bluuebunny/crossref_metadata_2025 huggingface dataset:
Quality of life, depression and anxiety in chronic lymphocytic leukemia during phases of “watchful waiting” and active treatment
Authors: Levin T.
Published: March 2020

6603

Background: Although chronic lymphocytic leukemia (CLL) accounts for 25–30% of leukemia cases in the USA, little is known about its quality of life (QOL) and psychosocial burden. The purpose of this study was to compare QOL, anxiety and depression in watch and wait versus actively treated CLL. Methods: Using a cross-sectional design, 105 patients were recruited from a CLL research database. 57 were classified as watch and wait and 48 as receiving or having received chemotherapy for CLL. The patients completed a battery of QOL measures including the SF-36, FACT-Lym, Beck Depression Inventory (BDI-II), Beck Anxiety Inventory (BAI) and the Patient Health Questionnaire. Results: No differences were found between the treatment groups on the main QOL outcome measures - Mental Component Score, Physical Component Score, FACT-G, FACT-lymphoma (15 item), BDI-II and BAI. There was a clear age effect: younger patients (<60 years old) have worse Mental Component (p=0.0001), FACT-G (p=0.060), depression (p=0.014), Role Emotional (p=0.042), Mental Health (p=0.001), FACT-Emotional (p=0.0001) and FACT-Social (p=0.002) scores. Younger watch and wait patients seem to be particularly vulnerable to anxiety (p=0.052). Social and emotional QOL are statistically similar in both newly diagnosed and patients diagnosed six or more years ago, although patients do carry a greater physical QOL burden with time (p=0.05). Conclusions: Overall QOL, depression and anxiety are remarkably similar in watch and wait versus actively treated CLL, despite the latter group having, by definition, later stage disease. Younger patients (<60 years old) seem particularly vulnerable to having a reduced emotional and social QOL and having more depression. Younger watch and wait patients stood out as suffering from more anxiety. Patients diagnosed for more than 6 years carry a greater physical QOL burden, but social and emotional QOL are similar to newly diagnosed patients. Implications of these findings are considered.

[Table: see text]

No significant financial relationships to disclose.
A multi-center, open-label study to evaluate the safety and efficacy of pentostatin, cytoxan, and rituxan (PCR) in the treatment of previously untreated or treated stage III or IV, low-grade CLL
Authors: Nyman D. W. , Mena R. , Robles R. , Auerbach M. , Pandit L.
Published: March 2020

6606

Background: The decision to treat indolent CLL is often based on progressive bulky disease, worsening symptoms, and increasing hematological derangement. When treatment is indicated, these lymphoproliferative disorders are sensitive to combination immunochemotherapies utilizing pentostatin (P), a purine analog, cyclophosphamide (C), a DNA alkylator, and rituximab (R), a potent anti-CD20 monoclonal antibody. P+C+R represents a promising new approach in the treatment of patients with low grade CLL. Methods: Eligibility criteria allow previously treated and treatment-naïve patients diagnosed with low-grade stage III/IV CLL (modified Rai classification). Treatment consisted of intravenous infusions of P (4 mg/m2), C (600 mg/m2), and R (375 mg/m2) on day 1 of a 21-day cycle for a total of 8 cycles. Clinical evaluation (including CT scan) was performed after cycles 2, 4, 6, and 8. Patients were stratified by disease and by prior treatment status. Results: The intent-to-treat (ITT) population consisted of 41 CLL patients (median age 64, range 36–85) who received a total of 207 cycles (median 4 per patient). ECOG status at enrollment was 0 (66%), 1 (27%) and 2 (7%). The overall response rate was 61% (CR 13%, PR 48%). One grade 4 neutropenia was documented. Four deaths have been recorded. An 81 YO patient was hospitalized 8 days after cycle 1; death, due to sepsis, occurred 22 days later. The death of an 83 YO was reported 10 days after cycle 2 as a result of an acute MI. An 83 YO patient, who developed gastroenteritis, was hospitalized 10 days after cycle 2. This progressed to dehydration and atrial flutter. Death came as a result of pulmonary edema and ASHD. An 82 YO man was hospitalized 4 days after completing cycle 2. He presented with extreme dyspnea but cause of death was CLL. Conclusions: This immunochemotherapeutic regimen is active in Grade III/IV CLL and the incidence of significant toxicities was low with deaths occurring only in elderly (>80 YO) patients. Updated results of this trial will be presented at the ASCO meeting.

No significant financial relationships to disclose.
Bone and cardiac status in 10-year survivors of breast cancer
Authors: Trudeau M. E. , Lickley H. L. , Zhang L. , Hawker G. , Narod S. , Sawka C.
Published: March 2020

681

Background: A prospective case-control study was carried out on 425 women treated for breast cancer who survived for 10 years without evidence of recurrence (cases) matched for age, race and length of follow-up from diagnosis to 425 women with benign breast disease followed for 10 or more years (controls). For cases, only 23% received chemotherapy and 33% hormone therapy. Methods: We examined multiple indicators of physical and emotional well-being and report here the results pertaining to cardiac and bone health. Bone mineral density (BMD) was assessed using DXA at the lumbar spine and hip, expressed as gm/cm2, and classified as normal/low bone mass/osteoporosis. Cardiac health was assessed using 10 year cardiovascular risk, calculated as low, moderate or high based on age, cholesterol and triglyceride levels, smoking history and blood pressure (according to the calculation published by Genest J et al. CMAJ 2003). Treatment received for both bone and cardiac disease was evaluated. The comparison of cases and controls was assessed using the Wilcoxon non-parametric or Chi-squared tests. Results: Body mass index (BMI) was significantly greater for cases versus controls (27.5 ± 2.4 vs 26.7 ± 4.9; p = 0.034). The mean BMD (corrected for weight) was 1.08 ± 0.05 g/cm2 at the spine for cases, compared with 1.11 ± 0.06 g/cm2 for controls (p <0.0001). Among those with osteoporosis at follow-up, 30% of cases compared with 35% of controls had been treated with bisphosphonates; 10% cases and 55% of controls with osteoporosis had received HRT. There were no significant differences in 10-year cardiovascular risk between the cases and controls. Overall, 78% were low, 18% moderate, and 4% high risk. Cholesterol-lowering medications were prescribed to only ≤23% of the moderate and high risk groups in both cases and controls. Conclusions: Despite greater BMI, cases had lower BMD and were less likely to have received treatment for osteoporosis than were controls. 10 year cardiovascular risk was not significantly different in the cases versus controls despite the greater use of HRT in the controls. Both groups appear to be undertreated with cholesterol-lowering medications by today’s standards of care. These findings can help to inform the content of survivorship programs.

No significant financial relationships to disclose.
Efficacy and safety of sunitinib in previously treated, advanced non-small cell lung cancer (NSCLC): Preliminary results of a multicenter phase II trial
Authors: Socinski M. A. , Novello S. , Sanchez J. M. , Brahmer J. A. , Govindan R. , Belani C. P. , Atkins J. N. , Gillenwater H. H. , Palleres C. , Chao R. C.
Published: March 2020

7001

Background: Sunitinib malate (SU11248) is an oral, multitargeted tyrosine kinase inhibitor targeting VEGFR, PDGFR, KIT, FLT3 and RET on tumor cells, tumor neovasculature and pericytes. This is the initial report of an open-label, two-stage, multicenter phase II trial evaluating the single-agent activity of sunitinib in refractory NSCLC. Methods: Eligibility criteria included confirmed diagnosis of NSCLC, ECOG PS 0–1, no recent gross hemoptysis, no brain metastases, patients (pts) previously treated with 1–2 chemotherapy regimens, and adequate end-organ function. Pts received sunitinib at 50 mg/day po for 4 weeks (wks) followed by 2 wks off treatment (6 wks considered a cycle). Results: A total of 64 pts were enrolled and 63 pts treated, median age 61 yrs (range 33–87); adenocarcinoma (64%), squamous cell carcinoma (22%), other (14%); 66% male; PS 0:1, 45%:55%; median number of prior regimens: 2 (range 1–4); median time since the prior regimen: 2 months (range 1–21). To date, 63 pts have started cycle 1, 46 cycle 2, 22 cycle 3, 6 cycle 4 and 1 cycle 5. Grade 3–4 toxicities included fatigue/asthenia (21%), nausea (7%), vomiting (7%), abdominal pain (7%), and hypertension (5%). Most toxicities were grade 1–2 and included asthenia/fatigue (68%), anorexia (40%), dyspnea (37%), cough (35%), nausea (33%), mucositis (32%), dysgeusia (25%), diarrhea (21%), vomiting (19%), and constipation (19%). Grade 5 toxicities include pulmonary hemorrhage (n=2) and cerebral hemorrhage (n=1). Thus far, 6 confirmed partial responses have been observed among 63 treated pts (9.5%, 95% CI: 3.6–19.6%). Stable disease has been observed in an additional 12 pts (19.0%). Survival data are pending and will be presented. Conclusions: Sunitinib has provocative single-agent activity in previously treated pts with recurrent and advanced NSCLC, with the level of activity similar to currently approved agents. Sunitinib is well tolerated in this population. The trial is being extended to explore a continuous dosing strategy of sunitinib at 37.5 mg/day po. Based on these results, further trials are warranted and are ongoing with sunitinib in combination with standard agents/regimens.

[Table: see text]
Adjuvant chemotherapy in stage IB non-small cell lung cancer (NSCLC): Update of Cancer and Leukemia Group B (CALGB) protocol 9633
Authors: Strauss G. M. , Herndon J. E. , Maddaus M. A. , Johnstone D. W. , Johnson E. A. , Watson D. M. , Sugarbaker D. J. , Schilsky R. A. , Vokes E. E. , Green M. R.
Published: March 2020

7007

Background: In 2004, preliminary results of CALGB 9633 demonstrated statistically significant evidence that adjuvant chemotherapy with paclitaxel and carboplatin (PC) improved disease-free (DFS) and overall survival (OS) in resected stage IB NSCLC. Indeed, the study was closed early by the DSMB after a planned interim analysis demonstrated a p value for OS less than a prespecified stopping boundary. However, two larger trials, NCIC-JBR10 and ANITA, have shown significant OS advantages with adjuvant chemo, but failed to demonstrate improved survival in the stage IB subset. This report provides more mature data from CALGB 9633. Methods: InCALGB 9633, stage IB patients (pts) were randomized following resection to paclitaxel 200 mg/m2 and carboplatin AUC 6 q3wks ×4 cycles or to observation. While initially planned to accrue 500 pts, the accrual rate was <50% of expected. Because slow accrual allowed longer observation times for each pt, the accrual target was reduced to 384 pts. OS is the primary endpoint. The redesigned study had 80% power to detect a hazard ratio (HR) of 0.67 after 150 observed deaths using a 1-tailed logrank test conducted at the 0.05 level of significance. Results: Between 9/15/96 and 11/26/03, 344 pts were randomized. Median follow-up is 54 mo. Demographics and toxicity has been previously reported (JCO Sup, 22:621a, 2004). The current intent-to-treat analysis shows a significant improvement in DFS favoring adjuvant chemo (HR=0.74; 90% 2-sided CI: 0.57–0.96; p=0.027). There is a trend toward improvement in OS that is not significant (HR=0.80; 90% CI: 0.60–1.07; p=0.10). There is, however, a significant advantage in 3-yr survival (79% vs. 70%; p=0.045). Five-yr survival is not different (60% vs. 57%; p=0.32), although median follow-up is <5 yrs and CIs are wide. Continued follow-up is planned since only 131 of 150 deaths required for final analysis have been observed. Conclusions: This updated but “preliminary” analysis no longer shows a significant OS advantage for adjuvant chemotherapy in stage IB NSCLC. However, the re-designed study does not have adequate power to detect small differences in OS that may be clinically significant. Advantages in DFS and 3-yr survival support continued consideration of adjuvant PC in stage IB NSCLC.

[Table: see text]
A randomized comparison of carboplatin/vinorelbine versus carboplatin/gemcitabine in advanced non-small cell lung cancer (NSCLC)
Authors: Helbekkmo N. , Sundtroem S. H. , Aaseboe U. , Brunsvig P. F. , Von Plessen C. L. , Bremnes R. M.
Published: March 2020

7033

Background: Carboplatin/vinorelbine (CV) and carboplatin/gemcitabine (CG) are novel 2-drug combinations in the treatment of NSCLC. In a randomized national multicenter phase III study in stage IIIB and IV patients (pts), we compared these regimens with respect to efficacy, toxicity and quality of life (QoL). Methods: Chemonaive pts with histologically or cytologically proven NSCLC, stage IIIB or IV and ECOG performance status (PS) 0–2 were eligible. There was no upper age limit. Pts received vinorelbine 25 mg/m2 or gemcitabine 1000 mg/m2, both administered on day 1 and 8, in combination with carboplatin (Chatelut AUC 4) at day 1. Three courses were administered in 3-week cycles. QoL questionnaires were completed at baseline, before each cycle and then every 8 weeks up to one year. Primary endpoints were survival and QoL and secondary endpoints toxicity and time to progression (TTP). Stratification was done for age, stage and PS, and the planned sample size per arm was minimum 200. The analyses were performed on an intention-to-treat basis Results: From Oct 2003 through Dec 2004, 433 pts from 33 institutions were randomized to CV (n=218) or CG (n=215). Follow-up was minimum one year. There was no difference in overall survival between the two arms (p=0.89). Median survival was 7.3 vs. 6.5 months and 1-year survival 28% and 31% in the CV and CG arm respectively. TTP was significantly longer in the CG arm (p=0.006) with median TTP 4.2 vs. 3.9 months. There was significantly more grade 3–4 anemia and thrombocytopenia in the CG arm (p<0.001) and more grade 3–4 leucopenia in the CV arm (p= 0.001). More pts in the CG arm needed transfusions of blood (p=0.003) or platelets (p=0.001). There was no difference between the arms with respect to neutropenic infections (p=0.87). QoL data are still being analyzed and will be presented at ASCO. Conclusions: Overall survival was similar in the two treatment arms. In the CG arm, the median TTP was longer, but grade 3–4 toxicity requiring interventions, was more frequent when compared to the VC arm.

No significant financial relationships to disclose.
Comparison of survival for non-small cell lung cancer (NSCLC) between premenopausal and postmenopausal women: An analysis of the National Surveillance, Epidemiology and End Results (SEER) Database
Authors: Oton A. B. , Belani C. , Cai C. , Owonikoko T. , Gooding W. , Siegfried J. , Ramalingam S.
Published: March 2020

7038

Background: Estrogen signaling has been implicated in lung cancer formation and progression by pre-clinical studies. Estrogen receptor (ER) Beta is overexpressed in NSCLC. To understand the clinical impact of the estrogen pathway, we analyzed the national SEER database to compare the outcomes for NSCLC in premenopausal vs. postmenopausal women. Methods: Data from the national SEER registry between the years of 1988–2002 was analyzed. Women between the ages 40–44 were chosen as representative of the pre-menopausal group and 55–59 year-old women represented the post-menopausal group. To control the effect of age alone as a determinant of outcome, we compared the survival between 1,534 men with ages of 40–44 and 8,807 men with ages of 55–59. Survival rates were analyzed by Kaplan-Meier method and compared by Z-test through SEER*Stat software version 6.1.4. Results: A total of 7,150 women, premenopausal (1,171) and postmenopausal (5,979) were included. Adenocarcinoma (ADC) was more commonly seen in premenopausal than in postmenopausal women (58% vs 47%). Distribution by stage at diagnosis was similar between the two groups. Premenopausal women with squamous cell carcinoma (SCC) or bronchioalveolar carcinomas (BAC) had inferior overall survival than postmenopausal women. Differences in outcome between men in the two age groups were not significant. Conclusions: Premenopausal women with SCC or BAC, but not ADC have inferior survival compared to postmenopausal women. Smaller and non-significant differences were observed between males of the same aged-groups. The results suggest varying estrogen effects between the histological sub-types of NSCLC and support clinical strategies to block the ER pathway for the treatment of NSCLC.

[Table: see text]

No significant financial relationships to disclose.
Second Japan-SWOG common arm analysis of paclitaxel/carboplatin in advanced stage non-small cell lung cancer (NSCLC): A model for testing population-related pharmacogenomics
Authors: Crowley J. , Furuse K. , Kawahara M. , Fukushima M. , Kawaguchi T. , Williamson S. , Lara P. N. , Mack P. C. , Gandara D. R.
Published: March 2020

7050

Background: Whether results of clinical trials performed outside the United States (US) can be fully extrapolated to US populations remains in question due to potential differences in trial designs, study-specific criteria, patient demographics, and population-related pharmacogenomics. The first of these comparisons, FACS-S0003 has been presented (Gandara, PASCO, 2004). Here we present the second comparative analysis. Methods: We prospectively designed & conducted 3 separate phase III trials in advanced NSCLC linked by a “common arm” with identical eligibility, staging, response & toxicity criteria, to: 1) determine similarities & differences in patient demographics & outcomes in cooperative group trials in Japan (in this analysis, the Japan Multinational Trial Organization LC03) & the US (SWOG 0003), 2) provide the basis for global standardization in clinical trials in NSCLC, and 3) facilitate regulatory changes needed for joint Japan-US studies. We performed a planned comparative analysis of the paclitaxel/carboplatin arms from LC03 & S0003, which had identical doses and schedules of paclitaxel dose (225mg/m2) and carboplatin (AUC 6). Conclusions: 1) This common arm analysis, as in our prior FACS-S003 report, shows great similarities in patient demographics between the LC03 and S0003. 2) Variable toxicities may be due to population-related pharmacogenomics (increased neutropenia & febrile neutropenia in LC03), and could be explained by polymorphisms in cytochrome P450 for paclitaxel metabolism (ongoing analysis). 3) Survival is increased in LC03. 4) Future joint Japan-US clinical trials should assess possible pharmacogenomic differences in drug disposition.

[Table: see text]

No significant financial relationships to disclose.
Retrospective study of clinical and radiographic risk factors associated with early onset, severe pulmonary hemorrhage in bevacizumab-treated patients with advanced non-small cell lung cancer (NSCLC)
Authors: Sandler A. B. , Johnson D. H. , Brahmer J. , Schiller J. H. , Ostland M. , Gray R. , Tran S. , Dimery I.
Published: March 2020

7068

Background: Bevacizumab (BV) added to chemotherapy prolongs survival in non-squamous NSCLC, but was uncommonly associated with serious pulmonary hemorrhage (PH) (Sandler A, et al, ASCO 2005). A retrospective study was conducted to potentially identify clinical or radiographic (CT) risk factors associated with early onset (<150 days from initial treatment) PH. Methods: A broad search of the E4599 database for selected bleeding terms among BV-treated patients was conducted. Cases of PH were identified and adjudicated. Associations between baseline clinical factors and incidence of PH were evaluated in the full cohort of E4599 patients. In addition, a separate case-control analysis, using controls matched on age and sex, was conducted to evaluate baseline CT variables. Chest CTs were evaluated by blinded independent assessment of lesion location, cavitation, size of largest tumor or nodal mass, vascular involvement, presence of an endobronchial tumor, and total number of intra-thoracic lesions. Additional analyses were also conducted including cases of late-onset PH, post-baseline variables such as unconfirmed tumor response at 6 weeks (RECIST) and cavitation, and combined CT data from E4599 and an earlier Ph II trial. Results: Of 425 BV-treated pts, 10 cases of PH were identified. Of these, 7 were PH without additional complicating factors, and 6 were of early-onset. The cohort analysis of these 6 early-onset cases is presented ( table ). The case-control analysis on CT risk factors is ongoing. Conclusion: PH was an uncommon event, and based on this, no evidence was observed for an association between the baseline clinical variables and the incidence of early-onset events of PH without additional complicating factors. Conclusions for the CT variables evaluated will be presented.

[Table: see text]

[Table: see text]
Randomized phase III trial of docetaxel and cisplatin combination chemotherapy versus mitomycin, vindesine and cisplatin combination chemotherapy with concurrent thoracic radiation therapy for locally advanced non-small cell lung cancer: Preliminary report
Authors: Kiura K. , Segawa Y. , Tabata M. , Takigawa N. , Kamei H. , Harita S. , Ueoka H. , Hiraki S. , Matsuo K. , Tanimoto M.
Published: March 2020

7101

Background: Standard treatment of locally advanced non-small cell lung cancer (NSCLC) is cisplatin-based chemotherapy with concurrent thoracic radiation therapy (TRT). Furuse et al. demonstrated a superiority of mitomycin, vindesine and cisplatin (MVP) chemotherapy with concurrent TRT over that with sequential TRT (JCO 17, 1999). We demonstrated that docetaxel plus cisplatin (DP) chemotherapy with concurrent TRT shows better response rate and survival (Kiura K et al. BJC 89, 2003). We conducted a randomized phase III trial that compared DP with MVP in locally advanced NSCLC patients when concurrently administered with TRT. Methods: We randomly assigned patients with good performance status (PS)-stage IIIA/IIIB NSCLC to receive DP or MVP chemotherapy. Chemotherapy consisted of docetaxel 40 mg/m2 and cisplatin 40 mg/m2 on days 1, 8, 29, & 36 in the DP arm and mitomycin 8 mg/m2 on days 1 & 29, vindesine 3 mg/m2 on days 1, 8, 29, & 36, and cisplatin 80 mg/m2 on days 1 & 29 in the MVP arm. In the both groups, TRT began on day 1 at a dose of 60 Gy (2 Gy per fraction and 5 fractions per week for a total of 30 fractions). Results: Two hundred patients entered the trial between July 2000 and July 2005. Pretreatment characteristics were well balanced between the two treatment arms as follows: male/female 92/7, 88/13; median age (range) 65 (40–75), 64 (34–75); stage IIIA/IIIB 33/66, 33/68; and PS of 0/1 46/53, 50/51, for the DP arm and for the MVP arm, respectively. The response rates for the DP arm and the MVP arm were 78.8% and 70.3%, respectively. The 1- and 2-year survival rates were 81.8% and 59.9% for the DP arm, and were 68.8% and 49.1% for the MVP arm, respectively. Median follow up time is 1.4 years in January 2006. Complete analysis will be fixed in July 2007. Conclusions: The DP arm is exactly reproducing the response rate and survival of the phase II trial we have previously reported. The MVP arm seems to reveal better results than that we expected. Radiation dose and schedule might explain the difference because Furuse et al. splitted 56 Gy of TRT in the MVP arm whereas we did not split 60 Gy of TRT.

No significant financial relationships to disclose.
A randomized double-blind phase II study to evaluate same-day vs next-day administration of pegfilgrastim with carboplatin and docetaxel in patients with NSCLC
Authors: Belani C. P. , Ramalingam S. , Al-Janadi A. , Eskander E. , Ghazal H. , Schwartzberg L. , Elliott M. , Shahin S. , Dreiling L.
Published: March 2020

7110

Background: Combination therapy with carboplatin and docetaxel has demonstrated activity against non-small cell lung cancer (NSCLC), but is associated with at least a moderate risk of febrile neutropenia (FN). Though pegfilgrastim is given only once-per-cycle 24 hours after chemotherapy (CT), administering pegfilgrastim on the same day as CT would be convenient for patients (pts). Methods: Pts ≥18 years with previously untreated stage IIIB or IV NSCLC and ECOG ≤2 who were candidates for carboplatin AUC 6 and docetaxel 75 mg/m2 were randomized 1:1 to receive pegfilgrastim 6 mg within 4 hours or approximately 24 hours after CT. The primary endpoint was the duration of grade 4 neutropenia (DSN) in cycle 1. Same-day administration was considered noninferior to next-day if the upper 95% confidence interval (CI) limit for the difference in DSN between groups in cycle 1 was <2 days. Results: As planned, 90 pts were enrolled. 88 pts received blinded study drug. Pts in the same-day and next-day groups had comparable mean baseline ANC and similar proportions of pts completed the study (43% vs 45%). In cycle 1, only 5% of pts in both groups experienced grade 4 neutropenia; resulting in a mean DSN of 0 days. Similarly in cycle 4, 10% (lasting for 1 day only) and 0% of pts in the same-day and next-day groups experienced grade 4 neutropenia. No pts experienced FN during the study. 44% of pts in the same-day and 33% of pts in the next-day group experienced serious adverse events. Conclusions: In this study of lung cancer patients receiving carboplatin and docetaxel, use of pegfilgrastim from the first cycle was well-tolerated in both treatment groups. Although the incidence of grade 3/4 neutropenia was lower than previously reported for this regimen, DSN appeared to be similar for patients in the same-day and next-day groups. Additionally, few patients experienced reductions or delays in CT delivery.

[Table: see text]

[Table: see text]
Effect of paclitaxel-carboplatin (PC) consolidation chemotherapy after weekly PC concurrent chemo-radiotherapy (CCR) for patients with locally advanced non-small cell lung cancer (LA-NSCLC): 3-year definitive results of the B001-phase III GERCOR-study
Authors: Colin P. , Jovenin N. , Ganem G. , Duhamel J. , Oster J. , Guichard F. , Cretin J. , Terrioux P. , Brechot J. , Morere J.
Published: March 2020

7112

Background: Local control rate of LA-NSCLC seems better after concurrent CCR than after sequential schedule; the role of additional chemotherapy is not clearly defined. A multi-institutional phase-III trial was conducted to evaluate the role of chemotherapy consolidation after CCR Methods: Eligibility criteria included mediastinoscopy-controlled unresectable NSCLC stage IIIA (27%) - IIIB (59%) and inoperable mediastinal recurrence after surgery (14%), PS < 3, clinical target volume compatible with a minimal 60 Gy dose radiation. After registration, patients (pts) were treated with combination of weekly P (45 mg/m2), C (AUC 2), and radiotherapy 60–66 Gy (5 × 2 Gy per week). The pts with response or stable disease were randomized either to receive 3 cycles of P (175 mg/m2) and C (AUC 5) consolidation on days 1–22–43 or observation. Primary endpoint was OS (log-rank test), planned sample was 122 pts. Results: Actually, 71 pts were enrolled. Thirty pts (42%) were not randomized because of progression (22%) and disease-related death (22%), toxicity (26%), refusal (9%), protocol violation (21%). Toxicity grade 3–4 per patient: for the PC-TRT sequence; neutropenia 5%, febrile neutropenia 5%, thrombopenia 5%, pneumonitis 5%, oesophagitis 19%. For the PC consolidation sequence; neutropenia 24%, febrile neutropenia 6%, thrombopenia 0% (no treatment-related death). After a minimal follow-up of 3 years, despite poor inclusion rate, OS and PFS were greater in the PC consolidation group with 3-year OS: 29.9% vs 10% (HR = 0.45; CI 0.95: 0.22–0.91) (p = 0.002) and 3-year PFS: 27.8% vs 10% (HR = 0.6; CI 0.95: 0.3–1.3) (p = 0.17). Nine pts developed metastasis in each treatment arm. Conclusions: The addition of PC consolidation to PC-CCR is not easily feasible for all LA-NSCLC. For selected pts (only 58% of pts in this trial), despite premature ending of the trial because of slow accrual, PC consolidation significantly improved the 3-year OS and probably PFS. Because no difference in the metastatic incidence was observed, the effect of chemotherapy dosage in the consolidation arm could be explained by delaying metastasis.

No significant financial relationships to disclose.
A prospective phase II study of single-agent gemcitabine at prolonged constant infusion at 10mg/m2/min rate (PCI-G) in first-line treatment of elderly patients (pts) with advanced non-small cell lung cancer (NSCLC): The MILES-2G study
Authors: De Maio E. , Morabito A. , Barbera S. , Robbiati S. F. , Piazza E. , Brancaccio L. , Rosetti F. , Foa P. , Verusio C. , Gridelli C.
Published: March 2020

7125

Background: Single-agent chemotherapy is the standard treatment for elderly pts with advanced NSCLC, following the results of the ELVIS and MILES-1 trials. Some hints that infusing gemcitabine at a fixed dose rate of 10 mg/m2/minute can optimize its pharmacokinetics have been reported. A prospective phase 2 study was conducted to describe activity and toxicity of PCI-G. Methods: Advanced (stage IV or IIIb with supraclavear nodes or pleural effusion) NSCLC pts, aged >70, PS 0–1, were eligible. 51 patients were required according to a single-stage phase 2 design to have 90% confidence in estimating a 25% ±10% response rate. Response was assessed with RECIST; toxicity was coded with NCI-CTC. Results: From October 2002 to June 2003, 51 pts were enrolled. 26 pts (51%) were older than 75 years. Two complete and seven partial responses were observed, for an overall response rate of 17.6% (95% exact CI: 8–31). The median progression-free survival was 16 wks (95% CI: 11–21) and the median overall survival was 41 wks (95% CI: 28–51). Two toxic deaths were recorded (1 bronchial bleeding and 1 hepatic toxicity). Other relevant toxicities were (% of pts): grade 3–4 neutropenia (11.8%), grade 3 thrombocytopenia (5.9%), grade 3 pulmonary toxicity (3.9%) and grade 3 liver toxicity (3.9%); platelet transfusion, grade 3 anemia, RBC transfusion, non-neutropenic infection, and grade 4 neurotoxicity were all reported in one pt each. Conclusions: In this phase 2 prospective study dedicated to elderly pts with advanced NSCLC, PCI-G was not sufficiently active to warrant further investigation.

No significant financial relationships to disclose.
Dose-dense pemetrexed (P) and gemcitabine (G) as neoadjuvant therapy in resectable non-small cell lung cancer (NSCLC)
Authors: Bepler G. , Robinson L. , Sommers E. , Sharma A. , Williams C. , Chiappori A. , Haura E. , Simon G. , Antonia S. , Tanvetyanon T.
Published: March 2020

7129

Background: Adjuvant chemotherapy is standard of care for NSCLC stage IB-III after complete resection. Neoadjuvant therapy has potential advantages. P and G are efficacious in NSCLC with low toxicity. In combination, they can be given dose-dense, which may result in better efficacy, lower toxicity, and higher patient acceptability than traditional platinum-based therapy. Methods: Patients with resectable IB-IIIA and selected IIIB, PS 0–1, w/o prior therapy were eligible. CT, PET, brain MRI, and mediastinoscopy were used for staging. P (500 mg/m2) and G (1,500 mg/m2) were given on d1, 15, 29, and 43. Imaging studies were repeated 7–14 days after treatment and response determined by RECIST. Patients had surgery 3–4 weeks after the last treatment. F/U was every 3 months for 2 years with imaging studies. The primary clinical endpoint is radiographic disease response rate. The secondary endpoints are overall and disease-free survival, pathologic response rate, treatment-related toxicity, and surgical respectability and outcome Results: From 4/04 to 12/05, 45 eligible patients were enrolled. The disease stages were IB in 17, IIA in 3, IIB in 10, IIIA in 12, and IIIB in 3 patient. 8 had adeno, 15 squamous, and 22 large cell or unspecified NSCLC on initial diagnosis. 27 had a PS of 0 and 18 PS 1. 3/45 had weight loss. 22 were women. The median age was 67 (range 42–83 years). 2 were never-smokers, 24 had quit, and 19 were active smokers. Disease response rates to PG were 3% CR, 34% PR, 55% SD, and 8% PD. An R0 resection was performed in 75% of patients, 15% had an incomplete resection, and 10% did not have a thoracotomy. There have been no deaths or unexpected morbidities related to surgery or chemotherapy. Conclusions: Dose-dense PG is well tolerated with acceptable side effects. It appears to be equally as efficacious as platinum-containing chemotherapy doublets in terms of radiographic response rates. Survival rates and the median survival time are forthcoming to allow for a better comparison of this regimen with platinum-containing doublets.

No significant financial relationships to disclose.
Phase I study of aerosolized SLIT cisplatin in the treatment of patients with carcinoma of the lung
Authors: Wittgen B. P. , Kunst P. W. , van der Born K. , Peters G. J. , Perez-Soler R. , Metzheiser B. , Nicholson S. , Perkins W. , Pilkiewicz F. , Postmus P. E.
Published: March 2020

7131

Background: Investigate the safety and pharmacokinetics of aerosolized SLIT (Sustained release Lipid Inhalation Targeting) cisplatin in patients with carcinoma of the lung. Methods: In this single-center, dose-escalating study patients received SLIT cisplatin for a maximum of 6 cycles. The dose level defines the cycle duration and number of inhalations per day. Safety data, including laboratory parameters, adverse events, pulmonary function tests, bronchial responsiveness, and radiographic imaging were collected and analyzed for all patients in order to determine toxicity. Pharmacokinetic data was collected during the first treatment course. Results: 17 patients and 1 patient on compassionate use received treatment. SLIT cisplatin was well tolerated. No dose limiting toxicity was observed. The maximum delivered dose was 60 mg/m2 in a 2 week schedule and 40 mg/m2 on a weekly schedule. Safety data showed no hematological toxicity, nephrotoxicity, ototoxicity, or neurotoxicity. Common side effects were nausea (66.7%), vomiting (44.4%), dyspnea (66.7%), hoarseness (27.8%), and fatigue (66.7%). Pharmacokinetic data showed very low systemic concentrations only at the higher doses. CTC grade-2 decrease in FEV1 and DLCO occurred both in 2 patients after 1 course, and grade-1 decrease in FEV1 and DLCO in 6 and 4 patients respectively. Best overall response was stable disease in 13 patients, while 4 had progressive disease (1 patient received only one course). These results indicate that high doses of aerosolized SLIT cisplatin can be inhaled safely. The therapeutic effect of the formulation will be tested in a phase II study. Conclusions: Inhaled SLIT cisplatin was found to be feasible and safe in patients with lung cancer.

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Delay in time to worsening of symptoms (TWS) of advanced non-small cell lung cancer (NSCLC) using gemcitabine (gem) maintenance therapy
Authors: Peterson P. , Zwitter M. , Krzakowski M. , Wenczl M. , Tzekova V. , Ramlau R. , Ciuleanu T. , Liepa A. , Zielinski C. , Brodowicz T.
Published: March 2020

7140

Background: Palliation of disease-related symptoms is an important clinical benefit. For advanced disease, this may be relief or delay of worsening of symptoms. Since benefit evaluation in clinical trials is usually focused on radiological assessments, development is needed to establish symptom improvement as an efficacy endpoint. Methods: To determine if gem maintenance therapy delayed the worsening of symptoms, retrospective analyses were performed using symptom data reported by patients (pts) with advanced NSCLC from a randomized trial of gem plus cisplatin followed by gem maintenance therapy plus best supportive care (GBSC) or best supportive care (BSC) (Krzakowski, ASCO 2004). Pts rated 6 symptoms using the Lung Cancer Symptom Scale (LCSS) at baseline and every cycle. Symptom worsening was retrospectively defined as a 15-mm increase in the severity score for any symptom (based on 100-mm scales) from randomization (start of maintenance therapy). Analyses were repeated for 10- and 20-mm increases. Data were analyzed using Kaplan-Meier (KM) plots and Cox regression, with censoring at the last LCSS for pts with no worsening. Results: At randomization, 73% were stage IV and 48% had Karnofsky performance status >80. Of the 206 pts randomized, 171 were included in the symptom analyses. Although not significant, the KM plot for TWS based on the 15-mm definition (defn) showed a separation between arms in favor of GBSC beginning ∼2.5 months after randomization (p = 0.24, HR = 0.79). TWS results for the 20-mm defn were significant in favor of GBSC (p = 0.013, HR = 0.59). When the same analysis was applied to individual symptoms, all symptoms showed the same numerical trend (HR<0.77) in favor of GBSC, with significant TWS advantage for GBSC (HR<0.56) for appetite loss and fatigue (15- and 20-mm defn) and for pain (20-mm defn). Additional analyses suggested a strong correlation between TWS and time to progressive disease. Conclusions: In addition to prolonging time to disease progression, gem maintenance therapy delays pt-reported worsening of symptoms. Correlation of TWS with time to progression suggests that delayed TWS may be a clinical benefit of delayed onset of progressive disease.

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High-dose 3D chemoradiotherapy trials in stage III non-small cell lung cancer (NSCLC) at the University of North Carolina: Long-term follow up and late complications
Authors: Lee C. B. , Socinski M. A. , Lin L. , Moore D. T. , Morris D. E. , Halle J. S. , Rosenman J. G.
Published: March 2020

7145

Background: Combined modality treatment is the standard of care for patients (pts.) with unresectable stage III NSCLC. Dose escalation of radiotherapy and the use of concurrent chemotherapy are two strategies attempting to improve survival and locoregional control. The intensification of therapy increases the risk of both early and late treatment related toxicities. Methods: From 5/1996 to 8/2004, 112 stage III NSCLC pts. were entered into 4 Phase I/II trials to assess the safety and feasibility of high-dose (74–90 Gy) thoracic conformal radiotherapy (TCRT) in QD or BID fractions. All pts. were treated with platinum-based induction chemotherapy; 3 of the trials also used concurrent chemotherapy. Results: The median follow up of survivors (29/112) on these trials was 4.9 years. The overall response rate after combined modality therapy was 47% (53/112) (CR 4%, 5/112; PR 43%, 48/112). 27% (30/112) had stable disease. The median survival (with 95% CI) was 24 months (18–31 months). 1-, 3-, and 5-year overall survival was 69% (60–77%), 36% (27–45%), and 24% (16–33%) respectively. Late complications of therapy (defined as >90 days post radiotherapy reported to date) are displayed in the table. Two pts. developed a second primary (1 lung, 1 liver carcinoid). In total, 22% (25/112) had late complications. These patients appear to have a significantly better overall survival (p = .007). 12% (13/112) had a brain-only recurrence, although this did not seem to significantly impact overall survival (p = .82). Conclusions: 1) High-dose TCRT is feasible and results in promising survival outcomes. 2) Late complications occur in a minority of patients suggesting the potential benefit of more aggressive TCRT is not outweighed by its risk. 3) Interestingly, brain-only recurrences did not significantly impact survival in these trials.

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Evaluation of epidermal growth factor receptor (EGFR) mutations as predictive and prognostic indicators in patients with adenocarcinoma of the lung treated with conventional chemotherapy
Authors: Fukui T. , Ohe Y. , Takano T. , Tsuta K. , Nomoto K. , Furuta K. , Sekine I. , Kunitoh H. , Matsuno Y. , Tamura T.
Published: March 2020

7165

Background: EGFR mutations are associated with the responses to EGFR-tyrosine kinase inhibitors (TKI) in patients (pts) with adenocarcinoma of the lung. The E746-A750 deletion and L858R substitution mutations are the most common, as previously described. However, their implications in pts treated with conventional chemotherapy are unclear. To evaluate the predictive and prognostic value of the EGFR mutations, we studied pts with adenocarcinoma of the lung treated with conventional chemotherapy. Methods: We reviewed pts with advanced or recurrent chemotherapy naïve adenocarcinoma of the lung who received systemic chemotherapy between January 1999 and July 2001. Deletion in exon 19 and missense mutation (L858R) in exon 21 from small biopsy or cytology samples were analyzed by a high-resolution DNA melting analysis technique. Results: A total of 101 pts, all Japanese, could be analyzed. Patient characteristics were as follows: median age: 62 (37–84) years; female/ male: 39/ 62; never/ former/ current smoker: 47/ 23/ 31; and platinum-based/ non-platinum regimen: 81/ 20 (18 pts received EGFR-TKI later). 43 pts (42.6%) had EGFR somatic mutations; deletion in 24 pts, and a point mutation (L858R) in 19 pts. PR/ SD/ PD/ NE was observed in 11/ 24/ 7/ 1 pts with EGFR mutations and in 13/ 28/ 15/ 2 pts without the mutations, respectively. The response rate was similar (26% vs. 22%, p = .71) in the two subgroups. The median survival duration of the pts with EGFR mutations was 14.9 months (n = 43, including the 11 pts treated with EGFR-TKI later), as compared with 11.0 months (n = 58, including the 7 pts treated with EGFR-TKI later) in the pts without EGFR mutations (p = .09). Another analysis which handle the start of gefitinib administration as a censoring showed similar results (p = .24). Conclusions: EGFR mutations were not good predictors of tumor response to conventional chemotherapy. The overall survival tended to be longer in the pts with EGFR mutations, but prognostic value of these mutations for survival in pts with advanced adenocarcinoma of the lung was not statistically significant.

No significant financial relationships to disclose.
Gastrointestinal hemorrhage in advanced non-small cell lung cancer (NSCLC) patients treated with erlotinib and celecoxib
Authors: Fidler M. J. , Argiris A. , Patel J. D. , Johnson D. H. , Sandler A. , Villaflor V. , Coon J. , Buckingham L. , Bonomi P.
Published: March 2020

7172

Background: Erlotinib (E) was associated with superior survival in a phase III trial of previously treated advanced NSCLC patients (pts). Celecoxib (C) has been shown to potentiate the apoptotic and growth inhibitory effects of E in pre-clinical models. Methods: This was a phase II trial of E plus C in advanced NSCLC pts that failed one prior chemotherapy regimen. Primary endpoint: efficacy; secondary endpoint: toxicity. Pts received C (400mg b.i.d.) and E (150mg daily) until disease progression. Planned accrual: 40 pts. Results: 26 pts with stage IIIB/IV NSCLC were enrolled. Patient (pt) characteristics: male 65%; median age 66; ECOG performance status 0/1- 96%. Eighteen pts had tissue available for FISH and EGFR mutation analysis: 50% had chromosome 7 polysomy (> 4 copies per cell); none had EGFR gains (>2 EGFR/chromosome 7). Two pts had an EGFR gene mutation (1 exon 19, 1 exon 21). Response results: partial response- 2 pts (1 with exon 19 mutation), stable disease- 8 pts, and progressive disease- 16 pts (1 with exon 21 mutation). Median progression free survival (PFS) and overall survival (OS): 1.9 and 10.2 months, respectively. Grade 3/4 upper gastrointestinal bleeding (GIB) occurred in 4 pts prompting study closure. One pt was on therapeutic dalteparin and two pts receiving warfarin developed marked INR prolongation (INR >10). The fourth pt had a history of peptic ulcer disease. Platelet counts at time of GIB: 142 - 559. Three pts had endoscopy and gastric or duodenal ulcers were found in all three cases. No pts were taking anti-acid medication at the time of GIB. No other pts were on therapeutic anticoagulation. Three pts without upper GIB were taking low-dose aspirin. Other toxicities: 85% grade 1/2 rash; 65% grade 1/2 diarrhea, 30% grade 1/2 nausea, 30% grade 1/2 fatigue (one grade 3 fatigue); one grade 3 pneumonitis, one grade 3 esophageal stricture. Conclusions: These observations suggest that C plus E may be associated with increased incidence of gastrointestinal ulceration and GIB and that the regimen should not be given to pts with a previous history of peptic ulcer disease or to pts requiring therapeutic anticoagulation. Based on response rate, PFS, and OS in this group of pts, it appears that results with E and C are similar to those reported for E alone.

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Cohort KBP-2000-CPHG: Evaluation of prognosis factors for survival in primary bronchial cancer (PBC)
Authors: Blanchon F. , Grivaux M. , Zureik M. , Asselain B. , Breton J. , Duvert B. , Legroumellec A. , Level M. , Berthiot G. , Carlier M.
Published: March 2020

7204

Background: PBC has a guarded prognosis despite advances in treatment. The main epidemiologic changes observed during the last fifteen years are the strong progression in its incidence in women and the increase in adenocarcinomas. A prospective study of overall survival and survival according to sex and prognosis factors was set up from the cohort of study KBP-2000-CPHG. Methods: KBP-2000-CPHG is a prospective epidemiological study conducted throughout the year 2000 on histologically confirmed PBC patients treated in general hospitals. 5,667 patients were included. A survival study based on patient outcomes was launched between September 2004 and March 2005 in 137 centres. Each centre had to provide information on the vital status of its patients with, in the event of death, the date and cause. In the absence of vital status data, a graduated tracing strategy was set up including the interrogation of various files: city hall of the place of birth,etc. Results: 135 investigator centres out of the 137 initial centres took part. The 2 non-participating centres represented 56 patients. The vital status could be defined for 5441 of the other 5611 patients (97.0%). 88.4% of these patients had died (average time between inclusion and death: 10.5–10.7 months). In univariate study, survival status is linked with age (p < 0.0001), tobacco consumption (p < 0.0001), performance status (p < 0.0001), cancer type (small versus non small cell lung cancer-NSCLC: p < 0.0001) and for the NSCLC, with histological type (p < 0.0001) and TNM stage (p < 0.0001). According to multivariate analysis, survival status is related to age, performance status, cancer type and among the NSCLC, to age, sex, performance status, histological type and TNM stage. Conclusions: The survival study on PBC is the first one in France, including more than 5,400 patients. The first results show the prognosis role of age, sex, histological type, performance status and TNM stage.

No significant financial relationships to disclose.