Epirubicin, cisplatin, oral UFT, and leucovorin combination chemotherapy in advanced and metastatic esophageal cancer

Background: The purpose of treatment in patients with advanced and metastatic esophageal cancer is to improve symptoms and maintain quality of life. Recently, the regimen including epirubicin, cisplatin, and 5-FU (ECF) has been used with protracted venous infusion (PVI), and has been reported to be an effective treatment for advanced and metastatic csophagastric cancer. However, complications and the inconvenience associated with PVI cannot be justified for the treatment of advanced esophageal cancer. Therefore, we provided treatment with oral UFT and leucovorin instead of 5-FU PVI to improve convenience and catheter related complications. Patients and Methods: Thirty-seven patients with advanced esophageal cancer were admitted between March 2002 and April 2005. The treatment schedule was as follows: epirubicin 50 mg/m² iv on d 1, cisplatin 60 mg/m² iv on d 1, oral UFT 300 mg/m² and leucovorin 75 mg for 21 consecutive days of treatment followed by a 7-d treatment-free interval. Results: The response rate was 45.9% including one complete response (95% CI: 29.8%–62%). The median survival was 13 mo (95% CI: 10–16 mo). Four patients had adenocarcinoma. Interestingly, their response rate was 75% including one complete response. Myelosuppression was the most important toxicity. Other toxicities were tolerable. Conclusion: The combination of epirubicin, cisplatin, UFT, and leucovorin (EPUL) could be another alternative to ECF in patients with advanced esophageal cancer. And this treatment might be more effective in adenocarcinoma of esophageal cancer.     

Biweekly docetaxel, cisplatin, and 5-fluorouracil (DCF) chemotherapy for advanced esophageal squamous cell carcinoma: a phase I dose-escalation study

Background and purpose

The optimal chemotherapeutic protocol for the treatment of esophageal cancer has not yet been established. A dose-escalation study of docetaxel combined with cisplatin and 5-fluorouracil (5-FU) was performed to determine the optimal dose in patients with advanced esophageal squamous cell carcinoma.

Patients and method

We studied a total of 18 patients who had previously untreated thoracic esophageal squamous cell carcinoma with T4 tumors and/or metastasis. The patients received an infusion of docetaxel at different dose levels (levels 1, 2, 3: 30, 35, 40 mg/m², respectively) and an infusion of cisplatin (40 mg/m²) on days 1 and 15 plus a continuous infusion of 5-FU (400 mg/m²/day) on days 1–5 and 15–19.

Results

Dose-limiting toxicities (DLT) included febrile neutropenia and leukopenia. DLT occurred in 2 of 6 patients at level 1, 2 and in 3 of 6 patients at level 3. The response rate was 88.9%, including a complete response rate of 33.3%.

Conclusions

To minimize toxicity and maximize dose intensity, we elected to investigate a biweekly regimen. The maximum tolerated dose was level 3, and the recommended dose was determined to be docetaxel 35 mg/m² with cisplatin 40 mg/m² plus 5-FU 400 mg/m², administered biweekly. This regimen was tolerable and highly active. A phase II study has been started.     

Phase II Trial of Concomitant Neoadjuvant Chemotherapy with Oxaliplatin and Capecitabine and Intensity-Modulated Radiotherapy (IMRT) in Rectal Cancer

Introduction and Purpose

The purposes of this study are to evaluate the activity and safety of preoperative intensity-modulated radiotherapy and concurrent capecitabine and oxaliplatin (Xelox), the accuracy of preoperative magnetic resonance (MRI) for predicting pathologic results, and the correlation between carcinoembryonic antigen (CEA) and the existence of a pathologic complete response (pCR).

Patients and Methods

Twenty-seven patients (pt) with T3/T4N0/N+ rectal cancer were included. Capecitabine was administered at 825 t.i.d. mg/m² the days of the radiotherapy (RT), and oxaliplatin was administered weekly at 50 mg/m². RT was planned to 50.4 Gy. Surgery was scheduled 6 to 8 weeks after completion of Xelox RT. Before the intervention, a pelvic MRI was performed and a CEA level was determined.

Results

After Xelox RT, 7 pt had pCR (26%), 2 pt progression disease, and 18 pt tumor downstaging. Presurgical MRI did not predict the pathological result in 21 pt. Main side effects were diarrhea grade (G) 3 in four pt, hand and foot G1 five Pt and G2 four pt. Paresthesias G1 ten pt, G2 seven pt, and leukopenia six pt G1. Median RT dose was 49.7 Gy (47.5–50.4 Gy). At a mean follow-up of 22.5 months, four pt presented metastatis. Mean pretreatment CEA was 6.8 ng/mL (2.1–17.0). A difference statistically significant when compared pretreatment CEA with presurgical CEA (p?<?0.001) was detected. We found a nadir of <5 ng/mL as significantly associated with pCR (p?=?0.036).

Conclusion

Preoperative chemoradiotherapy with oxaliplatin and capecitabine is safe and well tolerated, and offers an interesting ratio of pCR and of tumor downstaging. Presurgical CEA level should be studied as predictors of pCR.     

Pathological response and safety of two neoadjuvant strategies with bevacizumab in MRI-defined locally advanced T3 resectable rectal cancer: a randomized,noncomparative phase II study

BackgroundIn T3 rectal cancer (RC), preoperative chemoradiotherapy [5-fluorouracil (5-FU–RT)] reduces local recurrences, but does not affect overall survival. New therapeutic options are still necessary to improve clinical outcomes.Patients and methodsThis randomized, noncomparative, open-label, multicenter, two arms, phase II study was conducted in MRI-defined locally advanced T3 resectable RC. In arm A, patients received 12-week bevacizumab plus 5-FU, leucovorin and oxaliplatin (Folfox-4) followed with bevacizumab–5-FU–RT before total mesorectal excision (TME). In arm B, patients received only bevacizumab-5-FU–RT before TME. Primary end point was pathological complete response (pCR) rate.ResultsForty-six patients were randomized in arm A and 45 patients in arm B. In arm A, the rate of pCR was 23.8% [95% confidence interval (CI) 12.1% to 39.5%] statistically superior to the defined standard rate of 10%, P = 0.015. In arm B, the rate of pCR of 11.4% (95% CI 3.8% to 24.6%) was not different from 10%, P = 0.906. No death occurred during the study period, from the start until 8 weeks following surgery. Postoperative fistulas were reported for 16 patients (7 in arm A and 9 in arm B).ConclusionEven if the addition of bevacizumab induced manageable toxicities including an increased risk of postoperative fistula and no treatment-related death, arm B did not achieve the expected pCR rate in the population of patients included. Induction bevacizumab–Folfox-4 followed by bevacizumab–5-FU–RT is promising. It is however necessary to continue investigations in the management of locally advanced RC.Clinical Trials.gov IdentifierNCT 00865189.     

Phase 2 trial of induction and concurrent chemoradiotherapy with weekly irinotecan and cisplatin followed by surgery for esophageal cancer

BACKGROUND:

Preoperative chemoradiation improves survival in esophageal and gastroesophageal junction (GEJ) cancer. We evaluated irinotecan and cisplatin as induction chemotherapy followed by concurrent chemoradiation in esophageal cancer.

METHODS:

Patients with uT1N1M0 or uT2‐4NanyM0 resectable squamous cancer or adenocarcinoma of the esophagus or GEJ received irinotecan 65 mg/m² and cisplatin 30 mg/m² for 4 treatments in weeks 1 through 5, followed by 4 treatments in weeks 7 through 11 with 50.4 Gy in daily fractions, followed by surgery. The primary endpoint was pathologic complete response (pCR). Positron emission tomography (PET) scan was performed prior to chemotherapy and as restaging prior to radiotherapy.

RESULTS:

Fifty‐five patients were evaluable, 75% of whom had adenocarcinoma and 65% of whom had uT3N1 disease. Thirty‐eight patients underwent R0 resection (69%). The incidence of pCR was 16% (95% confidence interval, 8%‐29%). Median overall survival was 31.7 months. An exploratory analysis of PET response to induction chemotherapy indicated a correlation with pCR (32% vs 4%), R0 resection (84% vs 57%), progression‐free survival (24.1 vs 7.7 months), and overall survival (40.2 vs 25.5 months).

CONCLUSIONS:

Weekly treatment with irinotecan, cisplatin, and radiation achieved results no better and potentially inferior to other phase 2 chemoradiotherapy trials with a low rate of pCR. The use of PET scan after induction chemotherapy to direct chemotherapy during subsequent radiotherapy merits further study. Cancer 2011. © 2011 American Cancer Society.     

Phase II study of neoadjuvant therapy with docetaxel,cisplatin, panitumumab,and radiation therapy followed by surgery in patients with locally advanced adenocarcinoma of the distal esophagus (ACOSOG Z4051)

BackgroundPreoperative chemoradiotherapy (CRT) improves outcomes in patients with locally advanced but resectable adenocarcinoma of the esophagus. ACOSOG Z4051 evaluated CRT with docetaxel, cisplatin, and panitumumab (DCP) in this patient group with a primary end point of a pathologic complete response (pCR) ≥35%.Patients and methodsFrom 15 January 2009 to 22 July 2011, 70 patients with locally advanced but resectable distal esophageal adenocarcinoma were enrolled. Patients received docetaxel (40 mg/m²), cisplatin (40 mg/m²), and panitumumab (6 mg/kg) on weeks 1, 3, 5, 7, and 9 with RT (5040 cGy, 180 cGy/day × 28 days) beginning week 5. Resection was planned after completing CRT. PCR was defined as no viable residual tumor cells. Secondary objectives included near-pCR (≤10% viable cancer cells), toxicity, and overall and disease-free survival. Adverse events were graded using the CTCAE Version 3.0.ResultsFive of 70 patients were ineligible. Of 65 eligible patients (59 M; median age 61), 11 did not undergo surgery, leaving 54 assessable. PCR rate was 33.3% and near-pCR was 20.4%. Secenty-three percent of patients completed DCP (n = 70) and 92% completed RT. 48.5% had toxicity ≥grade 4. Lymphopenia (43%) was most common. Operative mortality was 3.7%. Adult respiratory distress syndrome was encountered in two patients (3.7%). At median follow-up of 26.3 months, median overall survival was 19.4 months and 3-year overall survival was 38.6% (95% confidence interval 24.5% to 60.8%).ConclusionsNeoadjuvant CRT with DCP is active (pCR + near-pCR = 53.7%) but toxicity is significant. Further evaluation of this regimen in an unselected population is not recommended.ClinicalTrials.gov IdentifierNCT00757172.     

A Phase II Study of Oxaliplatin, 5-Fluorouracil,Leucovorin, and High-Dose Capecitabine in Patients With Metastatic Colorectal Cancer

PurposeCapecitabine has shown similar efficacy to 5-fluorouracil (5-FU); a regimen containing 2 weeks of capecitabine/oxaliplatin (CapOx) has demonstrated noninferiority to infusional 5-FU/oxaliplatin/leucovorin (FOLFOX) for the treatment of metastatic colorectal cancer (mCRC). This phase II study explores the efficacy and safety of a 2-day course of oxaliplatin/capecitabine (2DOC), with oxaliplatin given on day 1 and capecitabine given orally every 8 hours in high doses over 6 doses, mimicking FOLFOX6.Patients and MethodsThis phase II study was conducted by the University of Wisconsin Carbone Cancer Center. Eligible patients with mCRC received oxaliplatin 100 mg/m² intravenously (I.V.) over 2 hours followed by leucovorin 20 mg/m² I.V. bolus and 5-FU 400 mg/m² I.V. bolus on day 1 and day 15. Capecitabine was administered at 1500 mg/m² orally every 8 hours over 6 doses starting on day 1 and day 15.ResultsA total of 45 patients were enrolled; 44 were evaluated for response. Seventeen patients (39%) had objective responses. Median time to progression was 6.8 months, and median overall survival (OS) was 17.5 months. The most common side effects were grade 1/2 neuropathy, fatigue, and nausea. Severe hand-foot syndrome (HFS) was rare.ConclusionThe overall response rate with the 2DOC regimen is similar to published CapOx regimens, and time to progression and OS are similar. The incidence of HFS, diarrhea, and mucositis were lower compared with published results of 2-week schedules of capecitabine. The 2DOC regimen merits further study as a more convenient regimen than infusional 5-FU with less HFS when compared with a 2-week administration of capecitabine.     

A phase II study of epirubicin, cisplatin and capecitabine as neoadjuvant chemotherapy in locally advanced or inflammatory breast cancer

AimTo assess the efficacy and safety of epirubicin, capecitabine and cisplatin (EXC) combination therapy in locally advanced breast cancer (LABC) and investigate the predictive value of selected biomarkers.MethodsNewly diagnosed LABC patients received four 3-weekly cycles of neoadjuvant EXC (epirubicin 60 mg/m² day 1; capecitabine 1000 mg/m² bid, days 1–14; cisplatin 60 mg/m²day 1) and two cycles of post-operative EXC.ResultsEight (17%) of 48 patients had inflammatory breast cancer. Overall response rate was 74% (95% CI: 59–86%), including complete responses in 13% (95% CI: 5–26%). Nine (22%; 95% CI: 11–38%) of 41 patients undergoing surgery achieved pathologic complete response (pCR), giving a pCR rate of 19% (95% CI: 9–33%) in the intent-to-treat population. Haematological toxicity was manageable. The most problematic toxicities were chemotherapy-induced nausea/vomiting and hypercoagulative disorders. None of the biomarkers investigated, including HER2, predicted response.ConclusionEXC showed high efficacy in LABC, with high clinical response and pCR rate. Nausea and vomiting were unexpectedly frequent, and more aggressive prophylaxis and management of these side effects is recommended in future studies of this combination.     

Docetaxel,cisplatin and 5-fluorouracil-based induction chemotherapy followed by intensity-modulated radiotherapy concurrent with cisplatin in locally advanced EBV-related nasopharyngeal cancer

BackgroundThis monocentric study evaluates the activity and tolerability of docetaxel (Taxotere), cisplatin and 5-fluorouracil (5-FU) (TPF) induction chemotherapy followed by intensity-modulated radiotherapy (IMRT) concurrent with high-dose cisplatin in Epstein–Barr virus -related locally advanced undifferentiated nasopharyngeal cancer.Patients and methodsWe retrospectively reviewed the records of patients who received induction docetaxel 75 mg/m² and cisplatin 75 mg/m² on day 1, and 5-FU 750 mg/m²/day (96-h continuous infusion). Following induction, patients received full doses of IMRT concurrently with cisplatin 100 mg/m² every 21 days for three cycles.ResultsThirty patients received three TPF cycles (median). Induction was well tolerated; the main toxicity was neutropenia (33%, grade 3–4). During chemoradiotherapy, neutropenia (40%) and mucositis (43%) were the most frequent grade 3–4 adverse events. Mean dose of IMRT was 68.8 Gy. Worst late toxicity was xerostomia. Complete response rate was 93%. At 35 months, two patients had locoregional recurrence, three had distant metastases, and one had both. Three-year progression-free survival and overall survival were 79% [95% confidence interval (CI) 64% to 94%] and 87% (95% CI 74%– to 100%), respectively.ConclusionsIn this high-stage nonendemic cancer population, TPF followed by high-dose cisplatin IMRT was promising; this treatment approach deserves evaluation in randomized trials.     

Cetuximab plus cisplatin–5-fluorouracil versus cisplatin–5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie

BackgroundThis study assessed the activity of the mAb cetuximab in combination with cisplatin and 5-fluorouracil (5-FU) in advanced esophageal squamous cell carcinoma.Patients and methodsFor a maximum of six 29-day cycles, patients received cisplatin 100 mg/m², day 1, plus 5-FU 1000 mg/m², days 1–5 (CF), either alone or in combination with cetuximab (CET–CF; 400 mg/m² initial dose followed by 250 mg/m² weekly thereafter). The primary end point was tumor response. Tumor material was obtained for analysis of KRAS mutation status.ResultsSixty-two eligible patients were included, 32 receiving CET–CF and 30 CF. Cetuximab did not exacerbate grade 3/4 toxicity, except for rash (6% versus 0%) and diarrhea (16% versus 0%). The overall response rate according to RECIST criteria was 19% and 13% and the disease control rate 75% and 57% for the CET–CF and CF arms, respectively. With a median follow-up of 21.5 months, the median progression-free survival was 5.9 and 3.6 months and median overall survival 9.5 and 5.5 months for CET–CF and CF, respectively. No KRAS codon 12/13 tumor mutations were identified in 37 evaluated samples.ConclusionCetuximab can be safely combined with CF chemotherapy and may increase the efficacy of standard CF chemotherapy.     

Multi-center phase II trial of chemo-radiotherapy with 5-fluorouracil, leucovorin and oxaliplatin in locally advanced esophageal cancer

Purpose  The aim of this study was to evaluate the activity and safety of oxaliplatin/5-fluorouracil-based chemo-radiotherapy in patients with not radically resectable locally advanced esophageal cancer. Methods  Fifty-nine patients with adeno or squamous-cell carcinoma received oxaliplatin (60 mg/m²), and leucovorin (20 mg/m² on days 1,8,15,29,36,43,50,57) followed by continuous infusion fluorouracil (200 mg/m² per day on days 1–22 and 29–64) with radiotherapy (1.8 Gy daily fractions to a total dose of 45 Gy, from days 29 to 64). When feasible, surgery was scheduled 6–8 weeks after chemo-radiotherapy completion. The primary endpoint was 1-year progression-free survival. Results  Forty (68%) patients completed treatment without modifications. An objective clinical response was seen in 35 patients (59%). Esophagectomy was possible in 33 patients and a complete resection (R0) was achieved in 26 (79%) with 6 pathologic complete responses (pCR) and 3 near pCR. At a median follow-up of 39.7 months for the surviving patients, the median progression-free and overall survivals were 11 months (95% CI 6.5–14) and 18.5 months (95% CI 13–29). The 1-year progression-free and overall survivals were 47.5% (95% CI 34–59.5%) and 63% (95% CI 49–74%). Major toxicities were esophagitis (20% G3 and 5% G4) and diarrhea (8.5% G3 and 8.5% G4). Hematological toxicity (7% G3 and 3% G4) was less common; severe neurotoxicity (3% G3) was infrequent. Conclusions  Concurrent oxaliplatin, leucovorin, fluorouracil and radiotherapy followed or not by esophagectomy has a tolerable toxicity and promising activity in locally advanced esophageal cancer. Presented in part at the 41st annual meeting of the American Society of Clinical Oncology, Orlando, FL, USA, May 13–17, 2005, the 107th Annual Meeting of the Italian Surgery Society, Cagliari, Italy, October 9–12, 2005 and the 17th ICACT Meeting, Paris, France, January 30–February 2, 2006.     

Randomized controlled phase II comparison study of concurrent chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil versus CCRT with cisplatin, 5-fluorouracil, methotrexate and leucovorin in patients with locally advanced squamous cell carcinoma of the head and neck

We compared concurrent chemoradiotherapy (CCRT) with docetaxel, cisplatin (CDDP), and 5-fluorouracil (5-FU) (TPF) with CCRT with CDDP, 5-FU, methotrexate and leucovorin (PFML) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) in terms of safety and efficacy on survival. A total of 100 patients were enrolled. The TPF group received CCRT with the TPF regimen [docetaxel (50 mg/m²: day 1), CDDP (60 mg/m²: day 4), and continuous 5-FU infusion (600 mg/m²/day: days 1–5)]. In the PFML group, patients received CCRT with the PFML regimen [CDDP (60 mg/m²: day 4)], continuous 5-FU infusion (600 mg/m²/day: days 1–5), methotrexate (30 mg/m²: day 1) and leucovorin (20 mg/m²/day: days 1–5)]. Both groups received 2 cycles of chemotherapy during definitive radiotherapy. The total radiation dose was between 66.6 and 70.2 Gray. The overall response rates after CCRT were 98 with 90% of a pathologically complete response (pCR) in the TPF group and 94 with 77% in the PFML group. For grade 3/4 adverse events, mucositis was more frequent in the PMFL group, and the TPF group showed a higher incidence of hematological toxicity. CCRT with TPF or PMFL for advanced SCCHN was tolerable and produced excellent survival rates.     

Concomitant chemoradiotherapy versus induction docetaxel,cisplatin and 5 fluorouracil (TPF) followed by concomitant chemoradiotherapy in locally advanced head and neck cancer: a phase II randomized study

BackgroundConcomitant chemoradiotherapy (CT/RT) is the standard treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN). We evaluated the efficacy of induction docetaxel (Taxotere), cisplatin, and 5-fluorouracil (TPF) before CT/RT versus CT/RT alone.Patients and methodsPatients with stage III–IVM0 SCCHN, Eastern Cooperative Oncology Group performance status of zero to one, were randomly assigned to receive CT/RT alone (arm A: two cycles of cisplatin 20 mg/m², days1–4, plus 5-fluorouracil 800 mg/m²/day 96 h continuous infusion, during weeks 1 and 6 of radiotherapy) or three cycles of TPF (arm B: docetaxel 75 mg/m² and cisplatin 80 mg/m², day 1, and 5-fluorouracil 800 mg/m²/day 96 h continuous infusion, every 3 weeks) followed by the same CT/RT. The primary end point was the rate of radiologic complete response (CR) at 6–8 weeks after the end of CT/RT.ResultsA total of 101 patients were randomly allocated to the study (51 arm A; 50 arm B). CR rates were 21.2% (arm A) versus 50% (arm B). Median progression-free survival and overall survival were, respectively, 19.7 and 33.3 months (arm A) and 30.4 and 39.6 months (arm B). Hematologic and non-hematologic toxic effects during CT/RT were similar in the two arms.ConclusionInduction TPF followed by CT/RT was associated with higher radiologic CR in patients with locally advanced SCCHN with no negative impact on CT/RT feasibility.     

Cetuximab in combination with weekly 5-fluorouracil/folinic acid and oxaliplatin (FUFOX) in untreated patients with advanced colorectal cancer: a phase Ib/II study of the AIO GI Group

BackgroundThis two-part phase Ib/II study investigated the feasibility of administering cetuximab in combination with oxaliplatin and infusional 5-fluorouracil (5-FU)/folinic acid (FA) in a weekly schedule (AIO FUFOX protocol) as first-line treatment in patients with epidermal growth factor receptor-detectable advanced colorectal cancer.Patients and methodsCetuximab was administered weekly: 400 mg/m² initial dose, then 250 mg/m² and FUFOX: oxaliplatin 50 mg/m², FA 500 mg/m² and 5-FU as a 24-h infusion at either 1500 or 2000 mg/m² administered for 4 weeks followed by a 1-week rest (one cycle).ResultsDose-limiting toxicity (grade 3 diarrhea) occurred in 3 of 14 assessable patients receiving 5-FU at standard 2000 mg/m². This dose was administered to a further 25 patients. Cetuximab combined with FUFOX was generally well tolerated with the most common grade 3/4 adverse events being diarrhea (27%) and paresthesia (16%). The confirmed response rate for patients receiving 5-FU at standard 2000 mg/m² (N = 41) was 56%, with a median duration of 9.3 months. Median progression-free and overall survival times including all 49 patients were 8.1 (95% confidence interval 6.0–9.7) and 28.2 months, respectively. Cetuximab pharmacokinetics seemed not to be different for combination with FUFOX compared with cetuximab/irinotecan combinations.ConclusionThis protocol is well tolerated and shows promising efficacy supporting further investigation.     

Feasibility of radiotherapy with concomitant gemcitabine and oxaliplatin in locally advanced pancreatic cancer and distal cholangiocarcinoma: a prospective dose finding phase I–II study

BackgroundThe prognosis of pancreaticobiliary tumors is poor. The aim was to assess the feasibility of radiotherapy (RT) and concomitant gemcitabine and oxaliplatin in locally advanced pancreatic cancer and distal cholangiocarcinoma.Patients and methodsTwenty-two patients with locally advanced pancreatic (n = 17) or biliary tract cancer (n = 5) were included. They received two cycles of gemcitabine/oxaliplatin followed by 5 weeks of RT in combination with a weekly fixed dose gemcitabine and an escalating dose of oxaliplatin from 40 up to 70 mg/m². National Cancer Institute—Common Toxicity Criteria 3.0 was used to score weekly the treatment-related toxicity.ResultsThe patients treated at a dose of 40 mg/m² of oxaliplatin had no dose-limiting toxicity. At 50 mg/m², two patients developed grade 4 thrombocytopenia. Nine patients received 60 mg/m², one developed grade 4 thrombocytopenia. Grade 4 thrombocytopenia in two patients and grade 3 diarrhea in one patient were observed with 70 mg/m². Median time to progression was 8 months and median overall survival was 17 months.ConclusionsRT in combination with gemcitabine and oxaliplatin is feasible in patients with locally advanced pancreaticobiliary cancer. The reported time to progression underlines the potential activity of this regimen. The dose of 60 mg/m² of oxaliplatin can be considered as the recommended dose.     

Phase III trial of cetuximab, bevacizumab, and 5-fluorouracil/leucovorin vs. FOLFOX-bevacizumab in colorectal cancer

BackgroundCetuximab (C), alone or with irinotecan, demonstrates activity in irinotecan-refractory colorectal cancer (CRC). Activity of 5-fluorouracil (5-FU), leucovorin (L), and bevacizumab (B), and preliminary data of cetuximab + bevacizumab, and toxicity profiles suggests that FOLF-CB (5-FU, L, C+B) may have activity with a favorable toxicity profile as first-line therapy.MethodsEligible patients were randomized at registration to either arm A (mFOLFOX6-B) (modified, 5-FU. L (folinic acid), oxaliplatin (O) + bevacizumab), administered days 1 and 15 of each 28-day cycle as bevacizumab 5 mg/kg, oxaliplatin 85 mg/m², leucovorin 400 mg/m², and 5-FU 400 mg/m² then 1200 mg/m²/day for 48 hours, or arm B (FOLF-CB), which included bevacizumab, leucovorin, and 5-FU as in arm A and cetuximab 400 mg/m² day 1 cycle 1; all other weekly cetuximab doses were 250 mg/m².ResultsTwo hundred forty-seven patients (arm A/arm B 124/123) were enrolled, and 239 were treated (118/121). Twelve-month progression-free survival (PFS) was 45%/32%, objective response rates (ORR) (complete response [CR] + partial response [PR]) were 52%/41%, disease control rates (CR+PR+stable disease [SD]) were 87%/83%, and median overall survival (OS) was 21/19.5 months, respectively. Grade 3-4 neutropenia was higher in arm A (28%/7%), as was grade 3 fatigue (12%/3%), and grade 3 neuropathy (11%/< 1%), whereas acneiform rash was confined to arm B. Retrospective analysis of KRAS mutational status did not demonstrate KRAS as a meaningful determinant of activity, except in arm B patients with KRAS-mutated tumors, which resulted in inferior PFS. Patient satisfaction favored the control (mFOLFOX6-B).ConclusionFOLF-CB was not superior to mFOLFOX6-B in terms of 12-month PFS and ORR, and was not more acceptable to patients. This trial supports the conclusion of other recently reported trials that concurrent cetuximab+bevacizumab should not be routinely used in metastatic CRC.     

Phase I study of 3-weekly docetaxel, capecitabine and oxaliplatin combination chemotherapy in patients with previously untreated advanced gastric cancer

Purpose

Adding docetaxel to cisplatin and 5-fluorouracil (5-FU) (DCF) significantly improved clinical efficacy in advanced gastric cancer (AGC). To further improve the efficacy and tolerability, we substituted oxaliplatin for cisplatin and capecitabine for 5-FU in the DCF regimen and performed a phase I study to determine the recommended dose (RD) and dose-limiting toxicity (DLT) of docetaxel, capecitabine and oxaliplatin (DXO) combination in patients with AGC.

Materials and methods

Previously untreated patients with histologically proven metastatic AGC and ECOG performance status 0–2 were enrolled. Docetaxel and oxaliplatin were administered i.v. on day 1. Capecitabine was administered orally bid on days 1–14. Each cycle was repeated every 3 weeks. DLTs were evaluated during the first two cycles of treatment.

Results

Twenty-one patients were enrolled: 15 patients in dose-escalation phase and 6 patients in the extension at the RD. Median age was 50 years (range 21–65 years). At dose level 3 (60 mg/m² docetaxel, 1,000 mg/m² capecitabine, 100 mg/m² oxaliplatin), 1 diarrhea (DLT) was found among 6 patients while at dose level 4 (60 mg/m² docetaxel, 800 mg/m² capecitabine, 130 mg/m² oxaliplatin), 2 DLTs (febrile neutropenia and diarrhea) were observed among 3 patients. Therefore, the dose level 3 was determined as RD. DLTs include grade 3 diarrhea and febrile neutropenia. Cumulative (all cycles) grade 3/4 toxicity included neutropenia (75%), leucopenia (50%), febrile neutropenia (25%), diarrhea (17%), and neuropathy (17%). Of 14 patients with measurable lesions, 11 achieved partial response and 3 showed stable disease.

Conclusion

The RD of the DXO regimen in patients with AGC is capecitabine 1,000 mg/m² twice daily on days 1–14, in combination with decetaxel 60 mg/m² (day 1) and oxaliplatin 100 mg/m² (day 1) repeated every 3 weeks. The DXO regimen seems to have promising activity and offers an easy alternative to DCF. The toxicities appear to be still substantial, but manageable.     

Neoadjuvant therapy with weekly docetaxel and cisplatin, 5‐fluorouracil continuous infusion,and concurrent radiotherapy in patients with locally advanced esophageal cancer produced a high percentage of long‐lasting pathological complete response

BACKGROUND:

This phase 2 study was aimed at defining the pathological response rate of a neoadjuvant schedule including weekly docetaxel and cisplatin, continuous infusion (c.i.) of 5‐fluorouracil (5‐FU) and concomitant radiotherapy (RT) in untreated stage II‐III adenocarcinoma and squamous cell carcinoma of mid‐distal thoracic esophagus.

METHODS:

The schedule consisted of a first phase of chemotherapy alone and of a second phase of concurrent chemoradiation. Doses were as follows: docetaxel 35 mg/m² and cisplatin 25 mg/m² on days 1, 8, 15, 29, 36, 43, 50, and 57 plus 5‐FU c.i. (180 mg/m² on days 1‐21 and 150 mg/m² on days 29‐63); RT (50 Gy) started at day 29. Surgery was planned 6 to 8 weeks after the completion of chemoradiation.

RESULTS:

A total of 74 patients were enrolled; pathological complete remission (pCR) was found in 47% (35 of 74) and near pCR (microfoci of tumor cells on the primary tumor without lymph nodal metastases) (pnCR) in 15% of the patients (11 of 74). Grade 3‐4 neutropenia, nonhematological toxicity, and toxic deaths occurred in 13.5%, 32.4%, and 4% of the patients, respectively. Median follow‐up was 55 months (range, 3‐108 months). Median survival of all 74 patients was 55 months, whereas it was not reached in the pCR subset. The 3‐ and 5‐year survival rates were, respectively, 83% and 77% for pCR, 73% and 44% for pnCR, and 21% and 14% for Residual Tumor subsets (P < .001).

CONCLUSIONS:

This study shows that 1) this intensive weekly schedule produced a high pathological response rate, 2) responders had high and long‐term durable survival rates. Cancer 2013. © 2012 American Cancer Society.     

A Phase II Trial of a Neoadjuvant Platinum Regimen for Locally Advanced Breast Cancer: Pathologic Response,Long-Term Follow-up,and Correlation With Biomarkers

PurposeThe purpose of this study is to determine the response, tolerability, and long-term outcome of a neoadjuvant platinum-containing regimen for locally advanced breast cancer (LABC) and to search for a correlation between pathologic complete response (pCR) and predefined biomarkers in this cohort.Patients and MethodsPatients with LABC received 8 cycles of either sequence A or B. Sequence A was doxorubicin 60 mg/m² and paclitaxel 175 mg/m² (AT) every 3 weeks × 4 followed by cisplatin (C) 60 mg/m² and paclitaxel 90 mg/m² (CT) every 2 weeks × 4. Sequence B was CT × 4 (with paclitaxel dose escalation) followed by AT × 4. In addition to estrogen receptor (ER) and HER2, immunohistochemistry for MDR-1, MRP-1, topoisomerase IIα (topo IIα), and p53 was performed.ResultsA total of 88 patients were evaluable for response and toxicity. Median follow-up was 97 months. The overall pCR rate was 21.5%. For subgroups ER+/HER2+, HER2+ and double negative (ER+/HER2+) disease, the pCR rates were 5.9%, 23.3%, and 35%, respectively (P = .006). Five-year overall survival for the entire cohort was 71.1%. Five-year overall survival was 88.1% (95% CI, 77.1%-99.1%) for the ER+/HER2+ group compared with 68.5% (95% CI, 51.3%-85.7%) and 49.5% (95% CI, 27.4%-71.6%) in the HER2+ and “double-negative” group, respectively (P = .0077). Overexpression of topo IIα was correlated with pCR (P < .001). There were no toxic deaths.ConclusionA platinum-containing neoadjuvant regimen was well tolerated and achieved a pCR comparable to other recent studies of multiagent chemotherapy. Further studies tailored for specific breast cancer subtypes are required.     

Neo-adjuvant treatment of rectal cancer with capecitabine and oxaliplatin in combination with radiotherapy: a phase II study

BackgroundPreoperative chemoradiation is now standard treatment for stages II–III rectal cancer. Capecitabine (CAP) and oxaliplatin (OX) are synergistic with radiotherapy (RT) and active in colorectal neoplasms.Patients and methodsTwo cycles of CAP 825 mg/m² b.i.d. (days 1–14) and OX 50 mg/m² (days 1 and 8) every 3 weeks were given concomitantly with pelvic conformal RT (45 Gy). Patients with a ≥T3 and/or node-positive rectal tumour were eligible. The pathologic tumour response was defined according to the tumour regression grade (TRG) scale.ResultsForty-six patients were enrolled. Gastrointestinal adverse events were mostly G1–G2; only two patients experienced G3 vomiting and diarrhoea and six patients had G1 peripheral neuropathy. Haematological toxicity was rare. G2 proctitis and anal pain occurred in two patients. Pathological complete response (TRG1) was observed in nine patients (20.9%; 95% CI 8.7%–33.1%); TRG2 in 19 patients (44.2%); TRG3 in 12 patients (27.9%); and TRG4 in three patients (7%). Overall, nine patients recurred: five with distant metastases, one with local recurrence, and three with both local recurrence and distant metastases.ConclusionsCAP–OX–RT as preoperative treatment for rectal cancer induces a remarkable rate of complete or near-complete pathologically documented response and is well tolerated.