bluuebunny/crossref_metadata_2025_split huggingface dataset:
Subgroup analyses of efficacy outcomes by baseline tumor size in the phase 3, open-label CLEAR trial.
Authors: Grünwald Viktor , Motzer Robert J. , Haanen John B. A. G. , Schmidinger Manuela , Staehler Michael D. , Goh Jeffrey C. , Voog Eric , Climent Miguel Ángel , George Saby , Burgents Joseph E. , Xie Ran , McKenzie Jodi , Porta Camillo 
Published: January 2024

364 Background: In the primary analysis of the phase 3 open-label CLEAR trial, lenvatinib + pembrolizumab (L+P) showed statistically significant and clinically meaningful improvements in progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) compared with sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC) (Motzer NEJM 2021). Outcomes were further corroborated by results of the final prespecified analysis of CLEAR (Motzer ASCO 2023). We report efficacy outcomes per baseline tumor size in the L+P arm of CLEAR. Methods: 1069 treatment-naïve pts with aRCC and a clear-cell component were randomized (1:1:1) to: L 20 mg PO QD + P 200 mg IV Q3W; or L 18 mg + everolimus 5 mg PO QD; or S 50 mg PO QD (4 wks on/2 wks off). Stratification factors included geographic region and MSKCC prognostic risk group. IMDC risk groups (derived programmatically) are presented in this analysis. Efficacy outcomes were evaluated by quartiles of baseline sums of diameters of target lesions. Tumor assessments were performed by independent imaging review per RECIST v1.1. Results: Pts were grouped into 4 categories: ≤Q1 (34.72 mm), >Q1 - ≤Q2 (60.06 mm), >Q2 - ≤Q3 (108.56 mm) and >Q3 per baseline tumor sizes (Table). For pts with ≤Q1 baseline tumor sizes, 40.7% and 58.0% were in the favorable and intermediate + poor IMDC risk subgroups, respectively. For pts with >Q3 baseline tumor sizes, 6.3% and 93.8% were in the favorable and intermediate + poor IMDC risk groups, respectively. Median OS, PFS, ORR, complete response (CR), partial response (PR), and near-CR (PR with maximum tumor shrinkage ≥75%) by baseline tumor size categories are in the Table. Conclusions: In CLEAR, clinically meaningful efficacy with L+P was observed across pts with aRCC irrespective of their baseline tumor sizes. These results support the use of L+P for the 1L treatment of aRCC across pts with both low and high baseline tumor size. Clinical trial information: NCT02811861 . [Table: see text]
First-in-human safety, imaging and dosimetry of [68Ga]Ga-DPI-4452, a novel CA IX-targeting peptide, in patients with clear cell renal cell carcinoma.
Authors: Hofman Michael S , Tran Ben , Feldman Darren R. , Pokorska-Bocci Anna , Pichereau Solen , Wessen Jonathan , Haskali Mohammad B. , Sparks Richard , Vlasyuk Olena , Galetic Ivana 
Published: January 2024

373 Background: Carbonic anhydrase IX (CA IX) is overexpressed in clear cell renal cell carcinoma (ccRCC) and is associated with aggressive tumor behavior, treatment resistance and overall poor outcomes. DPI-4452 is a first-in-class, cyclic peptide that binds with high affinity to CA IX. Radiolabeling DPI-4452 with gallium-68 ([68Ga]Ga-DPI-4452) or lutetium-177 ([177Lu]Lu-DPI-4452) is an innovative, theranostic approach for identifying and treating patients with CA IX-expressing tumors. Compared with existing antibody approaches, a radiolabeled peptide may confer better characteristics for both PET-CT imaging and therapy. This first-in-human study (NCT05706129) is evaluating the theranostic potential of [68Ga]Ga-DPI-4452 and [177Lu]Lu-DPI-4452 in patients with unresectable metastatic ccRCC, colorectal cancer or pancreatic ductal adenocarcinoma tumors. Here we report safety, tolerability, pharmacokinetics, dosimetry and imaging characteristics of [68Ga]Ga-DPI-4452 from the completed ccRCC imaging cohort. Methods: The DPI-4452 peptide contains a DOTA cage and is radiolabelled with [68Ga]Ga. Following intravenous injection of [68Ga]Ga-DPI-4452, patients underwent serial PET-CT imaging, urine and blood sampling to assess imaging characteristics, biodistribution, and dosimetry of [68Ga]Ga-DPI-4452. Patients were followed for 7 days post-injection for safety observations. Results: A mean activity of 185 MBq [68Ga]Ga-DPI-4452 was administered to 3 patients with ccRCC. No clinically significant toxicities were observed. PET-CT images showed rapid and sustained tumor uptake over 4 h, as well as rapid renal elimination. At 1 h, the maximum tumor standardized uptake value (SUVmax) across 36 lesions ranged from 6.8 to 211.6, with a mean of 64.6. Seventeen of these lesions (found in lymph nodes, lung, pancreas, parotid gland and other sites) were not detectable on prior contrast-enhanced CT. OLINDA dosimetry estimates revealed that the organs receiving the highest absorbed doses (mean [SD] mGy/MBq) were stomach wall (0.33 [0.10]), small intestine wall (0.33 [0.08]) and gallbladder wall (0.21 [0.12]), with a mean whole body effective dose of 0.06 [0.02] mSv/MBq. Absorbed doses in the kidney, liver and bone marrow were low. Over 80% of total administered radioactivity cleared from the bloodstream within 1 h. Conclusions: [68Ga]Ga-DPI-4452 provides exceptional images in patients with ccRCC without clinically significant toxicity. Very high SUVs and tumor-to-background ratios suggest potential for use in both diagnostics and patient selection for therapy. The tumor retention and rapid elimination support potential of [177Lu]Lu-DPI-4452 radioligand therapy. Clinical trial information: NCT05706129 .
Linear muscle segmentation for metastatic renal cell carcinoma.
Authors: Nicaise Edouard , Schmeusser Benjamin , Ali Adil , Midenberg Eric , Palacios Arnold Raul , Kearns Ethan , Ambadi Sriram , Patil Dattatraya H. , Joshi Shreyas S. , Narayan Vikram M , Psutka Sarah P. , Nazha Bassel , Brown Jacqueline T , Ogan Kenneth , Bilen Mehmet Asim , Master Viraj A. 
Published: January 2024

380 Background: Baseline sarcopenia and postoperative changes in muscle mass are independently associated with overall survival in patients with metastatic renal cell carcinoma (mRCC) undergoing cytoreductive nephrectomy (CN). Here we examine the relationship between preoperative (baseline) and postoperative changes in muscle quantity with survival outcomes following CN as determined by linear segmentation, a fast and clinic-friendly tool. Methods: Our nephrectomy database was reviewed for patients with clear cell, papillary, or chromophobe mRCC who underwent CN. Linear segmentation of bilateral psoas/paraspinal muscles was completed for baseline imaging within 60 days of surgery and imaging up to 1 year postoperatively. ANOVA for numerical and chi-square for categorical variables were used to test for differences according to change in linear muscle index (LMI, cm2/m2). Multivariable models estimated COX hazard ratios for cancer-specific survival (CSS) and overall survival (OS). Kaplan Meier curves estimated CSS and OS. Results: From 2004-2020, 190 patients were identified 48 stable LMI (25.3%; <5% change [0Δ]), 54 increase LMI (28.4%; +5% change [+Δ]), and 88 decrease LMI (46.3%; -5% change [-Δ]). Median time from baseline imaging to surgery was 18 days, while time from surgery to postoperative imaging was 119 days. Patients with +Δ had lower baseline LMI than -Δ or 0Δ (28.5 vs. 32.4 vs.32.5 cm2/m2; p=0.003). 0Δ LMI had lower rates of pN1 disease than other groups (27.1% [0Δ] vs. 42.6% [+Δ] vs. 45.5% [-Δ]; p=0.019). No other differences in pathology were noted. Median CSS and OS were highest among patients with 0Δ LMI (CSS: not reached [0Δ] vs. 61.9 [+Δ] vs. 37.4 [-Δ] months; p=0.0018 || OS: 67.2 [0Δ] vs. 48.5 [+Δ] vs. 26.4 [-Δ] months; p=0.0007). Median follow-up was 56 months for survivors. The table lists factors associated with increased risk of cancer-specific mortality. Conclusions: Change in muscle mass after CN, as measured by the linear muscle segmentation technique, is independently associated with OS and CSS in patients following CN. Of note, lack of change demonstrated greatest survival, potentially secondary to high baseline muscle mass. [Table: see text]
Erectile function in patients with metastatic renal cell carcinoma treated with first-line therapy.
Authors: Tsimafeyeu Ilya , Zukov Ruslan , Borisov Pavel S. , Leonenko Valentina , Kuznetsov Vladimir , Bondarenko Anastasia , Tishova Yulia 
Published: January 2024

383 Background: Sexual activity is an important part of social functioning and quality of life. Cancer diagnosis and concomitant treatment has a damaging effect on sexual function. The objective of this prospective study was to evaluate the incidence of erectile dysfunction (ED) in men with metastatic renal cell carcinoma (mRCC) receiving first-line therapy. Methods: All patients were evaluated for erectile function with the 5-item version of the International Index of Erectile Function (IIEF-5) and Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19) before first and after four cycles/months of the first-line therapy with nivolumab plus ipilimumab (IO-IO), pembrolizumab plus axitinib/lenvatinib (IO-TKI) or sunitinib, pazopanib and cabozantinib (TKI). Results: Two hundred eighty-two male patients with mRCC were enrolled. Median age was 60.5 years (range 39–71 years) and 164 (58%) patients had at least one cardiovascular risk factor. Sixty-seven (24%) patients had favorable IMDC risk, 208 (74%) had ECOG ≤1, 214 (76%) had ≥2 organs with metastases, and 11 (4%) had non-clear cell mRCC. All patients were treated with IO-IO (32%), IO-TKI (26%), and TKI (42%). At baseline, IIEF-5 mean score was 17 (SD, 2.9) in ITT population. Patients with 2 and more IMDC risk factors had a lower IIEF-5 mean score (13; SD, 1.4). 182 (64.5%) patients reported a negative change in their sexual life since the start of the therapy. 90 (32%) patients had no sexual activity. After four treatment cycles/months IIEF-5 mean score reduced to 9 (SD, 3.5), which was statistically significant (P<0.0001). The IIEF-5 scores were associated with type of anticancer treatment, with the minimal change observed in IO-IO group (P=0.2) and highest change in TKI group (P<0.0001). A correlation was no found between FKSI-19 and IIEF-5 scoring systems. Conclusions: A prospective assessment in a large group of male mRCC patients revealed mild ED (17/25) in previously untreated patients and moderate ED (9/25) after four cycles/months of first-line therapy, especially in patients receiving TKIs. These changes did not correlate with kidney symptom index.
Association between SPECT/CT total tumor volume (TTV) and new lesions (NLs) in early cycles of 177Lu-PSMA-617 (LuPSMA) and progression-free and overall survival (PFS and OS) in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Demirci Ridvan Arda , Gulati Roman , Nelson Peter , Cheng Heather H. , Hawley Jessica E. , Yezefski Todd , Haffner Michael C. , Montgomery Robert Bruce , Schweizer Michael Thomas , Yu Evan Y. , Chen Delphine L , Iravani Amir 
Published: January 2024

40 Background: LuPSMA is a newly established treatment in patients with mCRPC, but PSA and survival outcomes vary widely, and predictors of treatment responses are needed. LuPSMA delivers radiation to tumor tissues that can also be imaged with SPECT/CT which provides semiquantitative estimates of TTV and identification of NLs. This study investigates the use of SPECT/CT in early cycles to predict LuPSMA outcomes. Methods: Between June and December 2022, mCRPC patients who initiated the 2nd cycle of LuPSMA with SPECT/CT 24 hours post-treatment were retrospectively reviewed. We evaluated associations between TTV and the appearance of NLs at the start of the 2nd or 3rd cycle with PFS and OS using Cox regression analysis. NLs were classified as non-PSMA-avid with no or low uptake (< liver) with corresponding findings on CT and PSMA-avid (uptake > liver). All analyses were adjusted for change in PSA relative to baseline. Results: Sixty-six mCRPC patients (median age, 73.5) received a median of 4 (IQR: 3-5) cycles of LuPSMA. Median follow-up starting at 2nd cycle was 26 weeks (IQR: 21-36) with 47/66 (71%) alive at the time of the analysis. A reduction of ≥50% in PSA (PSA50) was noted in 33/66 (50%) patients. Changes in PSA and TTV at 2nd and 3rd cycle were apparently concordant in 50/66 (76%) and 42/51 (82%) and were significantly correlated (r= 0.55 and 0.56, both p<0.001). Patients with higher absolute TTV adjusted for PSA change at 2nd cycle had worse PFS and OS (HR=1.3 and 2.26) with consistent results at 3rd cycle (Table). NLs were detected in 13/66 (7/13 PSMA-avid, 6/13 non-PSMA-avid) and 7/51 patients (5/7 PSMA-avid, 2/7 non-PSMA-avid) at 2nd and 3rd cycle, respectively. Patients with NLs at 2nd cycle had higher risks of progression and death (HR=4.53 and 6.28). Conclusions: Higher SPECT/CT TTV at 2nd and 3rd cycle and detection of NLs at 2nd cycle were associated with higher risks of progression and death. Although changes in PSA and TTV were correlated, absolute SPECT/CT TTV in early cycles provided a complementary ability to predict outcomes of LuPSMA. [Table: see text]
Evaluating intermediate endpoints (IE) for overall survival (OS) in metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICI): An IMDC study.
Authors: Saliby Renee Maria , Xie Wanling , Wells J Connor , Saad Eddy , Eid Marc , Labaki Chris , Semaan Karl , Ferrier Evan , Lemelin Audreylie , Suárez Cristina , Ruiz-Morales Jose Manuel , Powles Thomas , Wood Lori , Ebrahimi Hedyeh , de Velasco Guillermo , Takemura Kosuke null , Agarwal Neeraj , Braun David A. , Heng Daniel Yick Chin , Choueiri Toni K. 
Published: January 2024

400 Background: In Ph3 trials, assessment for primary endpoint of OS necessitates extended follow-up (f/u) periods, larger pool of events, and higher associated costs. We sought to determine if shorter IEs like Time to Treatment Failure (TTF) and Time to Next Therapy (TTNT) are associated with OS in patients (pts) receiving ICI-based trt. Methods: We included all International mRCC Database Consortium (IMDC) pts who received contemporary approved first line(1L) ICI from 2013 to 2023. IEs were defined from ICI start until drug cessation or death for TTF, and initiation of next line or death for TTNT, or censored at date of last f/u. Associations of OS with TTF and TTNT status at 6-mo landmark were assessed using Cox regression adjusting for IMDC risk groups, metastatic sites, histology, age, and prior nephrectomy, stratified by treatment (trt) and yrs of ICI start. Endpoint associations across all f/u time were evaluated using Kendall’s Tau (KT) correlation by Clayton copula. A KT >0.49 indicates a strong correlation ( Wicklin R., 2023). Results: The cohort consisted of 1667 pts with a median f/u of 15.4 mo (IQR: 7.1-28.6). Median age at 1L start was 63 yrs (IQR: 56-70), with 73% being male and 65% undergoing nephrectomy before starting 1L. 1132 patients received dual ICI, while 535 received an ICI+TKI combination. Pts who discontinued their 1L regimen within the 6-mo landmark demonstrated poor OS, with a hazard ratio (HR) of 2.74 (95% CI: 2.15-3.49). Additionally, those who transitioned to a 2L therapy within the first 6 mo showed worse OS, reflected by an HR of 2.82 (2.22-3.59). KT correlation with OS across all follow up was 0.49 (0.45, 0.52) for TTF and 0.67 (0.64, 0.69) for TTNT. Consistent results were seen across all subgroups with the strongest association in the ICI+TKI group (Table). Conclusions: TTNT demonstrated the strongest association with OS, particularly in the ICI+TKI subgroup, making it a potentially clinically meaningful intermediate endpoint for evaluating efficacy in ICI-based regimens.[Table: see text]
Evolving metastatic renal cell carcinoma (mRCC) treatment landscape in the post vascular endothelial growth factor (VEGF) and immune checkpoint inhibitor (IO) setting.
Authors: Shah Neil J. , Bhattacharya Rituparna , Ning Ning , Shinde Reshma , Schmier Jordana , Tan Malinda , LeMasters Traci , Sundaram Murali , Perini Rodolfo F. , Motzer Robert J. 
Published: January 2024

406 Background: IO and VEGF based therapies have transformed the front-line treatment paradigm for patients with mRCC. This study's objective is to describe treatment patterns and clinical outcomes among mRCC patients in the post IO and VEGF setting. Methods: Adult patients diagnosed with mRCC between Jan 2015 - Dec 2022 and received IO and VEGF (in combination or sequence) in the first three lines of therapy after mRCC diagnosis were identified from Optum’s de-identified Clinformatics® Data Mart Database, a large retrospective claims database. Index date was defined as the date of the first (index) treatment in the post IO and VEGF setting. Patients were required to have continuous enrollment of 6 months prior to index date. Patients were categorized into 3 cohorts based on lines of index treatment (2L, 3L, 4L). Treatment patterns were described and real world (rw) time on treatment (ToT), time to next treatment (TTNT), and overall survival (OS) were estimated by Kaplan Meier analysis. Results: A total of 664 patients were included (2L:186, 3L:429, 4L:49). 37% received IO and VEGF in combination prior to index line of therapy. Median age at mRCC diagnosis was 67.0 years, with 72.7% male and 68.1% White; 11.6% died and 7.4% disenrolled during index treatment. Post IO and VEGF, cabozantinib was the most used therapy across 3 cohorts (2L: 43.5%, 3L: 35.2%, 4L: 30.6%) (Table). Median rwToT and rwTTNT for 2L, 3L, and 4L cohorts were 4.4, 5.0, and 5.6 months and 10.7, 11.7, and 9.5 months, respectively. Median OS from mRCC diagnosis was similar across the 3 cohorts (2L: 41.6, 3L: 38.7, 4L: 40.6 months); median OS from index date decreased with advancement in LOT (2L: 20.6, 3L: 14.1, 4L: 10.3 months). Conclusions: Our study is one of the largest and comprehensive study giving a unique perspective into evolving treatment patterns and outcomes for mRCC patients in the post IO and VEGF setting. Post IO+VEGF, the most common treatments were tyrosine kinase inhibitor-based treatments, and the median ToT was less than 6 months. Hence, novel treatments are needed to improve clinical outcomes for mRCC patients in the post IO and VEGF setting. [Table: see text]
Association between PET-based TheraP eligibility and 177Lu-PSMA-617 (LuPSMA) outcomes in VISION-eligible patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Demirci Ridvan Arda , Gulati Roman , Ghodsi Alireza , Nelson Peter , Cheng Heather H. , Hawley Jessica E. , Yezefski Todd , Haffner Michael C. , Montgomery Robert Bruce , Schweizer Michael Thomas , Yu Evan Y. , Chen Delphine L , Iravani Amir 
Published: January 2024

41 Background: The optimal threshold based on pre-treatment PET for patient selection for LuPSMA is yet to be defined. TheraP trial applied a high threshold for PSMA-expression on PSMA PET and utilized FDG PET to exclude FDG-avid/non-PSMA-avid disease while the VISION trial used only PSMA PET with a lower threshold of PSMA-expression. The stricter criteria in TheraP trial doubled the screening failure rate compared to VISION trial, 28% vs. 12.6%. In this study among VISION-eligible patients, we aimed to compare the outcome of those who were TheraP-Eligible (TheraP-E) to TheraP-Ineligible (TheraP-I). Further, the prognostic value of FDG-PET phenotyping is investigated. Methods: This retrospective cohort study evaluated consecutive VISION-eligible mCRPC patients who received at least one cycle of LuPSMA and had both PSMA- and FDG-PET within one month of each other between June 2022 and January 2023. Patients were blindly classified as TheraP-E vs. TheraP-I. We compared whole-body semiquantitative parameters including total tumor volume (TTV), SUVmean and SUVmax and outcomes including PSA decline of ≥50% relative to baseline (PSA50), PSA-progression-free survival (PSA-PFS), and overall survival (OS) between the groups. Separately, the patients were dichotomized to having dominant FDG-avid disease (uptake > liver in most sites of disease) vs. non-FDG-avid disease and OS were compared by Cox-regression. Results: 46 patients (median age: 72, ECOG 0-2: 89%, visceral disease: 28%) were included with a median follow-up of 10 months (IQR: 8-14). 14/46 (30%) patients assessed as TheraP-I and had lower PSMA-PET SUVmean and SUVmax compared to TheraP-E patients (5.6 vs. 8.8 and 23 vs. 53, p < 0.001 for both) while other PET parameters including PSMA TTV and FDG parameters (SUVmax, SUVmean and TTV) were not statistically different. TheraP-I patients had lower PSA50 response (21% vs. 56%, p = 0.029) but PSA-PFS and OS were not significantly different compared to TheraP-E patients (Table). 37/46 (80%) patients assessed as FDG-avid had an increased risk of death compared to non-FDG-avid counterparts (Table). Conclusions: In a VISION-eligible population receiving LuPSMA, TheraP imaging-based ineligibility was associated with worse PSA response but with no significant difference in PSA-PFS or OS. Clinical investigation of the more permissive VISION inclusion criteria and the importance of FDG-avid disease using a larger sample size is warranted. [Table: see text]
Pembrolizumab plus lenvatinib (P+L) versus alternative therapies in first-line (1L) advanced renal cell carcinoma (aRCC) by IMDC risk status: A network meta-analysis (NMA).
Authors: Rane Pratik , Yan Kevin , Schmidinger Manuela , Peer Avivit , Druyts Eric , Burgents Joseph E. , Sundaram Murali 
Published: January 2024

421 Background: The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk criteria is a widely used prognostic model in advanced RCC. Pembrolizumab plus lenvatinib (P+L) demonstrated a significant improvement in ORR, PFS, and OS versus sunitinib in subjects with cc aRCC in the KEYNOTE-581/CLEAR trial. This NMA indirectly compared the efficacy of P+L to other therapies in 1L aRCC subjects within IMDC risk groups using data from randomized clinical trials (RCTs). Methods: A systematic literature review was conducted to identify systemic therapies in 1L aRCC. Trials reporting results for IMDC favorable risk and/or intermediate+poor risk groups were included. A Bayesian NMA with fixed-effect models was performed to indirectly compare P+L to alternate therapies using sunitinib as the common comparator. Hazard ratios (HRs) for OS and PFS were calculated with 95% credible intervals (CrIs). The NMAs assuming constant hazard ratios (HRs) for OS and PFS were performed for all IMDC risk group categories. For the proportion of patients experiencing response, a binomial likelihood and logit link were used, and relative effects were expressed as odds ratios (OR). Results: For the IMDC favorable risk subgroup, P+L demonstrated statistically significant increase in ORR compared to nivolumab + ipilimumab (N+I) (OR=5.35; 95% CrI: 2.59, 11.41) and nivolumab (OR=8.41; 95% CrI: 1.84, 43.77). For PFS, P+L resulted in a statistically significant improvement in PFS compared to N+I (HR=0.31, 95% CrI: 0.17-0.56). For OS, no significant differences were observed compared to other alternatives in the network. For the IMDC intermediate+poor risk subgroup, P+L demonstrated statistically significant increase in ORR compared to nivolumab + cabozantinib (N+C) (OR=1.77; 95% CrI: 1.02, 3.10), N+I (OR=3.15; 95% CrI: 1.94, 5.10), and nivolumab + ipilimumab + cabozantinib (N+I+C) (OR=2.34; 95% CrI: 1.34, 4.12), pembrolizumab + axitinib (P+A) (OR=2.65; 95% CrI: 1.57, 4.44) and nivolumab (OR=4.68; 95% CrI: 1.84, 12.02). For PFS, P+L resulted in a statistically significant improvement compared to N+I (HR=0.59; 95% CrI: 0.41, 0.84) (P+A) (HR=0.64; 95% CrI: 0.44, 0.93), and avelumab + axitinib (A+A) (HR=0.65; 95% CrI: 0.46, 0.93). For OS, no significant differences were observed compared to other alternatives in the network. Conclusions: PFS analysis favored P+L over all alternative therapies in the network in favorable or intermediate+poor IMDC risk groups. ORR analysis favored P+L over all alternative therapies in the network in intermediate+poor IMDC risk groups. No significant difference in OS was observed between P+L and other alternative therapies in the network.