Total Neoadjuvant Therapy Significantly Increases Complete Clinical Response.

BACKGROUND: Increased experience with total neoadjuvant therapy for rectal cancer suggests significantly more tumor regression and increased rates of complete clinical response as measured by pathological complete response and clinical complete response. OBJECTIVE: This study aimed to assess outcomes after total neoadjuvant therapy versus standard neoadjuvant chemoradiotherapy for patients with locally advanced rectal cancer. DESIGN: This is a retrospective cohort study. SETTINGS: A database of patients with rectal cancer from 2015 to 2019 at a large integrated health care system was reviewed. PATIENTS: Demographics of the 2 groups revealed no significant difference in clinical stage or patient characteristics. Of 465 patients, 66 patients underwent total neoadjuvant therapy and 399 underwent standard neoadjuvant chemoradiotherapy. Fifty-six patients underwent consolidation chemotherapy, and 10 underwent induction chemotherapy. MAIN OUTCOME MEASURES: Complete clinical response, disease-free survival, proctectomy-free survival, and organ preservation rates were the main outcome measures. RESULTS: Complete clinical response was achieved in 36 patients (58.1%) versus 59 patients (14.8%; p < 0.001), favoring the total neoadjuvant therapy group. Three-year overall survival was similar between groups (85.6% standard neoadjuvant chemoradiotherapy versus 86.0% total neoadjuvant therapy). Three-year distant metastasis-free survival was 67.4% in the total neoadjuvant therapy group compared to 77.7% in the standard neoadjuvant chemoradiotherapy group. Three-year proctectomy-free survival was 44% in the total neoadjuvant therapy group compared to 6% in the standard neoadjuvant chemoradiotherapy group. Twenty-two patients (37.3% of complete clinical responders) in the standard neoadjuvant chemoradiotherapy group elected to pursue organ preservation, whereas 31 patients (86.1% of complete clinical responders) from the total neoadjuvant therapy group chose organ preservation. LIMITATIONS: This study is limited by its retrospective nature with a shorter follow-up of 3 years. CONCLUSIONS: Total neoadjuvant therapy for rectal cancer significantly increased complete clinical response. This allowed patients to have greater organ preservation with no significant difference in overall survival or disease control. See Video Abstract at http://links.lww.com/DCR/B934 . LA TERAPIA NEOADYUVANTE TOTAL AUMENTA SIGNIFICATIVAMENTE LA RESPUESTA CLNICA COMPLETA: ANTECEDENTES:La mayor experiencia con la terapia neoadyuvante total para el cáncer de recto sugiere una regresión tumoral significativamente mayor y mayores tasas de respuesta clínica completa, medidas por respuesta patológica completa y respuesta clínica completa.OBJETIVO:Este estudio evaluó los resultados después de la terapia neoadyuvante total versus la quimiorradioterapia neoadyuvante estándar para pacientes con cáncer de recto localmente avanzado.DISEÑO:Este es un estudio de cohorte retrospectivo.ESCENARIO:Se revisó una base de datos de pacientes con cáncer de recto de 2015 a 2019 en un sistema de salud integrado grande.PACIENTES:La demografía de los dos grupos no revela diferencias significativas en el estadio clínico o las características de los pacientes. De 465 pacientes, 66 pacientes recibieron terapia neoadyuvante total y 399 quimiorradioterapia neoadyuvante estándar. Cincuenta y seis se sometieron a quimioterapia de consolidación mientras que 10 pacientes a quimioterapia de inducción.PRINCIPALES MEDIDAS DE RESULTADO:Se midieron la respuesta clínica completa, la sobrevida libre de enfermedad, la sobrevida libre de proctectomía y las tasas de preservación de órgano.RESULTADOS:Se logró una respuesta clínica completa en 36 pacientes (58.1 %) frente a 59 pacientes (14.8 %) (p < 0,001) a favor del grupo de terapia neoadyuvante total. La sobrevida general a tres años fue similar entre los grupos (85.6 % quimiorradioterapia neoadyuvante estándar frente a 86.0 % terapia neoadyuvante total). La sobrevida libre de metástasis a distancia a los tres años fue del 67.4 % en el grupo de terapia neoadyuvante total y del 77.7 % en el grupo de quimiorradioterapia neoadyuvante estándar. La sobrevida sin proctectomía a los tres años fue del 44 % en el grupo de terapia neoadyuvante total frente al 6 % en el grupo de quimiorradioterapia neoadyuvante estándar. Veintidós pacientes (37.3 % con respuesta clínica completa) en el grupo de quimiorradioterapia neoadyuvante estándar optaron por la preservación de órgano, mientras que 31 pacientes (86.1 % respuesta clínica completa) del grupo de terapia neoadyuvante total eligieron la preservación de órgano.LIMITACIONES:Este estudio es un estudio retrospectivo con un seguimiento más corto de 3 años.CONCLUSIONES:La terapia neoadyuvante total para el cáncer de recto aumentó significativamente la respuesta clínica completa. Esto permitió a los pacientes tener una mayor preservación de órgano sin diferencias significativas en la sobrevida general o el control de la enfermedad. Consulte Video Resumen en http://links.lww.com/DCR/B934 . (Traducción-Dr. Jorge Silva Velazco ).

Prognostic impact of retropharyngeal lymphadenopathy in early-stage HPV-associated oropharyngeal cancer: Implications for staging optimization.

OBJECTIVES: We analyzed the prognostic impact of retropharyngeal lymphadenopathy (RPL) in stage I node-positive HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). MATERIALS AND METHODS: We performed a centralized and blinded radiographic review of the pre-treatment images of 234 consecutive patients with AJCC 8th edition stage I cT1-2N1 HPV-associated OPSCC treated with definitive chemoradiation from 2006 to 2016. Five-year disease control and survival outcomes were reported. The prognostic significance of RPL was evaluated through multivariable analysis adjusting for age, smoking history (<10 vs. >10 pack-years), and systemic regimen received. RESULTS: Median follow-up for surviving patients was 49 months (range: 16-121). RPL was associated with increased locoregional recurrence (LRR) (17.0% v. 3.4%, p = 0.01) and distant metastasis (DM) (29.1% v. 5.9%, p = 0.001) and inferior progression-free survival (PFS) (55.6% v. 88.2%, p < 0.001) and overall survival (OS) (60.6% v. 91.2%, p < 0.001). In stage I patients who did not receive high-dose cisplatin (HDC), RPL was associated with worse LRR (p = 0.04), DM (p = 0.03), PFS (p < 0.001), and OS (p < 0.001), whereas in those who did receive HDC, RPL was only associated with increased DM (p = 0.002) and inferior PFS (p = 0.04). CONCLUSION: This study suggests that RPL portends a poor prognosis in stage I node-positive HPV-associated OPSCC. The negative impact on LRR may have been mitigated by receipt of HDC. Outcomes of stage I disease with RPL were comparable to historical reports of patients with more advanced-stage disease. Incorporation of RPL into future disease staging should be considered in order to optimize risk-stratification and exclude unsuitable candidates from treatment de-intensification efforts.

Watch-and-Wait Compared to Operation for Patients with Complete Response to Neoadjuvant Therapy for Rectal Cancer.

BACKGROUND: Trimodality therapy with neoadjuvant chemoradiation (nCRT), surgery, and adjuvant chemotherapy is the standard treatment for locally advanced rectal cancer. There is evidence that surgery can be deferred in patients with complete response (CR) to nCRT, a strategy termed "watch-and-wait" (WW). We compare WW to surgery in patients with CR to nCRT. STUDY DESIGN: We reviewed records of patients treated with nCRT for nonmetastatic rectal cancer at our institution. Complete endoscopic response (CER) was defined as negative digital rectal exam and negative endoscopy at the end of neoadjuvant therapy (NAT). Clinical complete response (cCR) was defined as CER with negative rectal MRI. Patients with CER refusing surgery were offered WW, which included strict surveillance with digital rectal exam and endoscopy. RESULTS: From January 2015 through February 2019, 465 patients completed nCRT; 406 patients had response assessment, of which 95 (23%) had CER. Of these patients, 53 patients underwent WW and 42 patients had surgery. Median follow-up was 35 months. In the WW group, 3-year freedom from local regrowth was 85%. In the surgical and WW groups, 3-year overall survival, rectal cancer-specific survival, and freedom from nonregrowth recurrence were 100% vs 88% (p = 0.03), 100% vs 95% (p = 0.16), and 92% vs 85% (p = 0.36), respectively. Of the 6 WW patients with local regrowth, 5 (83%) eventually developed distant recurrence. CONCLUSIONS: WW in lieu of surgery appears to be a safe and feasible treatment approach for patients achieving CR to nCRT. Careful evaluation to confirm cCR after nCRT is valuable in selecting patients for WW.

Impact of chemotherapy regimen on treatment outcomes in patients with HPV-associated oropharyngeal cancer with T4 disease treated with definitive concurrent chemoradiation.

OBJECTIVES: Although human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is typically associated with a good prognosis, patients with T4 disease experience relatively high rates of treatment failure. Our aim was to identify predictors of relapse among patients with clinical T4 disease. MATERIAL & METHODS: A retrospective review was conducted of 93 consecutive patients who underwent definitive concurrent chemoradiation for HPV-associated OPSCC with clinical T4 disease from July 2006 to December 2015. Three-year outcomes, including locoregional recurrence (LRR), distant metastasis (DM), overall survival (OS), and cancer-specific survival (CSS), were examined and reported from the date of treatment completion. Multivariable analysis using a Cox proportional hazards model was performed to test associations between outcome and patient and disease characteristics as well as chemotherapy regimen (high-dose cisplatin (HDC) vs. other). RESULTS: Median follow-up for surviving patients was 50 months (range 18-133). For all-comers, 3-year rates of LRR, DM, OS, and CSS were 15%, 19%, 79%, and 86%, respectively. On multivariable analysis, the only factor prognostic for patient outcomes was the chemotherapy regimen. For patients who received HDC vs. an alternative regimen, 3-year LRR, DM, OS, and CSS, were 9% vs. 20% (p = 0.09), 10% vs. 28% (p = 0.04), 89% vs. 67% (p = 0.04), and 96% vs. 77% (p = 0.02), respectively. CONCLUSION: In patients with HPV-associated OPSCC bearing clinical T4 disease, receipt of a concurrent systemic agent other than HDC resulted in increased treatment failure and inferior survival. This analysis suggests that HDC should remain the preferred concurrent regimen for these patients.

Radiotherapy for brain metastases near the end of life in an integrated health care system.

BACKGROUND: To examine radiotherapy (RT) patterns-of-care and utilization at the end of life (EOL) among non-small cell lung cancer (NSCLC) patients with brain metastasis (BrM) in an integrated health care system. METHODS: Central tumor registry identified 5,133 patients diagnosed with NSCLC from 2007-2011. BrM were determined by imaging. Patient and clinical characteristics were obtained by chart abstraction. In addition to abstracted variables, graded prognostic assessment (GPA) score of 0-1 was derived by collected data and tested as a predictor of death within 14 or 30 days of RT. RESULTS: On NSCLC presentation, 10% harbored BrM while 7% developed BrM thereafter. Of 900 BrM patients, 15% were not referred for RT, with median time to death of 21 days. Median time to death for 5% not recommended RT was 48 days. Among those receiving brain RT, 11.9% died within 14 days and 23.3% (cumulatively) died within 30 days of treatment. Over 50% with GPA score 0-1 received RT, 11% within 14 days and 21% within 30 days of death; median survival of GPA score 0-1 patients was 49 days. GPA score 0-1 independently predicted for death within 30 days of RT receipt. CONCLUSIONS: BrM are common in NSCLC, and most patients are referred for brain RT. A surprising proportion of patients received treatment near the EOL, as 23% died within 30 days of RT. GPA score of 0-1 predicted for death within 30 days of treatment. RT referral, recommendation, and timing should be better tailored to life expectancy, and additional benchmarks for quality of care are needed.

Facility characteristics and quality of lung cancer care in an integrated health care system.

INTRODUCTION: In a national, integrated health care system, we sought to identify facility-level attributes associated with better quality of lung cancer care. METHODS: Adherence to 23 quality indicators across four domains (Diagnosis and Staging, Treatment, Supportive Care, End-of-Life Care) was assessed through abstraction of electronic records from 4804 lung cancer patients diagnosed in 2007 at 131 Veterans Health Administration facilities. Performance was reported as proportions of eligible patients fulfilling adherence criteria. With stratification of patients by stage, generalized estimating equations identified facility-level characteristics associated with performance by domain. RESULTS: Overall performance was high for the older (mean age 67.7 years, SD 9.4 years), predominantly male (98%) veterans. However, no facility did well on every measure, and range of adherence across facilities was large; 9% of facilities were in the highest quartile for one or more domain of care, more than 30% for two, and 65% for three. No facility performed consistently well across all domains. Less than 1% performed in the lowest quartile for all. Few facility-level characteristics were associated with care quality. For End-of-Life Care, diagnosis and treatment within the same facility, availability of cancer psychiatry/psychology consultation services, and availability of both inpatient and outpatient palliative care consultation services were associated with better adherence. CONCLUSIONS: Quality of Veterans Health Administration lung cancer care is generally high, though substantial variation exists across facilities. With the exception of the salutary impact of palliative care consultation services on end-of-life quality of care, observed facility-level characteristics did not consistently predict adherence to indicators, suggesting quality may be determined by complex local factors that are difficult to measure.

Patient preference and contraindications in measuring quality of care: what do administrative data miss?

PURPOSE: Prior studies report that half of patients with lung cancer do not receive guideline-concordant care. With data from a national Veterans Health Administration (VHA) study on quality of care, we sought to determine what proportion of patients refused or had a contraindication to recommended lung cancer therapy. PATIENTS AND METHODS: Through medical record abstraction, we evaluated adherence to six quality indicators addressing lung cancer-directed therapy for patients diagnosed within the VHA during 2007 and calculated the proportion of patients receiving, refusing, or having contraindications to recommended treatment. RESULTS: Mean age of the predominantly male population was 67.7 years (standard deviation, 9.4 years), and 15% were black. Adherence to quality indicators ranged from 81% for adjuvant chemotherapy to 98% for curative resection; however, many patients met quality indicator criteria without actually receiving recommended therapy by having a refusal (0% to 14%) or contraindication (1% to 30%) documented. Less than 1% of patients refused palliative chemotherapy. Black patients were more likely to refuse or bear a contraindication to surgery even when controlling for comorbidity; race was not associated with refusals or contraindications to other treatments. CONCLUSION: Refusals and contraindications are common and may account for previously demonstrated low rates of recommended lung cancer therapy performance at the VHA. Racial disparities in treatment may be explained, in part, by such factors. These results sound a cautionary note for quality measurement that depends on data that do not reflect patient preference or contraindications in conditions where such considerations are important.

Minimizing disparities in surgical care: a research focus for the future.

The wide array of questions and opportunities for surgical health services research offers important prospects for inquiry into surgical disparities. In this essay we discuss research that directly or indirectly addresses disparities in surgery, highlighting the strengths and the future directions such research efforts intimate as potential foci of collective attention. We then consider possible research approaches-including community-based participatory models-for confronting disparity and the potential role of research in quality improvement to help achieve the ultimate aim, an optimal level of health care for all.

Capnogram shape in obstructive lung disease.

Small, preliminary studies have suggested that capnograms of obstructive lung disease (OD) exhibit a characteristic shape and that this shape may be correlated to changes in forced expiratory volume in 1 s (FEV(1)). We evaluated the association between capnograms and spirometry from subjects with OD with normal and restrictive lung disease (RD) subjects. The study was conducted in a prospective, nonrandomized manner using a convenience sample of 262 subjects presenting to a pulmonary function laboratory. Capnograms were recorded before pulmonary function testing. Subjects with OD had capnograms that were significantly different from normal and RD subjects. These differences were progressive, increasing with disease severity. The average take-off angle of the ascending phase for severe OD was 7.2 degrees less (95% confidence interval [CI]: 4.0, 10.4) than for normals. The average alveolar plateau elevation angle was 0.8 degrees more (95% CI: 0.14, 1.4) for moderate OD than for normals, whereas the average elevation angle was 3.6 degrees more (95% CI: 2.9, 4.3) for severe OD than for normals. Differences between OD capnograms and normal and RD capnograms, correlating to changes in FEV(1), were sufficiently large enough to suggest that the capnogram could be used to discriminate between OD and normal.

Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma.

Thalidomide (Thal) can overcome drug resistance in multiple myeloma (MM) but is associated with somnolence, constipation, and neuropathy. In previous in vitro studies, we have shown that the potent immunomodulatory derivative of thalidomide (IMiD) CC-5013 induces apoptosis or growth arrest even in resistant MM cell lines and patient cells, decreases binding of MM cells to bone marrow stromal cells (BMSCs), inhibits the production in the BM milieu of cytokines (interleukin-6 [IL-6], vascular endothelial growth factor [VEGF], tumor necrosis factor-alpha [TNF-alpha]) mediating growth and survival of MM cells, blocks angiogenesis, and stimulates host anti-MM natural killer (NK) cell immunity. Moreover, CC-5013 also inhibits tumor growth, decreases angiogenesis, and prolongs host survival in a human plasmacytoma mouse model. In the present study, we carried out a phase 1 CC-5013 dose-escalation (5 mg/d, 10 mg/d, 25 mg/d, and 50 mg/d) study in 27 patients (median age 57 years; range, 40-71 years) with relapsed and refractory relapsed MM. They received a median of 3 prior regimens (range, 2-6 regimens), including autologous stem cell transplantation and Thal in 15 and 16 patients, respectively. In 24 evaluable patients, no dose-limiting toxicity (DLT) was observed in patients treated at any dose level within the first 28 days; however, grade 3 myelosuppression developed after day 28 in all 13 patients treated with 50 mg/d CC-5013. In 12 patients, dose reduction to 25 mg/d was well tolerated and therefore considered the maximal tolerated dose (MTD). Importantly, no significant somnolence, constipation, or neuropathy has been seen in any cohort. Best responses of at least 25% reduction in paraprotein occurred in 17 (71%) of 24 patients (90% confidence interval [CI], 52%-85%), including 11 (46%) patients who had received prior Thal. Stable disease (less than 25% reduction in paraprotein) was observed in an additional 2 (8%) patients. Therefore, 17 (71%) of 24 patients (90% CI, 52%-85%) demonstrated benefit from treatment. Our study therefore provides the basis for the evaluation of CC-5013, either alone or in combination, to treat patients with MM at earlier stages of disease.

Novel therapies for multiple myeloma.

Multiple myeloma (MM) continues to evade cure by conventional therapies, increasing the urgency for new, biologically based treatments. Reviewed in this discussion are novel chemotherapies under clinical trial that capitalize upon greater comprehension of tumor pathophysiology. In targeting tumor biology, these therapies serve as a model of treatment with great potential for improving outcomes in patients with MM.