Successful desensitization with cetuximab after an infusion reaction to panitumumab in patients with metastatic colorectal cancer

Background

Cetuximab and panitumumab are chimeric and fully human monoclonal antibodies, respectively, against epidermal growth factor receptor used in the treatment of metastatic colorectal cancer (mCRC). Incidence of documented infusion reaction (IR) is more common with cetuximab (all grades [g]: 15–21%, g 3/4: 2–5%) than panitumumab (all g: 4%, g 3/4: 1%). Anecdotal reports suggest successful challenge with panitumumab following IR with cetuximab (Saif et al. in Cancer Chemother Pharmacol 63(6):1017–1022, 2009). However, safety of cetuximab after IR with panitumumab is not known. We report two patients successfully desensitized with cetuximab after IR with panitumumab.

Patients and methods

A 42-year-old female with mCRC received panitumumab as a third-line agent. She developed severe chest tightness, pain, and shortness of breath (SOB), 5 min after first panitumumab infusion. A second 70-year-old male with mCRC developed severe facial flushing, back pain, SOB, tachycardia and hypotension, 5 min after second dose of panitumumab plus irinotecan as a second-line therapy. These two patients received desensitization protocol for cetuximab after a test dose of 20 mg IV over 10 min followed by a slow infusion 10% of original rate in 0–2 h, 25% of original rate in 2–2.5 h, 50% reduced rate in 2.5–3 h, and then 100% infusion rate after 3 h. Patients were observed 4 h after completion of infusion.

Results

First patient received a total of 12 cycles of cetuximab with stable disease, no recurrence of IR, and grade 1–2 acniform rash that first developed after third cycle. Second patient received a total of eight cycles uneventfully without IR.

Conclusions

To our knowledge, this is the first report of two patients with documented IR with panitumumab being desensitized successfully with cetuximab. Though anecdotal reports suggest safety of panitumumab in patients following IR with cetuximab, panitumumab can also cause severe IR. Our experience suggests that in case of limited options, such patients can be successfully challenged with cetuximab in a hospital after appropriate desensitization and premedication. Further studies focusing on desensitization and identifying hypersensitivity profile of different anti-epidermal growth factor receptor antibodies are warranted.     

Phase I study of primary treatment with 5-FU,oxaliplatin, irinotecan,levofolinate, and panitumumab combination chemotherapy in patients with advanced/recurrent colorectal cancer involving the wild-type <Emphasis Type="Italic">RAS</Emphasis> gene: the JACCRO CC-14 study

Background

FOLFOXIRI is now regarded as the chemotherapy regimen that offers the best platform for the treatment of colorectal cancer. However, the safety and efficacy of FOLFOXIRI + panitumumab has not been demonstrated. We conducted a phase I study to determine the recommended dose of FOLFOXIRI + panitumumab as first-line treatment for RAS wild-type metastatic colorectal cancer (mCRC).

Methods

Patients received combination therapy consisting of panitumumab (6 mg/kg on day 1) + FOLFOXIRI [irinotecan (CPT-11), oxaliplatin (L-OHP) 85 mg/m², and folinate (LV) 200 mg/m²] on day 1, followed by fluorouracil (5-FU) 3200 mg/m² infused as a 46-h continuous infusion starting on day 1) repeated every 2 weeks as first-line treatment of RAS wild-type mCRC patients. A decrease in CPT-11 dose was planned (started at level 1: CPT-11 165 mg/m²).

Results

Seven patients were enrolled, and six were assessed for safety and efficacy. Maximum tolerated dose was not reached at level 1; all patients were treated at these levels. The common Grade 3 or 4 relevant toxicities were diarrhea (50%), hypokalemia (33%) and stomatitis (33%). No treatment-related deaths occurred. Of the six patients assessed four had partial response and the two others had stable disease; hence, the response rate was 66.7% (95% confidence interval 28.9–100%) and the disease control rate was 100%. Time to protocol treatment failure was 7.2 (1.4–7.3) months.

Conclusion

The FOLFOXIRI + panitumumab chemotherapy regimen was well tolerated by our patients with mCRC and showed promising anti-tumor activity. The recommended phase II dose was determined to be the same as the standard doses of this regimen used worldwide.

     

Remnant liver volume-based predictors of postoperative liver dysfunction after hepatectomy: analysis of 625 consecutive patients from a single institution

Background

During hepatic resection, accurate estimation of remnant liver volume and hepatic function is crucial for avoiding postoperative liver failure. The purpose of this study was to identify preoperative factors related to postoperative liver dysfunction according to the percentage of future liver remnant volume (%FLR).

Methods

A total of 625 patients who underwent hepatectomy were enrolled in this study. Total bilirubin level >50 μmol/L and/or prothrombin time index <50 % on postoperative day 5 were used as criteria for postoperative liver dysfunction (PLD). Patients were classified into 3 groups according to the %FLR: 35–60 (n = 116), 60–80 (n = 157), and >80 (n = 351). Multivariate logistic regression analysis was performed to identify factors related to postoperative liver dysfunction in each group.

Results

Among the patients with 35–80 %FLR, the morbidity and mortality rates were significantly higher in patients with PLD than in patients without PLD. There was no postoperative death in patients with >80 %FLR . Multivariate analysis showed that PLD was associated with receptor index (LHL15) ≤0.93 (odds ratio [OR] = 7.96) in patients with 35–60 %FLR. The sensitivity and specificity for PLD were 87.5 and 96.1 %, respectively. In patients with 60–80 %FLR, PLD was associated with platelet count <10.0 × 10⁴/mL (OR = 6.12). The sensitivity and specificity for PLD were 73.3 and 96.2 %, respectively.

Conclusion

LHL15 ≤0.93 and platelet count <10.0 × 10⁴/mL are pivotal indicators for predicting PLD in patients with 35–60 %FLR and 60–80 %FLR, respectively.     

Panitumumab and irinotecan every 3 weeks is an active and convenient regimen for second-line treatment of patients with wild-type K-RAS metastatic colorectal cancer

Purpose

To evaluate the efficacy and safety profile of the combination of panitumumab and irinotecan every 3 weeks in a phase II trial as second-line treatment in patients with advanced wild-type (WT) K-RAS colorectal cancer (CRC).

Methods

Fifty-three patients received 9 mg/kg of panitumumab followed by 350 mg/m² of irinotecan every 21 days until disease progression, unacceptable toxicity or consent withdrawal.

Results

Median age of patients included was 67 years. All patients had previously received 5-fluorouracil, 84 % oxaliplatin and 8 % irinotecan as first-line treatment. Patients received a median of five infusions of panitumumab and irinotecan. On an intention-to-treat analysis, 12 patients (23 %) achieved partial responses and 22 patients (41 %) achieved disease stabilization. Median progression-free survival and overall survival were 4.5 and 15.1 months, respectively. The most frequent treatment-related severe toxicities per patient were diarrhoea (35.8 %), followed by skin rash (32.1 %), asthenia (18.9 %) and neutropenia (13.2 %). A significant association between clinical response and incidence and grade of skin toxicity was observed (p = 0.0032).

Conclusion

This study shows that the administration of panitumumab plus irinotecan every 3 weeks is safe, active and feasible as second-line treatment in patients with advanced WT K-RAS CRC.     

Retrospective analysis of pathological response in colorectal cancer liver metastases following treatment with bevacizumab

Aims

Pathological response has been shown to be a predictor for survival after preoperative chemotherapy and surgical resection of colorectal cancer liver metastases. This retrospective analysis evaluated the effect on pathological response of adding bevacizumab to standard neoadjuvant chemotherapy in patients with metastatic colorectal cancer (mCRC) and liver metastases.

Methods

Patient records from two Spanish centres were retrospectively examined for this analysis. Patients were included if they had stage IV mCRC with liver metastases, were unresectable or marginally resectable tumour before chemotherapy, and had oxaliplatin- or irinotecan-based chemotherapy, with or without bevacizumab, before resection. Tumour response was evaluated using response evaluation criteria in solid tumours (RECIST). Pathological response was assessed by pathologists blinded to treatment.

Results

Ninety-five patients were included. Good pathological responses (PR0/PR1) were observed in 37 patients (39 %). The RECIST response rate was 51 %. Only 42 % of patients with a good pathological response had a complete or partial response according to RECIST, while 57 % of those with a poor pathological response had a complete or partial response according to RECIST. RECIST response rates were similar with and without bevacizumab, although 49 % of bevacizumab-treated patients had a good pathological response versus 27 % of those receiving chemotherapy alone (χ ² P = 0.0302).

Conclusion

Pathological response may be a better indicator of treatment efficacy than RECIST for patients with mCRC receiving bevacizumab in the neoadjuvant setting. Adding bevacizumab to chemotherapy has the potential to increase pathological response rates. Well-designed prospective clinical studies are required to establish the efficacy and tolerability of this approach.     

Endobiliary Stent: Marker for Patient Alignment in Image-Guided Radiotherapy in Pancreatic and Periampullary Cancers

Purpose

The aim of this study was to analyse the possibility of using stent in pretreatment megavoltage computed tomography (MVCT) images with respect to that on planning kilovoltage computed tomography as tumour surrogate during matching for daily registration in cases of pancreatic and periampullary cancer treated on a TomoTherapy Hi-Art system.

Methods

Planning CT and pretreatment MVCT of the first and then after every three fractions were transferred to a FocalSim workstation for ten patients. Planning CT of each patient was independently fused with each of the seven MVCT images of that patient. The stent was contoured on all of the eight images for each patient. The difference between the three co-ordinates of centre of mass (CM) of the stent on the planning CT and seven MVCT images was found. The difference between CM of the liver and stents on the planning CT as well as on the MVCT for all seven fractions was also calculated. The mean of these differences across all patients was calculated and analysed.

Results

The mean difference in planning and MVCT CMs for stents in the X, Y and Z directions was 0.13 cm (±0.4), 0.16 cm (±2.2) and 0.35 cm (±0.7), respectively. Average difference between CM of the liver and stent on the planning CT in the X, Y and Z directions was found to be 1.832 cm (±1.64), 5.34 cm (±1.33) and 0.54 cm (±0.26), respectively. Average difference between CM of the liver and CM of stent on the MVCT for that day in the X, Y and Z directions was found to be 1.93 cm (±1.5), 4.6 cm (±1.03) and 0.654 cm (±0.35), respectively.

Conclusions

Endobiliary stents are stable tumour localisation surrogates and can be used to correct for interfraction target motion.     

A phase I trial of everolimus in combination with 5-FU/LV,mFOLFOX6 and mFOLFOX6 plus panitumumab in patients with refractory solid tumors

Purpose

This phase I study investigated the safety, dose-limiting toxicity, and efficacy in three cohorts all treated with the mTOR inhibitor everolimus that was delivered (1) in combination with 5-fluorouracil with leucovorin (5-FU/LV), (2) with mFOLFOX6 (5-FU/LV + oxaliplatin), and (3) with mFOLFOX6 + panitumumab in patients with refractory solid tumors.

Methods

Patients were accrued using a 3-patient cohort design consisting of two sub-trials in which the maximum tolerated combination (MTC) and dose-limiting toxicity (DLT) of everolimus and 5-FU/LV was established in Sub-trial A and of everolimus in combination with mFOLFOX6 and mFOLFOX6 plus panitumumab in Sub-trial B.

Results

Thirty-six patients were evaluable for toxicity, 21 on Sub-trial A and 15 on Sub-trial B. In Sub-trial A, DLT was observed in 1/6 patients enrolled on dose level 1A and 2/3 patients in level 6A. In Sub-trial B, 2/3 patients experienced DLT on level 1B and subsequent patients were enrolled on level 1B-1 without DLT. Three of six patients in cohort 2B-1 experienced grade 3 mucositis, and further study of the combination of everolimus, mFOLFOX6 and panitumumab was aborted. Among the 24 patients enrolled with refractory metastatic colorectal cancer, the median time on treatment was 2.7 months with 45 % of patients remaining on treatment with stable disease for at least 3 months.

Conclusions

While a regimen of everolimus in addition to 5-FU/LV and mFOLFOX6 appears safe and tolerable, the further addition of panitumumab resulted in an unacceptable level of toxicity that cannot be recommended for further study. Further investigation is warranted to better elucidate the role which mTOR inhibitors play in patients with refractory solid tumors, with a specific focus on mCRC as a potential for the combination of this targeted and cytotoxic therapy in future studies.     

Moderate renal dysfunction may not require a cisplatin dose reduction: a retrospective study of cancer patients with renal impairment

Objective

The aim of this study was to assess the tolerability of cisplatin (CDDP) in patients with moderate renal dysfunction.

Methods

To investigate the relationship between CDDP dose and nephrotoxicity, a retrospective chart review was conducted of patients with a creatinine clearance (Ccr) of 30–60 mL/min. Subjects were classified into three groups according to the CDDP dose, as determined by the physician, and the nephrotoxicity among these groups was compared. Additionally, we investigated the correlation coefficients between maximum serum creatinine (Scr) level or minimum estimated glomerular filtration rate (eGFR) and baseline Ccr.

Results

Fifty-six patients were included in this study. Among these patients, 13 patients received 30–40 mg/m² CDDP (group I), 18 patients received 40–70 mg/m² (group II), and 25 patients received 70–80 mg/m² (group III). No significant difference in nephrotoxicity was observed (median Scr 1.53, 1.61, and 1.53 mg/dL, respectively), and no correlation was observed between baseline Ccr and maximum Scr (r = 0.004, p = 0.979) or minimum eGFR (r = 0.21, p = 0.119). Only two patients (3.5 %) experienced grade 3 or 4 Scr elevation—one patient with a Ccr of 52.6 mL/min received 60 mg/m² CDDP, and the other patient with a Ccr of 52.1 mL/min received 70 mg/m² of CDDP. Hemodialysis was not observed.

Conclusion

CDDP was tolerated at doses of 35–80 mg/m² among patients with moderate renal impairment. Empiric dose reduction might create a risk of under-treatment.     

Final Analysis of Outcomes and RAS/BRAF Status in a Randomized Phase 3 Study of Panitumumab and Best Supportive Care in Chemorefractory Wild Type KRAS Metastatic Colorectal Cancer

Introduction

Tumor rat sarcoma gene (RAS) status is a negative predictive biomarker for anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer (mCRC). We analyzed outcomes according to RAS and v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutational status, and evaluated early tumor shrinkage (ETS) and depth of response (DpR) for patients with wild type RAS.

CA19-9 level as a prognostic and predictive factor of bevacizumab efficacy in metastatic colorectal cancer patients undergoing oxaliplatin-based chemotherapy

Purpose

The prognostic and predictive values of carbohydrate antigen 19-9 (CA19-9) levels in metastatic colorectal cancer (mCRC) remain unclear. We reviewed all mCRC patients at a single institution to evaluate the relationship between CA19-9 levels and survival.

Methods

Two hundred and fifty-two patients underwent first-line chemotherapy using oxaliplatin-based regimens between April 2005 and December 2009. The relationship between baseline CA19-9 levels and survival was analyzed. Moreover, we evaluated the relationship between baseline CA19-9 levels and clinicopathological factors.

Results

One hundred and fifty patients had elevated baseline CA19-9 levels (elevated group), and 79 patients had normal baseline CA19-9 (normal group) levels. Both KRAS and BRAF mutation rates were higher in the elevated group than in the normal group. Elevated CA19-9 level was a poor prognostic factor compared with normal CA19-9 levels (P = 0.0021). In the elevated group, the median survival time with bevacizumab was significantly longer with bevacizumab than without it (median OS, 27.8 vs. 15.3 months, P = 0.0019). However, the median survival time was not different with or without bevacizumab in the normal group (median OS, 36.5 vs. 38.0 months, P = 0.9515).

Conclusion

Our results suggest that baseline CA19-9 level is an independent prognostic factor in mCRC patients, and it correlated with the KRAS/BRAF mutation status. Bevacizumab exhibits clinical activity only for high CA19-9 levels in mCRC.     

Effect of Primary Tumor Location on Second- or Later-line Treatment Outcomes in Patients With RAS Wild-type Metastatic Colorectal Cancer and All Treatment Lines in Patients With RAS Mutations in Four Randomized Panitumumab Studies

Background

The primary tumor location has a prognostic impact in metastatic colorectal cancer (mCRC). We report the results from retrospective analyses assessing the effect of tumor location on prognosis and efficacy of second- and later-line panitumumab treatment in patients with RAS wild-type (WT) mCRC and on prognosis in all lines of treatment in patients with RAS mutant (MT) mCRC.

Microdialysis measurement of intratumoral temozolomide concentration after cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, in a U87 glioma model

Background

Combining anti-angiogenesis agents with cytotoxic agents for the treatment of malignant gliomas may affect the cytotoxic drug distribution by normalizing the blood–brain barrier (BBB). This study examines the intratumoral concentration of temozolomide (TMZ) in the presence and absence of the pan-VEGF receptor tyrosine kinase inhibitor, cediranib.

Methods

Seven nude rats bearing U87 intracerebral gliomas had a microdialysis probe centered within the tumor. Ten-days after tumor implantation, TMZ (50 mg/kg) was given orally. The extracellular fluid (ECF) concentrations of TMZ within the tumor were assessed via microdialysis for 6 h following TMZ administration. Cediranib (6 mg/kg) was then given orally, and 12 h later, TMZ was re-administered with subsequent microdialysis collection. A subset of animals also underwent functional MRI to assess angiogenesis in vivo at post-inoculation days 12 and 21, before and after the cediranib treatment.

Results

After dosing of oral TMZ only, ECF-TMZ mean-C _max and area under the concentration curve(AUC_0–∞) within the tumor were 0.59 μg/mL and 1.82 μg h/mL, respectively. Post-cediranib, ECF-TMZ mean-C _max and AUC_0–∞ were 0.83 μg/mL and 3.72 ± 0.61 μg h/mL within the tumor, respectively. This represented a 1.4-fold (p = 0.3) and 2.0-fold (p = 0.06) increase in the ECF-TMZ C _max and AUC_0–∞, respectively, after cediranib administration. In vivo MRI measurements of the various vascular parameters were consistent with a BBB “normalization” profile following cediranib treatment.

Conclusions

In the U87 intracerebral glioma model, within the first day of administration of cediranib, the intratumoral concentrations of TMZ in tumor ECF were slightly, but not statistically significantly, increased when compared to the treatment of TMZ alone with radiographic evidence of a normalized BBB.     

Clinical usefulness of KRAS, BRAF, and PIK3CA mutations as predictive markers of cetuximab efficacy in irinotecan- and oxaliplatin-refractory Japanese patients with metastatic colorectal cancer

Background

Anti-epidermal growth factor receptor (EGFR) antibodies, cetuximab, and panitumumab are established as a new treatment option for metastatic colorectal cancer (mCRC). Among activating mutations downstream of EGFR, the KRAS mutation, which is present in 30–45 % of CRC patients, has shown to be a predictive biomarker of resistance to anti-EGFR antibody therapy based on Caucasian studies.

Methods

Forty-three chemotherapy-refractory Japanese patients with mCRC were treated with cetuximab monotherapy or cetuximab plus irinotecan. KRAS, BRAF, and PIK3CA mutational status of tumors was assessed. The association between mutational status and treatment outcome was evaluated.

Results

Of 43 tumors, KRAS, BRAF, and PIK3CA mutations were identified in 12 (27.9 %), 2 (4.7 %), and 2 (4.7 %) tumors, respectively. The wild-type KRAS subgroup showed better clinical outcomes than the mutant KRAS subgroup in terms of response rate (RR) (31.3 % vs. 0 %, P = 0.034) and progression-free survival (PFS) (5.1 vs. 3.0 months, P = 0.017). No responder to treatment was shown in 16 (37.2 %) patients with tumors harboring mutations in any one of the three genes (KRAS, BRAF, and PIK3CA). The wild-type subgroup without any mutations in KRAS, BRAF, and PIK3CA had a better RR (37.0 %) and PFS (6.4 months) than did the wild-type KRAS subgroup.

Conclusion

Our data indicated that KRAS status is predictive of cetuximab response in the Japanese population. The additional analysis of BRAF and PIK3CA genes in wild-type KRAS patients could improve selection of patients who are most likely to benefit from anti-EGFR antibody therapy.     

Orally administered S-1 suppresses circulating endothelial cell counts in metastatic breast cancer patients

Background

S-1 is an oral cytotoxic preparation that contains tegafur. Gamma-butyrolactone (GBL) is a metabolite of tegafur that is known to suppress vascular endothelial growth factor (VEGF)-mediated angiogenic activity. The aim of this study was to determine the change in circulating endothelial cell (CEC) counts, GBL levels, and angiogenesis-related factors during S-1 administration in metastatic breast cancer (MBC) patients.

Methods

Patients with HER2-negative MBC were eligible. S-1 was administered orally twice daily in a 4 week on/2 week off cycle until disease progression or unacceptable toxicity occurred. Blood was collected on the following: days 1, 43, 85 (before each cycle of S-1 administration), days 15, 57 (1 h after S-1 administration), and day 29. The CellSearch^® system was used to count the CECs. The gas chromatographic–mass spectrometric method was used to measure plasma GBL and 5-FU levels. Levels of VEGF were assayed by enzyme-linked immunosorbent assay.

Results

A total of 18 patients were enrolled. The plasma GBL levels on days 15 and 57 were 41.3 ± 15.8 and 41.0 ± 11.2 ng/mL, respectively. The CEC levels decreased on day 15, and significantly low levels were maintained until day 85 (P = 0.002 vs day 1). The plasma VEGF levels significantly decreased on day 15 (P = 0.012 vs day 1) and had a tendency to decrease until day 57.

Conclusions

This exploratory study showed that GBL levels increased, VEGF levels decreased, and CEC levels were suppressed during S-1 administration. S-1 appears to have anti-angiogenic activity.     

Chemotherapy with bevacizumab for metastatic colorectal cancer: a retrospective review of 181 Japanese patients

Background

There has so far been little information on the clinical effect of bevacizumab against colorectal cancer in Japan. Hence, this study was conducted to retrospectively evaluate the safety and efficacy of bevacizumab in clinical practice.

Methods

A total of 181 patients with metastatic colorectal cancer (mCRC) received bevacizumab in combination with chemotherapy at 18 hospitals in Kumamoto prefecture, Japan. We surveyed the medical records of all patients regarding the patient characteristics, objective tumor responses, and adverse events. We analyzed their overall survival and the survival benefit when continuing the administration of bevacizumab beyond disease progression (progressive disease; PD) in patients who received bevacizumab-containing 1st line therapy.

Results

The response rate (RR) in all lines of therapy was 42 %. The 1st line patients showed significantly better survival in comparison to the patients who received further lines of treatment (P = 0.005). There were no significant differences in survival between the group with post-PD treatment with bevacizumab and the group with post-PD treatment without bevacizumab (P = 0.13). The most common grade 3 or greater adverse event associated with bevacizumab was hypertension (12.2 %). Especially, a high incidence of gastrointestinal (GI) perforation was shown in this study (4.4 %) and most of the patients with GI perforation had some risk factors for this complication.

Conclusion

Although the survival benefit of bevacizumab in Japanese patients with mCRC was similar to that observed in previous clinical trials, this study showed a high incidence of GI perforation in comparison to previous studies. Therefore, the careful selection of patients with few risk factors for this complication is likely to lead to a greater benefit from bevacizumab treatment.     

Health-related quality of life in patients with metastatic colorectal cancer treated with panitumumab in first- or second-line treatment

Background:

Panitumumab in combination with chemotherapy was evaluated in two pivotal clinical trials in first- and second-line treatment of metastatic colorectal cancer (mCRC), respectively. This analysis compared the health-related quality of life (HRQoL) of patients with or without panitumumab in the two trials.

Methods:

Patients with mCRC were randomised to FOLFOX (first-line trial) or FOLFIRI (second-line trial)±panitumumab. The EuroQoL 5-Dimensions Health State Index (EQ-5D HSI) and Visual Analogue Scale (EQ-5D VAS) were assessed at baseline and monthly follow-up until disease progression. Patients with wild-type KRAS mCRC with baseline and post-baseline HRQoL scores were included. Difference in change from baseline between treatment groups was evaluated using linear mixed and pattern-mixture models.

Results:

In the first-line trial, 576 patients with wild-type KRAS mCRC (284 panitumumab+FOLFOX4 and 292 FOLFOX4 alone) were included in the HRQoL analyses. In the second-line trial, 530 patients with wild-type KRAS mCRC were included in these analyses (263 panitumumab+FOLFIRI and 267 FOLFIRI alone). There was no significant difference in the change in EQ-5D HSI and VAS scores between treatment groups in either trial.

Conclusion:

The addition of panitumumab to FOLFOX4 or FOLFIRI in first- or second-line treatment of wild-type KRAS mCRC significantly improved progression-free survival without compromising HRQoL.     

A phase 1 study of linifanib in combination with carboplatin/paclitaxel as first-line treatment of Japanese patients with advanced or metastatic non-small cell lung cancer (NSCLC)

Introduction

Linifanib is a potent, orally active, and selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor kinase activities with clinical efficacy in non-small cell lung cancer (NSCLC). This phase 1 dose-escalation study evaluated the pharmacokinetics, safety, and efficacy of linifanib in combination with carboplatin/paclitaxel in Japanese patients with advanced NSCLC.

Methods

Carboplatin (AUC = 6 mg/mL/min) and paclitaxel (200 mg/m²) were administered on day 1 of each 21-day cycle up to a maximum of six cycles. Oral linifanib (7.5 mg) was given to six patients once daily throughout all cycles and escalated to 12.5 mg/day in a second cohort of six patients.

Results

Twelve patients received at least one dose of linifanib. The most common adverse events were hematologic and consistent with expected toxicities with carboplatin/paclitaxel. With 12.5 mg linifanib, grade 3/4 neutropenia, leukopenia, and thrombocytopenia occurred in 100, 83, and 83 % of patients, respectively. Dose-limiting grade 4 thrombocytopenia occurred in one patient at each dose level. Linifanib pharmacokinetics was similar to that in non-Japanese patients. At 12.5 mg, linifanib C _max was 0.32 μg/mL and AUC₂₄ was 4.29 μg h/mL. Linifanib C _max occurred at 2–3 h with both doses and when given alone or in combination with carboplatin/paclitaxel. Exposure to linifanib appeared to be increased by carboplatin/paclitaxel, and exposure to paclitaxel appeared to be increased by linifanib. Partial responses were observed in nine patients.

Conclusions

Linifanib added to carboplatin/paclitaxel is well tolerated in Japanese patients with advanced/metastatic NSCLC. The recommended dose of linifanib with carboplatin/paclitaxel is 12.5 mg, same as for US patients.     

Association between KRAS codon 13 mutations and clinical response to anti-EGFR treatment in patients with metastatic colorectal cancer: results from a meta-analysis

Purpose

To comparatively evaluate whether metastatic colorectal cancer (mCRC) patients with KRAS codon 13 mutations (codon 13 muts) can benefit from anti-EGFR treatment.

Methods

We performed a meta-analysis of relevant studies. Systematic searches of the PubMed, Embase, and Cochrane databases, as well as ASCO conference papers up to July 30, 2012, were retrieved, and the authors of included studies were contacted to obtain more individual data. Fixed effects meta-analytical models were used where indicated, and between-study heterogeneity was assessed. The primary study end points were the overall response rate (ORR). Secondary end points were progress-free survival (PFS) and overall survival (OS).

Results

A total of 7 studies were included in the final meta-analysis, consisting of 2,802 mCRC patients, 1,679 of whom were treated with anti-EGFR monoclonal antibodies. The ORR of mCRC patients with codon 13 mutation was 25.2 % (29/115), compared to 17.6 % (98/558) for other KRAS mutations (other mut) and 42.6 % (429/1,006) for KRAS WT patients. The overall pooled RR for ORRs of codon 13 mut versus other mut was 1.52 (95 % CI 1.10–2.09, P = 0.003), whereas the pooled RR for codon 13 mut versus WT was 0.61 (95 % CI 0.45–0.83, P = 0.002). The pooled progression-free survival (PFS) times were 6.4 months for codon 13 mut, 4.1 months for other mut, and 6.6 months for WT, whereas the pooled OS durations were 14.6, 11.8, and 17.3 months, respectively. Subgroup analysis was conducted on the basis of the line of treatment, anti-EGFR drug, study design, and detection method, respectively. The results implicated that KRAS codon 13 mut patients gain more benefit from Cetuximab in further line treatment.

Conclusions

Metastatic colorectal cancer patients with KRAS codon 13 mutations demonstrate a greater clinical response to anti-EGFR treatment than patients with other KRAS mutations.     

Cimetidine attenuates vinorelbine-induced phlebitis in mice by militating E-selectin expression

Purpose

We investigated E-selectin expression in mice and rabbits with vinorelbine-induced phlebitis and the effect of cimetidine. To find the relationship between E-selectin expression and vinorelbine-induced phlebitis.

Methods

Mouse and rabbit model of vinorelbine-induced phlebitis was established by intravenous infusion of vinorelbine. Pathological observation, molecular-biological determination of E-selectin and protein function of it was evaluated.

Results

Grossly, we observed swelling, edema and cord-like vessel changes in mice receiving vinorelbine but only mild edema in mice pretreated with cimetidine. Pathological scoring yielded a total score of 37 for vinorelbine-treated mice and 17 for mice pretreated with cimetidine (P < 0.05). ELISA revealed that rabbits treated with vinorelbine had markedly higher serum contents of E-selectin than normal saline (NS) controls (vinorelbine 1.534 ± 0.449 vs. NS 0.746 ± 0.170 ng/mL, P < 0.05), which was markedly attenuated by cimetidine (cimetidine 0.717 ± 0.468 vs. vinorelbine 1.534 ± 0.449 ng/mL, P < 0.05). Rose Bengal staining assays showed that vinorelbine markedly increased the adhesion rate of neutrophils for endothelial cells (vinorelbine 38.70 ± 8.34 % vs. controls 8.93 ± 4.85 %, P < 0.01), which, however, was significantly suppressed by cimetidine (9.93 ± 5.91 %, P < 0.01 vs. vinorelbine). In E-selectin knockout mice, we found no apparent difference in tail swelling in mice receiving vinorelbine or cimetidine and vinorelbine.

Conclusions

In conclusion, cimetidine attenuates vinorelbine-induced phlebitis in mice probably by suppressing increased expression of E-selectin.     

Left Versus Right: Does Location Matter for Refractory Metastatic Colorectal Cancer Patients in Phase 1 Clinical Trials?

Purpose

Location of the primary tumor is prognostic and predictive of efficacy with VEGF-inhibitors (I) versus EGFR-I given first-line to metastatic colorectal cancer (mCRC) patients. However, little is known regarding the effect of location on prognosis and prediction in refractory mCRC. We assessed the efficacy of VEGF-I and EGFR-I in regards to location of the primary tumor in patients with refractory mCRC enrolled in early phase studies.

Methods

A historical cohort analysis of mCRC patients, including 44 phase I trials our institution, from March 2004 to September 2012. Median Progression free survival (mPFS) and overall survival (mOS) were estimated from Kaplan-Meier curves and groups were statistically compared with the log-rank test.

Results

One hundred thirty-nine patients with a median age 59 (33–81). 73.9% received 3+ lines of therapy. All KRAS wild-type patients had received prior EGFR-I. Location: right 20.9%, left 61.9%, and transverse 4.3%. For survival analysis, transverse CRC were included with right. Of the 112 patients, mOS was left (N = 80) 6.6 months versus right (N = 32) 5.9 months, P = 0.18. mPFS was left (n = 86) 2.0 months versus right (N = 35) 2.0 months, P = 0.76. In subgroup analysis, survival was significant for KRAS wild-type patients with left-sided mCRC had mOS of 6.2 months with other agents versus 9.4 months with EGFR-I (P = 0.03).

Conclusions

In phase 1 clinical trials, although location alone was not prognostic in heavily pretreated patients, left-sided mCRC had improved survival with EGFR-I. Despite progression on EGFR-I, left-sided KRAS wild mCRC patients should be considered for phase 1 studies of agents targeting growth factor pathways.