Endpoint Of Tumor Response Research Articles

Outcome measures of phase III anticancer drug trials in China.

Outcome measures of phase III anticancer drug trials in China.

PCR167 At-Home Versus in-Clinic Patient Reported Outcome Compliance in Oncology Clinical Trials

There is increased regulatory emphasis on using patient reported outcomes (PROs) in oncology to provide additional information on clinical benefit beyond traditional survival and tumor response endpoints. Latest recommendations highlight core PROs to consider and the need for more frequent assessments for more accurate quality of life evaluation. To accommodate these recommendations, PRO collection is shifting from the clinic to patients’ homes to allow for more frequent data collection while reducing the burden of travel and site visit time. However, given disease progression characteristics, oncology studies are already at risk for low compliance, and unsupervised at-home PRO collection puts greater responsibility on patients. We aimed to determine the impact of at-home data collection on PRO compliance in oncology studies.

Tumor Response End Points as Surrogates for Overall Survival in Immune Checkpoint Inhibitor Trials: A Systematic Review and Meta-Analysis.

Many immune checkpoint inhibitors (ICIs) have been approved on the basis of tumor response end points in nonrandomized trials, including objective response rate (ORR) and duration and depth of response. We aimed to assess the validity of these end points as surrogate end points for overall survival (OS) in patients with advanced solid tumors treated with ICIs at trial and treatment arm levels. ICI trials in advanced solid cancers published between January 1, 2000, and March 31, 2020, were included. Correlations between ORR, durable response (DR) of ≥ 6 months, complete response (CR), and OS were assessed for treatment comparisons (trial-level) and for patients receiving ICI (arm-level), using weighted linear regression. Sixty-three trials were eligible, including 58 randomized controlled trials and 20 nonrandomized controlled trials (78 ICI arms and 30,815 patients). The majority were phase III (63%), and OS was the most common primary end point (40%). In relative treatment comparisons, correlations between ORR risk ratio and OS hazard ratio (HR), 6-month DR ratio and OS HR, and CR ratio and OS HR were r = 0.58, r = 0.62, and r = 0.42, respectively. Exploratory studies in melanoma, non-small-cell lung cancer, and other tumors showed similar results, although 6-month DR ratio was strongly correlated with OS HR (r = 0.89). Within ICI arms only, correlations between ORR and 12-month OS, 6-month DR and 12-month OS, and CR and 12-month OS were r = 0.76, r = 0.84, and r = 0.50, respectively, in all eligible trials. Relative measures of tumor response (ORR, 6-month DR, and CR) are poor surrogate end points for OS in ICI studies. However, ORR and 6-month DR are prognostic of 12-month OS in ICI studies supporting their use for screening activity of novel agents in early-phase nonrandomized trials.

Pemetrexed plus erlotinib as a salvage treatment in high EGFR-expressing metastatic colorectal cancer patients following failure of standard chemotherapy: A phase II single-arm prospective study.

104 Background: We conducted a single-arm, phase II study to evaluate the combination of pemetrexed and erlotinib as a salvage treatment in high EGFR-expressing (2+ or 3 on immunohistochemistry (IHC)) metastatic colorectal cancer (CRC) patients who failed to show a benefit after standard chemotherapy. Methods: We investigated pemetrexed and erlotinib (pemetrexed 500 mg/m2 on Day 1 and erlotinib 100 mg/m2 on Days 1–21) as a salvage treatment, given every three weeks, until disease progression or intolerable toxicity. The primary outcome was overall response rate (RR). Results: From May 2017 to April 2018, 29 metastatic CRC patients with high EGFR expression who previously received the standard therapies were enrolled into this trial. The regimen was well tolerated. Skin rash, vomiting, fatigue, and anorexia were common toxic effects but were mostly manageable and controllable side effects of only grades 1 or 2. In intent-to-treat analysis, three partial responses (PRs) were observed in enrolled patients, revealing an overall RR of 10.3%. This value supported the statistical hypothesis of this study. Fifteen patients had stable disease and the disease control rate (DCR) was 62.1%. All three patients who achieved a PR had an expression of EGFR 3+ in a tumor. Among eight patients with a tumor expressing an EGFR value of 3+, the RR and DCR were 37.5% and 75.0%, respectively. Conclusions: This phase II trial using pemetrexed and erlotinib in metastatic CRC with high EGFR expression met the primary endpoint of tumor response. Clinical trial information: NCT03086538.

Integrating subgroups with mixed-type endpoints in early phase oncology trials.

Testing anti-cancer agents with multiple disease subtypes is challenging and it becomes more complicated when the subgroups have different types of endpoints (such as binary endpoints of tumor response and progression-free survival endpoints). When this occurs, one common approach in oncology is to conduct a series of small screening trials in specific patient subgroups, and these trials are typically run in parallel, independent of each other. However, this approach does not consider the possibility that some of the patient subpopulations respond similarly to therapy. In this article, we developed a simple approach to jointly model subgroups with mixed-type endpoints, which allows borrowing strength across subgroups for efficient estimation of treatment effects.

The Clinical Significance of Effect Sizes for Survival and Tumor Response Endpoints Using the Empirical Rule Effect Size

Context: In planning oncology phase II and phase III clinical trials, the size of the expected effect for endpoints such as tumor response and overall survival are key parameters driving the sample size. We applied the empirical rule effect size approach, also known as the ½ standard deviation (SD) method, to define clinically significant effect sizes for overall survival and tumor response endpoints in a series of clinical trials. Methods: The observed effect size was calculated for 12 phase II and 27 phase III completed cancer clinical trials identified by experts as being notable. Results: The effect sizes of the phase II and phase III clinical trials ranged from -0.32 to 0.84 and 0.01 to 0.44 SDs respectively. Effect sizes for all but four of the phase II trials were less than a ½ SD. For phase III studies, the effect sizes for all but one study were below 0.4 SD and roughly 67% of them had an effect size smaller than 0.2 SDs. There were no differences across disease sites, although colorectal and breast trials did have slightly larger effect sizes. Conclusions: Even highly noteworthy existing phase II and phase III oncology clinical trials rarely achieve the ½ SD level of clinical significance. This method allows for more ready interpretation of the clinical significance of overall survival and tumor response endpoints. It allows for cross-study comparison across different endpoints. The method also facilitates study design as it directly builds clinical significance into the study.

Combining Survival and Toxicity Effect Sizes from Clinical Trials: NCCTG 89-20-52 (Alliance).

Background:How can a clinician and patient incorporate survival and toxicity information into a single expression of comparative treatment benefit? Sloan et al. recently extended the ½ standard deviation concept for judging the clinical importance of findings from clinical trials to survival and tumor response endpoints. A new method using this approach to combine survival and toxicity effect sizes from clinical trials into a quality-adjusted effect size is presented.Methods:The quality-adjusted survival effect size (QASES) is calculated as survival effect size (ESS) minus the calibrated toxicity effect sizes (EST) (QASES=ESS-EST). This combined effect size can be weighted to adjust for the relative emphasis placed by the patient on survival and toxicity effects.Results:As an example, consider clinical trial NCCTG 89–20-52 which randomized patients to once-daily thoracic radiotherapy (ODTRT) versus twice-daily treatment of thoracic radiotherapy (TDRT) for the treatment of lung cancer. The ODTRT vs. TDRT arms had median survival time of 22 vs. 20 months (p=0.49) and toxicity rate of 39% vs. 54%, (p<0.05). The QASES of 0.18 standard deviations translates to a quality-adjusted survival difference of 5.7 months advantage for the ODRT arm over the TDRT treatment arm (22(16.3) months), p<0.05). Similar results are presented for the four possible case combinations of significant/non-significant survival and toxicity benefits using completed clinical trials.Conclusions:We used a novel approach to re-analyze clinical trial data to produce a single estimate for each treatment that combines survival and toxicity data. The QASES approach is an intuitive and mathematically simple yet robust approach.

Effects of EUS-guided intratumoral injection of oligonucleotide STNM01 on tumor growth, histology, and overall survival in patients with unresectable pancreatic cancer

Carbohydrate sulfotransferase 15 (CHST15) promotes tumor growth and invasion and is considered to be an emergent therapeutic target for pancreatic cancer. The aim of this study wasto evaluate the safety and efficacy of EUS-guided fine-needle injection (EUS-FNI) of STNM01, the double-stranded RNA oligonucleotide that specifically represses CHST15, for use in patients with pancreatic cancer. Six patients with unresectable pancreatic cancer, treated at Tokyo Metropolitan Geriatric Hospital, were used in this open-labeled, investigator-initiated trial. A total of 16 mL STNM01 (250 nM) was injected into the tumor through EUS-FNI. The study's primary endpoint was safety, with a secondary endpoint of tumor response 4 weeks after the initial injection. Some patients received a series of infusions as extensions. The local expression of CHST15 and overall survival (OS) were also evaluated. There were no adverse events. The mean tumor diameter changed from 30.7 to 29.3mm 4 weeks after injection. Four patients exhibited necrosis of tumor in biopsy specimens. CHST15 was highly expressed at baseline, with 2 patients showing large reductions of CHST15 at week 4. The mean OS of these 2 patients was 15 months, whereas it was 5.7 months for the other 4 patients. EUS-FNI of STNM01 in pancreatic cancer is safe and feasible. The CHST15 reduction could predict tumor progression and OS. Injections of STNM01 during the beginning of treatment may reduce CHST15 and warrants further investigation.

How health-related quality of life assessment should be used in advanced colorectal cancer clinical trials

Traditionally, the efficacy of cancer treatment in patients with advance or metastatic disease in clinical studies has been studied using overall survival and more recently tumor-based end points such as progression-free survival, measurements of response to treatment. However, these seem not to be the relevant clinical end points in current situation if such end points were no validated as surrogate of overall survival to demonstrate the clinical efficacy. Appropriate, meaningful, primary patient-oriented and patient-reported end points that adequately measure the effects of new therapeutic interventions are then crucial for the advancement of clinical research in metastatic colorectal cancer to complement the results of tumor-based end points. Health-related quality of life (HRQoL) is effectively an evaluation of quality of life and its relationship with health over time. HRQoL includes the patient report at least of the way a disease or its treatment affects its physical, emotional and social well-being. Over the past few years, several phase III trials in a variety of solid cancers have assessed the incremental value of HRQoL in addition to the traditional end points of tumor response and survival results. HRQoL could provide not only complementary clinical data to the primary outcomes, but also more precise predictive and prognostic value. This end point is useful for both clinicians and patients in order to achieve the dogma of precision medicine. The present article examines the use of HRQoL in phase III metastatic colorectal cancer clinical trials, outlines the importance of HRQoL assessment methods, analysis, and results presentation. Moreover, it discusses the relevance of including HRQoL as a primary/co-primary end point to support the progression-free survival results and to assess efficacy of treatment in the advanced disease setting.

Phase II study of dovitinib in patients progressing on anti-vascular endothelial growth factor therapy

BackgroundPrior work identified the fibroblast growth factor (FGF) pathway as a mediator of resistance to anti-vascular endothelial growth factor (VEGF) therapy. We tested dovitinib, an inhibitor of both FGF and VEGF receptors, in patients progressing on anti-VEGF treatment. MethodsPatients with measurable advanced colorectal or non-small cell lung cancer with progression despite anti-VEGF treatment within 56 days, good performance status and adequate organ function were eligible. A research tumor biopsy was followed by treatment with dovitinib 500mg on a 5-day on /2-day off schedule for 28-day cycles. The primary endpoint of tumor response was evaluated every 2 cycles. Secondary endpoints included toxicity and 8-week disease control rate. Intratumor mRNA expression of angiogenic mediators was analyzed using a next generation sequencing based expression array. ResultsTen patients treated previously with bevacizumab or ziv-aflibercept enrolled. The study closed with termination of dovitinib development. No responses were observed in 7 evaluable patients. The best response was stable disease in 1 patient. Common toxicities included gastrointestinal, metabolic, and biochemical derangements. All patients experienced at least one grade ≥3 treatment-related adverse event, most commonly fatigue, elevated GGT, and lymphopenia. Expression of multiple angiogenic mediators was common in tumors progressing on anti-VEGF therapy including high levels of FGFR1 and VEGFA. ConclusionsWe found no evidence for the activity of dovitinib in patients who had recently progressed on anti-VEGF therapy and toxicities were significant. In tumors progressing despite anti-VEGF therapy, a multitude of pro-angiogenic mediators are expressed, including members of the FGF pathway.

DocOx (AIO-PK0106): A phase II trial with docetaxel and oxaliplatin as a second-line systemic therapy for patients with advanced and/or metastatic adenocarcinoma of the pancreas—Final results.

352 Background: Pancreatic ductal adenocarcinoma still remains a major cause of cancer related deaths in the western world. The current study was conducted to confirm the activity and feasibility of docetaxel/ oxaliplatin combination in second line treatment of advanced pancreatic ductal adenocarcinoma. Methods: Prospective single arm, non-randomized, multi-center, Simon’s two stage phase II trial using docetaxel (75 mg/m2, 60 min, d 1) and oxaliplatin (80 mg/m2, 120 min, d 2) in 21-day cycles. Duration of the trial was scheduled up two 8 cycles. Primary endpoint was tumor response according to RECIST 1.0. Secondary endpoints were progression free survival, overall survival, safety/toxicity, quality of life and clinical benefit. Results: Data represents the intention to treat analysis of 44 patients included between 2008 and 2012. The majority of patients received a gemcitabine based first-line chemotherapy (95.5%). The primary endpoint of tumor response was achieved in 15.9% (7 partial remissions, no complete remission), with a disease control rate of 48% after the first two treatment cycles. Median progression free survival was 7 weeks (CI 6-15.9 weeks) and overall survival 40 weeks (CI 20.4-56.4 weeks). No unexpected adverse events occured. The recorded AEs were mainly hematologic (neutropenia grade 3/4 63.6%, febrile neutropenia 4.6%), gastrointestinal (29.6% grade 3/4 AEs) and infectious (18.2% grade 3/4 AEs). Conclusions: In this single-arm second line trial for the treatment of advanced PDAC, the combination of docetaxel and oxaliplatin shows promising results comparable with other second line protocols such as OFF (oxaliplatin, 5-FU, leucovorin) or liposomal irinotecan (MM-398) plus 5-FU/leucovorin (NAPOLI 1-trial). Some patients seem to benefit particularly as indicated by long periods of treatment in this setting. Even after 8 cycles of treatment with DocOx, partial response was observed in 2 patients and stable disease in another 6 patients corresponding to a disease control rate of 18%. The toxicity profile was quite tolerable and comparable to other second line studies. Clinical trial information: NCT00690300.

Phase 2 Trial of Paclitaxel Polyglumex with Capecitabine for Metastatic Breast Cancer

Capecitabine and paclitaxel are established effective treatments, alone and combined with other cytotoxic and targeted agents, for metastatic breast cancer (MBC). Paclitaxel polyglumex (a macromolecular conjugate of paclitaxel bound to poly-L-glutamic acid) has potential advantages over conventional paclitaxel, including little alopecia, short infusion time with no premedication, enhanced tumor permeability/retention effect, and improved tolerability. We therefore examined tolerability and efficacy of paclitaxel polyglumex with capecitabine in patients with MBC. This was a single-stage phase 2 study, with interim analysis conducted with endpoints of tumor response, adverse events (toxicities), time to progression, and overall survival. The main eligibility criteria were: age >18 years, no prior MBC chemotherapy, Eastern Cooperative Oncology Group performance score <2, disease measurable by RECIST criteria, no HER2 overexpression or amplification, no brain metastases or peripheral sensory neuropathy. Treatment consisted of paclitaxel polyglumex (135 mg/m) by intravenous infusion on day 1+capecitabine (825 mg/m) orally twice daily on days 1 to 14, repeated on a 3-week cycle. Forty-one evaluable patients were required to test the null hypothesis that the complete and partial tumor response rate (CR+PR) was at the most 40% against the alternative of at least 60%. Paclitaxel polyglumex+capecitabine would be considered promising in this population if ≥21 responses were observed among first 41 evaluable patients. Forty-eight patients were enrolled between April 2006 and April 2007; all patients were evaluable. The median number of treatment cycles administered was 6. Eighteen patients [38%; 95% confidence interval (CI), 24%-53%] had a confirmed tumor response (2 CR, 16 PR) by RECIST criteria. Fifteen (38%; 95% CI, 23%-53%) responses occurred in first 41 patients, falling short of prespecified goal of 21 responses. Median duration of tumor response was 13.2 months. Three of the responders were progression free at last follow-up with a median follow-up of 43 months. Median progression-free survival was 5.1 months (95% CI, 4.0-7.6 mo). Six-month progression-free survival was 42% (95% CI, 30%-58%). Median dose level administered was paclitaxel polyglumex (135 mg/m) and capecitabine (825 mg/m) for cycles 1 to 7. Most common severe (grade 3/4) toxicities (at least possibly related to study drug) were: leukopenia 9 (19%), neutropenia 8 (17%), neurosensory 4 (8%), skin reaction-hand/foot 4 (8%), and dyspnea 2 (4%). Forty-six percent (22/47) of patients experienced grade ≥3 toxicity and 8% (4/48) experienced grade ≥4 toxicity. No alopecia was reported. Although the trial failed to reach goal of 21 confirmed tumor responses among the first 41 evaluable patients, paclitaxel polyglumex and capecitabine is well tolerated and effective in MBC.

A phase II evaluation of AMG 102 (rilotumumab) in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma: A Gynecologic Oncology Group study

ObjectiveThis open-label, multi-institutional phase II trial evaluated activity and safety of rilotumumab (AMG 102), a monoclonal antibody that targets HGF (hepatocyte growth factor), the ligand for the MET receptor, in women with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancer. Patients and methodsWomen were eligible for treatment with rilotumumab if they had measurable disease, a performance status of 0, 1 or 2, previously received platinum-based therapy with a progression-free interval of <12months or a second recurrence, and adequate bone marrow and organ function. Patients received rilotumumab 20mg/kg IV every 14days until evidence of unacceptable toxicity or disease progression. The study utilized co-dual primary endpoints of tumor response and six-month PFS to assess the efficacy of rilotumumab. Secondary endpoints included the frequency and severity of adverse events and the duration of progression-free and overall survival. ResultsThirty-one women enrolled and received rilotumumab. All were eligible for analysis. One patient achieved a complete response (3.2%; 90% CI 0.2–14%), and two women had 6-month PFS (6.5%; 90% CI 1.1–19%). Most adverse events were grade 1 or 2, with no grade 4 adverse events. Grade 3 adverse events were gastrointestinal (4), metabolic (3) anemia (3), a thromboembolic event (1), ventricular tachycardia (1), hypotension during infusion (1) and fatigue (1). The study was stopped after the first stage of accrual. ConclusionRilotumumab was well-tolerated, but had limited activity. The level of activity does not warrant further evaluation of rilotumumab as a single agent in patients with ovarian cancer.

Tumor response and progression‐free survival as potential surrogate endpoints for overall survival in extensive stage small‐cell lung cancer

AbstractBACKGROUND:The authors investigated the putative surrogate endpoints of best response, complete response (CR), confirmed response, and progression‐free survival (PFS) for associations with overall survival (OS), and as possible surrogate endpoints for OS.METHODS:Individual patient data from 870 untreated extensive stage small‐cell lung cancer patients participating in 6 single‐arm (274 patients) and 3 randomized trials (596 patients) were pooled. Patient‐level associations between putative surrogate endpoints and OS were assessed by Cox models using landmark analyses. Trial‐level surrogacy of putative surrogate endpoints were assessed by the association of treatment effects on OS and individual putative surrogate endpoints. Trial‐level surrogacy measures included: R2 from weighted least squares regression model, Spearman correlation coefficient, and R2 from bivariate survival model (Copula R2).RESULTS:Median OS and PFS were 9.6 (95% confidence interval [CI], 9.1‐10.0) and 5.5 (95% CI, 5.2‐5.9) months, respectively; best response, CR, and confirmed response rates were 44%, 22%, and 34%, respectively. Patient‐level associations showed that PFS status at 4 months was a strong predictor of subsequent survival (hazard ratio [HR], 0.42; 95% CI, 0.35‐0.51; concordance index 0.63; P &lt; .01), with 6‐month PFS being the strongest (HR, 0.41; 95% CI, 0.35‐0.49; concordance index, 0.66, P &lt; .01). At the trial level, PFS showed the highest level of surrogacy for OS (weighted least squares R2 = 0.79; Copula R2 = 0.80), explaining 79% of the variance in OS. Tumor response endpoints showed lower surrogacy levels (weighted least squares R2≤0.48).CONCLUSIONS:PFS was strongly associated with OS at both the patient and trial levels. PFS also shows promise as a potential surrogate for OS, but further validation is needed using data from a larger number of randomized phase 3 trials. Cancer 2011. © 2010 American Cancer Society.

Complementary and Alternative Medicine: Believe it or not?

Complementary and Alternative Medicine: Believe it or not?

Phase II trial of paclitaxel polyglumex (PPX) with capecitabine (C) for metastatic breast cancer (MBC)

1063 Background: C is an established effective treatment, alone and combined with paclitaxel (P), for MBC. P causes alopecia, infusion reactions, requires corticosteroid premedication and lengthy infusion time which make therapy problematic. PPX (macromolecular conjugate of P bound to poly-L-glutamic acid) has potential advantages over P including little alopecia, short infusion time with no premedication, enhanced tumor permeability/retention effect, and estrogen-influenced metabolism which may improve tolerability and efficacy. We therefore examined tolerability and efficacy of PPX + C in patients with MBC. Methods: Single stage phase II study, interim analysis conducted with endpoints of tumor response, adverse events (AE), time to progression and overall survival. Main eligibility: age >18, no prior MBC chemotherapy, ECOG PS<2, RECIST-measurable disease, HER2-neg, no brain mets or neuropathy. Treatment: PPX 135 mg/m2 day 1 + C 825 mg/m2 BID days 1–14, 3-week cycle. 41 evaluable patients required to test null hypothesis that complete and partial tumor response rate (CR + PR) was at most 40% against the alternative of at least 60%. PPX + C would be considered promising in this population if ≥21 responses observed among first 41 evaluable patients. Results: 48 patients enrolled April 2006- April 2007; all patients evaluable. Median cycles administered = 6. 20 patients (42%; 95% CI: 28–57%) had tumor response (2 CR, 18 PR) by RECIST criteria. All 20 (49%, 95% CI: 33%-65%) responses occurred in first 41 patients, falling short of trial goal of 21. Median duration of tumor response = 11.9 months. Median follow-up = 7.6 months. Median progression-free survival = 5.7 months (95% CI: 4.2–10.0 months). 6-month overall survival = 86% (95% CI: 76–97%); progression free survival = 45% (95% CI: 32–62%). Median dose level administered = 135 mg/m2 PPX, 825 mg/m2 C for cycles 1–7. Most common severe (grade 3/4) AE: leukopenia 9 (18%), neutropenia 8 (20%), neuro-sensory 4 (9%), skin reaction-hand/foot 4 (9%), dyspnea 3 (6%). 53% (25/47) of patients experienced a grade ≥3 AE and 13% experienced a grade ≥4 AE. No alopecia was reported. Conclusions: Although the trial failed to reach goal of 21 confirmed tumor responses in the first 41 evaluable patients, PPX + C is well tolerated and active in MBC. No significant financial relationships to disclose.

Tumor burden is not related to quality of life in patients with metastatic colorectal cancer

4017 Background: The significance of tumor burden (TB), as both a prognostic and an outcome measure in colorectal cancer patients (pts) has recently come under scrutiny. Tumor response endpoints have been poor predictors of overall survival (OS). There has been mounting evidence that QOL has prognostic significance (Sloan, JCO, 1998). The purpose of this study was to describe the relationship between TB and QOL in pts with metastatic colorectal cancer (MCRC). Methods: 989 pts with MCRC participating in Intergroup study N9741 provided data at baseline (bl) and every 12 weeks (wk) on overall QOL and fatigue (single-item numerical analogues), and total symptom distress (McCorkle Symptom Distress Scale [SDS]). TB was represented by actual tumor measurements (TM) and as an ordinal tumor response. A 10-point change on a 0–100 point scale was defined a priori as clinically meaningful in QOL-related variables. The sample size provided over 90% power to detect all but the smallest effect size (<0.1 Standard Deviation) for all statistical procedures involved, so p-values alone are of limited relevance. Results: We observed weak correlations among TM at bl and QOL (-0.07), fatigue (-0.18), and symptom distress (-0.14), indicating lack of any strong relationship. Changes from bl scores to 12 wk in TM were not associated with changes in QOL, fatigue, or symptom distress (correlations of -0.003, 0.06, and 0.05 respectively). Correlation between QOL and bl TM remained consistently low across subsets based on patient performance status and age. Concordance between patients reporting a tumor response and a clinically meaningful improvement at 12 wk in QOL, fatigue, or symptom distress was only 12.9%, 9.6%, and 11.9% respectively. Similarly, only 67.7%, 57%, and 59.7% of the patients reporting a clinically significant improvement in QOL, fatigue, and symptom distress had a tumor response. Conclusions: There was little evident relationship between the QOL-related variables and TB in these patients, suggesting that changes in TB have little impact on how the patient feels. These data raise questions about the value of tumor response as an endpoint with immediate clinical relevance for patients with advanced colorectal cancer (ACRC). No significant financial relationships to disclose.

Systematic review of the clinical effect of glucocorticoids on nonhematologic malignancy

BackgroundGlucocorticoids are often used in the treatment of nonhematologic malignancy. This review summarizes the clinical evidence of the effect of glucocorticoid therapy on nonhematologic malignancy.MethodsA systematic review of clinical studies of glucocorticoid therapy in patients with nonhematologic malignancy was undertaken. Only studies having endpoints of tumor response or tumor control or survival were included. PubMed, EMBASE, the Cochrane Register/Databases, conference proceedings (ASCO, AACR, ASTRO/ASTR, ESMO, ECCO) and other resources were used. Data was extracted using a standard form. There was quality assessment of each study. There was a narrative synthesis of information, with presentation of results in tables. Where appropriate, meta-analyses were performed using data from published reports and a fixed effect model.ResultsFifty four randomized controlled trials (RCTs), one meta-analysis, four phase l/ll trials and four case series met the eligibility criteria. Clinical trials of glucocorticoid monotherapy in breast and prostate cancer showed modest response rates. In advanced breast cancer meta-analyses, the addition of glucocorticoids to either chemotherapy or other endocrine therapy resulted in increased response rate, but not increased survival. In GI cancer, there was one RCT each of glucocorticoids vs. supportive care and chemotherapy +/- glucocorticoids; glucocorticoid effect was neutral. The only RCT found of chemotherapy +/- glucocorticoids, in which the glucocorticoid arm did worse, was in lung cancer. In glucocorticoid monotherapy, meta-analysis found that continuous high dose glucocorticoids had a detrimental effect on survival. The only other evidence, for a detrimental effect of glucocorticoid monotherapy, was in one of the two trials in lung cancer.ConclusionGlucocorticoid monotherapy has some benefit in breast and prostate cancer. In advanced breast cancer, the addition of glucocorticoids to other therapy does not change the long term outcome. In GI cancer, glucocorticoids most likely have a neutral effect. High dose continuous glucocorticoids have a detrimental effect in nonhematologic malignancy. Glucocorticoid therapy might have a deleterious impact in lung cancer.

Potentiation of antitumor efficacy of paclitaxel by recombinant tumor necrosis factor-alpha.

We studied the combination of tumor necrosis factor (TNF) and paclitaxel. Our aim was to determine whether TNF increases the antitumor efficacy of paclitaxel and if so whether the increase is mediated through the enhancement of apoptosis induction by paclitaxel. Mice bearing 6 mm MCa-K or MCa-4 mammary carcinomas, OCa-I ovarian carcinomas, or HCa-I hepatocarcinomas in their legs were treated with TNF, paclitaxel of their combination. TNF was administered i.p. daily at a dose of 10 micrograms per mouse for 7 days; paclitaxel at a dose of 40 mg/kg per mouse was given as a single i.v. injection 1 h before the second dose of TNF. Tumor growth delay was used as the endpoint of tumor response to the treatments. The results showed that the combination was either additive or supraadditive; supraadditive action occurred in three of the four tumors tested. The enhancement factors (EFs) were 1.24 for MCa-K, 1.53 for MCa-4, 1.0 for OCa-I and 2.17 for HCa-I. Histological analysis of treated MCa-K tumors revealed that TNF alone did not induce apoptosis of tumor cells, but in the combination it enhanced the apoptotic response to paclitaxel. Thus, TNF increased the antitumor efficacy of paclitaxel by enhancing cellular sensitivity to paclitaxel's induction of apoptosis. The results imply that the combination of TNF and paclitaxel has potential as a treatment for cancer.

Cisplatin, Vinblastine, and Bleomycin in Advanced and Recurrent Ovarian Germ-Cell Tumors

Study objective To evaluate the efficacy of cisplatin-based combination chemotherapy in patients with advanced ovarian germ-cell tumors. Design Nonrandom prospective trial with endpoints of tumor response, results of repeat surgical exploration, progression-free interval, and survival. Setting Cooperative university-based cancer study comprising 27 participating institutions. Patients Ninety-seven patients were treated and all were evaluable. Of these, 8 had dysgerminoma and 89 had other cell types. Interventions Patients received 3 to 4 courses of cisplatin. vinblastine, and bleomycin (PVB). After chemotherapy, suitable patients had re-staging laparotomy. Maintenance vinblastine therapy was originally given but was discontinued for all patients in 1981. Patients with persistent or recurrent disease were treated with vincristine, dactinomycin, and cyclophosphamide (VAC) or etoposide plus cisplatin (EP). Results Of 35 patients with tumors other than dysgerminoma who had clinically measurable disease, 15 (43%; CI, 26% to 61%) had complete responses. Forty of fifty-six second-look laparotomies (71%; CI, 58% to 83%) revealed no tumor or mature teratoma. Forty-seven patients are still disease-free and 59 are alive. The survival rate is 71% (CI, 62% to 89%) and the disease-free rate is 51% (CI, 41% to 62%) at 2 years. Eight patients had durable remissions with second- or third-line therapy. Seven of eight patients with dysgerminoma are also disease-free. Conclusions Cisplatin-based chemotherapy is effective for patients with ovarian germ-cell tumors, is superior to previous regimens, and will cure a substantial number of patients.