The impact of the California state lockdown during the COVID-19 pandemic on management of patients with pancreatic ductal adenocarcinoma.

BACKGROUND AND OBJECTIVES: The SARS-COVID-19 pandemic significantly limited healthcare access. We sought to evaluate whether California's lockdown in March 2020 affected staging and time to treatment of pancreatic ductal adenocarcinoma (PDAC). We hypothesized that patients diagnosed after the lockdown would have longer time to treatment and higher stage at presentation. METHODS: We retrospectively identified and categorized 1294 patients presenting to five University of California healthcare systems with a new diagnosis of PDAC into "pre-lockdown" and "post-lockdown" groups based on timing of pathologic diagnosis. RESULTS: In the 12 months pre-lockdown, 835 patients were diagnosed with PDAC, and 459 patients in the 6 months post-lockdown. Demographics, staging, and treatment type were similar between eras. There was a decreased male:female ratio post- versus pre-lockdown (0.97 vs. 1.25; p = 0.03). Time from symptom onset to first treatment was significantly increased among females post-lockdown (p = 0.001). However, overall time from diagnosis to first treatment was shorter in the post-lockdown era (median 23 vs. 26 days, p < 0.001). CONCLUSIONS: The COVID-19 lockdown did not significantly delay initial presentation, diagnosis, or treatment of newly diagnosed PDAC patients. Time from diagnosis to first treatment was shorter post-lockdown. Reduced healthcare utilization for minor complaints and increased telehealth utilization may have contributed.

Regionalization of pancreatic surgery in California: Benefits for preventing postoperative deaths and reducing healthcare costs.

Introduction: Pancreatic cancer (PC) surgery has been associated with improved outcomes and value when performed at high-volume centers (HVC; ≥20 surgeries annually) compared to low-volume centers (LVC). Some have used these differences to suggest that regionalization of PC surgery would optimize patient outcomes and expenditures. Methods: A Markov model was created to evaluate 30-day mortality, 30-day complications, and 30-day costs. The differences in these outcome measures between the current and future states were measured to assess the population-level benefits of regionalization. A sensitivity analysis was performed to evaluate the impact of variations of input variables in the model. Results: Among 5958 new cases of pancreatic cancer in California in 2021, a total of 2443 cases (41 %) would be resectable; among patients with resectable PC, a total of 977 (40 %) patients would undergo surgery. In aggregate, HVC and LVC 30-day postoperative complications occurred in 364 patients, 30-day mortality in 35 patients, and healthcare costs expended managing complications were $6,120,660. In the predictive model of complete regionalization to only HVC in California, an estimated 29 fewer complications, 17 fewer deaths, and a cost savings of $487,635 per year would occur. Conclusions and relevance: Pancreatic cancer (PC) surgery has been associated with improved outcomes and value when performed at high-volume centers (HVC; ≥20 surgeries annually) compared to low-volume centers (LVC). Complete regionalization of pancreatic cancer surgery predicted benefits in mortality, complications and cost, though implementing this strategy at a population-level may require investment of resources and redesigning care delivery models.

Disparities in treatment and survival in early-stage hepatocellular carcinoma in California.

BACKGROUND AND OBJECTIVES: Curative intent therapy is the standard of care for early-stage hepatocellular carcinoma (HCC). However, these therapies are under-utilized, with several treatment and survival disparities. We sought to demonstrate whether the type of facility and distance from treatment center (with transplant capabilities) contributed to disparities in curative-intent treatment and survival for early-stage HCC in California. METHODS: We performed a retrospective analysis of the California Cancer Registry for patients diagnosed with stage I or II primary HCC between 2005 and 2017. Primary and secondary outcomes were receipt of treatment and overall survival, respectively. Multivariable logistic regression and Multivariable Cox proportional hazards regression were used to evaluate associations. RESULTS: Of 19 059 patients with early-stage HCC, only 36% (6778) received curative-intent treatment. Compared to Non-Hispanic White patients, Hispanic patients were less likely, and Asian/Pacific Islander patients were more likely to receive curative-intent treatment. Our results showed that rural residence, public insurance, lower neighborhood SES, and care at non-National Cancer Institute-designated cancer center were associated with not receiving treatment and decreased survival. CONCLUSIONS: Although multiple factors influence receipt of treatment for early-HCC, our findings suggest that early intervention programs should target travel barriers and access to specialist care to help improve oncologic outcomes.

Survival After Contralateral Secondary Breast Cancer by Age Group in California.

PURPOSE: Breast cancer (BC) is the most common secondary cancer and has poorer survival than primary BC (pBC) after any prior malignancy. For BC survivors, developing a contralateral secondary BC (CSBC) is the most frequent second-cancer event and is currently treated similarly to pBC. Identifying survival differences between pBC and CSBC could influence future counseling and treatments for patients with CSBC. METHODS: Women (≥15 years) diagnosed with pBC from 1991 to 2015 in the California Cancer Registry (n = 377,176) were compared with those with CSBC (n = 15,586) by age group (15-39 years, n = 406; 40-64 years, n = 6814; ≥ 65 years, n = 8366). Multivariable logistic regression models assessed factors associated with CSBC. Multivariable Cox proportional hazards regression models assessed BC-specific survival (BCSS), while accounting for the competing risk of death. RESULTS: Across all ages, CSBC patients were more likely to have smaller tumors (T2 vs. T1a; 15-39 yeras: OR 0.25, CI 0.16-0.38; 40-64 years: OR 0.41, CI 0.37-0.45; ≥ 65 years: OR 0.46, CI 0.42-0.51) and lymph node-negative disease (positive vs. negative; 15-39 years: OR 0.86, CI 0.69-1.08; 40-64 years: OR 0.88, CI 0.83-0.93; ≥ 65 years: OR 0.89, CI 0.84-0.94). Additionally, CSBC was associated with worse survival compared with pBC across all ages (15-39 years: HR 2.73, CI 2.30-3.25; 40-64 years: HR 2.13, CI 2.01-2.26; ≥ 65 years: HR 1.52, CI 1.43-1.61). CONCLUSION: BCSS is worse among all women diagnosed with CSBC compared with pBC, with the strongest impact seen in adolescent and young adult women. Worse survival after CSBC, despite associations with smaller tumors and lymph node negativity, suggests that CSBC may need eventual treatment reconsideration.

Breast Cancer Recurrence by Subtype in a Diverse, Contemporary Cohort of Young Women.

BACKGROUND: Young breast cancer (YBC) patients are a unique subpopulation that are often underrepresented in randomized clinical trials. Furthermore, large national cancer databases lack detailed information on recurrence, a meaningful oncologic outcome for young patients. STUDY DESIGN: A retrospective review of YBC patients (age 40 years or younger) with stage I to III breast cancer diagnosed from 2008 to 2018 was performed. Information on clinicopathologic characteristics, demographics, and outcomes was obtained from the electronic health record and chart review. Chi-square and Fisher's exact tests were used for comparisons of categorical variables and parametric and nonparametric tests for continuous variables. RESULTS: The cohort included 1,431 women with a median follow-up of 4.8 years (range 0.3 to 12.9 years). The median age was 37 years (interquartile range 34 to 39). The study population included 598 (41.8%) White, 112 (7.8%) Black, 420 (29.4%) Asian/Pacific Islander, 281 (19.6%) Hispanic, and 20 (1.4%) "other" race/ethnicity patients. Tumor subtype was as follows: [1] hormone receptor (HR) + /human epidermal growth factor 2 (HER2 - ), grade (G) 1 to 2 = 541 (37.8%); [2] HR + /HER2 - , G3 = 268 (18.7%); [3] HR + /HER2 + = 262 (18.3%); [4] HR - /HER2 + = 101 (7.1%); [5] HR - /HER2 - = 259 (18.1%). The majority (64.2%) presented with stage II/III disease. There were 230 (16.1%) recurrences during follow-up; 74.8% were distant. Locoregional-only recurrence was seen in 17 of 463 (3.7%) patients who underwent breast conservation vs 41 of 968 (4.2%) patients undergoing mastectomy (p < 0.001). Recurrence varied by tumor subtype: [1] HR + /HER2 - , G1 to 2 (14.0%); [2] HR + /HER2 - , G3 (20.9%); [3] HR + /HER2 + (11.1%); [4] HR - /HER2 + (22.8%); [5] HR - /HER2 - (17.8%) (p = 0.005). CONCLUSIONS: In this large, diverse YBC cohort, recurrences were most frequent among HR + /HER2 - , G3, or HR - /HER2 + invasive tumors; most were distant. There were numerically similar locoregional-only recurrences after breast conservation vs mastectomy. Additional research is needed to identify predictors of recurrence.

Human soft tissue sarcomas harbor an intratumoral viral microbiome which is linked with natural killer cell infiltrate and prognosis.

BACKGROUND: Groundbreaking studies have linked the gut microbiome with immune homeostasis and antitumor immune responses. Mounting evidence has also demonstrated an intratumoral microbiome, including in soft tissue sarcomas (STS), although detailed characterization of the STS intratumoral microbiome is limited. We sought to characterize the intratumoral microbiome in patients with STS undergoing preoperative radiotherapy and surgery, hypothesizing the presence of a distinct intratumoral microbiome with potentially clinically significant microbial signatures. METHODS: We prospectively obtained tumor and stool samples from adult patients with non-metastatic STS using a strict sterile collection protocol to minimize contamination. Metagenomic classification was used to estimate abundance using genus and species taxonomic levels across all classified organisms, and data were analyzed with respect to clinicopathologic factors. RESULTS: Fifteen patients were enrolled. Most tumors were located at an extremity (67%) and were histologic grade 3 (87%). 40% were well-differentiated/dedifferentiated liposarcoma histology. With a median follow-up of 24 months, 4 (27%) patients developed metastases, and 3 (20%) died. Despite overwhelming human DNA (>99%) intratumorally, we detected a small but consistent proportion of bacterial DNA (0.02-0.03%) in all tumors, including Proteobacteria, Bacteroidetes, and Firmicutes, as well as viral species. In the tumor microenvironment, we observed a strong positive correlation between viral relative abundance and natural killer (NK) infiltration, and higher NK infiltration was associated with superior metastasis-free and overall survival by immunohistochemical, flow cytometry, and multiplex immunofluorescence analyses. CONCLUSIONS: We prospectively demonstrate the presence of a distinct and measurable intratumoral microbiome in patients with STS at multiple time points. Our data suggest that the STS tumor microbiome has prognostic significance with viral relative abundance associated with NK infiltration and oncologic outcome. Additional studies are warranted to further assess the clinical impact of these findings.

Using the canine microbiome to bridge translation of cancer immunotherapy from pre-clinical murine models to human clinical trials.

The microbiome has clearly been established as a cutting-edge field in tumor immunology and immunotherapy. Growing evidence supports the role of the microbiome in immune surveillance, self-tolerance, and response to immune checkpoint inhibitors such as anti PD-L1 and CTLA-4 blockade (1-6). Moreover, recent studies including those using fecal microbial transplantation (FMT) have demonstrated that response to checkpoint immunotherapies may be conferred or eliminated through gut microbiome modulation (7, 8). Consequently, studies evaluating microbiota-host immune and metabolic interactions remain an area of high impact research. While observations in murine models have highlighted the importance of the microbiome in response to therapy, we lack sufficient understanding of the exact mechanisms underlying these interactions. Furthermore, mouse and human gut microbiome composition may be too dissimilar for discovery of all relevant gut microbial biomarkers. Multiple cancers in dogs, including lymphoma, high grade gliomas, melanomas and osteosarcoma (OSA) closely resemble their human analogues, particularly in regard to metastasis, disease recurrence and response to treatment. Importantly, dogs with these spontaneous cancers also have intact immune systems, suggesting that microbiome analyses in these subjects may provide high yield information, especially in the setting of novel immunotherapy regimens which are currently expanding rapidly in canine comparative oncology (9, 10). Additionally, as onco-microbiotic therapies are developed to modify gut microbiomes for maximal responsiveness, large animal models with intact immune systems will be useful for trialing interventions and monitoring adverse events. Together, pre-clinical mechanistic studies and large animal trials can help fully unlock the potential of the microbiome as a diagnostic and therapeutic target in cancer.

Locoregional Liver-Directed Therapies to Treat Unresectable Colorectal Liver Metastases: A Review

An estimated 70% of patients with colorectal cancer will develop liver metastases during the course of their disease. While the first-line treatment for hepatic metastases is resection, most patients with colorectal liver-only or liver-dominant metastases (CRLM) present with unresectable disease and are not surgical candidates. In the past decade, locoregional liver-directed therapies have demonstrated safety and efficacy in the treatment of patients with unresectable CRLM and chemotherapy-refractory disease. These treatments can be used to attempt conversion to surgical resectability, can control local disease progression, and have the potential to prolong survival. However, they have not yet become the standard of care in many practices. Each treatment has unique risks, and the clinical data are heterogeneous and thus difficult to interpret. In this article, we will review the most recent, high-impact literature on 3 common locoregional therapies used in the treatment of patients with unresectable CRLM: hepatic artery infusion pump chemotherapy, stereotactic body radiation therapy, and selective internal radiation therapy with yttrium-90 embolization. Ultimately, for this patient population, clinical decision-making requires a multidisciplinary discussion which should take into account individual patient characteristics and clinical expertise available at the treatment facility.

The Impact of Preexisting Psychiatric Disorders on Outcomes After Pancreatic Cancer Surgery.

OBJECTIVES: Comorbid psychiatric illness has been associated with worse outcomes after some major surgical procedures. We hypothesized that patients with preexisting mood disorders would have worse postoperative and oncologic outcomes after pancreatic cancer resection. METHODS: This retrospective cohort study analyzed Surveillance, Epidemiology, and End Results patients with resectable pancreatic adenocarcinoma. A preexisting mood disorder was classified if a patient was diagnosed and/or treated with medication approved for depression/anxiety within 6 months before surgery. RESULTS: Of 1305 patients, 16% had a preexisting mood disorder. Mood disorders had no impact on hospital length of stay (12.9 vs 13.2 days, P = 0.75), 30-day complications (26% vs 22%, P = 0.31), 30-day readmissions (26% vs 21%, P = 0.1), or mortality (30 days: 3% vs 4%, P = 0.35); only an increased 90-day readmissions rate (42% vs 31%, P = 0.001) was observed. No effect on adjuvant chemotherapy receipt (62.5% vs 69.2%, P = 0.06) or survival (24 months, 43% vs 39%, P = 0.44) was observed. CONCLUSIONS: Preexisting mood disorders influenced 90-day readmissions after pancreatic resection, but not other postoperative or oncologic outcomes. These findings suggest that affected patients should be expected to have outcomes similar to patients without mood disorders.

Is Improved Survival in Early-Stage Pancreatic Cancer Worth the Extra Cost at High-Volume Centers?

BACKGROUND: Volume of operative cases may be an important factor associated with improved survival for early-stage pancreatic cancer. Most high-volume pancreatic centers are also academic institutions, which have been associated with additional healthcare costs. We hypothesized that at high-volume centers, the value of the extra survival outweighs the extra cost. STUDY DESIGN: This retrospective cohort study used data from the California Cancer Registry linked to the Office of Statewide Health Planning and Development database from January 1, 2004 through December 31, 2012. Stage I-II pancreatic cancer patients who underwent resection were included. Multivariable analyses estimated overall survival and 30-day costs at low- vs high-volume pancreatic surgery centers. The incremental cost-effectiveness ratio (ICER) and incremental net benefit (INB) were estimated, and statistical uncertainty was characterized using net benefit regression. RESULTS: Of 2,786 patients, 46.5% were treated at high-volume centers and 53.5% at low-volume centers. There was a 0.45-year (5.4 months) survival benefit (95% CI 0.21-0.69) and a $7,884 extra cost associated with receiving surgery at high-volume centers (95% CI $4,074-$11,694). The ICER was $17,529 for an additional year of survival (95% CI $7,997-$40,616). For decision-makers willing to pay more than $20,000 for an additional year of life, high-volume centers appear cost-effective. CONCLUSIONS: Although healthcare costs were greater at high-volume centers, patients undergoing pancreatic surgery at high-volume centers experienced a survival benefit (5.4 months). The extra cost of $17,529 per additional year is quite modest for improved survival and is economically attractive by many oncology standards.

Management of early hepatocellular carcinoma: results of the Delphi consensus process of the Americas Hepato-Pancreato-Biliary Association.

BACKGROUND: There are many potential treatment options for patients with early stage hepatocellular carcinoma (HCC) and practice patterns vary widely. This project aimed to use a Delphi conference to generate consensus regarding the management of small resectable HCC. METHODS: A base case was established with review by members of AHPBA Research Committee. The Delphi panel of experts reviewed the literature and scored clinical case statements to identify areas of agreement and disagreement. Following initial scoring, discussion was undertaken, questions were amended, and scoring was repeated. This cycle was repeated until no further likelihood of reaching consensus existed. RESULTS: The panel achieved agreement or disagreement consensus regarding 27 statements. The overarching themes included that resection, ablation, transplantation, or any locoregional therapy as a bridge to transplant were all appropriate modalities for early or recurrent HCC. For larger lesions, consensus was reached that radiofrequency ablation and microwave ablation were not appropriate treatments. CONCLUSION: Using a validated system for identifying consensus, an expert panel agreed that multiple treatment modalities are appropriate for early stage HCC. These consensus guidelines are intended to help guide physicians through treatment modalities for early HCC; however, clinical decisions should continue to be made on a patient-specific basis.

The Role of Radiation Therapy in Addition to Lumpectomy and Hormone Therapy in Men 70 Years of Age and Older with Early Breast Cancer: A NCDB Analysis.

PURPOSE: Current treatment guidelines for male breast cancer are guided by female-only trials despite data suggesting distinct clinicopathologic differences between sexes. We sought to evaluate whether radiation therapy (RT) after lumpectomy was associated with equivalent survival among men > 70 years of age with stage I, estrogen receptor (ER) positive tumors, as seen in women from the Cancer and Leukemia Group B (CALGB) 9343 trial. METHODS: We performed a retrospective analysis of 752 stage I, ER-positive male breast cancer patients ≥ 70 years who were treated with hormone therapy and surgery, with or without RT, from the National Cancer Database between 2004 and 2014. Patients were categorized based on surgery and RT (lumpectomy alone, lumpectomy with RT, and mastectomy alone). Multivariable Cox proportional hazards regression analysis was used to compare overall survival between treatment groups. RESULTS: Most patients underwent total mastectomy, with only 32.6% treated with lumpectomy. Of those who underwent lumpectomy, 72.7% received adjuvant RT. In multivariate analysis, there was no statistical difference in overall survival when comparing lumpectomy alone and lumpectomy with RT (aHR 0.72 [95% CI 0.38-1.37], p = 0.31) or when comparing lumpectomy (alone or with RT) and mastectomy (aHR 1.28 [95% CI 0.88-1.87], p = 0.20). CONCLUSIONS: In this national sample of elderly men with ER-positive early-stage disease treated with endocrine therapy, there were no significant differences in overall survival when comparing lumpectomy alone and lumpectomy with RT, or lumpectomy (alone or with RT) and mastectomy. These results suggest that less aggressive treatment may be appropriate for a subset of male breast cancer patients.

Structural Optimization and Enhanced Prodrug-Mediated Delivery Overcomes Camptothecin Resistance in High-Risk Solid Tumors.

Camptothecins are potent topoisomerase I inhibitors used to treat high-risk pediatric solid tumors, but they often show poor efficacy due to intrinsic or acquired chemoresistance. Here, we developed a multivalent, polymer-based prodrug of a structurally optimized camptothecin (SN22) designed to overcome key chemoresistance mechanisms. The ability of SN22 vs. SN38 (the active form of irinotecan/CPT-11) to overcome efflux pump-driven drug resistance was tested. Tumor uptake and biodistribution of SN22 as a polymer-based prodrug (PEG-[SN22]4) compared with SN38 was determined. The therapeutic efficacy of PEG-[SN22]4 to CPT-11 was compared in: (i) spontaneous neuroblastomas (NB) in transgenic TH-MYCN mice; (ii) orthotopic xenografts of a drug-resistant NB line SK-N-BE(2)C (mutated TP53); (iii) flank xenografts of a drug-resistant NB-PDX; and (iv) xenografts of Ewing sarcoma and rhabdomyosarcoma. Unlike SN38, SN22 inhibited NB cell growth regardless of ABCG2 expression levels. SN22 prodrug delivery resulted in sustained intratumoral drug concentrations, dramatically higher than those of SN38 at all time points. CPT-11/SN38 treatment had only marginal effects on tumors in transgenic mice, but PEG-[SN22]4 treatment caused complete tumor regression lasting over 6 months (tumor free at necropsy). PEG-[SN22]4 also markedly extended survival of mice with drug-resistant, orthotopic NB and it caused long-term (6+ months) remissions in 80% to 100% of NB and sarcoma xenografts. SN22 administered as a multivalent polymeric prodrug resulted in increased and protracted tumor drug exposure compared with CPT-11, leading to long-term "cures" in NB models of intrinsic or acquired drug resistance, and models of high-risk sarcomas, warranting its further development for clinical trials. SIGNIFICANCE: SN22 is an effective and curative multivalent macromolecular agent in multiple solid tumor mouse models, overcoming common mechanisms of drug resistance with the potential to elicit fewer toxicities than most cancer therapeutics.