Southwest Oncology Group Research Articles

“PROBE”ing the Role of Cytoreductive Nephrectomy in Advanced Renal Cancer

The Southwest Oncology Group (SWOG)1931 trial, also known as PROBE (ClinicalTrials.gov Identifier: NCT04510597) is a phase III study evaluating the role of cytoreductive nephrectomy (CN) in metastatic renal cell cancer (RCC). Kidney cancer presenting with synchronous metastases has demonstrated shorter survival outcome compared to the patients relapsing with metastases after nephrectomy. Previously, CN has been associated with survival improvement when interferon-based systemic therapy was used. In the setting of antivascular therapy sunitinib, a prospective randomized clinical trial demonstrated no benefit of CN. Immune checkpoint-based combination therapy has now become the standard-of-care in the frontline setting for RCC. The role of nephrectomy or primary resection has not been evaluated in the setting of immune checkpoint-based systemic therapy. The sequence and optimal timing of nephrectomy is also not established. The PROBE study design attempts to answer the question whether CN has an impact on overall survival outcomes in RCC within the context of immune checkpoint-based combination regimens. The study requires starting with systemic therapy; any one of the FDA approved immunotherapy-based regimens at the time the study was activated are permitted. The disease status and response are evaluated at 9–12 weeks of therapy and then consented patients are randomized 1:1 to receive CN or to continue systemic therapy. The patients who have rapid disease progression are considered ineligible for randomization as they need a switch in systemic therapy. Both groups should continue systemic therapy as long as they are tolerating the treatment and continuing to derive clinical benefit. Quality-of-life, tumor genomic testing, microbiome, radiomics and circulating tumor DNA assessments as predictive biomarkers are planned as study correlatives. The study hypothesis is that CN will improve OS in synchronous metastatic RCC when surgery is performed after starting systemic immune checkpoint-based combination therapy. A potential mechanism leading to improved survival is the broader antigen spread and higher neoantigen load enabled by the primary tumor enhancing the efficacy of the immune therapy. CN after initial systemic therapy would help select the patient subset most likely to benefit and will potentially enable eradication of immune resistant clones within the primary tumor.

Characteristics and Outcomes of Non-Transplanted Patients with Newly Diagnosed Multiple Myeloma (NDMM) Initiating Treatment with Bortezomib, Lenalidomide, and Dexamethasone (VRd) As First-Line of Therapy

Introduction: In the US, bortezomib, lenalidomide, and dexamethasone (VRd) is one of the preferred treatment regimens in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM) based on the results from the phase 3 Southwest Oncology Group (SWOG) S0777 study. Although the efficacy of VRd in transplant-ineligible or -deferred NDMM patients was demonstrated in SWOG S0777, clinical trials have strict eligibility criteria that may not translate to the real-world. There is limited real-world data on the characteristics and outcomes of non-transplanted patients with NDMM treated with VRd, especially in older, frail patients with comorbidities. This study aimed to address these knowledge gaps by evaluating the characteristics and outcomes of patients with NDMM who received VRd as first-line of therapy (LOT) in US oncology practice.Methods: This retrospective observational study included patients from the Flatiron Multiple Myeloma Core Registry who received VRd as first LOT between November 1, 2015 and February 28, 2021. The index date was defined as the first observed record of the VRd regimen. Non-transplanted patients were defined as those who did not receive a stem cell transplant (SCT) from the diagnosis date to the index date. Patients were excluded if they were <18 years of age on index date; were enrolled in a clinical trial; had other malignancies prior to the index date; had a diagnosis of amyloid light-chain amyloidosis prior to the index date; or had a SCT prior to index date. Demographics, clinical characteristics, and outcomes were assessed in the overall study cohort and among specific subgroups: older adults (≥75 years of age on index date); frail patients (frailty score ≥2, calculated using age on index date, Charlson Comorbidity Index during the pre-index period, and Eastern Cooperative Oncology Group performance status [ECOG PS] score on the closest date to the index date ≤90 days prior to and ≤7 days after the index date, patients with missing ECOG were not excluded); patients with high-risk cytogenetics, and patients with acute renal impairment ([RI], serum creatinine >2 mg/dL on the closest date to the index date or having diagnosis codes of ICD-9-CM 584.5-584.9, ICD-9-CM 586, ICD-10-CM N17.0-2, N17.8-9, and N19, measured ≤90 days prior to and ≤7 days after the index date). Duration of therapy was measured as the time between the index date and end of the LOT. Progression-free survival (PFS) was measured as time between the index date and disease progression or death, whichever occurred first. PFS did not account for treatment discontinuation for reasons other than progression or death. Disease progression was defined as a clinically meaningful increase in serum M-protein, urine M-protein, or the free light chain ratio according to the International Myeloma Working Group criteria. PFS was analyzed using the Kaplan-Meier method.Results: A total of 2342 eligible NDMM patients treated with VRd as first LOT were identified, with a median follow-up of 21.0 months. A majority of patients were ≥65 years (64.3%), with the mean (SD) age at index date being 67 (±10) years. Most patients were male (53.3%), had International Staging System [ISS] stage I/II (48.4%; 33% missing) and the ECOG PS score 0/1 (63.5%; 22% missing). Of the 2342 patients, 597 (25.5%) patients were categorized as older adults (≥75 years of age); 1122 (47.9%) as frail; 374 (16.0%) as patients with high-risk cytogenetics; and 250 (10.7%) as patients with RI. About 28% of the patients received a SCT within 1-year of the index date. The median duration of therapy was 5.6 months. The median PFS for the overall study group was 33.2 months. Median PFS was substantially shorter for patients who were ≥75 years of age (22.8 months), were frail (28.7 months), had high-risk cytogenetics (25.1 months), or had RI (25.1 months) (Figure).Conclusions: The majority of patients with NDMM treated with VRd in the real-world setting were aged ≥65 years, were ISS stage I or II, had an ECOG PS score of 0 or 1, and had standard-risk cytogenetics. Median PFS observed in the real-world setting was shorter than that observed in the SWOG S0777 clinical trial. Patients who were ≥75 years of age, were frail, had high-risk cytogenetics, or had RI demonstrated shorter median PFS than patients in the overall study population. Alternate treatment options with demonstrated efficacy in the older, frail, and transplant ineligible patients are available. [Display omitted] DisclosuresMedhekar: Janssen: Current Employment. Ran: Janssen Scientific Affairs, LLC: Current Employment. Fu: Janssen: Current Employment. Patel: Janssen: Current Employment. Kaila: Janssen Scientific Affairs, LLC: Current Employment. OffLabel Disclosure:Bortezomib, and lenalidomide are both FDA approved agents for treating multiple myeloma. The combination of bortezomib, lenalidomide, and dexamethasone is commonly used in clinical practice and is listed as a preferred regimen in NCCN guidelines.

The association between lesion tracer uptake on 68Ga-DOTATATE PET with morphological response to 177Lu-DOTATATE therapy in patients with progressive metastatic neuroendocrine tumors.

To determine in a group of patients with progressive metastatic neuroendocrine tumors (PM-NETs) treated with 177Lu-DOTATATE whether a correlation exists between somatostatin receptor (SSTR)-2 expression in various tumors on baseline 68Ga-DOTATATE PET and their response to therapy. A secondary aim was to determine whether an association exists between tumor product of diameter (POD) and PET-derived Krenning score. Patients treated PM-NETs who had SSTR-2 overexpression (SSTR-RADS 5) on screening 68Ga-DOTATATE PET and CT at baseline and 3 months after therapy completion were included. Marker lesions on baseline CT were reassessed on CT after therapy using adapted Southwest Oncology Group solid tumor evaluation criteria. For each lesion, bidimensional diameter on CT and SSTR expression on PET (SSTR-RADS uptake score & PET-derived Krenning score) were recorded. Logistic regression models fitted through generalized estimating equations were used to assess for an association between SSTR expression and response to therapy, or lesion's POD. Forty-one patients with SSTR-RADS 5 PM-NETs treated with 177Lu-DOTATATE were included. There were 135 marker lesions (mean 3.2 lesions/patient) with Krenning score of 4 (n = 74), 3 (n = 44) or 2 (n = 17). There was no association found between SSTR-2 expression, as determined by SSTR-RADS uptake score or PET-derived Krenning score, and POD or response to therapy. In patients with SSTR-RADS 5 PM-NETs treated with 177Lu-DOTATATE, there was similar response to therapy for all lesions with PET-generated Krenning score ≥2. No correlation was found between lesion's POD and level of tracer uptake.

The "Chinese Expert Consensus on the Clinical Application of the Chinese Modified Triplet Combination with Irinotecan (CPT-11), Oxaliplatin (LOHP), Continuous Infusion 5-Fluorouracil, and Leucovorin for Colorectal Cancer".

Colorectal cancer is the second most common malignant tumor in China. The FOLFOXIRI regimen, which combines 5-fluorouracil/leucovorin, oxaliplatin, and irinotecan, is a high-intensity and highly effective chemotherapy regimen. However, the original regimen is poorly tolerated in Chinese patients. In order to promote the standardization and rational application of FOLFOXIRI regimen by clinicians in China, the “Chinese Expert Consensus on the Clinical Application of the Chinese Modified Triplet Combination with Irinotecan (CPT-11), Oxaliplatin (LOHP), Continuous Infusion 5-Fluorouracil, and Leucovorin for Colorectal Cancer” was formulated by the Committee of Colorectal Cancer in Chinese Southwest Oncology Group. Based on the mechanism underlying the combined three drugs and toxicity profile, the dosage of Chinese modified FOLFOXIRI (cmFOLFOXIRI) regimen and the management of adverse reactions are proposed. This consensus recommended that the FOLFOXIRI regimen be used in neoadjuvant, conversion, and palliative therapy for colorectal cancer under specific conditions. This consensus aimed to drive the application of cmFOLFOXIRI in the field of colorectal cancer in order to bring benefits to colorectal cancer patients.

Survival Trends Among Patients with Acute Myeloid Leukemia with Favorable Cytogenetics in the United States

Background:Cytogenetics remains the single most important prognostic factor in patients with acute myeloid leukemia (AML). t(8; 21), inv(16) and t(16;16) are the favorable cytogenetic risk groups. Karyotyping not only predicts outcome but also provides an important guidance for therapy. A Southwest Oncology Group (SWOG)/ Eastern Cooperative Oncology Group (ECOG) intergroup study revealed an estimated 5-year survival rates of 55% in this subset of patients [1]. Population based study to estimate survival pattern in this subset of patients is lacking. We conducted this study to evaluate survival rates in AML patients with favorable cytogenetics over 15 years in the United States.Methodology:Surveillance, Epidemiology and End Result (SEER-18) database was utilized to identify adult patients (≥ 18 years) with AML (as first primary) with favorable cytogenetics from 2000 to 2014. 1-year relative survival rates (RS) with 95% Confidence Interval (CI) were calculated using SEER stat at different time intervals (2000-2004, 2005-2009 and 2010-2014) and compared utilizing Z-test among different cohorts categorized by race, age and sex. Also, a Kaplan Meier Curve and log rank test were used to compare overall survival (OS) in months between AML patients with and without favorable cytogenetics.Results:The database identified 30,618 AML patients. Among them, only 984 patients (3.2%) were found to have favorable risk cytogenetics. Out of these, 554 were males. Median age at diagnosis was 51 years. 785 of them were Caucasian, 82 were African Americans and 113 were from other races.In all the time periods, younger age at diagnosis was associated with better survival rate (RS for 18- 59 years: 84.8%, CI 79.6-88.7% vs. RS for 60-79 years: 49.6%, CI 39.0-59.3% vs. RS for ≥ 80 years was 14.9%, CI 5.4-28.8% in 2010-2014).Races other than Caucasian and African American (AA) had better survival than Caucasian or AA. The RS for Caucasian were better than AA for the time period 2000-2004 and 2005-2009. However, AA had better RS compared to Caucasian in the recent years (RS: 80.3%, CI 62.1-90.4% vs. 66.1%, CI 60.4-71.2%).The survival was significantly better for those with favorable cytogenetics as compared to those without favorable cytogenetics (RS: 69.7%, CI 64.8-74.1% vs. 41.1%, CI 40.1-42.2%; 3-year OS: 47.5±1.7 vs. 19.2±0.2, 2-year OS: 52.8±1.7 vs. 23.5±0.3, 1-year OS: 65.2±1.6 vs. 35.4±0.3 in 2010-2014). And the median OS was 28 months vs. 6 months, p<0.001.Conclusion:Most AML patients with favorable cytogenetics achieve a complete response after induction therapy. They continue to remain in long-term remission after consolidation or autologous transplant. Our study demonstrated a significant survival benefit in AML patients with favorable cytogenetics at a population level. Also, the survival rates have increased significantly in recent years. Improved supportive care and increased rate of transplant likely have contributed to this improvement in survival.

Chinese expert consensus on the clinical application of the Chinese modified triplet combination with irinotecan, oxaliplatin and continuous infusional 5-fluorouracil/leucovorin for colorectal cancer

Colorectal cancer is the second most common malignant tumor in China. The FOLFOXIRI regimen, which combines 5-fluorouracil/leucovorin, oxaliplatin, and irinotecan, is a high-intensity and highly effective chemotherapy regimen. However, the original regimen is poorly tolerated in Chinese patients. In order to promote the standardized and rational application of FOLFOXIRI regimen by clinicians in China, "Chinese Expert Consensus on the Clinical Application of the Chinese Modified Triplet Combination with Irinotecan, Oxaliplatin, and Continuous Infusional 5-Fluorouracil/Leucovorin for Colorectal Cancer" was formulated by the Committee of Colorectal Cancer in Chinese Southwest Oncology Group. Based on the mechanism underlying the combined three drugs and toxicity profile, the dosage of Chinese modified FOLFOXIRI (cmFOLFOXIRI) regimen and the management of related adverse reactions is proposed. This consensus recommended that the FOLFOXIRI regimen be used in neoadjuvant, conversion, and palliative therapy for colorectal cancer under specific conditions. This consensus aimed to drive the application of cmFOLFOXIRI in the field of colorectal cancer, in order to bring benefits to CRC patients and improve the treatment efficacy.

Peptide receptor radionuclide therapy in patients with metastatic progressive pheochromocytoma and paraganglioma: long-term toxicity, efficacy and prognostic biomarker data of phase II clinical trials

BackgroundPheochromocytoma and paraganglioma (PPGL) have currently only limited treatment options available for patients in the metastatic phase (mPPGL) in either post-surgery or inoperable settings. However, these rare tumors overexpress somatostatin receptors and can thus be treated with peptide receptor radionuclide therapy (PRRT). We present data about our 10-year experience treating 46 consecutive mPPGL patients with 90Y-DOTATOC or 177Lu-DOTATATE.Patients and methodsAll patients (20 men and 26 women, median age 52 years) showed positive scintigraphic imaging at 111In-octreotide or 68Ga-DOTATOC positron emission tomography/computed tomography (PET/CT). 90Y-DOTATOC was administered in 12 patients, with cumulative dosages ranging from 7.4 to 11 GBq, while 34 patients received 18.5 or 27.5GBq of 177Lu-DOTATATE. We used Southwest Oncology Group Response Evaluation Criteria in Solid Tumors criteria to evaluate treatment efficacy and Common Terminology Criteria for Adverse Events criteria to assess toxicity. The prognostic role of primary tumor site, hormone secretion, succinate dehydrogenase (SDHx) mutation, and metastatic involvement was also evaluated.ResultsBoth 90Y-DOTATOC and 177Lu-DOTATATE PRRT were well tolerated by patients without significant renal or bone marrow toxicity. The median follow-up was 73 months (range 5-146 months). The overall disease control rate (DCR) was 80% [95% confidence interval (CI) 68.9% to 91.9%] with a mean five cycles of therapy. However, 177Lu-DOTATATE patients showed a longer median overall survival (mOS) than those receiving 90Y-Dotatoc and a better DCR when higher dosages were administered, even if a direct comparison was not carried out. Syndromic patients had a poorer mOS. SDHx mutations did not interfere with treatment efficacy.ConclusionsPRRT is safe and effective for the treatment of patients with progressive mPPGL, especially at higher dosages. The longer mOS of 177Lu-DOTATATE-treated patients in our protocols indicates the former radiopharmaceutical as the better candidate for further clinical application.

P0748 - Recurrence-free survival following resection of low-grade, Non-Muscle-Invasive Urothelial Cancer (NMIBC): A Southwest Oncology Group (SWOG) S0337 post-hoc analysis

P0748 - Recurrence-free survival following resection of low-grade, Non-Muscle-Invasive Urothelial Cancer (NMIBC): A Southwest Oncology Group (SWOG) S0337 post-hoc analysis

Comparison of Single Monthly Instillations of Intra-Vesical Bacillus Calmette-Guerin Maintenance Therapy with Southwest Oncology Group Regimen in Non-Muscle Invasive Bladder Cancer Patients-A Retrospective Analysis In a Single Institute.

To compare the efficacy and complication rate of monthly instillations of Bacillus Calmette-Guerin (BCG) as maintenance therapy in intermediate and high risk Non-Muscle Invasive Bladder Cancer (NMIBC) patients with the current standard Southwest Oncology Group (SWOG) protocol. In this observational retrospective study, 40 intermediate and high risk NMIBC patients, receiving standard BCG maintenance regimen, were compared with another 40 NMIBC patients, undergoing monthly intra-vesical instillations of BCG with regard to recurrence, progression and major and minor adverse effects. The two groups were similar in their basic characteristics except for the older age in the monthly instillation group ( 70.95 ± 9.66 years vs. 64 ± 8.8, p = 0.001). Study objectives between the monthly instillation group and the standard group, including recurrence ( 17.5 % vs. 25%, p = 0.34) and progression rate ( 7.5% vs. 10%, p = 0.54) did not show statistically significant difference. Major and minor complication rate also did not show any difference between the two groups. In addition to the currently recommended standard protocol of BCG maintenance therapy, our study shows that the monthly regimen can be recommended in intermediate and high risk NMIBC patients without compromising the efficacy of the treatment.

First Person Profile: Cheryl Willman, MD: As director and CEO of the University of New Mexico Comprehensive Cancer Center, Dr. Willman has led major health equity initiatives while making pioneering discoveries in precision medicine.

First Person Profile: Cheryl Willman, MD: As director and CEO of the University of New Mexico Comprehensive Cancer Center, Dr. Willman has led major health equity initiatives while making pioneering discoveries in precision medicine.

Effect of Celecoxib vs Placebo Added to Standard Adjuvant Therapy on Disease-Free Survival Among Patients With Stage III Colon Cancer

Aspirin and cyclooxygenase 2 (COX-2) inhibitors have been associated with a reduced risk of colorectal polyps and cancer in observational and randomized studies. The effect of celecoxib, a COX-2 inhibitor, as treatment for nonmetastatic colon cancer is unknown. To determine if the addition of celecoxib to adjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) improves disease-free survival in patients with stage III colon cancer. Cancer and Leukemia Group B (Alliance)/Southwest Oncology Group 80702 was a 2 × 2 factorial design, phase 3 trial conducted at 654 community and academic centers throughout the United States and Canada. A total of 2526 patients with stage III colon cancer were enrolled between June 2010 and November 2015 and were followed up through August 10, 2020. Patients were randomized to receive adjuvant FOLFOX (every 2 weeks) for 3 vs 6 months with or without 3 years of celecoxib (400 mg orally daily; n = 1263) vs placebo (n = 1261). This report focuses on the results of the celecoxib randomization. The primary end point was disease-free survival, measured from the time of randomization until documented recurrence or death from any cause. Secondary end points included overall survival, adverse events, and cardiovascular-specific events. Of the 2526 patients who were randomized (mean [SD] age, 61.0 years [11 years]; 1134 women [44.9%]), 2524 were included in the primary analysis. Adherence with protocol treatment, defined as receiving celecoxib or placebo for more than 2.75 years or continuing treatment until recurrence, death, or unacceptable adverse events, was 70.8% for patients treated with celecoxib and 69.9% for patients treated with placebo. A total of 337 patients randomized to celecoxib and 363 to placebo experienced disease recurrence or died, and with 6 years' median follow-up, the 3-year disease-free survival was 76.3% for celecoxib-treated patients vs 73.4% for placebo-treated patients (hazard ratio [HR] for disease recurrence or death, 0.89; 95% CI, 0.76-1.03; P = .12). The effect of celecoxib treatment on disease-free survival did not vary significantly according to assigned duration of adjuvant chemotherapy (P for interaction = .61). Five-year overall survival was 84.3% for celecoxib vs 81.6% for placebo (HR for death, 0.86; 95% CI, 0.72-1.04; P = .13). Hypertension (any grade) occurred while treated with FOLFOX in 14.6% of patients in the celecoxib group vs 10.9% of patients in the placebo group, and a grade 2 or higher increase in creatinine levels occurred after completion of FOLFOX in 1.7% vs 0.5% of patients, respectively. Among patients with stage III colon cancer, the addition of celecoxib for 3 years, compared with placebo, to standard adjuvant chemotherapy did not significantly improve disease-free survival. ClinicalTrials.gov Identifier: NCT01150045.

New prognostic models for extranodal natural killer T-cell lymphoma, nasal-type using Cox regression and machine learning.

BackgroundThe prognostic index of natural killer lymphoma (PINK) is recommended for use as a prognostic model for determining the best non-anthracycline–based treatment for extranodal natural killer T-cell lymphoma, nasal-type (ENKTL). However, this model does not provide an accurate individual risk estimation for patients; therefore, our retrospective study was conducted to determine this risk.MethodsClinical data from 250 patients with ENKTL treated with non-anthracycline-based regimens were analyzed. The statistically significant clinical characteristics were selected as the parameters for our models. The patient data from 250 patients were randomly divided into 5 groups for 5-fold cross validation before final models were established on all of the patients’ data. A statistical model nomogram based on a Cox proportional hazards model, and a machine learning model based on the lightGBM algorithm, were constructed. Concordance index (C-index) and calibration curve, areas under the curve (AUC) values, and binary error were used to evaluate two models.ResultsFive variables [age, the Chinese Southwest Oncology Group and Asia Lymphoma Study Group ENKTL (CA) staging system, Eastern Cooperative Oncology Group (ECOG) score, B symptoms, and lactate dehydrogenase (LDH)] were significant and were selected as parameters for creating the statistical model nomogram, while lesion sites (anatomical regions, lymph nodes and primary lesion site) took place of CA staging system in machine learning model. During cross validation, the mean C-indices of training cohort and validation cohort for statistical model nomogram and PINK were 0.851±0.008, 0.843±0.029, 0.758±0.019 and 0.757±0.080, respectively, while the mean 3-year AUC for machine learning model were 0.920±0.010 and 0.865±0.035, respectively. The calibration curves and binary errors showed a good correlation between the predicted result and the reality.ConclusionsThese two models could provide ENKTL patients with an accurate individual risk estimation in the era of non-anthracycline-based treatment.

Molecular analysis and clinical outcome of adult APL patients with the type V PML-RARα isoform: results from Intergroup protocol 0129: Presented in part at the 38th annual meeting of the American Society of Hematology, Orlando, FL, December 6-10, 1996, and was published in abstract form in Blood 1996;88:635a (abstract 2528). This study is based on an Intergroup clinical trial (INT-0129)

Molecular analysis and clinical outcome of adult APL patients with the type V PML-RARα isoform: results from Intergroup protocol 0129: Presented in part at the 38th annual meeting of the American Society of Hematology, Orlando, FL, December 6-10, 1996, and was published in abstract form in Blood 1996;88:635a (abstract 2528). This study is based on an Intergroup clinical trial (INT-0129)

Association of PML-RARα Fusion mRNA Type With Pretreatment Hematologic Characteristics But Not Treatment Outcome in Acute Promyelocytic Leukemia: An Intergroup Molecular Study

AbstractIn each case of acute promyelocytic leukemia (APL) one of three PML-RARα mRNA types is produced, depending on the break/fusion site in the PML gene that is linked to a common RARα gene segment: a short (S)-form type, PML exon 3 RARα exon 3; a long (L)-form type, PML exon 6 RARα exon 3; or a variable (V)-form type, variably deleted PML exon 6 RARα exon 3. We evaluated whether PML-RARα mRNA type is associated with distinct pretreatment clinical characteristics and therapeutic outcome in previously untreated adult APL patients registered to protocol INT 0129 by the Eastern Cooperative Oncology Group, the Southwest Oncology Group, and the Cancer and Leukemia Group B. Of 279 clinically eligible cases, 230 were molecularly evaluable, and of these, 111 were randomized to receive remission induction therapy with all-trans retinoic acid (ATRA) and 119 with conventional chemotherapy. Nine cases not excluded by central pathology review were PML-RARα negative, and notably, none of five of these cases treated with ATRA achieved complete remission (CR). Among 221 PML-RARα–positive cases, there were 82 S-form cases (37%), 121 L-form cases (55%), and 18 V-form cases (8%). Before any antileukemic therapy, the S-form type, compared with the L-form type, was associated with higher values for the white blood cell (WBC) count (median 2,500/μL v 1,600/μL; P = .009), the percentage of blood blasts plus promyelocytes (median 29% v 8.5%; P = .03), and the absolute blood blasts plus promyelocytes (884/μL v 126/μL; P = .019). Also, an increased percentage of S-form versus L-form cases had the M3 variant phenotype, 24% v 12% (P = .036). There were no differences between S-form and L-form cases in either CR rate (79% v 69%; P = .14) or disease free survival distribution (multivariate analysis adjusting for the association of S-form type and higher WBC count; P = .40). We conclude that the S-form type is associated with previously-identified adverse risk WBC parameters but that the identification of the S-form or L-form type of PML-RARα mRNA, per se, does not predict clinical outcome or add to the value of an increased WBC count as a negative prognostic indicator in APL patients.

Association of PML-RARα Fusion mRNA Type With Pretreatment Hematologic Characteristics But Not Treatment Outcome in Acute Promyelocytic Leukemia: An Intergroup Molecular Study

In each case of acute promyelocytic leukemia (APL) one of three PML-RAR alpha mRNA types is produced, depending on the break/fusion site in the PML gene that is linked to a common RAR alpha gene segment: a short (S)-form type, PML exon 3 RAR alpha exon 3; a long (L)-form type, PML exon 6 RAR alpha exon 3; or a variable (V)-form type, variably deleted PML exon 6 RAR alpha exon 3. We evaluated whether PML-RAR alpha mRNA type is associated with distinct pretreatment clinical characteristics and therapeutic outcome in previously untreated adult APL patients registered to protocol INT 0129 by the Eastern Cooperative Oncology Group, the Southwest Oncology Group, and the Cancer and Leukemia Group B. Of 279 clinically eligible cases, 230 were molecularly evaluable, and of these, 111 were randomized to receive remission induction therapy with all-trans retinoic acid (ATRA) and 119 with conventional chemotherapy. Nine cases not excluded by central pathology review were PML-RAR alpha negative, and notably, none of five of these cases treated with ATRA achieved complete remission (CR). Among 221 PML-RAR alpha-positive cases, there were 82 S-form cases (37%), 121 L-form cases (55%), and 18 V-form cases (8%). Before any antileukemic therapy, the S-form type, compared with the L-form type, was associated with higher values for the white blood cell (WBC) count (median 2,500/microL v 1,600/microL; P = .009), the percentage of blood blasts plus promyelocytes (median 29% v 8.5%; P = .03), and the absolute blood blasts plus promyelocytes (884/microL v 126/microL; P = .019). Also, an increased percentage of S-form versus L-form cases had the M3 variant phenotype, 24% v 12% (P = .036). There were no differences between S-form and L-form cases in either CR rate (79% v 69%; P = .14) or disease free survival distribution (multivariate analysis adjusting for the association of S-form type and higher WBC count; P = .40). We conclude that the S-form type is associated with previously-identified adverse risk WBC parameters but that the identification of the S-form or L-form type of PML-RAR alpha mRNA, per se, does not predict clinical outcome or add to the value of an increased WBC count as a negative prognostic indicator in APL patients.

Cell cycle regulatory gene abnormalities are important determinants of leukemogenesis and disease biology in adult acute lymphoblastic leukemia

AbstractTo test the hypothesis that cell cycle regulatory gene abnormalities are determinants of clinical outcome in adult acute lymphoblastic leukemia (ALL), we screened lymphoblasts from patients on a Southwest Oncology Group protocol for abnormalities of the genes, retinoblastoma (Rb), p53, p15(INK4B), and p16(INK4A). Aberrant expression occurred in 33 (85%) patients in the following frequencies: Rb, 51%; p16(INK4A), 41%; p53, 26%. Thirteen patients (33%) had abnormalities in 2 or more genes. Outcomes were compared in patients with 0 to 1 abnormality versus patients with multiple abnormalities. The 2 groups did not differ in a large number of clinical and laboratory characteristics. The CR rates for patients with 0 to 1 and multiple abnormalities were similar (69% and 54%, respectively). Patients with 0 to 1 abnormality had a median survival time of 25 months (n = 26; 95% CI, 13-46 months) versus 8 months (n = 13; 95% CI, 4-12 months) for those with multiple abnormalities (P < .01). Stem cells (CD34+lin−) were isolated from adult ALL bone marrows and tested for p16(INK4A) expression by immunocytochemistry. In 3 of 5 patients lymphoblasts and sorted stem cells lacked p16(INK4A) expression. In 2 other patients only 50% of sorted stem cells expressed p16(INK4A). By contrast, p16 expression was present in the CD34+ lin− compartment in 95% (median) of 9 patients whose lymphoblasts expressed p16(INK4A). Therefore, cell cycle regulatory gene abnormalities are frequently present in adult ALL lymphoblasts, and they may be important determinants of disease outcome. The presence of these abnormalities in the stem compartment suggests that they contribute to leukemogenesis. Eradication of the stem cell subset harboring these abnormalities may be important to achieve cure.

Frequency and Clinical Significance of the Expression of the Multidrug Resistance Proteins MDR1/P-Glycoprotein, MRP1, and LRP in Acute Myeloid Leukemia. A Southwest Oncology Group Study

Therapeutic resistance is a major obstacle in the treatment of acute myeloid leukemia (AML). Such resistance has been associated with rapid drug efflux mediated by the multidrug resistance gene 1 (MDR1; encoding P-glycoprotein) and more recently with expression of other novel proteins conferring multidrug resistance such as MRP1 (multidrug resistance-associated protein 1) and LRP (lung resistance protein). To determine the frequency and clinical significance of MDR1, MRP1, and LRP in younger AML patients, we developed multiparameter flow cytometric assays to quantify expression of these proteins in pretreatment leukemic blasts from 352 newly diagnosed AML patients (median age, 44 years) registered to a single clinical trial (SWOG 8600). Protein expression was further correlated with functional efflux by leukemic blasts [assessed using two substrates: Di(OC)(2) and Rhodamine 123] and with the ability of MDR-reversing agents to inhibit efflux in vitro. MDR1/P-glycoprotein expression, which was highly correlated with cyclosporine-inhibited efflux, was noted in only 35% of these younger AML patients, distinctly lower than the frequency of 71% we previously reported in AML in the elderly (Blood 89:3323, 1997). Interestingly, MDR1 expression and functional drug efflux increased with patient age, from a frequency of only 17% in patients less than 35 years old to 39% in patients aged 50 years (P =.010). In contrast, MRP1 was expressed in only 10% of cases and decreased with patient age (P =. 024). LRP was detected in 43% of cases and increased significantly with increasing white blood cell counts (P =.0015). LRP was also marginally associated with favorable cytogenetics (P =.012) and French-American-British (FAB) AML FAB subtypes (P =.013), being particularly frequent in M4/M5 cases. Only MDR1/P-glycoprotein expression and cyclosporine-inhibited efflux were significantly associated with complete remission (CR) rate (P(MDR1) =.012; P(efflux) =.039) and resistant disease (RD; P(MDR1) =.0007; P(efflux) =.0092). No such correlations were observed for MRP1 (P(CR) =.93; P(RD) =.55) or LRP (P(CR) =.50; P(RD) =.53). None of these parameters were associated with overall or relapse-free survival. Unexpectedly, a distinct and nonoverlapping phenotype was detected in 18% of these cases: cyclosporine-resistant efflux not associated with MDR1, MRP1, or LRP expression, implying the existence of other as yet undefined efflux mechanisms in AML. In summary, MDR1 is less frequent in younger AML patients, which may in part explain their better response to therapy. Neither MRP1 nor LRP are significant predictors of outcome in this patient group. Thus, inclusion of MDR1-modulators alone may benefit younger AML patients with MDR1(+) disease.

The evolving role of lymphadenectomy for bladder cancer: why, when, and how.

Radical cystectomy (RC) represents a standard treatment for non-metastatic muscle-invasive and select high-risk non-muscle invasive bladder cancer. Lymphadenectomy performed at time of RC identifies nodal metastases in up to 25% of patients despite normal imaging. There has been an increasing utilization of pelvic lymph node dissection (PLND) with RC since 1950, and in fact lymph node dissection is now recommended in contemporary National Comprehensive Cancer Network (NCCN) guidelines. Benefits of removing of nodal disease include improved staging, guidance for adjuvant treatment, and potentially improved oncologic outcomes. Advantages of dissection have been suggested among both node-negative and node-positive patients. Numerous studies have attempted to define the optimal dissection characteristics of lymphadenectomy with regard to nodal yield and anatomic boundaries of dissection. The ideal extent of lymphadenectomy remains uncertain due to the retrospective and non-randomized nature of the majority of existing reports, which are thereby limited by significant confounding and selection bias. Two randomized controlled trials have investigated this issue, one of which LEA AUO AB 25/02 recently reported its outcomes, demonstrating no significant improvement in 5-year outcomes with an extended dissection. Meanwhile, the Southwest Oncology Group 1011 trial has completed enrollment and data are maturing. While current data preclude definitive recommendations, herein we review the why, when, and how to perform a PLND for bladder cancer.

Association of Diet Quality With Survival Among People With Metastatic Colorectal Cancer in the Cancer and Leukemia B and Southwest Oncology Group 80405 Trial

Diet has been associated with survival in patients with stage I to III colorectal cancer, but data on patients with metastatic colorectal cancer are limited. To examine the association between diet quality and overall survival among individuals with metastatic colorectal cancer. This was a prospective cohort study of patients with metastatic colorectal cancer who were enrolled in the Cancer and Leukemia Group B (Alliance) and Southwest Oncology Group 80405 trial between October 27, 2005, and February 29, 2012, and followed up through January 2018. Participants completed a validated food frequency questionnaire within 4 weeks after initiation of first-line treatment for metastatic colorectal cancer. Diets were categorized according to the Alternative Healthy Eating Index (AHEI), Alternate Mediterranean Diet (AMED) score, Dietary Approaches to Stop Hypertension (DASH) score, and Western and prudent dietary patterns derived using principal component analysis. Participants were categorized into sex-specific quintiles. Multivariable hazard ratios (HRs) and 95% CIs for overall survival. In this cohort study of 1284 individuals with metastatic colorectal cancer, the median age was 59 (interquartile range [IQR]: 51-68) years, median body mass index was 27.2 (IQR, 24.1-31.4), 521 (41%) were female, and 1102 (86%) were White. There were 1100 deaths during a median follow-up of 73 months (IQR, 64-87 months). We observed an inverse association between the AMED score and risk of death (HR quintile 5 vs quintile 1, 0.83; 95% CI, 0.67-1.04; P = .04 for trend), but the point estimates were not statistically significant. None of the other diet scores or patterns were associated with overall survival. In this prospective analysis of patients with metastatic colorectal cancer, diet quality assessed at initiation of first-line treatment for metastatic disease was not associated with overall survival.

Low-Dose Erlotinib Treatment in Elderly or Frail Patients With EGFR Mutation–Positive Non–Small Cell Lung Cancer

Although the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for EGFR gene mutation-positive non-small cell lung cancer is well established, optimal dosing remains to be established, especially in elderly or frail patients. To investigate the efficacy and safety of low-dose erlotinib in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer. Single-arm phase 2 trial with the Southwest Oncology Group (SWOG) 2-stage design that enrolled frail patients from 21 Japanese institutions after meeting the inclusion criteria. Chemotherapy-naive patients with EGFR-activating mutation-positive non-small cell lung cancer who were considered frail based on age, the Charlson Comorbidity Index, and Eastern Cooperative Oncology Group performance status were eligible for the study. Patients were initially administered 50 mg/d erlotinib for 4 weeks, which was modified based on response or adverse events. Dose increase was permitted for patients with stable disease after 4 weeks. The primary end point was the independent review committee-confirmed objective response rate (ORR) at the dose of 50 mg/d. The study also evaluated the pharmacokinetics of low-dose erlotinib and influence of ABCB1 gene polymorphisms. Eighty patients were enrolled, with a median (range) age of 80 (49-90) years; 54 (68%) were men. An independent review committee confirmed a significant ORR of 60.0% (90% CI, 50.2%-69.2%). The disease control rate was 90.0% (90% CI, 82.7%-94.9%), median progression-free survival was 9.3 months (95% CI, 7.2-11.4 months), and median overall survival was 26.2 months (95% CI, 21.9-30.4 months). Mild adverse events were observed in some participants, with few patients exhibiting grade 3 or greater adverse events. Low-dose erlotinib treatment was temporarily suspended for 10 patients owing to adverse events. Five of 80 patients (6%) had their erlotinib dose reduced to 25 mg because of oral mucositis, paronychia, erythema multiforme, diarrhea, and anorexia. Two patients discontinued treatment because of adverse events (cutaneous ulcer and bone infection, and oral mucositis, respectively). There were no cases of interstitial lung disease or treatment-related deaths. The median (range) erlotinib plasma concentration was measured at 685 (153-1950) ng/mL. Seventy-three patients discontinued study treatment owing to disease progression (n = 60), death (n = 3), AEs (n = 4), and patient requests (n = 6). No clear association was observed between the pharmacokinetics of low-dose erlotinib and the treatment outcome. Low-dose erlotinib appears to be safe and effective in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer and can be a valid treatment option. UMIN-CTR Identifier: UMIN000015949.