Brielle Benyon

The combination of transarterial chemoembolization (TACE), lenvatinib (Lenvima), and PD-1 checkpoint blockade demonstrated tolerable safety and efficacy in patients with unresectable advanced hepatocellular carcinoma (uHCC), according to data presented during the 2022 ASCO Gastrointestinal Cancers Symposium.

“There are few scientific trials to back up the safety and efficacy of TACE+ TKI+PD-1 antibody for the treatment of uHCC and conversion resection. In this study, we explored the safety and efficacy of the TACE+TKI+PD-1 antibody in uHCC,” the study authors wrote.

The prospective, multicenter, cohort study (NCT04997850) enrolled 38 patients who received TACE plus 12 mg of lenvatinib if their weight was 60 kg or higher, and 8 mg of lenvatinib for those who weighed less than 60 kg, plus camrelizumab and sintilimab. Individuals in the control group only received TACE.

To be eligible for the trial, patients had to be between the ages of 18 and 70, and have HCC confirmed by histopathology or cytology. Participants could not have had system treatment history, and needed an ECOG PS score of 0-1, Child-Pugh A/B, BCLC stage B/C.

The majority of study participants (92.1%) were male. Disease etiology categories consisted of the following: HBV, 76.3% (n=29); HCV, 2.6% (n=1); non-HBV or HCV, 21.1% (n=8). Thirty-six patients (94.7%) had an ECOG score of 0, while 2 patients (5.3%) had a score of 1. Nineteen patients (50%) had 1 tumor; 15 patients (39.5%) had 2 tumors; and 4 patients (10.5%) had 3.

Results showed that at a median follow-up of 33.34 weeks, the conversion resection rate was 50% (n=19), and the conversion success rate was 52.6% (n=20). Among the 19 patients who converted to resection, 5 achieved a complete pathological response and 1 had a major pathological response, per mRECIST criteria.

At 48 weeks, the overall survival (OS) rate was 96.4% (95% CI, 92.9-99.9%) and the progression-free survival (PFS) rate was 91.7% (95% CI, 85.8%-97.4%).

These findings support Chinese HCC guidelines, which recommend TACE, TKI and anti—PD-1 therapy for patients with intermediate or advanced HCC — a population that makes up more than 70% of HCC cases.

While there were no level 4 or 5 treatment-related adverse events (TRAEs), 22 patients experienced level 3 TRAEs. Three led to dose reduction and 0 had to stop therapy as a result of TRAEs.

The most common all-grade TRAEs were abdominal pain (71%; n=27), aspartate aminotransferase increase (65.8%; n=25), alanine aminotransferase increase (65.8%; n=25), and hypertension (57.9%; n=22).

“TACE + lenvatinib + PD-1 antibody is safe and effective, and conversion resection after triple-treatment is feasible for uHCC,” the authors concluded.

Zhang X, Zhu X, Liu C, et. al. The safety and efficacy of transarterial chemoembolization (TACE) + lenvatinib + programmed cell death protein a (PD-1) antibody of advanced unresectable hepatocellular carcinoma. Presented at: 2022 ASCO Gastrointestinal Cancers Symposium. Jan. 20-22, 2022.

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The combination of transarterial chemoembolization, lenvatinib, and PD-1 checkpoint blockade demonstrated tolerable safety and efficacy in patients with unresectable advanced hepatocellular carcinoma.

TACE Plus Lenvatinib and a PD-1 Antibody Appears Safe, Effective in Advanced uHCC 

Findings presented during the ASH Annual Meeting & Exposition 2021 showed that having knowledge of incurable disease correlate with higher rates of psychosocial distress and symptom burden and lower quality of life (QOL) in patients with multiple myeloma. Further, some patients still believed that they could still be cured.

“Multiple myeloma is an incurable hematologic malignancy requiring long-term continuous therapy. Despite its chronic and unrelenting course, studies examining quality of life, psychosocial distress and prognostic awareness by line of therapy are lacking,” study author Betsy O’Donnell, MD, director of Lifestyle Medicine and medical oncologist in the Multiple Myeloma Disease Center at Massachusetts General Hospital said while presenting the findings.

In an attempt to fill this research need, O’Donnell and her team conducted a cross-sectional, multi-site study of 180 patients with multiple myeloma. Sixty patients were newly diagnosed, 60 underwent 2-3 lines of therapy, and 60 underwent 4 or more lines of therapy. Individuals on maintenance therapy were excluded. A validated questionnaire was used to analyze patient’s feelings of QOL, symptom burden, fatigue, psychological distress, and perceptions of prognosis.

The average age of study participants was 68, 52% were female, and 89% were white.

Findings revealed that there was no significant difference in QOL, symptom burden, fatigue, depression, anxiety, or PTSD symptoms by line of therapy. Overall, 24% of patients were experiencing clinical depression, 24% anxiety and 24% PTSD.

The majority (84%) of patients reported that it was “extremely” or “very” important to know about their prognosis, with 66% stating that they received adequate information on their prognosis.

“Patients reported that prognostic information was extremely or very helpful in making decisions about treatment, coping with disease and preparing for thefuture,” O’Donnell explained.

Interestingly, 85% of patients reported that their oncologist told them that their cancer was curable, but only 31% acknowledged that they were terminally ill, and 42% reported that they believed their cancer was curable.

Patients who were receiving 2-3 lines of therapy were more likely than those getting their first line of therapy to acknowledge their terminal illness (36.7% versus 19.6%; 

=0.045) and that their disease was not curable (90% versus 75.9%; 

“With regard of treatment goals, nearly 23% of all patients report that their primary goal of therapy was cure, and 18% reported that their oncologists’ primary goal was cure,” O’Donnell said. “Although the majority reported that their oncologist had told them their cancer was incurable, a substantial proportion still report that they believe that they were curable.”

The patients who acknowledged their terminal illness reported higher rates of depression, anxiety, and symptom burden, as well as lower QOL.

O’Donnell concluded, “Multiple myeloma patients undergoing treatment experience impaired quality of life and elevated psychological distress across the disease and continued irrespective of their line of therapy … Interventions are needed to improve patient QOL, reduce their psychological distress and cultivate adaptive coping strategies that may help improve the patient experience over the multiple myeloma disease course.”

O’Donnell E, Shapiro Y, Nadeem O, et al. Quality of life, psylogical distress, and prognostic awareness in patients with multiple myeloma. Presented at: Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 4082

Having knowledge that their multiple myeloma was incurable was associated with poor quality of life outcomes in patients.

Prognostic Awareness in Patients with Multiple Myeloma Negatively Affects Quality of Life

Encouraging response rates and improved well-being were observed in patients with diffuse relapsed/refractory large B-cell lymphoma (DLBCL) and other non-Hodgkin B-cell lymphomas (B-NHL) who were treated with naratuximab emtansine in combination with rituximab (Rituxan) according to data presented at the 63rd Annual ASH Meeting and Exposition.

“Patients with DLBCL are treated with curative intent and oftentimes are cured. However, not all patients are cured, and patients with relapsed/refractory non-Hodgkin lymphoma and particularly aggressive lymphomas like DLBCL who are not candidates for stem cell transplant or chimeric antigen receptor [CAR] T-cell therapy have a particularly poor prognosis and there’s clearly a medical need for new treatment options,” investigator Moshe Y. Levy, MD, a hematologist at Texas Oncology-Baylor Charles A. Sammons Cancer Center, said during the ASH presentation.

The open-label, phase 2 study included 100 patients: 80 with DLBCL, 14 with follicular lymphoma, and 6 with mantle cell lymphoma. All participants were ineligible for stem cell transplant and were previously treated with 1-6 prior therapies.

Part 1 of the study was a safety run-in followed by expansion, where patients received 0.7 mg/kg of naratuxumab emtansine (an antibody-drug conjugate) plus 375 mg/m2 of rituximab every 3 weeks (Q3W).

Then, Part 2 of the study involved only patients with relapsed/refractory DLBCL (n = 66). Patients in this portion of the research were assigned to either cohort A, which was the Q3W regimen (n = 33), or cohort B (n = 30), where participants received 0.4, 0.2, and 0.2 mg/kg of naratuximab emtansine on days, 1,8, and 15 of a 21-day cycle plus 375mg/m2 of rituximab on day 1. Patients underwent 6 cycles of treatment with the option for extension.

“This study did include a lot of patients that are often excluded from DLBCL trials, and the inclusion criteria here were quite broad and very consistent with patients that we routinely see in our clinic,” Levy said.

The primary endpoints of the study were safety and overall response rate (ORR), and the researchers also evaluated pharmacokinetics and pharmacodynamics, as well as quality of life as described by the FACTLym quality of life questionnaire.

Follow-up was up to 1 year after a patient received his or her first dose on the trial.

The ORR in the efficacy evaluable patients with DLBCL was 44.7%, which included 24 patients (31.6%) who experienced a complete response (CR) and 10 (13.2%) with partial responses (PR). Nine patients (11.8%) had stable disease (SD) and 33 (43.4%) had progressive disease.

In Part 1, there were 16 patients with DLBCL who were efficacy evaluable: 6 were primary refractory and 10 were refractory to the last line. In this cohort, the ORR was 25%.

There were 30 efficacy evaluable patients in each of cohorts A and B in Part 2 of the study. Each cohort had an ORR of 50%, with 43.3% and 33.3% CR in cohorts A and B, respectively. Median duration of response (DOR) in the DLBCL patients was not reached (lower 95% CI, 12 months), and median duration of follow-up in patients who responded was 15 months (95% CI, 9-18 months).

For patients with follicular lymphoma, the ORR was 57%, including 5 CRs, 3 PRs, 3 SD, and 3 PD. At a mediation duration of follow-up of 21.8 months, average DOR was not reached (lower 95% CI, 19 months). In patients with mantle cell lymphoma, 4 of the 6 were efficacy evaluable. Two patients had CR and 2 had PD.

Regarding quality of life, patients with DLBCL in cohorts A and B who responded to treatment reported a clinically meaningful improvement of 3 points (SD 6.6) on the lymphoma subscale of the FACT-Lym QoL.

“Change from baseline until the last assessment up to and including the end of treatment was assessed in both responders and non-responders. On this index, 38% of the responders had a clinically important improvement of at least 7 points, versus only 8% of non-responders,” Levy said. “So we concluded that the treatment was associated with a significant increase in well-being in 38% of responders.”

Most observed grade 3 or 4 treatment-emergent adverse events (AEs) were hematologic events, which were “certainly quite manageable and oftentimes not as consequential,” Levy explained.

The most common AE was neutropenia (54%), which included 5% pneumonia or lung infection and febrile neutropenia in 4%. Eight patients discontinued therapy due to AEs, and of the 10 grade 5 AEs, only 2 were considered to be related to treatment. There were 3 liver-related AEs greater than grade 3, and 2 cases of non-serious neuropathy that was stage 3 or higher.

“Naratuximab plus Rituxan can certainly represent a new treatment option for relapsed/refractory non-Hodgkin lymphoma, especially relapsed/refractory DLBCL, which is still a particularly important unmet need for folks not candidates for potentially curative therapy with CAR-T or high-dose chemotherapy and autologous stem cell rescue,” Levy said. “Furthermore, the AE profile as well as efficacy of this treatment lends itself quite well to additional combinations to be explored.”

Levy MY, Jagadeesh D, Grudeva-Popova Z, et. al. Safety and efficacy of CD37-targeting naratixumab emtansine plus rituximab in diffuse large B-cell lymphoma and other non-Hodgkin lymphomas – a phase 2 study. Presented at: 2021 ASH Annual Meeting; December 9-14, 2021; Atlanta, GA. Abstract 526.

The efficacy and safety of naratuximab emtansine plus rituximab appear impressive for patients with B-cell non-Hodgkin lymphomas who are ineligible for stem cell transplant or chimeric antigen receptor T-cell therapy.

Naratuximab Emtansine Plus Rituximab May Be an Alternative to CAR T Cells and Other Standard Therapies for R/R DLBCL

In patients with cancer, anxiety and depression can influence how they view cancer clinical trials, which leads to low enrollment, according to findings presented at the 2021 American Society of Hematology Annual Meeting and Exposition.

“Although thousands of cancer clinical trials are available today, engagement remains low, with only 2-7% of cancer patients in the United States participating in cancer clinical trials,” study author Victoria Morris, PhD, research director at the Cancer Support Community, said while presenting the findings. “There are many systemic and person-level factors that can contribute to this lack of engagement…However, another contributing factor that can impact participation is attitudinal barriers such as fear-based perceptions about what it means to participate in a cancer clinical trial.”

The observational, cross-sectional study involved 625 patients with blood cancer (46.4% myeloma; 19.5% chronic lymphocytic leukemia; 11.4% non-Hodgkin lymphoma; 4.0% acute myeloid leukemia; 3.5% Hodgkin lymphoma; 3.2% chronic myeloid leukemia; 1.6% acute lymphocytic leukemia; 1.3% myeloproliferative neoplasm; 7.4% other lymphoma; and 1.8% other leukemia).

Participants filled out Cancer Support Community’s Cancer Experience Registry, which includes sociodemographic and clinical data as well as ranking on a scale of 0 (strongly disagree) to 4 (strongly agree) on 8 statements about clinical trials. Participants also completed the Anxiety and Depression subscales from the Patient-Reported Outcomes Measurement Information System (PROMIS-29v2.0).

PROMIS responses were averaged to determine the level of depression and anxiety on a 5-point scale, while 8 hierarchical regression models were examined — one for each of the clinical trial perception variables — to determine the impact that depression and anxiety had on how patients think of clinical trials. Clinical history and sociodemographic variables were controlled for.

“Regression models indicated that psychosocial distress comprised of both depression and anxiety accounted for a significant amount of variance in 7 of the 8 clinical trial perceptions, above and beyond the controls,” Morris said. “Depression and anxiety — 2 psychosocial factors that are highly prevalent in the cancer space — can bias attention in was that alter perceptions, thus potentially playing a role in trial perceptions.”

The average anxiety and depression score was 1.91 (SD = .93). These psychosocial effects were predictors for the following perceptions:

“I would be unable to fulfill trial requirements due to logistical barriers.” (15% of participants responded “agree” or “strongly agree”; 

“I don’t trust the medical establishment and fear I will be used as a ‘Guinea pig.’” (13%; 

“I am uncomfortable being randomly assigned.” (53%; 

“I fear receiving a placebo (for example, a sugar pill) in a clinical trial.” (49%; 

“I don’t understand what clinical trials are.” (8%; 

“There are no clinical trials available in my community.” (30% 

“I fear side effects that might come with treatment on a clinical trial.” (46% 

The only perception that anxiety and depression did not impact, however, was the belief that insurance would not cover the clinical trial.

These findings show that clinicians should consider psychosocial barriers when discussing the options of clinical trial participation to patients.

“While attempts to alter perceived barriers to participation in cancer clinical trials often focus on information dissemination to address misconceptions about cancer clinical trials, the present study indicates that underlying person-level psychological factors may shape perceptions about cancer clinical trials and need to be considered,” Morris said

This study should just be the first of more research that should analyze the magnitude and directionality of these findings, according to Morris.

“But one thing is clear: the decision about whether to engage in a cancer clinical trial is complex and multi-faceted, and any and all barriers to participation need to be considered so that we can better empower patients in their treatment decision making.”

1. Rogers K, Morris V, Miller M, LeBlanc T. The relationship between depression, anxiety, and clinical trial perceptions among patients with hematologic cancer. Presented at: 63rd ASH Annual Meeting and Exposition; December 11-14, 2021. Atlanta, GA. Abstract 1901.

In patients with cancer, anxiety and depression can influence how they view cancer clinical trials, which leads to low enrollment.

Patient Perceptions of Cancer Clinical Trials Affected by Anxiety, Depression

In the TULIP trial, treatment with [vic]-trastuzumab duocarmazine (SYD985) extended progression-free survival (PFS) over standard physician’s choice chemotherapy in patients with pretreated HER2-positive locally advanced or metastatic breast cancer (MBC), according to data presented at the ESMO Congress 2021.

“([vic]-trastuzumab duocarmazine) can provide a new treatment option for patients with pretreated, locally advanced or metastatic HER2-positive breast cancer,” said study author Cristina Saura Manich, MD, PhD, head of the Breast Cancer Unit of the Service of Medical Oncology at Vall d’Hebron University Hospital in Barcelona, Spain, while presenting the findings.

The phase III TULIP trial (NCT03262935) involved 437 patients with HER2-positive locally advanced MBC who underwent 2 or more previous treatments or at least 1 previous treatment with T-DM1. Participants were randomized 2:1 to receive either 1.2 mg/kg of [vic]-trastuzumab duocarmazine every 3 weeks (n=291) or physician’s choice chemotherapy (n=146), which included lapatinib plus capecitabine; trastuzumab (Herceptin) plus capecitabine; trastuzumab plus vinorelbine; or trastuzumab plus eribulin. Patients continued treatment until progression or unacceptable toxicity.

“The baseline demographics, disease characteristics and prior treatments related to breast cancer were similar between the treatment groups,” Manich said, explaining that the median number of prior treatments was 4 (range, 1-16) in the experimental group and 5 in the physician’s choice group. Time from MBC diagnosis to study enrollment was 4.0 years and 5.0 years in the [vic]-trastuzumab duocarmazine and control arms, respectively.

The most common prior treatments were trastuzumab (89.3% and 86.4% in the [vic]-trastuzumab duocarmazine and physician’s choice arms, respectively), ado-tarstuzumab emtansine (87.6% and 87.5%, respectively), and pertuzumab (Perjeta) (60.8% and 57.5%, respectively).

The primary endpoint of centrally reviewed improved PFS was met, with a centrally reviewed median PFS of 7.0 months (95% CI, 5.4-7.2 months; 

 =0.002) for patients on [vic]-trastuzumab duocarmazine compared with 4.9 months (95% CI, 4.0-5.5 months) for physician’s choice chemotherapy. Investigator-assessed PFS was also better with [vic]-trastuzumab duocarmazine, at 6.9 months (95% CI, 6.0-7.2 months) versus 4.6 months (95% CI, 4.0-5.6 months).

Secondary endpoints included overall survival (OS), which was 20.4 months and 16.3 months, (HR 0.83; 95% CI, 0.62-1.09; 

 =0.153), which was not statistically significant. Overall response rate (ORR) and health-related quality of life (HRQoL) were also secondary endpoints, though there was no statistically significant difference between [vic]-trastuzumab duocarmazine and physician’s choice chemotherapy observed in the study.

“These preliminary results are supportive to the primary analysis of PFS, and subsequent analysis of the OS will be planned when the data (are) more mature,” Manich said.

[vic]-trastuzumab duocarmazine is an antibody drug conjugate that targets the HER2 protein and is composed of trastuzumab that is bound to duocarmycin, a linker drug.

The most frequently observed adverse events (AEs) for [vic]-trastuzumab duocarmazine were conjunctivitis (38.2%), keratitis (38.2%), and fatigue (33.3%). Interstitial lung disease/pneumonitis occurred in 7.6% of patients on the drug, including 5.2% grade 1-2 events, and 2 grade 5 events. More than a third (35.4%) of patients discontinued treatment with [vic]-trastuzumab duocarmazine due to adverse events, most frequently citing eye disorders (20.8%) or respiratory disorders (6.3%).

Manich CS, O’Shaughnessy J, Aftimos PG, et al. LBA15 – Primary outcome of the phase III SYD985.002/TULIP trial comparing [vic-]trastuzumab duocarmazine to physician’s choice treatment in patients with pre-treated HER-positive locally advanced or metastatic brast cancer. Presented at: 2021 ESMO Annual Congress. September 16-21, 2021.

Progression-free survival after [vic]-trastuzumab duocarmazine treatment in patients with pretreated, metastatic HER2-positive breast cancer was improved compared with physician’s choice chemotherapy. 

[vic]-Trastuzumab Duocarmazine Prolongs PFS in Pretreated, HER2+ mBC

Improved survival outcomes were reported with the addition of nivolumab (Opdivo) to either ipilimumab (Yervoy) or chemo-therapy vs chemotherapy alone in the frontline treatment of patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC). Updated data from the phase 3 CheckMate 648 trial (NCT03143153) were presented at the 2021 American Society of Clinical Oncology Annual Meeting.

“Advanced [ESCC] carries a poor prognosis, with a median survival of around 10 months,” said Ian Chau, MD, consultant medical oncologist at the Royal Mardsen Hospital in the United Kingdom.

CheckMate 648 is a randomized phase 3 trial evaluating the efficacy of the following treatment regimens in adult patients with histologically confirmed squamous cell carcinoma or adenosquamous cell carcinoma of the esophagus that is deemed inoperable and cannot be treated with chemoradiation with curative intent:

Nivolumab plus chemotherapy: nivolumab 240 mg on day 1 and day 15; fluorouracil 800 mg/m² per day on day 1 -5 for 5 days; and cisplatin 80 mg/m² on day 1 of the 4-week cycle (n = 321).

Nivolumab plus ipilimumab: nivolumab 3 mg/kg every 2 weeks, followed by ipilimumab 1mg/kg every 6 weeks until unacceptable toxicity or disease progression (n = 325).

Chemotherapy alone: cisplatin and fluorouracil (n = 324).

Eligible patients had an ECOG performance score of 0 to 1, measurable disease, and no prior systemic treatment for advanced disease. The primary end points in the trial were overall survival (OS) and progression-free survival (PFS) in patients whose tumors had PD-L1 expression greater than or equal to 1%.

Secondary end points were OS and PFS in all patients, as well as objective response rate (ORR), both in patients with PD-L1 greater than or equal to 1% and all patients.

At a minimum follow-up of 12.9 months, median OS in patients with PD-L1 greater than or equal to 1% in the nivolumab plus chemotherapy arm (n = 158) was 15.4 months (95% CI, 11.9-19.5), and was 13.7 months (95% CI, 11.217.0) in the nivolumab plus ipilimumab arm (n = 158). In the patients who were PD-L1 positive in the chemotherapy alone arm (n = 157) median OS was 9.1 months (95% CI, 7.7-10.0; 

“This translates into over 6 months improvement in median OS when comparing nivolumab plus chemotherapy to chemotherapy alone,” Chau said. “But importantly, if you look at the latter parts of the [OS] curve, they’re widely separated in favor of nivolumab plus chemo-therapy, meaning that there were more patients with prolonged [OS].”

In the overall study population, the median OS in the nivolumab plus chemotherapy arm was 13.2 months (95% CI, 11.1-15.7); 12.8 months in the nivolumab plus ipilimumab arm (95% CI, 11.3-15.5 months); and 10.7 months in the chemo arm (95% CI, 9.4-11.9; 

The primary end point of PFS per blind independent committee review was not met in patients whose tumors were PD-L1 positive (HR, 1.02; 95% CI, 0.73-1.43). The ORR in patients with PD-L1–positive tumors given nivolumab plus ipili-mumab was 35% (95% CI, 28-43). In the chemotherapy arm it was 20% (95% CI, 14-27). In all patients, ORR was 28% (95% CI, 23-33) and 27% (95% CI, 22-32) in the nivolumab plus ipilimumab and nivolumab plus chemotherapy arms, respectively.

Regarding safety, the most common (occur-ring in 10% or more) treatment-related adverse events (TRAEs) for the chemotherapy-contain-ing arms were nausea, decreased appetite, and stomatitis. For the nivolumab/ipilimumab arm, common TRAEs were rash, pruitis, and hypothyroidism. Notably, incidence of TRAEs was consistent with all treated patients across all arms for patients whose tumor cell had PD-L1 expression greater than or equal to 1%.

Ultimately, these regimens have the potential to drastically improve outcomes in patients with unresectable advanced or metastatic esophageal squamous cell carcinoma—a group that tends to have poor prognoses.

“Nivolumab plus chemotherapy [and] nivolumab plus ipilimumab each represent a new potential first-line standard of care for patients with advanced [ESCC], based on the results of CheckMate 648, the largest randomized control trial conducted in this setting to date,” Chau said.

1. Chau I. First results from the CheckMate 648 study evaluating nivolumab plus ipilimumab or nivolumab plus chemotherapy versus che-motherapy as first-line treatment for advanced esophageal squamous cell carcinoma. Presented at: 2021 ASCO Annual Meeting Press Program, May 28, 2021.

2. A study to evaluate efficacy in subjects with esophageal cancer treat-ed with nivolumab and ipilimumab or nivolumab combined with fluorouracil plus cisplatin versus fluorouracil plus cisplatin (CheckMate 648). Clinical-Trials.gov. Updated May 7, 2021. Accessed June 1, 2021. https://clinical-trials.gov/ct2/show/NCT03143153

Improved survival outcomes were reported with the addition of nivolumab to either ipilimumab or chemo-therapy vs chemotherapy alone in the frontline treatment of patients with unresectable advanced or metastatic esophageal squamous cell carcinoma.