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Early tumor shrinkage (ETS) has been highlighted as a favorable prognostic factor related to progression-free survival (PFS) and overall survival (OS) in cytotoxic treatment of metastatic colorectal cancer. Data from a randomized phase III study comparing infusional 5-fluorouracil plus irinotecan (FUFIRI) versus irinotecan plus oxaliplatin (mIROX) were evaluated. Patient groups were analyzed according to the relative change in maximum tumor diameter between baseline and after 7 weeks of treatment. The ETS cohort was defined as a decrease of ≥20%. Additionally, the non-ETS cohort was subdivided into “minor shrinkage” (0–19%), “tumor progression” (any increase) and development of “new metastatic lesions”. Progression-free survival and OS were estimated in all patient subgroups. Assessment of ETS was possible in 201 patients. Early tumor shrinkage was observed in 47% (94/201) and non-ETS in 53% (107/201) of patients. Patients with ETS had a more favorable outcome with regard to PFS (9.9 months vs 6.1 months, P = 0.029) and OS (27.5 months vs 17.8 months, P = 0.002). In the non-ETS subgroups, patients with “minor shrinkage” (PFS 8.4 months, OS 21.6 months) showed a markedly better outcome than patients with “early tumor progression” (PFS 4.0 months, OS 15.3 months) or with “new metastatic lesions (PFS 2.2 months, OS 7.6 months). In conclusion, ETS assessment offers accelerated response evaluation when compared to RECIST. In patients treated with chemotherapy alone, ETS ≥20% is associated with excellent outcome. Non-ETS is a heterogeneous subgroup where patients with minor shrinkage clearly benefit from treatment, and patients with early progression or development of new lesions have an unfavorable prognosis.
In both, daily clinical routine and in clinical trials, evaluation of treatment response in metastatic colorectal cancer (mCRC) is based on changes in tumor size or size of metastases by imaging techniques, predominantly computed tomography (CT). Nowadays, the response evaluation criteria in solid tumors (RECIST 1.1 [Response Evaluation Criteria in Solid Tumors]) are widely used to quantify the change of lesions and classify treatment response in clinical trials. In the absence of pretreatment predictors of response, early on-treatment imaging changes have been investigated to identify those patients who benefit from first- or second-line chemotherapy treatment and may serve clinicians and investigators as decision-making tools.
Relating to this, the measurement of tumor shrinkage at first evaluation (6 or 8 weeks) was reported to predict outcome in mCRC in previously untreated and chemorefractory patients. A retrospective analysis of the BOND trial indicated tumor shrinkage at 6 weeks as a strong predictor of time to tumor progression and overall survival (OS) in patients treated with cetuximab with or without irinotecan in the second-line setting. Recently, Piessevaux et al. reported a retrospective analysis of the CRYSTAL study where KRAS-wt patients with tumor size shrinkage (sum of all lesions according to RECIST) of at least 20% after 8 weeks of FOLFIRI + cetuximab had a median OS of 30.0 months and a median progression-free survival (PFS) of 14.1 months in comparison to 18.6 and 7.3 months for patients without “early shrinkage”. By contrast, a much smaller difference was observed in the chemotherapy only arm (median OS of 24.1 months vs 18.6 months; median PFS of 9.7 months vs 7.4 months). These findings were also present in the pooled analysis of the CRYSTAL and the OPUS trials using oxaliplatin-based chemotherapy and cetuximab in first-line KRAS wildtype mCRC. Early tumor shrinkage (ETS) was therefore reported as a hallmark of cetuximab activity, featuring distinctive and rapid effects on tumor size leading to favorable long-term survival unrelated to the effect of cytotoxic chemotherapy alone. It was therefore suggested to use ETS as a potential surrogate parameter of treatment efficacy in cetuximab-based therapy.
Suzuki et al. reported a retrospective analysis of 567 patients from a multicenter randomized phase III (Nordic VI trial) comparing irinotecan with either the Nordic bolus 5-FU and folinic acid schedule (FLIRI) or the de Gramont schedule (Lv5FU2-IRI).(,) The change in tumor size at the first follow-up CT (8 weeks) was found to be strongly prognostic for PFS and OS in this chemotherapy-only trial. Development of new target lesions was identified as a subgroup with worst prognosis.
The purpose of this retrospective analysis of an irinotecan-based first-line trial was to confirm ETS as a prognostic factor in cytotoxic chemotherapy for mCRC, to search for predictors of ETS, and to better define the group of patients previously denoted as non-ETS patients. Additionally, the relationship between early on treatment response evaluation (i.e. ETS and non-ETS subgroups) and the achievement of best response according to RECIST version 1.1 during the trial was analyzed.
Material and Methods
The FIRE-1 trial was selected for the present analysis since it represents mCRC treatment in an unselected patient population, which was conducted in the treatment era without the use of targeted therapy. The FIRE-1 trial was a multicenter phase III study comparing first line chemotherapy with either 5-fuorouracil/folinic acid/irinotecan (FUFIRI) or modified irinotecan plus oxaliplatin (mIROX) conducted from July 2000 until October 2004 at 48 German study centers (Fig. 1, CONSORT diagram). In the standard arm, FUFIRI consisted of irinotecan 80 mg/m2 as a 0.5 h infusion followed by folinic acid 500 mg/m2 applied over 2 h and 5-fluorouracil 2000 mg/m2 given as a 24 h infusion. In the experimental mIROX arm, patients received irinotecan 80 mg/m2 as a 0.5-hour infusion weekly times 6 plus oxaliplatin 85 mg/m2 as 2 h infusion on days 15 and 29 of each cycle. In both arms, treatment was repeated every 49 days. Tumor assessments were performed as previously indicated. Progression-free survival was 7.2 months in the mIROX arm and 8.2 months in the FUFIRI arm (hazard ratio = 1.14; 95% confidence interval [CI] 0.94–1.37; P = 0.178). Comparable results were also obtained for OS (18.9 vs 21.8), (hazard ratio = 1.08, P =0.276). Both regimens induced an identical objective response rate (ORR) of 41%. For this reason, we performed a joined evaluation of both trial arms.
Evaluation of ETS
Since in the FIRE-1 trial tumor response was evaluated according to World Health Organization (WHO) criteria, recalculation of results into RECIST criteria (version 1.1.) was performed. Relative changes in the sum of the largest tumor diameters at baseline and the sum of the same target lesions after one cycle (50 days, first follow-up) were compared in both treatment arms. As a first step, the change between baseline and tumor diameters at day 50 (7 weeks) was analyzed as a continuous variable. In an effort to use ETS in the clinically most relevant way, the following subgroups were evaluated separately: ETS was defined as tumor shrinkage by ≥20%; a decrease by 0–19% was termed “minor shrinkage”. In addition, patients with any increase of tumor size beyond baseline (“tumor progression”) and patients developing new metastatic lesions during initial treatment (“new metastatic lesions”) were evaluated separately. To show individual tumor response on treatment, a waterfall plot has been illustrated. For comparison of the early on-treatment response evaluation at 7 weeks and best response during the trial, RECIST criteria (version 1.1) defining complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) were applied. To avoid guarantee-time bias only those patients were included into the analysis of whom sufficient information on ETS status could be obtained.
Median progression-free survival and median overall survival (OS) were defined as time from randomization to the date of any progression or death. Patients alive or free of tumor progression were censored. For the comparison of categorical variables between two groups, the chi-squared test or Fisher's exact test was applied were appropriate. The Cox proportional hazards multiple regression model was used to estimate hazard ratios and 95% confidence intervals (CIs). Progression-free survival and OS were estimated using the Kaplan–Meier method and the log-rank test was used for statistical comparison. A two-sided P-value of <0.05 was considered statistically significant. Statistical analyses were carried out using IBM spss Version 20 (SPSS Inc., Chicago, IL, USA).
Patient characteristics at baseline
The present analysis included 201 patients where a treatment response evaluation according to RECIST criteria version 1.1. was available (Fig. 1, CONSORT diagram). Baseline characteristics of patients with ETS versus non-ETS were comparable. Only baseline tumor load was significantly greater in ETS- than in non-ETS-patients (81.5 mm vs 68.0 mm, P = 0.030) (Table 1). No imbalances regarding study-treatment (FUFIRI versus mIROX) were observed between groups. Also the use of second-line therapy in ETS and non-ETS patients was similar (Table 1). There was no significant difference in baseline characteristics between the presently analyzed 201 patients and the whole population of the FIRE-1 study (data not shown).
Table 1. Baseline characterization
ETS n = 94
Non-ETS n = 107
Total n = 201
Characteristics of patients, percentages based on non-missing data. P-values: chi-squared test/Fisher's exact test, except age: independent samples: Mann–Whitney U-test. CEA, carcinogenic embryonic antigen; FUFIRI, 5-fuorouracil/folinic acid/irinotecan; LDH, lactate dehydrogenase; mIROX, modified irinotecan plus oxaliplatin; NA, not assessable; ULN, upper limit of normal; WBC, white blood cell count.
Karnofsky performance status
Primary tumor site
Time from diagnosis to randomization
No. of metastatic sites
Localization of metastasis
Tumor diameter- Median (Range) at
Second line treatment
RECIST best response in relation to ETS versus non-ETS
As expected, overall response rate (ORR) according to RECIST 1.1 criteria is high in ETS patients reflecting high sensitivity towards the chemotherapy applied, achieving CR in 16% and PR in 60% of patients (Table 2). By comparison, in the cohort having only minor shrinkage at 7 weeks (ETS 0–19%) best overall response rates of 7.7% for CR (five patients) and 36.9% for PR (24 patients) were achieved. Interestingly, nearly 70% of patients classified as “tumor progression” at the 7-weeks time-point reached SD according to RECIST during further continuation of chemotherapy treatment, and half of these patients showed stable disease for more than 6 months (data not shown). The remaining 30% of patients also progressed according to RECIST 1.1 criteria. As expected, the development of new metastatic lesions at 7 weeks resulted in PD according to RECIST in all patients.
Table 2. Early tumor shrinkage (ETS) and achievement of best overall response according to RECIST 1.1
Response evaluation according to RECIST 1.1. CI, confidence interval; CR, complete response; HR, hazard ratio by Cox-regression; PD, progressive disease; PFS, progression-free survival; PR, partial response; OS, overall survival; SD, stable disease.
Minor tumor shrinkage
New metastatic lesions
Median time to best response (range)(weeks)
Median PFS (months)
10.2 (95% CI 8.3–12.1)
HR 0.52 (0.40–0.69) P < 0.001
Median OS (months)
32.5 (95% CI 26.5–38.5)
16.8 (95% CI 14.7–19.0)
HR 0.39 (0.28–0.53) P < 0.001
The relation between ETS and outcome clearly depends on the selection of cutoffs. When the cutoff for ETS was set at 10% (data not shown) six patients (CR = 1, PR = 3, SD = 3) moved from “minor tumor shrinkage” to ETS. To illustrate the individual change of tumor size between baseline and first response evaluation and the best overall response achieved according to RECIST criteria a waterfall plot is shown in Figure 2.
In patient subgroups according to RECIST, median time to best response was 14 weeks. Patients responding to treatment (CR + PR) did so more rapidly, than patients with SD (12.0 weeks and 11.0 weeks vs 27.5 weeks). Patients with progressive disease under treatment had documented progress within a median time of 8 weeks, only. Comparing RECIST responding (CR + PR) versus non-responding patients (SD + PD), responding patients had significantly prolonged PFS and OS (10.2 months vs 5.5 months, P < 0.001; 32.5 months vs 16.8 months, P < 0.001, respectively; Table 2).
Progression-free survival in relation to ETS versus non-ETS
Median PFS in the whole group of 201 evaluable patients was 8.4 months (95% CI, 7.4–9.3 months). Patients with ETS ≥20% (n = 94) had a favorable PFS when compared to non-ETS patients (n = 107; 9.9 months vs 6.1 months, HR 0.78, P = 0.029; Table 3, Fig. 3). Patients responding with “minor shrinkage” (n = 65) had a PFS of 8.4 months, while patients with a “tumor progression” (n = 36) progressed after 4.0 months. Development of “new metastatic lesions” during chemotherapy (n = 6) resulted in a PFS of only 2.2 months (Table 4, Fig. 4).
Table 3. Progression-free survival and overall survival according to early tumor shrinkage (ETS) and non-ETS patients
ETS n = 94
Non-ETS n = 107
Total n = 201
P-value (Log rank)
CI, confidence interval; ETS, early tumor shrinkage; HR, hazard ratio by cox-regression; PFS, progression-free survival; OS, overall survival.
Table 4. Progression-free survival and overall survival according to non-early tumor shrinkage (ETS) patient subgroups
Minor tumor shrinkage n = 65
Tumor progression n = 36
New target lesions n = 6
P-value (Log rank)
CI, confidence interval; HR, hazard ratio by cox-regression; PFS, progression-free survival; OS, overall survival.
Overall survival in relation to ETS versus non-ETS
In unselected patients (n = 201), OS was 22.4 months (95% CI, 18.8–26.0 months). Evaluation of OS favored ETS- versus non-ETS-patients (27.5 months vs 17.8 months, HR 0.58, P = 0.002; Table 3, Fig. 5). Patients with “minor tumor shrinkage” had a median OS of 21.6 months, while early “tumor progression” resulted in a 6 months shorter survival (15.3 months; Table 4, Fig. 6). By comparison, those six patients developing new lesions had the worst outcome with a median OS of only 7.6 months (Table 4, Fig. 6).
Progression-free survial and OS in relation to ETS versus non-ETS in RECIST-responding patients
In the subgroup of patients responding according to RECIST 1.1 (n = 100), PFS and OS were calculated separately. Patients with ETS showed a prolonged, but not significant OS with an increase of more than 7 months when compared to non-ETS patients in the RECIST-responder group (32.7 months, vs 25.4 months, HR 1.41, P = 0.241). This trend could not be observed in PFS, were times were almost identical (9.9 months vs 10.1 months, HR 0.79, P = 0.361; Table 5).
Table 5. Progression-free survival and overall survival according to early tumor shrinkage (ETS) and non-ETS patients in patients with complete response (CR) + partial response (PR) according to RECIST 1.1 (n = 100)
ETS n =71
Non-ETS n =29
Total n =100
P-value (Log rank)
CI, confidence interval; ETS, early tumor shrinkage; HR, hazard ratio by cox-regression; OS, overall survival; PFS, progression-free survival.
Analyses of the irinotecan-based first-line trials, AVF2107 and N9741, suggest that objective response rate (ORR) is not a predictor of benefit from standard CT with or without bevacizumab.[9-11] This led to the conclusion that tumor response is not a necessary determinant of individual therapeutic benefit in mCRC. In addition, the evaluation of ORR as a valid surrogate endpoint for OS has failed in mCRC, and PFS is now widely used as a primary endpoint in clinical trials.(,) A contrasting message was obtained when ETS was analyzed in studies evaluating first-line treatment of mCRC plus or minus cetuximab. These studies indicate that ETS is, in fact, associated with favorable outcome.([2-4],[14-16],)
In the present retrospective analysis of 201 patients from a randomized first-line trial investigating irinotecan-based chemotherapy we were able to confirm previous findings of ETS being associated with favorable outcome. This was also present in patients who achieved CR or PR at best response according to RECIST. Furthermore, patients previously denoted as “non-ETS patients” were investigated separately and were found to belong to a heterogeneous subgroup of patients showing minor response or tumor progression. Patients with new metastatic lesions showed the worst outcome supporting a previous analysis of the Nordic VI trial.
From a clinician's perspective, it may be argued that ETS may outline a specific post-randomization patient selection of “responders” where patients with better baseline characteristics simply do better than others. In this context, it is important to note that the role of baseline characteristics has not yet been investigated with regard to the development of ETS. In the present analysis, patients with ETS ≥20% were found to have comparable baseline characteristics regarding age, sex, tumor localization, pattern of metastasis, laboratory results and use of second-line treatment. Surprisingly, baseline tumor load (sum of largest tumor diameters at baseline) was found to be significantly higher in the ETS >20% group than in the other groups (Table 1). Recently, Mansmann et al. performed a pooled analysis of several randomized first-line trials (including data from the present trial) and also reported an ETS of more than 20% prognostic for PFS and OS. This effect was even more evident for larger sized tumors at baseline.
When comparing time to best response versus ETS, the 7 week time point for ETS assessment in the present analysis was half of the RECIST best response documentation time (median 14 weeks; Table 5). Even in patients with CR or PR, who responded rapidly within 12.0 or 11.0 weeks, ETS assessment would have accelerated response evaluation and clinical decision-making. Relating to this, patients who achieve ETS are clearly sensitive to treatment and should proceed with unmodified therapy if conversion to secondary metastasectomy is the goal of treatment. Continuation with chemotherapy remains also a feasible option in patients developing minor shrinkage (0–20% decrease). Relating to this, more than 45% of patients with “minor shrinkage” achieved PR or CR at best response. By contrast, in patients with “tumor progression” or the development of “new target lesions” at the 7-week time-point the optimal treatment strategy remains less clear: While nearly 70% of patients with tumor progression after 7 weeks achieved SD according to RECIST at best response (median time 27.5 months), none of the patients with new metastatic lesions did so. These patients routinely proceed to subsequent chemotherapy. To conclude this, the clinical-decision making after assessment of ETS should be carefully investigated in prospective clinical trials that also assess the surrogacy of ETS in mCRC. It is also important to note, that in analogy to ORR, the development of ETS does not take into account duration of tumor response, which is discussed to have a significant effect on survival. Grothey and others therefore proposed to confirm SD after ≥12 weeks in order to strengthen SD as a response criterion.[9-11] In our analysis, half of the patients who showed an increase in tumor diameter at 7 weeks and later achieved SD did so for more than 6 months (data not shown).
One limitation of the present data is its retrospective nature and its restriction to a fraction of the whole study population where retrospective recalculation from WHO into RECIST was possible. Furthermore, the response evaluation according to RECIST was not performed in a central review. However, baseline characteristics were comparable between the present subgroup analyses and the entire study population except for the percentage of patients with only one metastatic site (77% vs 63%). The median PFS (8.4 months) and OS (22.4 months) observed in the present subgroup analysis of 201 patients are comparable to the outcome data obtained for the entire study population. Another limitation of the present analysis is its restriction to only one time point of follow-up (7 weeks). In analogy with previous reports, neither the optimal cut-off value for tumor shrinkage nor the optimal time point of its determination can be elucidated.( ,[2-4],) To avoid guarantee-time bias in the present analysis, only patients who were alive and evaluable after 7 weeks of treatment were included. Accordingly, the length of survival itself did not influence the chance of being classified as ETS or non-ETS patient.
In conclusion, the assessment of ETS can identify sensitivity towards chemotherapy treatment at an earlier time point (7 or 8 weeks) compared to the best overall response evaluation according to RECIST (in the present analysis median 14 weeks). This finding was present in patients who responded (PR + CR) according to RECIST, also. Early tumor shrinkage therefore appears to be sensitive and applicable across chemotherapy- and cetuximab-based studies. While the present definition of ETS with a cut-off of 20% clearly has a prognostic value, future analyses may also include the baseline tumor diameters relating to the absolute magnitude of tumor shrinkage. Finally, it appears to be of great importance that non-ETS is a heterogeneous group where careful and differential medical decision-making is necessary.
The FIRE trial was funded by Sanofi and Pfizer. This particular work was not financially supported. We thank all patients and their families, and the participating centers of the FIRE-trial who contributed to patient care. We also thank Matthias Wolff for expert secretarial help and organization.
Sebastian Stintzing received honoraria from MERCK and ROCHE. Volker Heinemann received honoraria and is a member of advisory boards at AMGEN, MERCK and ROCHE. Clemens Giessen, Ruediger Paul Laubender, Ludwig Fischer von Weikersthal, Andreas Schalhorn, Dominik Paul Modest, Michael Haas and Ulrich Robert Mansmann have no conflict of interest.