting, the ideal therapy approach continues to be a topic of discussion and current recommendations are platinum-based combination chemotherapy. Phase III clinical trials which led to the approval of pembrolizumab or nivolumab for head and neck squamous cell carcinoma (HNSCC) specifically excluded NPC. No immune checkpoint inhibitor therapy, to date, has been approved by the FDA to treat NPC although the National Comprehensive Cancer Network (NCCN) recommendations do include use of these agents. Hence, this remains the major challenge for treatment options. Nasopharyngeal carcinoma is challenging as it is really 3 different diseases, and much research is required to determine best options and sequencing of those options. This article is going to address the data to date and discuss ongoing research in EBV + and EBV - inoperable recurrent/metastatic NPC patients.

Early Stage and Locally Advanced Nasopharyngeal Carcinoma Treatment from Present to Future: Where Are We and Where Are We Going?

OPINION STATEMENT: Nasopharyngeal carcinoma (NPC) is a rare malignancy, endemic in China, that is commonly diagnosed in locally advanced scenarios. Its pathogenesis is strongly associated with Epstein-Barr virus (EBV), an infection for which measuring EBV plasma DNA levels has helped as a prognostic factor guiding treatment options, including a stronger treatment in those with high titers. Additionally, tobacco and alcohol are often implicated in EBV-negative patients. The local disease is treated with radiotherapy alone, preferentially intensity modulated radiotherapy. For locally advanced disease, the backbone treatment is concurrent chemoradiotherapy with the ongoing research dilemma being adding adjuvant chemotherapy or induction chemotherapy. The ongoing research is focused not only on identifying patients that will benefit from adjuvant or induction chemotherapy, but also on identifying the best chemotherapeutic regimen, regimen alternatives to diminish toxicity, the role that immune checkpoint inhibitors play, and the use of molecularly guided treatment targeting patients with NPC whether driven by EBV or tobacco and alcohol. Knowing the precise oncogenesis of NPC not only offers a better understanding of the role that EBV plays in this tumor but also helps create targeted therapies that could potentially block important pathways such as the NF-κB pathway. Much is yet to be done, but the prognosis and management of NPC patients have changed drastically, offering precise treatment methods and excellent control of the disease, even in locally advanced scenarios.

How many lymph nodes are enough? Assessing the adequacy of lymph node yield for staging in favorable histology wilms tumor.

PURPOSE: Current investigational priorities in the treatment of favorable histology Wilms tumor (FHWT) center on accurate staging and risk-stratification. The extent of lymph node (LN) sampling has not been clearly defined; its importance cannot be overstated as it guides adjuvant therapy. The identification of a minimum LN yield to minimize the risk of harboring occult metastatic disease could help development of surgical guidelines. This study focuses on using the beta-binomial distribution to estimate the risk of occult metastatic disease in patients with FHWT. MATERIALS & METHODS: The National Cancer Database was queried for patients with unilateral FHWT from 2004 to 2013. Data were used to characterize nodal positivity for patients who underwent surgery and had ≥1 positive LN and ≥2 LNs examined. The probability of missing a positive LN (i.e., false negative) for a given LN yield was calculated using an empirical estimation and the beta-binomial model. Patients were then stratified by tumor size. RESULTS: 422 patients met study criteria. To limit the chance of missing a positive LN to ≤10%, the empirical estimation and beta-binomial model estimated that 6 and 10 LNs needed to be sampled, respectively. Tumor size did not influence the result. Internal validation showed little variation to maintain a false negative rate ≤ 10%. CONCLUSIONS: Using mathematical modeling, it appears that the desired LN yield in FHWT to reduce the risk of false-negative LN sampling to ≤10% is between 6 and 10. The current analysis represents an objective attempt to determine the desired surgical approach to LN sampling to accurately stage patients with FHWT. LEVEL OF EVIDENCE: II.

Factors Influencing Overall Survival of Children, Adolescents, and Young Adults With High-risk Renal Tumors.

OBJECTIVE: To identify factors impacting overall survival (OS) in children, adolescents, and young adults with high-risk renal tumors (HRRTs). METHODS: The National Cancer Database was queried for patients ≤30 years old diagnosed with anaplastic Wilms tumors (AWT), clear cell sarcoma of the kidney (CCSK), or rhabdoid tumor of the kidney (RTK) between 2004 and 2013. Demographic, clinical, and OS data were abstracted. OS between groups was compared with a Kaplan-Meier curve. Univariate and multivariate survival analyses were performed. RESULTS: A total of 349 patients were identified meeting criteria; 133 (38.1%) AWT, 120 (34.4%) CCSK, and 96 (27.5%) RTK. Patients with RTK were less likely to undergo surgery than those with AWT or CCSK (77.1% vs 94% vs 99%, P < .001) and less likely to receive chemotherapy (84.4% vs 96.2% vs 95%, P = .013) or radiation (52.1% vs 81.2% vs 86.7%, P < .001). Estimated 5-year OS was 76.1% (95% confidence interval [CI] 67.9-84.4) for AWT, 92.7% (95% CI 87.4-97.9) for CCSK, and 33.5% (95% CI 23.1-43.9) for RTK (P < .001). On multivariate analysis, AWT (HR 3.372, P = .032) and RTK histology (HR 12.595, P < .001) were significantly associated with worse OS, while receiving radiation (HR 0.43, P = .006) was associated with improved OS. LN positivity, margin status, and undergoing surgery were not. Analyzing the HRRTs individually, for AWT, undergoing surgery was associated with OS (HR 0.308, P = .031). For RTK, factors associated with OS included undergoing surgery (HR 0.209, P = .007) and radiation (HR 0.411, P = .008). CONCLUSION: Within the HRRTs, RTK is associated with worse outcomes than either AWT or CCSK. Receiving radiation is significantly associated with improved outcomes, and surgery is important for those with AWT and RTK.

Patterns of Fractionation and Boost Usage in Adjuvant External Beam Radiotherapy for Ductal Carcinoma in Situ in the United States.

BACKGROUND: While the roles of hypofractionated (HFxn) radiotherapy and lumpectomy boost in the adjuvant management of invasive breast cancer are supported by the results of clinical trials, randomized data supporting their use for ductal carcinoma in situ (DCIS) are forthcoming. We sought to evaluate current national trends and identify factors associated with HFxn and boost usage using the National Cancer Database. PATIENTS AND METHODS: We queried the National Cancer Database for women diagnosed with DCIS from 2004 to 2014 undergoing external beam radiotherapy after breast conservation surgery. Patients were categorized as receiving either conventional fractionation (CFxn) or HFxn and as either receiving or not receiving a boost. Multiple logistic regression was performed to identify demographic, clinical, and treatment factor associations. RESULTS: A total of 101,615 women were identified, with 87,641 (86.2%) receiving CFxn, 13,974 (13.8%) receiving HFxn, and most patients in each group (84.9% and 57.7%, respectively) receiving a boost. Implementation of HFxn increased from 4.3% in 2004 to 33.0% in 2014, and the use of a boost declined from 83.3% to 74.6%. HFxn receipt was independently associated with later year of diagnosis, older age, higher income, greater distance from treatment facility, greater facility volume, academic facility type, Western residence, smaller lesions, and nonreceipt of a boost. Factors associated with boost receipt included earlier year of diagnosis, younger age, higher income, community facility type, adverse pathologic features, and nonreceipt of HFxn. CONCLUSION: Although CFxn with a boost remains the most common external beam radiotherapy strategy for DCIS, implementation of HFxn without a boost appears to be increasing. Practice patterns at present seem to be driven by guidelines for invasive breast cancer and nonclinical factors.

Patterns of Care for Locally Advanced Pancreatic Adenocarcinoma Using the National Cancer Database.

OBJECTIVES: The role of radiotherapy (RT) in locally advanced pancreatic cancer (LAPC) is uncertain. This study examines patterns of care and survival outcomes of LAPC undergoing chemotherapy alone versus chemotherapy plus RT (C + RT). METHODS: The National Cancer Database was queried for nonmetastatic LAPC patients who received chemotherapy alone or C + RT. RESULTS: Of the 13,695 patients included, 5306 underwent chemotherapy alone and 4971, C + RT. Use of C + RT declined from 2003 to 2011 (73%-53%), whereas chemotherapy alone increased. Of those receiving RT, rates of intensity-modulated radiotherapy (IMRT) increased (27%-72%), whereas 3-dimensional (3D) RT decreased (73%-28%). Unadjusted 1-year overall survival (OS) was longer for versus chemotherapy (45.6% vs 38.7%), as was 2-year OS (12.9% vs 11.9%) (hazard ratio, 0.88; 0.85-0.91; P < 0.001). Under multivariate analysis, C + RT was associated with improved OS (hazard ratio, 0.84; 0.81-0.87; P < 0.001). On subgroup analysis comparing C + IMRT, C + 3D RT, and chemotherapy alone, 1-year OS was 49.1%, 45.1%, and 38.7%, and 2-year OS was 13.1%, 11.6%, and 11.9% accordingly. CONCLUSIONS: Utilization of RT in LAPC is decreasing, whereas chemotherapy alone is increasing. Of patients undergoing RT, rates of IMRT are increasing. Whereas C + IMRT appeared to be associated with improved OS compared with chemotherapy alone, 3D RT was not.

Prostate brachytherapy, either alone or in combination with external beam radiation, is associated with longer overall survival in men with favorable pathologic Group 4 (Gleason score 8) prostate cancer.

PURPOSE: Conventional prostate cancer risk stratification results in considerable heterogeneity within each prognostic group. Men with pathologic grade Group 4 (Gleason score 8) but otherwise low-risk features have been identified as a favorable subset of high-risk prostate cancer. Given recent randomized data supporting improved cancer outcome with brachytherapy in intermediate- and high-risk prostate cancer, we sought to evaluate brachytherapy utilization and overall survival (OS) for these patients. METHODS AND MATERIALS: We queried the National Cancer Database for clinical T1c-T2a N0 M0 prostate cancer with prostate-specific antigen <10 ng/mL and Gleason score 8 adenocarcinoma on biopsy. All patients received androgen deprivation therapy and either external beam radiation therapy (EBRT) alone, brachytherapy alone, or a combination of EBRT with brachytherapy boost (brachytherapy + EBRT). Kaplan-Meier OS estimates as well as univariate and multivariate Cox proportional hazards regression analyses were performed. Propensity score-matched analyses were performed to further control for baseline confounders. RESULTS: Four thousand four hundred ninety-six patients were identified with a median followup of 62.5 months (range, 2.3-119.8). Median age was 72 years (range, 41-90+). Utilization of brachytherapy decreased from 2004 to 2009. The odds ratio for brachytherapy by year (continuous variable) was 0.86 (p < 0.001). Five-year OS was 84%, 88%, and 89% for the EBRT alone, brachytherapy alone, and brachytherapy + EBRT groups, respectively. On multivariate analysis, higher median income, low comorbidity score, and treatment with brachytherapy alone (hazard ratio, 0.66; p = 0.005) or brachytherapy + EBRT (hazard ratio, 0.70; p = 0.001) remained associated with longer OS. Propensity score matching confirmed longer OS associated with either brachytherapy regimen. CONCLUSIONS: Of those men with World Health Organization pathologic grade Group 4 (Gleason score 8) prostate cancer and otherwise favorable prognostic features treated with androgen deprivation therapy and radiation therapy, longer OS was achieved when prostate brachytherapy was included, whether used alone or in combination with supplemental EBRT. In spite of these excellent outcomes, prostate brachytherapy utilization is declining in the United States.

Patient characterization and usage trends of proton beam therapy for localized prostate cancer in the United States: A study of the National Cancer Database.

PURPOSE: To evaluate usage trends and identify factors associated with proton beam therapy (PBT) compared to alternative forms of external beam radiation therapy (RT) (EBRT) for localized prostate cancer. PATIENTS AND METHODS: The National Cancer Database was queried for men with localized (N0, M0) prostate cancer diagnosed between 2004 and 2013, treated with EBRT, with available data on EBRT modality (photon vs. PBT). Binary multiple logistic regression identified variables associated with EBRT modality. RESULTS: In total, 143,702 patients were evaluated with relatively few men receiving PBT (5,709 [4.0%]). Significant differences in patient and clinical characteristics were identified between those men treated with PBT compared to those treated with photon (odds ratio [OR]; 95% CI). Patients treated with PBT were generally younger (OR = 0.73; CI: 0.67-0.82), National Comprehensive Cancer Network low-risk compared to intermediate (0.71; 0.65-0.78) or high (0.44; 0.38-0.5) risk, white vs. black race (0.66; 0.58-0.77), with less comorbidity (Charlson-Deyo 0 vs. 2+; 0.70; 0.50-0.98), live in higher income counties (1.55; 1.36-1.78), and live in metropolitan areas compared to urban (0.21; 0.18-0.23) or rural (0.14; 0.10-0.19) areas. Most patients treated with PBT travelled more than 100 miles to the treatment facility. Annual PBT utilization significantly increased in both total number and percentage of EBRT over time (2.7%-5.6%; P<0.001). PBT utilization increased mostly in men classified as National Comprehensive Cancer Network low-risk (4%-10.2%). CONCLUSION: PBT for men with localized prostate cancer significantly increased in the United States from 2004 to 2013. Significant demographic and prognostic differences between those men treated with photons and protons were identified.

Brachytherapy should not be omitted when treating locally advanced neuroendocrine cervical cancer with definitive chemoradiation therapy.

PURPOSE: Neuroendocrine cervical cancer is a rare malignancy with a poor prognosis, yet there is a paucity of data to guide treatment decisions when managing patients with this diagnosis. Specifically, there are little data to aid practitioners in deciding if there is added value to brachytherapy given the additional time, cost, discomfort, and toxicity to patients. METHODS AND MATERIALS: We used the National Cancer Data Base to identify women with locally advanced neuroendocrine cervical cancer treated with definitive chemoradiotherapy to determine if the addition of brachytherapy improves outcomes in this disease. We also assessed outcomes based on chemotherapy timing in this cohort. RESULTS: We identified 100 patients with locally advanced nonmetastatic neuroendocrine cervical cancer that were treated with definitive chemoradiotherapy between 2004 and 2012. There was a substantial improvement in overall survival when brachytherapy was administered in addition to external beam radiotherapy. In multivariate analysis, the addition of brachytherapy, compared with external beam radiotherapy alone, was associated with an improved median survival of 48.6 vs. 21.6 months (hazard ratio (HR), 0.475; 95% CI, 0.255-0.883; p = 0.019). We observed no difference in overall survival for patients treated with neoadjuvant chemotherapy compared with the group who received chemotherapy started concurrently with radiation (HR, 0.851; 95% CI, 0.483-1.500; p = 0.578). CONCLUSIONS: Brachytherapy should be considered an essential component of definitive chemoradiotherapy for the treatment of neuroendocrine cervical cancer. Chemotherapy timing, however, does not impact outcome.

Treatment Selection and Survival Outcomes With and Without Radiation for Unresectable, Localized Intrahepatic Cholangiocarcinoma.

PURPOSE: Most patients with intrahepatic cholangiocarcinoma present with locally advanced disease not amenable to surgical resection. For these inoperable patients, chemotherapy alone is generally considered the standard of care, with limited data regarding the role of radiotherapy. We used the National Cancer Database to investigate care patterns and the impact of radiation as a component of combined modality therapy on overall survival. METHODS: We queried the National Cancer Database for patients with nonmetastatic intrahepatic cholangiocarcinoma diagnosed from 2001 to 2011. Those undergoing surgery were excluded. All included patients were coded as having received chemotherapy. Kaplan-Meier overall survival estimates and univariate and multivariate Cox proportional hazards regression analyses were performed. Propensity score-matched analysis was performed to account for indication bias and mitigate heterogeneity between treatment groups. RESULTS: One thousand six hundred thirty-six patients were identified with a median follow-up of 11.3 months. Median age was 63 years; 23% received combined modality therapy with radiation. Two-year overall survival for the entire cohort was 21%, and for the chemotherapy-alone and combined modality therapy groups, it was 20% versus 26%, respectively. On univariate analysis, overall survival was improved with combined modality therapy. On multivariate analysis, combined modality therapy remained significantly associated with improved overall survival, as did younger age, female sex, higher median income, lower comorbidity score, and earlier stage. Propensity score matched analysis confirmed the overall survival benefit associated with combined modality therapy. DISCUSSION: In this largest reported analysis of combined modality therapy for localized, inoperable intrahepatic cholangiocarcinoma, the addition of radiation to chemotherapy was associated with an improvement in overall survival. Three quarters of inoperable patients in the United States do not receive radiation. Survival remains relatively poor for all patients, and we enthusiastically support ongoing randomized trials seeking to incorporate radiotherapy as a possible means to improve outcomes.

21-Gene Recurrence Score Assay As a Predictor of Adjuvant Chemotherapy Administration for Early-Stage Breast Cancer: An Analysis of Use, Therapeutic Implications, and Disparity Profile.

PURPOSE: The 21-gene Recurrence Score (RS) assay is used to predict disease recurrence and benefit of chemotherapy in estrogen receptor-positive, lymph node-negative early-stage breast cancer (EBC). Our study is the first analysis of trends and differences in the use of the RS assay and its impact on recommending chemotherapy in a population-based data set. METHODS: Patients with EBC diagnosed from 2004 to 2012 and included in the National Cancer Data Base were analyzed. Multivariate logistic regression analysis was used to estimate the covariates associated with use of the test and its impact on chemotherapy decisions. RESULTS: The RS assay was ordered for 54.0% of the 143,032 identified patients. Of all the variables, RS assay had the strongest association with recommendation for chemotherapy, with an adjusted odds ratio (AOR) of 83 for high assay scores. When indicated, test use was significantly associated with younger age, white race, academic centers, private insurance, and pT2/pN0(i+) grade 2 to 3 disease. Black patients (AOR, 1.31; 95% CI, 1.20 to 1.43) and those treated in community facilities (AOR, 1.49; 95% CI, 1.35 to 1.63) were more likely to be tested outside the National Comprehensive Cancer Network guidelines. Black patients (AOR, 1.51; 95% CI, 1.31 to 1.69) and those with high tumor grade (AOR, 30.76; 95% CI, 26.48 to 35.73) had significantly higher assay scores. Younger black patients (AOR, 1.33; 95% CI, 1.16 to 1.54) were more likely to receive chemotherapy despite low assay scores. CONCLUSION: The RS assay significantly influences clinicians' recommendations for chemotherapy in patients with EBC. Black patients tended to have higher assay scores, which may reflect use patterns or less favorable tumor biology for estrogen receptor-positive disease. There are significant differences in use and clinical implications of the test on the basis of race, insurance, and type of facility.

Dose painting to treat single-lobe prostate cancer with hypofractionated high-dose radiation using targeted external beam radiation: Is it feasible?

Targeted focal therapy strategies for treating single-lobe prostate cancer are under investigation. In this planning study, we investigate the feasibility of treating a portion of the prostate to full-dose external beam radiation with reduced dose to the opposite lobe, compared with full-dose radiation delivered to the entire gland using hypofractionated radiation. For 10 consecutive patients with low- to intermediate-risk prostate cancer, 2 hypofractionated, single-arc volumetric-modulated arc therapy (VMAT) plans were designed. The first plan (standard hypofractionation regimen [STD]) included the entire prostate gland, treated to 70 Gy delivered in 28 fractions. The second dose painting plan (DP) encompassed the involved lobe treated to 70 Gy delivered in 28 fractions, whereas the opposing, uninvolved lobe received 50.4 Gy in 28 fractions. Mean dose to the opposing neurovascular bundle (NVB) was considerably lower for DP vs STD, with a mean dose of 53.9 vs 72.3 Gy (p < 0.001). Mean penile bulb dose was 18.6 Gy for DP vs 19.2 Gy for STD (p = 0.880). Mean rectal dose was 21.0 Gy for DP vs 22.8 Gy for STD (p = 0.356). Rectum V70 (the volume receiving ≥70 Gy) was 2.01% for DP vs 2.74% for STD (p = 0.328). Bladder V70 was 1.69% for DP vs 2.78% for STD (p = 0.232). Planning target volume (PTV) maximum dose points were 76.5 and 76.3 Gy for DP and STD, respectively (p = 0.760). This study demonstrates the feasibility of using VMAT for partial-lobe prostate radiation in patients with prostate cancer involving 1 lobe. Partial-lobe prostate plans appeared to spare adjacent critical structures including the opposite NVB.