bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II trial of gemcitabine/carboplatin (GC) followed by paclitaxel (P) in patients with performance status = 2,3 or other significant co-morbidity (HIV infection or s/p organ transplantation) in advanced non-small cell lung cancer (NSCLC)
Authors: Bridges B. B. , Thomas L. , Hausner P. , Doyle L. A. , Bedor M. , Smith R. , Brahmer J. , Edelman M. J.
Published: March 2020

7661

Introduction: The role of chemotherapy (Rx) in patients (pts) with advanced NSCLC and poor performance status (PPS) defined as PS = 2 or 3 is unclear. While survival appears to be enhanced, serious toxicity may occur. In addition, no treatment options have been defined for the growing population of pts with HIV infection or post organ transplantation. Based on a prior study (Cancer 2001;92:146–152), we evaluated the efficacy of sequential, dose attenuated GC followed by P in patients with PS=2,3, HIV infection or s/p solid organ transplantation. Patients and Methods: Rx naive patients with PPS and adequate organ function received G: 1,000 mg/m2 d 1,8 C: AUC=5 d 1 q 21d × 2 followed by P 80 mg/m2 q wk × 6 followed by a 2 wk break and then repeated until progression. Results: 47 of a projected 47 pts have been enrolled. Stage IIIb/IV: 8/39, PS 2/3= 26/19, HIV infection=2, solid organ transplantation=2. 12 (25%) had brain metastases. Thirty-nine pts completed two cycles of GC and 29 pts received at least one cycle of P. Overall response rate:19% (95% CI 1.2%-31.7%). Median survival: 5.8 mo. One year survival: 8.4%. Median event free survival: 3.3 months. Toxicity rates for GC: Grade (gr) 3 neutropenia, anemia and thrombocytopenia = 29.8%, 14.9%, 23.4% respectively, gr 4 neutropenia=19% and 10.6% had gr 4 thrombocytopenia. There were 2 gr 1 bleeding episodes, two pts received platelets and 8 pts received red cells. 8.5% had gr 3 fatigue and 10.6% had gr 3 febrile neutropenia, 4.3% had grade 3 nausea, vomiting. Gr 4 nonhematologic toxicities: Thromboembolism = 1 pt (2.1%), Fever = 1 (2.1%). Toxicity rates for P phase: 2.1% had gr 3 neutropenia and anemia. 4.3% had gr 3 neuropathy. There was 1 episode of gr 4 hemoptysis. Two patients received red cells. Conclusions: 1) Sequential GC to P is well tolerated and active in this population. 2) Survival is comparable to that of other regimens utilized in PS = 2 pts with superior tolerability. 3) The prognosis for these pts is very poor even with Rx.4. This is the first trial to prospectively evaluate Rx for pts with HIV disease or organ transplantation and NSCLC. Supported by Bristol Myers Squibb.

No significant financial relationships to disclose.
Elderly subgroup analysis of a randomized phase 3 trial of gemcitabine (G) in combination with carboplatin (Cb) or paclitaxel (P) compared to paclitaxel plus carboplatin in advanced (stage IIIB, IV) non-small cell lung cancer (NSCLC)
Authors: Ansari R. H. , Gonin R. , Socinski M. , Edelman M. , Catalano R. , Marinucci D. , Comis R. , Obasaju C. , Treat J. A. , Belani C. P.
Published: March 2020

7665

Background: Efficacy and safety of platinum-based chemotherapy doublets in elderly (ELD) NSCLC pts with good PS have been reported to be similar to those in younger pts (N-ELD). However, little data exists about which of the standard regimens are suitable for the ELD. To compare efficacy and safety of doublet regimens in the ELD, we conducted a retrospective age-specific subgroup analysis of our Phase 3 randomized trial comparing 3 regimens for advanced NSCLC (Treat, et al: Abst#7025, Proc ASCO 2005). Methods: A Phase 3 study in advanced (Stage IIIB/IV) NSCLC chemonaive patients with ECOG PS <2 was designed to compare the efficacy of a G-containing platinum regimen GCb (G 1000 mg/m2 IV D 1, 8 plus Cb AUC 5.5, D 1) to a nonplatinum G doublet GP (G 1000 mg/m2 IV D 1,8 plus P 200 mg/m2, D 1) and a reference regimen of PCb (P 225 mg/m2 plus Cb AUC 6.0, D 1). Outcome data of ELD pts (age =70) vs. N-ELD pts (age <70) were compared. Survival (OS) was the primary endpoint with secondary endpoints being response rate (RR), time to progression (TTP) and toxicity. Data from all 3 arms were pooled for this analysis. Results: A total of 314 ELD and 746 N- ELD pts were analyzed (GCb 111/245, GP 100/251, PCb 103/250). There were no significant differences in the OS or TTP distributions in ELD compared to N-ELD pts ( Table 1 ). In general, the incidence and grade of toxicity in ELD vs. N-ELD were comparable. ELD experienced moderately higher incidences of Grade 3–4 constitutional (12.6% vs. 7.1%), neurologic (16.1% vs. 8.9%), and pulmonary (12.3% vs. 7.9%) toxicities compared with N-ELD pts. Conclusion: Use of G-containing doublets as first-line chemotherapy showed similar efficacy to the standard PCb regimen in ELD and N-ELD patients with advanced/metastatic NSCLC as defined by OS, RR, and TTP. ELD tolerated these regimens well despite experiencing slightly more toxicity than younger patients.

No significant financial relationships to disclose.

[Table: see text]
Sex differences in non-small cell lung cancer (NSCLC) patients (p) participating in Spanish Lung Cancer Group (SLCG) trials
Authors: Isla D. , Felip E. , Garrido P. , Viñolas N. , García-Campelo R. , Lianes P. , Bover I. , Terrasa J. , Sánchez J. J. , Rosell R.
Published: March 2020

7679

Background: Previous findings about differences by sex in lung cancer have prompted us to undertake a retrospective analysis of clinicopathologic and genetic features in women (W) with advanced NSCLC participating in first-line chemotherapy (CT) SLCG trials. Methods: Data on age, histology, PS, CT schedule, XRCC3 (DNA repair capacity gene) single nucleotide polymorphisms (SNPs) assessment in DNA from peripheral blood lymphocytes and CT outcomes were obtained. Smoking history was not available. Results: 1,191 p included in 4 SLCG trials from 2001 to 2005 treated with CT based on CDDP/GEM, CDDP/DOC or DOC/GEM were analysed. 163 p (14.9%) were W. W were significantly younger than men (M) (median, 57 yrs vs 61 yrs, P<0.0001). Adenocarcinoma was the most frequent histology subtype for W but not for M (77.3% vs 46.8%, P<0.0001). There were not significant differences by sex considering PS (0/1) (P<0.85), stage (IIIB/IV)(P<0.18) or overall response rate (P<0.45). Median time to progression (TTP) was 6.8 months (m) vs 5.3 m (P<0.009) in favour of W. Median overall survival (OS) was 12.9 m for W vs 9.3 m for M (P<0.001). XRCC3 SNPs were distributed similarly between sexes. Both SNPs genotyping of XRCC3 241Met/Met and Thr/Met conditioned better survival in W vs M (P<0.05 and P<0.008). In a multivariate analysis, sex was an independent predictive marker for both OS (HR 1.5, 95% CI 1.2–1.9, P<0.0001) and TTP (HR 1.4, 95% CI 1.1- 1.7, P<0.001), others independent variables found were PS, age, type of CT (only for OS), but not XRCC3 241 genotype. Conclusions: Significant differences have been detected in advanced NSCLC by sex in this retrospective first-line SLCG trials analysis according to age, histology and survival favouring W that are in agreement with previous data. Undertaking prospective sex-specific research is crucial in order to determine the best treatment choice and it could be considered gender as a stratification factor in future phase III trials.

No significant financial relationships to disclose.
DN101–004: A multicenter, open label, dose ranging study of DN-101 and docetaxel in patients with stage IIIB or IV non-small cell lung cancer (NSCLC) after platinum-based chemotherapy
Authors: West H. J. , Lee S. , Reyno L. , Fehrenbacher L. , Cohn A. L. , Hopkins J. O. , Irwin D. H. , Smith D. A. , Boyd T. E. , Olsen M. R.
Published: March 2020

7685

Background: DN-101 is a high-dose oral formulation of calcitriol, the most potent natural ligand of vitamin D receptor. Calcitriol has various anti-neoplastic effects on malignant cells and increases activity of cytotoxic agents, including taxanes. DN-101 in combination with docetaxel was associated with improved survival in a phase II study in androgen-independent prostate cancer and ASCENT 2, a phase III confirmatory study is underway. The objective of the study was to determine the maximum tolerated dose, response rate (ORR), progression-free survival (PFS), and overall survival (OS) of DN-101 in combination with docetaxel in advanced NSCLC patients (pts). Methods: Eligible pts had Stage IIIB or IV NSCLC that progressed on or after platinum-based chemotherapy, ECOG = 1, and measurable disease by RECIST criteria. DN-101 was administered on day 1 in doses of 45 (n=5), 75 (n=4), 135 (n=3), or 180 μg (n=53) in the q21d group, or 180 μg on day 1, followed by 45 (n=5), 90 (n=4), or 180 μg (n=12) on days 8 and 15 in the q7d group. Docetaxel (75 mg/m2 BSA) was given on day 2 q21d for all pts. Results: A total of 86 pts were treated. No unexpected toxicities were reported with DN-101. Grade 3/4 (G3/4) toxicities and fatal adverse events (AEs) were consistent with the reported toxicity of docetaxel alone. Stomatitis (0% in q7d, 9% in q21d) and G3/4 asthenia and fatigue (5% in q7d, 14% in q21d) were less frequent on DN-101 compared to published reports on docetaxel. No pt on DN-101 q21d developed hypercalcemia while 2 pt on DN-101 q7d (180 μg cohort) developed G3/4 hypercalcemia. Three fatal AEs included 2 on DN-101 q21d (1 lung infiltration, 1 pneumonitis) and 1 on DN-101 q7d (intestinal perforation). The ORR was 5.9% (CI 0.1%, 28.7%) and 6.6% (1.8%, 15.9%), median PFS 14.1 (6.0, 20.0) and 11.6 (8.4, 17.4) weeks, median OS 8.8 (7.1, NA) and 6.9 (5.5, 9.7) months, and 1 year survival rate 40% (15.2%, 64.8%) and 31% (18.9%, 42.2%) for the q7d and q21d group, respectively. Conclusions: DN-101 in combination with docetaxel is well-tolerated in advanced NSCLC. The observation of improved PFS, OS, and 1 year survival with weekly DN-101 administration supports further investigation.

[Table: see text]
Exclusive high dose rate brachytherapy (HDR-BT) for early stage non-small cell lung carcinoma: Results of a retrospective study in 226 patients
Authors: Aumont M. , Mahe M. A. , Prevost B. , Sunyach M. P. , Peiffert D. , Maingon P. , Thomas L. , Begue M. , Willaume D. , Lerouge D. , Campion L.
Published: March 2020

7688

Objective: To evaluate efficacy and toxicity of HDR BT in non operable endobronchial carcinoma from a retrospective multicentric study. Patients and Methods: Criteria for selection: non small cell carcinoma accessible to fiberoptic bronchoscopy, no extrabronchial extension on CT, contraindication to surgery and external radiation therapy (ERT). Statistical analysis: survival curves calculated with the Kaplan-Meier method and compared with the Logrank test; Cox model to evaluate in uni and multivariate analysis the impact on survival and complications of these parameters: location of tumor: lobar or segmental vs main stem bronchus, previous ERT vs no, total dose:= 30 Gy vs less, dose per fraction:= 5 Gy vs more, number of catheter(s):1 vs = 2. Results: Between 1991 and 2006, 226 patients from 9 radiotherapy departments were included. Main characteristics of tumors: squamous-cell histology: 96%, stage Tis: 60, T1: 153, T2: 9, Tx 4; lobar or segmental location: 91%. 51 patients (22.5%) had received ERT for previous lung cancer(s). Characteristics of HDR BT were: total dose = 30 Gy: 70%, dose per fraction = 5 Gy: 66%, 1 catheter: 46%. Dose was prescribed at 1 cm from the radius. Mean follow-up was 30.4 months (9- 116). Histologic evaluation was performed at 3 months in 137 patients. 92% had a complete response. 128 patients were died: intercurrent disease 45, local failure 35, complications 13. Two and 5-year survival: overall: 57%, 29%; specific (death of lung cancer) 81%, 56%; local- relapse free (LRF) 68%, 50%. Toxicity included 1.3% pneumothorax, hemoptysis 6.6% (5% fatal), bronchitis 20%. In univariate analysis: overall, specific and LRF survival were better for lobar or segmental location vs main stem bronchus (p=0.0001), overall and specific survival were higher with no previous ERT (p=0.006). In multivariate analysis, lobar or segmental location was associated with improved overall (p=0.0001) and LRF (p=0.003) survival. LRF survival was better in patients treated with = 2 catheters (p=0.007). No factor influence frequency of complications. Conclusion: This large retrospective study confirmed that HDRBT is efficient and safe in medically inoperable patients particulary with lobar or segmental endobronchial carcinoma.

No significant financial relationships to disclose.
Navelbine (NVB) oral (o) with cisplatin (CDDP) as induction and concomitant to radiotherapy (RT): Final results of an international phase II trial in stage III non-small cell lung cancer (NSCLC)
Authors: Utracka-Hutka B. , Krzakowski M. , Provencio M. , Villa E. , Codes M. , Kuten A. , Riggi M. , Caux N. , Longerey B. , Dubray B.
Published: March 2020

7691

Background: NVB i.v. with CDDP has reported an optimal activity/tolerance ratio when used in combination with RT. The new oral formulation of NVB should be easier to use assuming a similar activity profile. An international phase II trial with NVBo + CDDP as induction followed by NVBo+CDDP+RT was implemented in order to evaluate the efficacy of this combination. Methods: Patients (pts) between 18 and 70 years, with histologically proven untreated locally advanced inoperable stage IIIA/IIIB (supraclavicular LN and pleural effusion excluded) NSCLC, adequate bone marrow, hepatic and renal function, KPS ≥ 80% were treated with NVBo D1,8 60 mg/m2 cycle 1 and 80 mg/m2 cycle 2 (if no haematological/non-haematological grade 3–4 toxicity) and CDDP 80 mg/m2 every 3 weeks for 2 cycles as induction. OR/NC pts received NVBo D1,8 40 mg/m2 and CDDP 80 mg/m2 every 3 weeks for 2 more cycles and RT 66 Gy in 6.5 weeks. Results: Between 12/01 and 12/03 54 pts were enrolled; stages IIIA 48%, IIIB 52%; squamous 59%; median age 57 years (range 41;71), median KPS 100% (range 80; 100%) 7% pts ≥ 5% weight loss at baseline. RDI of NVBo/CDDP were 86%/93% and 97%/98% at induction and in combination with RT, respectively. Forty-one pts (76%) during induction increased NVBo from 60 to 80 mg/m2. Reasons for non- escalation: haematological 7 pts, non-haematological 2, mistake 4. After 2 cycles of CT induction, OR (ITT) in the 54 pts was 37%. Toxicity during induction: G3–4 Neutropenia (28%), febrile neutropenia (7%), G3 nausea (11%), G3–4 vomiting (9%), G3 anorexia (4%) G4 diarrhoea (2%); G3 constipation (2%). Forty-seven out of 54 pts received CT-RT. Median RT delivered dose: 66 Gy. Tolerance: 9% G3 Neutropenia; no G3/4 oesophagitis; 2% G3 radiation dermatitis. Late pulmonary fibrosis 1 pt. One month after CT-RT completion the overall RR (ITT) in the 54 pts was 54% (95% CI: 40%; 67%). Median PFS/OS: 12.5 (95% CI: 9.6; 16.4) /23.4 (95% CI: 17.6; 29.8) months, respectively. Conclusion: NVB Oral with CDDP is effective in stage IIIA/IIIB pts. The excellent tolerance profile allowed to complete the CT/RT treatment in 94% of pts. NVB oral is a new and promising option which facilitates the concomitant administration of CT/RT.

[Table: see text]
Acute radiation esophagitis in a phase I dose-escalation trial evaluating helical tomotherapy for inoperable non-small cell lung cancer (NSCLC)
Authors: Cannon G. M. , Jaradat H. A. , Tome W. A. , Khuntia D. , Mehta M. P. , Bentzen S. M.
Published: March 2020

7694

Background: In an attempt to improve the poor local control in patients with locally advanced and medically inoperable lung cancer we investigated helical tomotherapy as a means to decrease radiation dose to critical normal structures while escalating tumor dose. Methods: Thirty-six patients with Stage I-IV NSCLC requiring definitive radiotherapy and judged not to be surgical candidates due to medical comorbidities or advanced tumor stage were enrolled in this phase I trial. Chemotherapy was given sequentially but not allowed concurrently. Pts were placed in 1 of 4 dose-per-fraction bins, all treated for 25 fractions, with dose per fraction ranging from 2.28 to 3.22 Gy. Bins were calculated to yield normalized total dose (NTD) equivalents in 2 Gy fractions of 60–100 Gy. Dose escalation limiting constraints included esophageal maximum NTD, lung NTD mean, and esophageal effective volume (Veff). Radiotherapy was limited to the primary site and clinically proven or suspicious nodal regions. Elective nodal irradiation (ENI) was not performed. A graded-response logistic regression analysis was performed to identify dosimetric and clinical factors associated with esophagitis. Results: No grade 3 (CTCAE v3.0 and RTOG) acute esophageal toxicities were observed. Only 6 patients (16.7%) required narcotic analgesia (RTOG gr. 2 toxicity). Average mean NTD dose to the esophagus (Dmean)=15.3 Gy. Average volume of the esophagus receiving NTD 55 Gy (V55)=3.65%. Both Dmean and V55 were significantly associated with the grade of esophagitis, with P- values of 0.018 and 0.010, respectively. In this limited series, there was no significant effect of sequential chemotherapy, in agreement with previous studies. Conclusions: 1) Acute esophageal toxicity was minimal despite dose escalation via helical tomotherapy for inoperable NSCLC cancer. 2) The observed significant associations between V55, Dmean, and grade of esophagitis validate improved dose distribution as a strategy to permit radiation dose escalation. Pending acceptable rates of radiation pneumonitis the addition of concurrent chemotherapy is anticipated. Supported by NIH Grant CA-88960.

No significant financial relationships to disclose.
Prognostic role of VEGF, EGFR, COX-2, cERB-b2 and ER-alpha in stage 1 non-small cell lung cancers
Authors: Sadasiwan C. , Medendorp S. , Sreedhar R. , Raji A. , Blum M. , DeHoyas A. , Patel J. , Yeldandi A.
Published: March 2020

7696

Introduction: Five-year survival rates for pathologic stage one NSCLC are between 57–67%. We looked at VEGF, EGFR, COX-2, cERB-b2 and ER-a in relationship to predicting recurrence. Methods: Tumors from 65 consecutive patients with stage I NSCLC were included. After marking representative areas on the slides, tissue microarrays were prepared and stained immunohistochemically using commercially available antibodies. The scoring was done by the pathologist and the principal investigator and is calculated as the product of staining intensity, the percentage of positively stained tumor cells and extent of membrane involvement. Results: 27 (42%) males/38 (58%) females. 75% stage IA/25% stage IB. Median smoking history was 40 pack-years (range 0–160pyr). 77% adenocarcinomas/23% squamous cell carcinomas. 19 (29%) patients had a recurrence of which 14 (74%) recurred locally and 5 (26.%) recurred at distant sites. The most common site of recurrence was the lung. Median time to recurrence was 30 months (range 4–97 mos). Scores for the molecular markers are reported in table 1 . Logistic regression of all the variables on multivariate analysis showed that VEGF scores predicted recurrence (p=0.021, Odds Ratio of 1.021). Scores of >200 for VEGF were even more discriminatory. (p =0.034, Odds Ratio of 7.22). The rate of recurrence in this subgroup of patients was 39.5% as opposed to a rate of 14.8% among those with scores of less than 200. EGFR, COX-2, cERB-B2 and ER alpha were not found to be significant predictors of recurrence. Table 1 . Univariate analysis: Conclusion: VEGF scores predict risk of recurrence in stage I Non Small Cell Lung Cancers. We propose the use of high scores of VEGF, in Stage I Non Small Cell Carcinoma using immunohistochemistry to select those patients who are likely to recur.

No significant financial relationships to disclose.

[Table: see text]
Impact of pathological staging on survival in patients with epithelial mesothelioma treated with extrapleural pneumonectomy
Authors: Sugarbaker D. , Richards W. G. , Alsup C. A. , Jaklitsch M. T. , Corson J. M. , Godleski J. J. , Chirieac L. R. , Bueno R. , Zellos L.
Published: March 2020

7706

Objective: There is no universally accepted staging system in malignant pleural mesothelioma (MPM). A seventeen-year single institution experience of surgically treating a large epithelial MPM cohort with extrapleural pneumonectomy (EPP) gives insight to the applications and limitations of BWH/ DFCI and AJCC staging systems. Methods: We retrospectivly reviewed 526 consecutive patients with epithelial MPM who were surgically explored at our institution since 1988 with intent to perform EPP. Pathologic diagnoses of mesothelioma were confirmed and clinicopathologic data were recorded. Kaplan-Meyer survival from diagnosis was calculated. Those who underwent EPP were staged using BWH / DFCI (J Thorac Cardiov Surg 117:5463;1999) and AJCC (6th Edition) criteria. Operative deaths were included in the analysis and patients received varied adjuvant regimens. Results: Of 526 patients explored for potential EPP, 53 (10%) underwent alternative pleurectomy and 55 (11%) were unresectable. The remaining 418 (79%) underwent EPP. Of these, 307 (73%) were male. Median age at diagnosis was 57.9 years (17–78). Operative mortality was 5%. Median follow-up was 16 months and 23% of observations were censored. Overall median, 1-yr, 3-yr and 5-yr survival was: 18.9 mo., 68.8%, 26.3%, and 13.9%. The table below presents Kaplan-Meyer survival by stage. Conclusions: 1) Both pathological staging systems stratify survival in this cohort, although each system is limited in that a majority of patients are classified as stage 3. 2) BWH / DFCI criteria identify more stage 1–2 patients with favorable prognosis, 164 (39%) vs 46 (11%). 3) AJCC criteria classify more patients to stage 4, 76 (18%) vs 4 (1%), but appear to identify some patients with relatively favorable prognosis. 4) Selected criteria from both systems might be combined to optimally stratify patients with epithelial MPM undergoing EPP.

No significant financial relationships to disclose.

[Table: see text]
Open-label study of pemetrexed alone for chemonaive patients and pre-treated patients with malignant pleural mesothelioma: Outcomes of the International Expanded Access Program (EAP)
Authors: Taylor P. , von Pawel J. , Castagneto B. , Dark G. , Marangolo M. , van Klaveren R. , van Meerbeeck J. , Adachi S. , Blatter J.
Published: March 2020

7709

Background: In a previous phase II study of chemonaive malignant pleural mesothelioma (MPM) patients (pts), single-agent pemetrexed (P) resulted in a 14.1% response rate (RR) and median survival of 10.7 mos (95% CI 7.7–14.5) (Scagliotti 2003). Likewise, the P arm in a phase III study of pre-treated MPM pts yielded an 18.7% RR (40.7% with stable disease, SD) and median survival of 8.4 mos (95% CI 6.2–10.5) (Jassem 2006). The EAP provided 3311 MPM pts with access to P alone, P plus cisplatin, or P plus carboplatin in 13 countries. In this abstract we report on the safety and efficacy data of those MPM pts treated with P alone. Methods: Eligible pts had histologic or cytologic diagnosis of MPM and were either chemonaïve or previously treated with =1 line(s) of chemotherapy. Pts pre-treated with P were allowed if they had experienced clinical benefit from the prior P. Treatment consisted of P (500 mg/m2) once (day 1) every 21 days with standard pre-medication of vitamin B12, folic acid, and dexamethasone. Investigator-determined response (RR) and survival data (with censoring) were recorded at the end of study participation. Myelosuppression data (CTC) were also collected. Results: 812 MPM pts (319 chemonaïve; 493 pre-treated) received =1 dose of P and were evaluated for safety, and 643 pts (247 chemonaïve; 396 pre-treated) were evaluated for efficacy (RR and survival). In chemonaïve pts with MPM, the median age was 69 yrs (range: 39–87 yrs), 78.1% were male, and 71.6% had a KPS ≥80 (of the 93% who had PS evaluated). In pre-treated pts with MPM, the median age was 63 yrs (range: 31–85 yrs), 75.9% were male, and 74.5% had a KPS ≥80 (of the 95% who had PS evaluated). Both groups received a median of 4 cycles (chemonaive group range 1–18; pretreated group range 1–23). See the table for efficacy and safety data. Conclusions: Results of the EAP confirm earlier phase II and phase III studies.

No significant financial relationships to disclose.

[Table: see text]
Effect of the combination of pegylated liposomal doxorubicin and bortezomib on time to progression (TTP) and overall survival of patients with relapsed/refractory multiple myeloma compared with bortezomib alone
Authors: Harousseau J. L. , Nagler A. , Sonneveld P. , Bladé J. , Hajek R. , Spencer A. , Robak T. , Xiu L. , Zhuang S. H. , Orlowski R. Z.
Published: March 2020

8002

Background: Proteasome inhibition with bortezomib is a standard of care for patients with relapsed/refractory multiple myeloma (MM). Recently, we reported the results of an interim analysis for the DOXIL-MMY-3001 study, a large multi-national, phase III, randomized study of patients with previously treated MM demonstrating that the combination of pegylated liposomal doxorubicin (PLD) and bortezomib resulted in a 45% risk reduction of experiencing disease progression over bortezomib alone (Orlowski et al, 2006 ASH Meeting, Abstract #404). The improvement in TTP was associated with an overall survival (OS) trend favoring the combination therapy (P=0.113; hazard ratio[HR], 1.48, 95% Confidence Interval [CI], 0.91 to 2.41). We now present an updated survival analysis with a median follow up of 11 months. Methods: 646 patients at 123 centers in 18 countries received either intravenous bortezomib, 1.3 mg/m2, on days 1, 4, 8, and 11 of every 21-day cycle, or the same bortezomib regimen with PLD, 30 mg/m2, on day 4. Results: As previously reported, median TTP was improved from 6.5 months for bortezomib alone to 9.3 months for the PLD+bortezomib combination (P=0.000004; HR, 1.82; 95% CI, 1.41 to 2.35). The complete+partial response rate was 43% for bortezomib and 48% for PLD+bortezomib (P=0.251). Median duration of response was increased from 7.0 months (95% CI, 5.9 to 8.3) to 10.2 months (95% CI, 10.2 to 12.9) with combination therapy (p=0.0008). Updated OS analysis showed PLD+bortezomib significantly improved OS (p<0.05; HR, 1.41, 95% CI, 1.002 to1.97). Both groups received a median of 5 cycles of treatment. The safety profile of the combination was consistent with the known toxicities of the two agents. Grade 3/4 adverse events were more frequent in the combination group primarily due to increase in myelosuppression and GI toxicities. Conclusions: PLD with bortezomib is superior to bortezomib monotherapy for the treatment of patients with relapsed/refractory MM.

[Table: see text]
A prospective trial of involved field radiation (IFRT) + chemotherapy compared to extended field (EFRT) radiation for favorable Hodgkin disease: Survival differences and implications of mature follow-up for current combined modality therapy
Authors: Horning S. J. , Hoppe R. T. , Advani R. H. , Breslin S. , Allen J. , Hancock S. L. , Rosenberg S. A.
Published: March 2020

8014

Background: We conducted a prospective randomized trial from 1980–88 comparing IFRT plus VBM (vinblastine, bleomycin, methotrexate) chemotherapy to extended field radiation (EFRT) in patients with favorable stage I-IIIA disease to limit radiation exposure and define an effective treatment regimen that preserved fertility and did not increase the risk of leukemia. Methods: Patients (pt) with favorable, laparotomy-staged disease were defined as those with no bulky mediastinal disease, no or minimal abdominal disease (<5 cm), no or minimal splenic disease, and <1 extranodal site. VBM was given for 6 cycles after 44 Gy IFRT. EFRT was subtotal lymphoid for stage I-IIA and total lymphoid irradiation for I-IIB, IIIA pt. We previously reported (J Clin Oncol 6:1822, 1988) no survival differences in this study. Follow-up was similar for both arms and was further supplemented by an approved SSA Epidemiologic Vital Status Data Record application. Results: 72 pt were randomized, 34 to IFRT + VBM and 38 to EFRT. Median follow-up is 20.8 yr (10.3–25.1) and just 8 pt were censored at <15 yr. Twenty-one yr freedom from progression is 96% for IFRT + VBM vs 74% for EFRT (p= 0.035). A single death at 18 yr was recorded in IFRT + VBM pt (3%) whereas 11 deaths occurred among EFRT pt (29%). Overall survival (OS) at 21 yr is 95% for IFRT + VBM vs 68% for EFRT (p=0.003). As previously reported, fertility was informally assessed, but premature menopause was not observed and both men and women conceived after IFRT + VBM. Conclusion: The reduction of radiation to IFRT, combined with a less toxic chemotherapy in our study, resulted in excellent long-term OS that was significantly superior to EFRT. The survival data with IFRT + VBM also compare favorably with our historical EFRT experience. Moreover, these results have implications for current combined modality therapy where much lower doses of RT, more limited fields and brief chemotherapy should lead to even less late morbidity and mortality.

No significant financial relationships to disclose.
Long-term responses to thalidomide and rituximab in Waldenstrom's macroglobulinemia
Authors: Soumerai J. D. , Branagan A. R. , Patterson C. J. , Hunter Z. R. , Treon S. P.
Published: March 2020

8017

Background: Rituximab is active in Waldenstrom's macroglobulinemia (WM), producing response rates of 40–50%. Lower response rates are observed among patients with the FcγRIIIA-158 FF polymorphism; high B2M (≥3.0 mg/dL), and high serum IgM levels (≥6,000 mg/dL). Thalidomide enhances rituximab-mediated ADCC of lymphoplasmacytic cells and produces response rates of 25% in WM. As such, we conducted this phase II study using thalidomide and rituximab in patients naïve to either agent. Methods: Intended therapy was: Weeks 1–52: Thalidomide (200 mg po qHS for 2 wks, then 400 mg po qHS) Weeks 2–5, 13- 16: Rituximab (375 mg/m2/wk) Twenty-five patients were enrolled, 20 of whom were previously untreated, with a baseline median age of 62 (range 44–86 yrs), BM involvement of 40 (range 5–80%), serum IgM of 3,670 (range 924–8,610 mg/dL), B2M of 2.6 (range 1.4–8.3 mg/L), Hct of 34.1 (range 23.6–42.6%). Results: Grade ≥2 toxicities to thalidomide included neuroparesthesias (n=11); somnolence (n=3); confusion (n=3); rash (n=2); tremors (n=2); bradycardia (n=2) and palpitations (n=1). Among patients experiencing neuroparesthesias, 10 demonstrated resolution to grade 1 (n=3) or complete resolution (n=7) at a median of 6.7 (range 0.4- 22.5 months). Dose reduction of thalidomide occurred in all patients and led to discontinuation in 11 patients. Twenty-three patients were evaluable. Responses among evaluable patients: CR (n=1); PR (n=15); MR (n=2); SD (n=1) for an overall and a major response rate of 78% and 70%, respectively. Median serum IgM decreased from 3,670 (924–8,610 mg/dL) to 1,590 (36–5,230 mg/dL) (p<0.001), while median hematocrit rose from 33.0 (23.6–42.6%) to 37.6 (29.3–44.3%) (p=0.004) at best response. With a median follow-up of 42+ months, the median TTP for all evaluable patients on study was 35 months, and 38+ months for responders. Overall response was associated with median cumulative thalidomide dose: CR/PR/MR (29,275 mg) vs. SD/NR (7,400 mg); p=0.004. Overall responses were unaffected by FcγRIIIA-158 polymorphism status (81% vs. 71% for VV/FV vs. FF); serum IgM (78% vs. 80% for <6,000 vs. ≥6,000 mg/dL); and B2M levels (71% vs. 89% for <3 vs. ≥3 g/dL); p=NS. Conclusions: Thalidomide in combination with rituximab is highly active and produces long- term responses in patients with WM.

No significant financial relationships to disclose.
Survival outcomes for multiple myeloma over three decades: A Surveillance, Epidemiology, and End Results (SEER) analysis
Authors: Jawed I. , Lee C. M. , Tward J. D. , Macdonald O. K. , Martincic D. , Vudarla N. , Fairbanks R. K. , Kaya H.
Published: March 2020

8019

Background: There is limited data regarding survival outcomes for multiple myeloma in the literature. The purpose of this study was to analyze how patient characteristics and decade of treatment affect overall survival (OS) and cause-specific survival (CSS) for patients within a large United States (US) population database. Methods: Data were obtained from the Surveillance, Epidemiology, and End Results Program (SEER) of the US National Cancer Institute for the years 1973–2003. Patient characteristics (gender, race, age) and year of diagnosis were analyzed by multivariate Cox regression analysis for both OS and CSS endpoints. Results: 40,538 patients were included in the analysis. The mean age at diagnosis was 68.3 (median 69) years. Mean survival for the entire cohort was 41 (median 24) months. Females had better OS than males, hazard ratio (HR) 0.91 (CI 0.89–0.93, P = 0.0001), and CSS, HR 0.96 (CI 0.93–0.98, P = 0.004). There were no significant differences in OS between white and black race (P = 0.34), but black race was associated with improved CSS, HR 0.89 (CI 0.86–0.93, P = 0.0001). Younger age (age <40, 41–60, 61–70, and 71–80) was associated with improved OS and CSS (all P = 0.0001). Early treatment decade (1973–1985) was associated with diminished OS and CSS on multivariate analysis with HR 1.11 (CI 1.08–1.14, P = 0.0001) and HR 1.12 (CI 1.08–1.16, P = 0.001), respectively. Conclusions: This is the largest reported population analysis of survival outcomes for multiple myeloma. It covers three decades of care in the United States. This study reveals that improved OS and CSS are associated with younger age, female gender, and recent decade of treatment. We believe that survival improvement in recent treatment decades may be due to advances in supportive care and/or earlier diagnosis as the standard treatment for myeloma did not significantly change during this time period. Follow up studies may show dramatic improvements in survival outcomes due to modern myeloma therapies in this decade.

No significant financial relationships to disclose.

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Phase II study of total therapy 3 (TT3) with added bortezomib (V) for multiple myeloma (MM)
Authors: Barlogie B. , Anaissie E. , Shaughnessy J. D. , van Rhee F. , Hollmig K. , Pineda-Roman M. , Mohiuddin A. , Zangari M. , Tricot G. , Crowley J.
Published: March 2020

8020

Background: Building on the success of TT2 with OS exceeding a median of 8 yr, TT3 incorporated V into induction and consolidation/maintenance of melphalan (MEL)-based tandem transplants. Methods: Newly diagnosed patients with MM up to age 75 yr (>59 yr, 47%) were enrolled in TT3, consisting of 2 cycles of V, thalidomide, dexamethasone, cisplatin, adriamycin, cyclophosphamide, etoposide (VTD-PACE) as induction prior to and as consolidation after MEL transplants, followed by maintenance with monthly VTD in year 1 and TD in years 2 and 3. The primary endpoint was complete response (CR). Results: 303 eligible patients were accrued between 02/04 and 07/06; median follow-up is 19 mo. Tandem transplants were completed in 84% with TT3 and 66% with TT2 (p<0.0001) with similar 12-mo TRM (4% v 5%). At 24 mo, 84% v 68% achieved n-CR including 59% v 44% CR (both p<0.0001). 24-mo EFS is superior (83% v 75%, p=0.02; <65 yr: 86% v 76%, p=0.008) while 24-mo OS is still similar (86% v 85%, p=0.44; <65 yr: 88% v 85%, p=0.16). In gene array-based high-risk MM, 24-mo EFS was 62% v 27% (p=0.006) and 24-mo OS was 74% v 43% (p=0.06). Independent adverse parameters for OS with TT3 were LDH>=190 U/L (27%; HR=3.78, p=0.002), high-risk gene array (14%; HR=3.30, p=0.006) and age >=65 yr (29%; HR=2.23, p=0.044). Compared to the T arm of TT2, fewer patients in TT3 experienced grade >2 tremor (3% v 13%, p<0.001), constipation (6% v 14%, p=0.002), syncope (1% v 12%, p<0.001) and thrombo-embolic events (27% v 38%, p=0.004). Conclusion: Compared to TT2, added V and shortened induction in TT3 increased tandem transplant compliance, effected higher CR and n-CR rates and extended EFS with a strong trend for superior OS in high-risk MM in patients <65 yr. TT3 toxicity was reduced in comparison with the T arm of TT2.

No significant financial relationships to disclose.
Final results of a phase II PETHEMA trial of alternating bortezomib and dexamethasone as induction regimen prior autologous stem cell transplantation (ASCT) in younger patients with multiple myeloma (MM): Efficacy and clinical implications of tumor response
Authors: Rosiñol L. , Oriol A. , Mateos M. , Sureda A. , Díaz-Mediavilla J. , Herrero C. , Liu X. , Van de Velde H. , San Miguel J. , Bladé J.
Published: March 2020

8024

Background: Dexamethasone-based combinations are the standard induction regimens for younger patients with MM prior ASCT. This is the first study in which bortezomib and dexamethasone were administered on an alternating basis. Aims: efficacy and kinetics of response. Methods: patients with newly diagnosed MM under the age of 66 years were treated with bortezomib at 1.3 mg/m2 on days 1, 4, 8 and 11 (cycles 1, 3, 5) and dexamethasone 40 mg p.o. on days 1–4, 9–12 and 17–20 (cycles 2, 4 and 6), followed by ASCT with melphalan-200. Responses were evaluated by the EBMT criteria but a VGPR was included. Random effects models were utilized to analyze the tumor response kinetics to bortezomib and dexamethasone with the absolute value of M-protein overtime and decrease by cycle. Because the nonlinearity in the change of M-protein overtime, a piecewise linear model was employed. Results: between August, 2005 and March, 2006, 40 patients (median age 57) were enrolled. The response rate was 82% with 12% CR plus 10% VGPR. The response was quick with 82% M-protein reduction achieved with the first 2 cycles. There was no further decrease of the mean M-protein in cycles 5 and 6. The M-protein decrease was not different with dexamethasone and with bortezomib (p=0.48). Chromosome 13 deletion as well as t(4;14) and t(14;16) did not had a negative impact on response. Toxicity was very low: ten (25%) patients had mild peripheral neuropathy (grade 1:9 cases, grade 2:1 case) and 11 grade 1 thrombocytopenia. Grade 3 toxicity was observed in 7 patients (neutropenia 6, skin/liver 1 case). No patient developed grade 4 toxicity. In all patients stem cells could be adequately collected (median of CD34+ 5 ×106/Kg). The overall response rate after ASCT was 90% with 40% CR plus 20% VGPR. Conclusions: Bortezomib alternating with dexamethasone is highly effective as up-front therapy in patients with MM, and is associated with a very low toxicity. The results of the tumor response kinetics analysis support a short program of alternating bortezomib and dexamethasone (i.e., maximum of 4 cycles) as an effective and safe therapy for younger myeloma patients prior ASCT.

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Incidence and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: The impact of the addition of rituximab to CHOP chemotherapy
Authors: Villa D. , Savage K. J. , Sehn L. H. , Connors J.
Published: March 2020

8037

Background: The addition of rituximab to CHOP (CHOP-R) chemotherapy improves outcome in patients with diffuse large B- cell lymphoma (DLBCL). However, limited data suggests that it may not impact the risk of central nervous system (CNS) relapse. We evaluated the risk of CNS relapse and associated predictive factors in a large population-based cohort of patients with DLBCL. Methods: All patients with DLBCL diagnosed from September 1, 1999 to January 14, 2005 at the British Columbia Cancer Agency were identified, including those from a recently published report (Sehn, J Clin Onc. 2005). Patients were included if they were ≥16 years old with advanced stage (stage III /IV, or stage I /II with B symptoms or bulky disease (≥10 cm)), or limited stage with testicular involvement and excluded if HIV-positive or known to have CNS involvement at diagnosis. From Sept 1999 to Feb 2001 patients were treated with CHOP- type chemotherapy. After March 1, 2001 patients received CHOP-R. Results: A total of 435 patients with DLBCL were identified; 125 (29%) were treated with CHOP and 310 (71%) with CHOP-R. There were 28 CNS relapses with no significant difference in frequency between CHOP-treated (11 (9%)) or CHOP-R-treated (17 (5%)) patients (p=0.202). The median time to CNS relapse (8.1 mos vs 6.7 mos) and median survival after CNS relapse (2.7 mos vs 3.8 mos, p=0.665) were similar in the CHOP and CHOP-R treated patients, respectively. In univariate analysis, testicular involvement, renal involvement, advanced stage, and LDH ≥2x ULN were associated with increased risk of CNS relapse. In a multivariate analysis, testicular (OR 7.44, p=0.013) or renal (OR 6.23, p=0.012) involvement, and stage IV disease (OR 4.43, p=0.034) were independent predictors of CNS relapse. Conclusions: Consistent with prior reports, the addition of rituximab does not appear to significantly influence the risk of CNS relapse in patients with DLBCL, possibly due to poor CNS penetration. Risk factors for CNS relapse in the rituximab era are similar to those noted in prior reports based on anthracycline-treated patients. The overall survival of patients with CNS relapse is dismal and new strategies to reduce its incidence warrant further evaluation.

No significant financial relationships to disclose.
Rituximab induces long-term remissions in patients with HIV-associated multicentric Castleman's disease
Authors: Bower M. , Powles T. , Williams S. , Newsom-Davis T. , Atkins M. , Stebbing J. , Montoto S. , Nelson M. , Webb A. , Kelleher P.
Published: March 2020

8049

Background: HIV associated multicentric Castlemans (MCD) is rare lympohproliferative disorder and most treatment options to date, have proved largely unsuccessful. This study investigated the efficacy of the anti CD20 monoclonal antibody rituximab in patients with this disease. Methods: Between 2003 and 2006, patients with histological proven HIV related MCD received a course of 4 infusions of rituximab 375mg/m2 at weekly intervals. Results: Twenty one consecutive patients (18 male) were recruited into this study and the median follow-up is 12 months (range 1–49). The median age was 37 years and all patients were either on highly active antiretroviral therapy (HAART) (62%) or started HAART at the time of MCD diagnosis (38%). The median CD4 cell count at MCD diagnosis was 275/mm3 (range 77–725). One died within 2 weeks of starting rituximab (not evaluable); 20 evaluable patients all achieved clinical remission of symptoms and 71% achieved a radiological response according to RECIST criteria. Rituximab lead to a significant fall in anaemia, thrombocytopenia, CRP, ESR, serum HHV8 viral load and IL-10. Rituximab caused transitory fall in the CD19 count, but had no effect on the CD4, CD8 and NK cell counts or plasma HIV viral load. The disease free survival at 2 years is 79% (95%CI: 49–100%) and overall survival is 95% (95%CI: 86–100%). Two patients have relapsed after 1.6 & 2.8 years and were successfully retreated with rituximab therapy. Conclusions: Rituximab therapy results in a sustained clinical, radiological and biochemical remission in patients with HIV related MCD.

No significant financial relationships to disclose.
Phase I/II study of bortezomib (B) in patients with systemic AL-amyloidosis (AL)
Authors: Reece D. E. , Sanchorawala V. , Hegenbart U. , Merlini G. , Palladini G. , Fermand J. , Vescio R. A. , Liu X. , Elsayed Y. A. , Comenzo R. L.
Published: March 2020

8050

Background: AL is characterized by deposition of monoclonal immunoglobulin light chains leading to multi-organ failure and death. B (Velcade®) is a specific inhibitor of the 26S proteasome with activity in several malignancies. This mechanism of action raises concern of enhancing the amyloidogenic protein deposition and worsening of AL. This phase I/II study is to determine the maximum tolerated dose (MTD) and toxicity profile of B in pts previously treated for AL. Secondary objectives include the rate and duration of hematologic and organ responses. Methods: A 3+3 dose escalation design was used for the phase I part. Eligibility criteria included previously treated AL with organ involvement, LVEF =40% and adequate organ function. Pts with prior B treatment, infection, significant cardiac disease, bleeding or gr. 2 neuropathy were excluded. Seven cohorts are planned to examine two administration schedules. A weekly schedule administering 0.7,1.0,1.3 or 1.6 mg/m2 of B on day 1, 8, 15, 22 of a 35-day cycle. In the bi-weekly schedule, 0.7, 1.0 or 1.3 mg/m2 are given on day 1,4,8, 11 of a 21-day cycle. Pts were assessed at specified intervals and dose-limiting toxicities (DLT) were assessed during cycle 1. Results: At this time, 15 pts were treated in the 4 weekly cohorts. Median age was 59 yrs (38–74). All pts had previously received systemic therapy; 100% had received melphalan (58% with prior SCT), 83% steroids, 58% thalidomide. 75% of pts had = 2 organs involved at baseline, renal 42%, cardiac 33%, neuropathy 33%. One DLT (worsening CHF) was observed in cohort 1.6 mg/m2. Two pts discontinued early due to CHF and hypotension. Grade 3/4 AEs were reported in 42% of pts and the most frequent were fatigue 17%, infection 17%, CHF 8% and retinal detachment 8%. The most frequent grade 1/2 AEs were diarrhea 67%, nausea 42%, fever 33%, dizziness 33% and neuropathy 8%. There were no treatment-related deaths. Of the 11 evaluable pts for response, 5 (45%) had objective hematological responses (2 CR and 3 PR) and 4 pts (36%) have stable disease > 6 months. Dose escalation on the biweekly schedule is ongoing. Conclusions: B has significant activity in patients with relapsed AL in this preliminary analysis and tolerance to B is satisfactory. The MTD for the weekly schedule is 1.6 mg/m2. Further assessment is planned in the phase II part.

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Preliminary results from a phase II study of lenalidomide oral monotherapy in relapsed/refractory aggressive non-Hodgkin lymphoma
Authors: Wiernik P. H. , Lossos I. S. , Tuscano J. , Justice G. , Vose J. M. , Pietronigro D. , Takeshita K. , Ervin-Haynes A. , Zeldis J. , Habermann T.
Published: March 2020

8052

Background: Lenalidomide (Revlimid), an immunomodulatory drug of the IMiDs class, is approved in the US for treatment of relapsed/refractory multiple myeloma and myelodysplastic syndromes associated with a deletion 5q[31] cytogenetic abnormality. Lenalidomide also has activity in chronic lymphocytic leukemia and cutaneous T-cell lymphoma. This study was designed to assess the safety and efficacy of lenalidomide in patients with relapsed/refractory aggressive non-Hodgkin's lymphoma (NHL). Methods: Patients with relapsed/refractory aggressive NHL with measurable disease after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Results: As of enrollment cut-off, 50 patients were enrolled and 49 received drug. Forty-one patients were evaluable for response. The median age was 65 (46–84) and 18 were female. Histology was diffuse large B-cell lymphoma [DLBCL] (n=21), follicular center lymphoma grade 3 [FL] (n=3), mantle cell lymphoma [MCL] (n=14) and transformed [TSF] (n=3). Median time from diagnosis to lenalidomide was 3.2 (0.4–32) years and median number of prior treatment regimens was 3 (1–7). Fourteen patients (34%) exhibited an objective response (5 complete responses unconfirmed (CRu) and 9 partial responses (PR)), 12 had stable disease (SD) for a tumor control rate (TCR) of 63% and 15 progressive disease (PD). Responses were seen in each of the aggressive histologic subtypes studied: DLBCL (5/21), MCL (6/14), FL (2/3), and TSF (1/3). Five of 11 patients (45%) with a prior stem cell transplant responded. Progression free survival although ongoing is currently > 239 (>191 - >373) days in patients experiencing CRu and > 160 (>54 - >251) days in patients with PR. Most common Grade 4 adverse events were neutropenia (8.2%) and thrombocytopenia (8.2%) while most common Grade 3 adverse events were neutropenia (22%), leukopenia (14%) and thrombocytopenia (12%). Conclusion: Lenalidomide oral monotherapy is active with manageable side effects in relapsed/refractory aggressive NHL.

No significant financial relationships to disclose.