Use of the ratio of time to progression following first- and second-line therapy to document the activity of the combination of oxaliplatin with 5-fluorouracil in the treatment of colorectal carcinoma

Bonetti, Andrea; Zaninelli, Marta; Leone, Roberto; Franceschi, T.; Fraccon, Anna Paola; Pasini, Felice; Sabbioni, R.; Cetto, Gian Luigi; Sich, D.; Brienza, S.; Howell, Stephen B.

doi:10.1023/a:1008354909478

Cited by 18 publications

(15 citation statements)

References 32 publications

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“…Although our data are observational and the statistical analysis that could be performed was limited, we noted an overall link between apparent clinical benefit and increases in PFS ratios. The PFS ratio is a new endpoint that is still debated in the literature [ 17 ] and may be vulnerable to ascertainment bias [ 14 ] but has been shown to give an indication of treatment effect in clinical studies where patients act as their own controls [ 13 , 18 , 19 ]. Our observations concur with these results.…”

Section: Discussionmentioning

confidence: 99%

Clinical Outcomes of Patients with Rare and Heavily Pretreated Solid Tumors Treated according to the Results of Tumor Molecular Profiling

Dean

Byrne

Marinova

et al. 2016

BioMed Research International

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Patients with heavily pretreated advanced cancer or with rare tumors are difficult to treat. Molecular profiling (MP) of tumors to identify biomarkers that predict potential outcomes with individual therapies is an emerging strategy to guide treatment decisions. Patients with rare tumors for which standard-of-care therapy was unavailable or more common tumors for which standard-of-care options had been exhausted underwent MP at a single Australian center. Data regarding treating physicians' choice of therapy, MP results and recommendations, and patient outcomes were collected. Seven patients had received prior standard first-line therapy (PST), 16 had rare tumors, and 31 had been heavily pretreated (HPT; ≥2 prior lines). Most treatments suggested by MP (541/594; 91.1%) were common chemotherapy drugs available in generic formulations. MP-guided therapy recommendations differed from physician's recommendations in 48 patients (88.9%). MP-guided therapy produced clinical benefit (improved QOL and/or performance status, symptoms, bodyweight, or RECIST) in 19/31 (61.3%), 11/16 (68.8%), and 3/7 (42.9%) patients with HPTs, rare tumors, and PSTs, respectively, and had a PFS ratio ≥1.3 in 22/37 evaluable patients (59.5%; 95% confidence interval 44–76%). The null hypothesis that ≤15% of these patients would have a PFS ratio ≥1.3 was rejected (one-sided p < 0.0001). In conclusion, using MP to guide therapy selection is feasible in clinical practice and may improve patient outcomes.

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Section: Discussionmentioning

confidence: 99%

Clinical Outcomes of Patients with Rare and Heavily Pretreated Solid Tumors Treated according to the Results of Tumor Molecular Profiling

Dean

Byrne

Marinova

et al. 2016

BioMed Research International

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“…Scatter plot of T 2 against T 1 for the data from a trial reported by Bonetti et al and reconstructed from Figure of Kovalchik and Mietlowski . Dotted line represents line of T 2 = T 1 …”

Section: Examplementioning

confidence: 99%

“…The data from a trial reported by Bonetti et al is used to illustrate study designs using proposed methods. In the trial, treatment efficacy was assessed by GMI for a second‐line therapy (combination of LV‐modulated 5‐FU and oxaliplatin) in patients with advanced colon carcinoma after failure of a first‐line chemotherapy (LV‐modulated 5‐FU or raltitrexed).…”

Section: Examplementioning

confidence: 99%

“…Several published trials used a GMI‐based approach to assess the activity of second‐line treatments. For example, Bonetti et al conducted a trial using GMI as the primary endpoint and has pointed out that further research is needed in order to define the appropriate sample size, and the amount of benefit required to conclude that a new regimen used in second‐, third‐, or fourth‐line treatment is effective in a given type of malignancy. With the advances in cancer drug development described above, our institution has been pursuing precision medicine trials on patients with targetable molecular alterations as well as combination targeted and immunotherapy trials for the treatment of relapse or refractory cancer patients.…”

Section: Introductionmentioning

confidence: 99%

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Phase II trial design with growth modulation index as the primary endpoint

Chen

Wei

et al. 2018

Pharmaceutical Statistics

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Molecularly targeted, genomic-driven, and immunotherapy-based clinical trials continue to be advanced for the treatment of relapse or refractory cancer patients, where the growth modulation index (GMI) is often considered a primary endpoint of treatment efficacy. However, there little literature is available that considers the trial design with GMI as the primary endpoint. In this article, we derived a sample size formula for the score test under a log-linear model of the GMI. Study designs using the derived sample size formula are illustrated under a bivariate exponential model, the Weibull frailty model, and the generalized treatment effect size. The proposed designs provide sound statistical methods for a single-arm phase II trial with GMI as the primary endpoint. KEYWORDS accelerated failure time model, clinical trial design, growth modulation Index, paired time-to-progression, sample size 212

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“…Time to further tumour progression (TTP 2 ) was evaluated from the date of study entry to the date of documented progressive disease. The TTP 2 /TTP 1 ratio was calculated to obtain the growth modulation index (GMI) (Von Hoff, 1998;Bonetti et al, 2001). Probability of progression-free and overClinical L-OHP+TOM+LFA/FU in advanced colorectal cancer P Comella et al all survival was calculated with actuarial method from the date of accrual to the date of progression, death, or last follow-up, respectively (Kaplan and Meier, 1958).…”

Section: Statistical Consideration and Sample Sizementioning

confidence: 99%

Oxaliplatin plus raltitrexed and leucovorin-modulated 5-fluorouracil i.v. bolus: a salvage regimen for colorectal cancer patients

Comella

Casaretti

Crucitta³

et al. 2002

Br J Cancer

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The aim of the present study was to define the activity and tolerability of a triplet regimen including oxaliplatin 130 mg m 72 (2 h i.v. infusion) and raltitrexed 3.0 mg m 72 (15 min i.v. infusion) given on day 1, followed by levo-folinic acid 250 mg m 72 (2 h i.v. infusion) and 5-fluorouracil 1050 mg m 72 i.v. bolus on day 2, every 2 weeks, in pretreated colorectal cancer patients. From April 1999 to December 2000, 50 patients were enrolled: 26 were males and 24 females, their median age was 63 (range, 43 -79) years; ECOG performance status was 0 in 26 patients, 51 in 24 patients; 26 patients had received previous adjuvant chemotherapy, 40 patients had been exposed to one or two lines of palliative chemotherapy (including irinotecan in 31 cases); 18 patients were considered chemo-refractory. A total of 288 cycles were administered, with a median number of 6 (range 1 -12) courses per patient. A complete response was obtained in three patients, and a partial response in nine patients, giving a major response rate of 24% (95% confidence interval, 13 -38%), while 15 further patients showed a stable disease, for an overall control of tumour growth in 60% of patients. Three complete responses and three partial responses were obtained in patients pretreated with irinotecan (response rate, 19%); among refractory patients, three achieved partial responses (response rate, 13%). After a median follow-up of 18 (range, 10 -30) months, 40 patients showed a progression of disease: the growth modulation index ranged between 0.2 and 2.5: it was 51.33 (showing a significant delay of tumour growth) in 16 (40%) patients. Actuarial median progression-free survival time was 7.6 months, and median survival time was 13.6 months: estimated probability of survival was 55% at 1 year. Main severe toxicity was neutropenia: World Health Organisation grade 4 affected 32% of patients; non-haematological toxicity was mild: World Health Organisation grade 3 diarrhoea was complained of by 8%, and grade 3 stomatitis by 4% of patients; neurotoxicity (according to Lévi scale) was scored as grade 3 in 8% of patients. In conclusion, this regimen was manageable and active as salvage treatment of advanced colorectal cancer patients; it showed incomplete cross-resistance with irinotecan-based treatments, and proved to delay the progression of disease in a relevant proportion of treated patients.

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Use of the ratio of time to progression following first- and second-line therapy to document the activity of the combination of oxaliplatin with 5-fluorouracil in the treatment of colorectal carcinoma

Abstract: This study demonstrates the utility of the GMI as a tool for assessing the activity of novel second-line therapeutic programs.

Cited by 18 publications

References 32 publications

Clinical Outcomes of Patients with Rare and Heavily Pretreated Solid Tumors Treated according to the Results of Tumor Molecular Profiling

Clinical Outcomes of Patients with Rare and Heavily Pretreated Solid Tumors Treated according to the Results of Tumor Molecular Profiling

Phase II trial design with growth modulation index as the primary endpoint

Oxaliplatin plus raltitrexed and leucovorin-modulated 5-fluorouracil i.v. bolus: a salvage regimen for colorectal cancer patients

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