Pre-operative bevacizumab, capecitabine, oxaliplatin and radiation among patients with locally advanced or low rectal cancer: a phase II trial

Background

To evaluate the safety and efficacy of pre-operative chemoradiation, using capecitabine, oxaliplatin and bevacizumab with standard doses of radiation, in patients with high-risk rectal cancer.

Methods

Patients with locally advanced or low rectal cancer were treated with capecitabine 825 mg/m² twice daily on days 1-14 and 22-35, oxaliplatin 50 mg/m² on days 1, 8, 22 and 29, bevacizumab 5 mg/kg on days 14, 1, 15 and 29, and radiation 50.4 Gy in 28 fractions including boost. Total mesorectal excision was performed 7-9 weeks after chemoradiation. The primary end-point was complete tumour regression (ypT0NX) by central review.

Findings

Forty-two evaluable patients were enrolled, and 38 proceeded to definitive surgery. Eighteen patients (43%) had clinical T4 tumours and/or N2 tumours. Mean relative dose intensity was >90% for all systemic agents, and 97% for radiation. Grade 3/4 diarrhoea occurred in 10 patients (24%) and pain in 4 patients (10%) pre-operatively, while grade 3/4 pain, fatigue and infection were each reported among 5 patients (13%) post-operatively. Re-operation due to complications occurred in 4 patients (11%). Complete tumour regression (ypT0) was seen in 9 patients (23.7%) of which two had N1 disease and the pathological complete response (pCR) rate (ypT0N0) was 18.4%. Central review changed pathologic stage in six cases (16%).

Interpretation

In this study, pre-operative bevacizumab added to oxaliplatin, capecitabine and radiation was safe and resulted in a promising tumour regression rate. Surgical complications were closely monitored and occurred with the expected frequency. Central pathology review should be considered for trials with pathologic response as the primary end-point.

Funding

British Columbia Cancer Agency, Hoffmann-La Roche Canada and Sanofi-Aventis.     

A randomised phase II study of docetaxel/oxaliplatin and docetaxel in patients with previously treated non-small cell lung cancer: an Alpe-Adria Thoracic Oncology Multidisciplinary group trial (ATOM 019)

Introduction

To date, no combination regimen has proven superior to single agent chemotherapy as a second-line treatment for non-small cell lung cancer (NSCLC).

Methods

This multicenter, non-comparative randomised phase II trial evaluated the activity of docetaxel (75 mg/m² on day 1) with oxaliplatin (70 mg/m² on day 2) every 3 weeks in previously treated NSCLC patients; the reference arm was single-agent docetaxel (75 mg/m² on day 1 every 3 weeks). It was designed as a one-stage, three-outcome phase II trial; 21 evaluable patients were required in each arm. The primary end-point was response rate; secondary end-points were toxicity, progression free survival (PFS) and overall survival.

Results

Fifty patients were enrolled. Patient characteristics included male/female, 76/24%; median age 62 years; ECOG PS 0/1, 36/64%; previous platinum-based chemotherapy, 98%. Partial response was seen in 20% and 8%, stable disease in 52% and 32%, of patients treated with docetaxel/oxaliplatin and docetaxel, respectively. Main grade 3-4 toxicities were neutropenia 56% and 64%; febrile neutropenia 4% and 8%; diarrhoea 12% and 4% for docetaxel/oxaliplatin and docetaxel, respectively. Median PFS was 5.0 and 1.7 months, median survival 11.0 and 7.1 months, and 1-year survival 44% and 32% for docetaxel/oxaliplatin and docetaxel, respectively.

Conclusions

The study met its pre-defined study end-point; docetaxel/oxaliplatin and more generally platinum-containing doublets warrant further evaluation as second-line therapy for patients with NSCLC.     

A phase I trial combining oral cisplatin (CP Ethypharm) with radiotherapy in patients with locally advanced head and neck squamous cell carcinoma

Purpose

To determine the maximum tolerated dose (MTD) of oral cisplatin (CP Ethypharm®) in combination with radiotherapy in head and neck squamous cell carcinoma (HNSCC) and the recommended dose for phase II trials.

Patients and methods

Phase I, multicenter, open-labelled, non-comparative and dose escalating trial. CP Ethypharm® was administered on five consecutive days every other week for 7 weeks (4 treatment cycles) in combination with radiotherapy. Eighteen patients with locally advanced HNSCC were allocated to four cisplatin dose levels: 10 mg/m²/day: 4 patients; 15 mg/m²/day: 4, 20 mg/m²/day: 5 and 25 mg/m²/day: 5. The inclusion of patients was dictated by occurrence of dose limiting toxicities (DLTs) at each dosing level.

Results

The most frequently experienced AEs were gastrointestinal (GI) disorders. Five DLTs were observed, including three at 25 mg/m² level (two grade 2 renal toxicities, one grade 3 GI and renal toxicities), one at 20 mg/m² level (grade 3 GI disorders), one at 10 mg/m² level (grade 4 mucositis). PK analysis showed no significant difference of C_max values between day 1 and day 5 of treatment at each dose level (total & ultrafilterable platinum).

Conclusion

Due to 3 DLTs experienced at 25 mg/m²/day, MTD was reached and the recommended dose for phase II studies was determined as 20 mg/m²/day.     

Preoperative concomitant boost intensity-modulated radiotherapy with oral capecitabine in locally advanced mid-low rectal cancer: A phase II trial

Purpose

We aimed to assess the safety and efficacy of preoperative intensity-modulated radiotherapy (IMRT) with oral capecitabine in patients with locally advanced mid-low rectal cancer using a concomitant boost technique.

Materials and methods

Patients with resectable locally advanced mid-low rectal cancer (node-negative ?T3 or any node-positive tumor) were eligible. The eligible patients received IMRT to 2 dose levels simultaneously (50.6 and 41.8 Gy in 22 fractions) with concurrent capecitabine 825 mg/m² twice daily 5 days/week. The primary end point included toxicity, postoperative complication, and pathological complete response rate (ypCR). The secondary endpoints included local recurrence rate, progression-free survival (PFS), and overall survival (OS).

Results

Sixty-three eligible patients were enrolled; five patients did not undergo surgery. Of the 58 patients evaluable for pathologic response, the ypCR rate was 31.0% (95% CI 19.1-42.9). Grade 3 toxicities included diarrhea (9.5%), radiation dermatitis (3.2%), and neutropenia (1.6%). There was no Grade 4 toxicity reported. Four (6.9%) patients developed postoperative complications. Two-year local recurrence rate, PFS, and OS were 5.7%, 90.5%, and 96.0%, respectively.

Conclusions

The design of preoperative concurrent boost IMRT with oral capecitabine could achieve high rate of ypCR with an acceptable toxicity profile.     

Efficacy and safety of low-dose metronomic chemotherapy with capecitabine in heavily pretreated patients with metastatic breast cancer

Aim

Registered dose capecitabine monotherapy is active against metastatic breast cancer (MBC), but retrospective analyses indicate that lower doses may be as effective and better tolerated. This study was conducted to assess the safety and efficacy of metronomic capecitabine in heavily pretreated patients with MBC.

Patients and methods

In this phase II study 60 MBC patients received continuous metronomic capecitabine monotherapy (1500 mg once a day). Primary endpoint was clinical benefit rate, secondary end points were clinical benefit rates (CBRs), tumour response rates (RRs), overall survival (OS), time to progression (TTP), duration of response (DOR) and toxicity.

Results

Fifty eight assessable patients received two or more 28-day cycles of metronomic capecitabine. The CBR was 62%. Median DOR was 7 months. Median TTP and OS were 7 and 17 months, respectively. Two partial responses and 7 cases of stable disease were recorded in 13 patients who had previously received capecitabine intermittently (2000 mg/m²/day on days 1-14 every 21 days) as first- or subsequent-line treatment for MBC. Grade 3-4 adverse events were uncommon; haematologic toxicity was infrequent (5%) and consistently mild.

Conclusion

This regimen of metronomic capecitabine displayed good activity and excellent tolerability in MBC patients, including those who had previously received the drug at standard doses.     

Phase I study of concurrent real-time tumor-tracking thoracic radiation therapy with paclitaxel and carboplatin in locally advanced non-small cell lung cancer

Introduction

Although paclitaxel with carboplatin and thoracic radiotherapy has improved survival for patients with locally advanced unresectable non-small cell lung cancer (NSCLC), the optimal dose of paclitaxel has not been well defined in Japan. This study was conducted to determine the maximum tolerated dose (MTD) and recommended dose (RD) of paclitaxel in combination with carboplatin and concurrent real-time tumor-tracking thoracic radiation therapy (thoracic RTRT).

Patients and methods

Previously untreated patients with histologically confirmed, locally advanced unresectable NSCLC were eligible. Before treatment, gold markers were inserted into the lung and the mediastinum of all patients. RTRT comprised a total of 66 Gy at 2 Gy/fraction, 5 days/week, for 7 weeks. Patients received paclitaxel at a starting dose of 40 mg/m² followed by carboplatin at a fixed area under the curve (AUC) of 2, as a weekly regimen with RTRT. The dose of paclitaxel was escalated by 5 mg/m² per level.

Results

Eight patients with locally advanced unresectable NSCLC were enrolled and treated with two dose levels of paclitaxel (40 mg/m² and 45 mg/m²), carboplatin (AUC = 2) and RTRT. No dose limiting toxicities (DLTs) were observed at Level 1 (paclitaxel, 40 mg/m² and carboplatin, AUC = 2). At Level 2 (paclitaxel, 45 mg/m² and carboplatin, AUC = 2), two of five patients experienced DLTs, in the form of esophagitis and discontinuation of chemotherapy more than twice. The MTD and RD of paclitaxel were thus defined as 45 mg/m² and 40 mg/m², respectively.

Conclusions

This phase I study was well tolerated and the RD of paclitaxel and carboplatin with RTRT is 40 mg/m² at AUC = 2, respectively. Further studies are warranted to evaluate the efficacy of this regimen.     

A multicentre dose-escalating study of cabazitaxel (XRP6258) in combination with capecitabine in patients with metastatic breast cancer progressing after anthracycline and taxane treatment: a phase I/II study

Background

Most patients with metastatic breast cancer (MBC) progress after chemotherapy. Cabazitaxel (XRP6258) is a new taxoid that is active in chemotherapy-resistant tumour cell lines. The objectives of this phase I/II study were to assess the maximum tolerated dose (MTD), safety profile, pharmacokinetics, and activity of cabazitaxel plus capecitabine in patients with MBC who had been previously treated with taxanes and anthracyclines.

Patients and methods

In part I, we used a 3 + 3 dose-escalation scheme to assess the MTD of intravenous cabazitaxel (day 1) with oral capecitabine twice daily (days 1-14) every 3 weeks. In part II, we evaluated the objective response rate (ORR) at the MTD.

Results

Thirty-three patients were enrolled and treated (15 in part I; 18 in part II). Cabazitaxel 20 mg/m² plus capecitabine 1000 mg/m² was the MTD. Pharmacokinetic analysis showed no apparent drug-drug interaction. In all patients, the main grade 3-4 toxicities were asthenia (n = 5), hand-foot syndrome (n = 5), neutropenia (n = 21), neutropenic infection (n = 1), and neutropenic colitis (n = 1). One patient had febrile neutropenia. Antitumour activity was observed at all dose-levels with two complete responses, five partial responses (PRs), and 20 disease stabilisations (seven unconfirmed PR). At the MTD, 21 patients were evaluable for efficacy. The ORR was 23.8% (95% CI: 8.2-47.2%). The median response duration was 3.1 months (95% CI: 2.1-8.4 months), with four of five lasting for more than 3 months. Median time to progression was 4.9 months.

Conclusions

Cabazitaxel combined with capecitabine is active, has a safety profile consistent with a taxane plus capecitabine combination and warrants further investigation in patients with MBC.     

Synchronous chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck using capecitabine: a single-centre, open-label, single-group phase II study

Aim

To evaluate the efficacy of concurrent oral capecitabine with accelerated hypofractionated radical radiotherapy in locally advanced squamous cell carcinoma of the head and neck (SCCHN).

Materials and methods

Between 2001 and 2004, 50 patients with stage III/IV SCCHN (0 to 2 performance status) were enrolled into this study. The capecitabine dose was between 450 and 550 mg/m² twice daily, continuously for 28 days. The radiotherapy dose was 5500 cGy in 20 fractions over 4 weeks. No intensity-modulated radiation was used. We evaluated the complete response rate, toxicity, locoregional control, overall survival, disease-free survival and cancer-specific survival.

Results

The median age was 55 (range 38-76) years; 72% had stage IV disease. The median follow-up was 6 years on the 30 surviving patients. Eighty-two per cent of patients completed the course of capecitabine and 94% completed prescribed radiotherapy. There were no treatment-related deaths, grade 3/4 haematological or renal toxicity. Five patients developed drug-related grade 3/4 acute toxicity (cardiac, skin, bowel); 47 developed grade 3/4 mucositis from chemoradiotherapy. Twenty-two (44%) patients required tube feeding and the tube dependency rate at 1 year was 6%. The complete response rate at 3 months was 90% (45/50 patients). Relapse occurred in 17/50 (34%) patients by 5 years. The locoregional control, overall survival, cancer-specific survival and disease-free survival rates at 3 years were 78, 72, 82 and 62%, respectively, and at 5 years were 72, 64, 75 and 56%, respectively.

Conclusion

This schedule of synchronous capecitabine for locally advanced SCCHN is well tolerated. The local control in this series compares favourably with other synchronous chemoradiotherapy reports. Chronic dysphagia and tube dependence is uncommon with this approach. Capecitabine as targeted therapy given with each fraction of radiotherapy and administered orally may have significant advantages over intravenous, 3 weekly cisplatin.     

Phase III trial of irinotecan plus infusional 5-fluorouracil/folinic acid versus irinotecan plus oxaliplatin as first-line treatment of advanced colorectal cancer

Purpose

To determine whether irinotecan plus oxaliplatin (mIROX) is superior to irinotecan plus infusional 5-fluorouracil, leucovorin (FUFIRI) as first-line therapy of patients with metastatic colorectal cancer (mCRC).

Patients and methods

A phase III, randomised, open-label multicentre study compared standard treatment with FUFIRI (irinotecan 80 mg/m², 5-fluorouracil 2000 mg/m², folinic acid 500 mg/m² weekly times 6) to mIROX using an identical schedule of irinotecan plus oxaliplatin 85 mg/m² applied on days 1, 15 and 29 of a 7-week cycle. The primary end-point was progression-free survival (PFS).

Results

A total of 479 eligible patients were randomly assigned. 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 overall survival time with 19 months in the mIROX-arm and 22 months in the FUFIRI-arm (hazard ratio = 1.08, P = 0.276). Both regimens induced an identical objective response rate (ORR) of 41%, but disease control rate (ORR plus stable disease) was significantly greater in the FUFIRI group (81% versus 68%, P = 0.001). Most frequent grades 1-4 side-effects of mIROX and FUFIRI treatment were nausea (80% versus 73%) and delayed diarrhoea (79% versus 68%). Grades 3-4 toxicities were generally below 10%, except for diarrhoea which was more frequent in the mIROX-arm compared to the FUFIRI-arm (19% versus 30%, P = 0.006)

Conclusion

mIROX failed to show superior activity compared to high-dose 5-FU/folinic acid plus irinotecan. Due to better tolerability the combination of high-dose 5-FU/folinic acid and irinotecan remains a standard of care in first-line treatment of metastatic colorectal cancer.     

Phase II trial of Uracil/Tegafur plus leucovorin and celecoxib combined with radiotherapy in locally advanced pancreatic cancer

Background and purpose

To investigate the efficacy and toxicity of a short intensive Uracil/Tegafur (UFT) based chemoradiotherapy scheme combined with celecoxib in locally advanced pancreatic cancer.

Material and methods

The Academic Medical Centre, Amsterdam and the Erasmus Medical Centre, Rotterdam enrolled 83 eligible patients with unresectable pancreatic cancer in a prospective multicentre phase II study. Median age was 62 years, median tumour size 40 mm and the majority of the patients (85%) had pancreatic head cancers. Treatment consisted of 20 × 2.5 Gy radiotherapy combined with UFT 300 mg/m² per day, leucovorin (folinic acid) 30 mg and celecoxib 800 mg for 28 days concomitant with radiotherapy. Four patients were lost to follow-up.

Results

Full treatment compliance was achieved in 55% of patients, 80% received at least 3 weeks of treatment. No partial or complete response was observed. Median survival was 10.6 months and median time to progression 6.9 months. Toxicity was substantial with 28% grades III and IV gastro-intestinal toxicity and two early toxic deaths.

Conclusions

Based on the lack of response, the substantial toxicity of mainly gastro-intestinal origin and the reported mediocre overall and progression free survival, we cannot advise our short intensive chemoradiotherapy schedule combined with celecoxib as the standard treatment.     

The effect of prophylactic calcium and magnesium infusions on the incidence of neurotoxicity and clinical outcome of oxaliplatin-based systemic treatment in advanced colorectal cancer patients

Background

Peripheral sensory neurotoxicity is a frequent and potentially debilitating side effect of oxaliplatin treatment. Calcium and magnesium (Ca/Mg) infusions are frequently used to prevent this toxicity. However, concerns about a negative impact of Ca/Mg infusions on outcome have been raised. We retrospectively assessed the effect of Ca/Mg infusions on the incidence of neurotoxicity and on clinical outcome in advanced colorectal cancer (ACC) patients treated in the phase III CAIRO2 study.

Materials and methods

Seven hundred and fifty five previously untreated ACC patients were randomised between treatment with capecitabine, oxaliplatin and bevacizumab or the same combination with the addition of cetuximab. Patients were retrospectively divided into two groups: patients in the Ca/Mg⁺ group received Ca/Mg at least during their first treatment cycle, and patients in the Ca/Mg^- group did not.

Results

Seven hundred and thirty two patients were evaluable for this analysis. The Ca/Mg⁺ group consisted of 551 patients, the Ca/Mg^- group consisted of 181 patients. The incidence of all grade neurotoxicity in the Ca/Mg⁺ group and the Ca/Mg^- group was 85% and 92%, respectively (p = 0.02), and the incidence of grade ? 2 neurotoxicity was 40% and 45%, respectively (p = 0.22). The median PFS in the Ca/Mg⁺ versus Ca/Mg^- group was 10.1 versus 10.7 months (p = 0.92), the median OS was 19.8 versus 20.7 months (p = 0.10), and the response rate was 43.1% versus 50% (p = 0.11), respectively.

Conclusions

In this largest retrospective analysis to date we observed that Ca/Mg infusions significantly reduced all grade oxaliplatin-related neurotoxicity. Ca/Mg infusions did not affect the clinical efficacy of treatment.     

Concurrent and adjuvant docetaxel with three-dimensional conformal radiation therapy plus androgen deprivation for high-risk prostate cancer: Preliminary results of a multicentre phase II trial

Background and purpose

We evaluate the feasibility of concomitant and adjuvant docetaxel combined with three-dimensional conformal radiotherapy (3D-CRT) and androgen deprivation in high-risk prostate carcinomas.

Methods

Fifty men with high-risk localized prostate cancer (16), locally advanced (28) or very high-risk prostate cancer (6) were included. Seventy Gy were delivered on prostate and seminal vesicles in 35 fractions, concurrently with weekly docetaxel (20 mg/m²). Three weeks after the completion of 3D-CRT, docetaxel was given for 3 cycles (60 mg/m²), every 3 weeks. Patients had to receive LHRH agonist during 3 years.

Results

The intent to treat analysis shows that four patients out of 15 stopped prematurely the chemotherapy due to grade 3-4 acute toxicity. In the per protocol analysis, 46 patients completed a full-dose chemoradiation regimen representing 413 cycles: five patients experienced a grade 3 toxicity, and 15 patients experienced a grade 2 toxicity. With a median follow-up of 54 months, the 5-year clinical disease-free survival was 66.72% and the 5-year survival was 92.15%.

Conclusions

3D-CRT with androgen deprivation and concurrent weekly docetaxel, followed by three cycles of adjuvant docetaxel may be considered as feasible in high-risk prostate cancer and deserved to be evaluated in a phase III randomized trial.     

Preoperative radio-chemotherapy in early breast cancer patients: Long-term results of a phase II trial

Purpose

This phase II trial aimed to investigate the efficacy of concurrent radio- (RT) and chemotherapy (CT) in the preoperative setting for operable, non-metastatic breast cancer (BC) not amenable to initial breast-conserving surgery (BCS).

Patients and methods

From 2001 to 2003, 59 women were included. CT consisted of four cycles of 5-FU, 500 mg/m²/d, continuous infusion (d1-d5) and vinorelbine, 25 mg/m² (d1 and d6). Starting concurrently with the second cycle, RT delivered 50 Gy to the breast and 46 Gy to the internal mammary and supra/infra-clavicular areas. Breast surgery and lymph node dissection were then performed. Adjuvant treatment consisted of a 16 Gy boost to the tumor bed after BCS, FEC (four cycles of fluorouracil 500 mg/m², cyclophosphamide 500 mg/m², and epirubicin 100 mg/m², d1; d21) for pN1-3 and hormone-therapy for positive hormone receptors BC.

Results

The in-breast pathological complete response rate was 27%. BCS was performed in 41 (69%) pts. Overall and distant-disease free survivals at 5 years were respectively 88% [95% CI 80-98] and 83% [95% CI 74-93] whereas locoregional and local controls were 90% [95% CI 82-97] and 97% [95% CI 92-100]. Late toxicity (CTCAE-V3) was assessed in 51 pts (86%) with a median follow-up of 7 years [5-8]. Four (8%) experienced at least one grade III toxicities (one telangectasia and three fibroses). Cosmetic results, assessed in 35 of the 41 pts (85%) who retained their breasts, were poor in four pts (11%).

Conclusion

Preoperative concurrent administration of RT and CT is an effective regimen. Long-term toxicity is moderate. This association deserves further evaluations in prospective trials.     

Tumor perfusion increases during hypofractionated short-course radiotherapy in rectal cancer: Sequential perfusion-CT findings

Purpose

The purpose of this study was to investigate perfusion of rectal tumors and to determine early responses to short-course hypofractionated radiotherapy (RT).

Material and methods

Twenty-three rectal cancer patients were included, which underwent perfusion-CT imaging before (pre-scan) and after treatment (post-scan). Contrast-enhancement was measured in tumor and muscle tissues and in the external iliac artery. Perfusion was quantified with three pharmacokinetic parameters: K^trans, v_e and v_p. Perfusion differences between tumor and normal tissue and changes of the pharmacokinetic parameters between both scans were evaluated.

Results

The median tumors K^trans values increased significantly from the pre-scan (0.36 ± 0.11 (min⁻¹)) to the post-scan (0.44 ± 0.13 (min⁻¹)) (p < 0.001). Also, histogram analysis showed a shift of tumor voxels from lower K^trans values towards higher K^trans values. Furthermore, the median K^trans values were significantly higher for tumor than for muscle tissue on both the pre-scan (0.10 ± 0.05 (min⁻¹), p < 0.001) and the post-scan (0.10 ± 0.04 (min⁻¹), p < 0.001). In contrast, no differences between tumor and muscle tissues were found for v_e and v_p. Also, no significant differences were observed for v_e and v_p between the two pCT-imaging time-points.

Conclusions

Hypofractionated radiotherapy of rectal cancer leads to an increased tumor perfusion as reflected by an elevated K^trans, possibly improving the bioavailability of cytotoxic agents in rectal tumors, often administered early after radiotherapy treatment.     

Concurrent high-dose radiotherapy with low-dose chemotherapy in patients with non-small cell lung cancer of the superior sulcus

Background and purpose

In the treatment of patients with tumours of the sulcus superior (SST), achieving local control is essential because residual or recurrent disease is associated with severe locoregional problems. This study evaluates the efficacy of concurrent daily low-dose cisplatin (6 mg/m²) and high-dose radiotherapy (66 Gy) followed by surgical resection in selected patients.

Material and methods

Clinical charts, imaging and pathology reports were retrospectively reviewed. Survival was analysed using the Kaplan-Meier method.

Results

Forty-nine patients with stage II/III SST were treated with concurrent high-dose radiotherapy and low-dose chemotherapy (CRT). Mean follow-up was 49 months (range 2-152).Nineteen patients underwent additional resection after CRT. In 53% a pathological complete response (pCR) was observed (10/19pts). Acute severe toxicity occurred in 49% (9/19pts). Late severe toxicity occurred in 3 patients. The 2- and 5-year overall survival was 74% and 33%, respectively. Local tumour control was 100%. Thirty patients received CRT only. Acute severe toxicity occurred in 23% (7/30pts). Treatment-related mortality was 2%. The 2- and 5-year overall survival was 31% and 18%, respectively. Locoregional disease-free survival was 48% at 5 years.

Conclusions

Concurrent high-dose (66 Gy) radiotherapy and daily low-dose cisplatin was associated with a high pCR rate. Excellent local control was achieved after additional resection in selected patients. However, the occurrence of severe toxicity in long-term survivors after concurrent chemoradiation followed by surgery must be considered.     

Concurrent doxorubicin and radiotherapy for anaplastic thyroid cancer: A critical re-evaluation including uniform pathologic review

Background and purpose

Anaplastic thyroid carcinoma (ATC) is a rare, aggressive malignancy. The potential for pathologic misclassification complicates interpretation of published data. One standard treatment option for locoregionally advanced disease is weekly low-dose doxorubicin with concurrent radiation therapy, and was previously developed at our institution. We evaluated our more recent experience with this approach, which included pathologic confirmation of all cases.

Materials and methods

A retrospective review was performed on patients identified through the Memorial Sloan-Kettering Cancer Center (MSKCC) Cancer Database. Inclusion criteria: pathologically confirmed ATC; locoregional disease encompassable within a radiation portal; treatment with curative intent at MSKCC with planned weekly doxorubicin (10 mg/m²) and concurrent radiation. Principle outcomes assessed were locoregional progression-free survival (LR-PFS) and overall survival (OS).

Results

Thirty-seven patients were included. Median radiotherapy dose was 57.6 Gy, and was ?50 Gy in 29 (78%), administered through hyperfractionated or once-daily schedules. One-year outcomes were LR-PFS, 45%; OS, 28%.

Conclusion

The prognosis of patients with ATC remains grim and our current results appear inferior to those reported previously by our institution. More accurate histologic diagnoses and patient selection in the present series compared to the prior one may be responsible in part. Better therapy is desperately needed for this aggressive disease.     

Concurrent cetuximab and radiotherapy after docetaxel-cisplatin induction chemotherapy in stage III NSCLC: Satellite—A phase II study from the Swedish Lung Cancer Study Group

Background

Several attempts to increase the locoregional control in locally advanced lung cancer including concurrent chemotherapy, accelerated fractionation and dose escalation have been made during the last years. As the EGFR directed antibody cetuximab has shown activity concurrent with radiotherapy in squamous cell carcinoma of the head and neck, as well as in stage IV NSCLC combined with chemotherapy, we wanted to investigate radiotherapy with concurrent cetuximab in locally advanced NSCLC, a tumour type often over expressing the EGF-receptor.

Methods

Between February 2006 and August 2007 75 patients in stage III NSCLC with good performance status (PS 0 or 1) and adequate lung function (FEV1 > 1.0) were enrolled in this phase II study at eight institutions. Treatment consisted of 2 cycles of induction chemotherapy, docetaxel 75 mg/m² and cisplatin 75 mg/m² with 3 weeks interval. An initial dose of cetuximab 400 mg/m² was given before start of 3D-CRT to 68 Gy with 2 Gy per fraction in 7 weeks concurrent with weekly cetuximab 250 mg/m². Toxicity was scored weekly during radiotherapy (CTC 3.0), and after treatment the patients were followed every third month with CT-scans, toxicity scoring and QLQ.

Results

Seventy-one patients were eligible for analysis as four were incorrectly enrolled. Histology: adenocarcinoma 49%, squamous cell carcinoma 39% and other NSCLC 12%. The majority had PS 0 (62.5%), median age 62.2 (42-81), 50% were women and 37% had a pre-treatment weight loss > 5%. Toxicity: esophagitis grade 1-2: 72%; grade 3: 1.4%. Hypersensitivity reactions grade 3-4: 5.6%. Febrile neutropenia grade 3-4: 15.4%. Skin reactions grade 1-2: 74%; grade 3: 4.2%. Diarrhoea grade 1-2: 38%; grade 3: 11.3%. Pneumonitis grade 1-2: 26.8%; grade 3: 4.2%; grade 5: 1.4%. The median follow-up was 39 months for patients alive and the median survival was 17 months with a 1-, 2- and 3-year OS of 66%, 37% and 29% respectively. Until now local or regional failure has occurred in 20 patients and 22 patients have developed distant metastases. Weight loss, PS and stage were predictive for survival in univariate as well as in multivariate analysis.

Conclusion

Induction chemotherapy followed by concurrent cetuximab and RT to 68 Gy is clearly feasible with promising survival. Toxicity, e.g. pneumonitis and esophagitis is low compared to most schedules with concurrent chemotherapy. This treatment strategy should be evaluated in a randomised manner vs. concurrent chemoradiotherapy to find out if it is a valid treatment option.     

Prospective, randomized trial comparing 5-FU/LV with or without oxaliplatin as adjuvant treatment following curative resection of gastric adenocarcinoma

Background

To investigate the efficacy and toxicity of FOLFOX4 regimen and LV5Fu2 regimen in patients with advanced gastric adenocarcinoma after curative gastrectomy.

Methods

Eighty patients with gastric adenocarcinoma after curative gastrectomy were randomized to receive a 2-h infusion of leucovorin (LV; 200 mg/m²/d) followed by a 5-fluorouracil (5-FU) bolus (400 mg/m²/d) and 22-h infusion (600 mg/m²/d) for 2 consecutive days every 2 weeks, either alone or together with oxaliplatin 85 mg/m² as a 2-h infusion on day 1 (FOLFOX4 regimen or LV5Fu2 regimen). The observation points were recurrence free survival, overall survival and toxicity of the two groups.

Results

All patients had received curative gastrectomy (R0 resection) before received either of the two regimens. The 3-year recurrence free survival rate and the 3-year overall survival rate in FOLFOX4 group were all significantly better than those in the control group (median, 30.0 months vs. 16.0 months, P < 0.05; 36.0 months vs. 28.0 months, P < 0.05). COX multivariant analysis was used to evaluate the prognostic factors and oxaliplatin was found to be the independent prognostic factor and could improve the survival rate in FOLFOX4 group. Grade 3/4 peripheral neuropathy occurred in 19% in FOLFOX4 group. There was no significant difference between the two groups in neutropenia, leukopenia, anemia, gastrointestinal reaction and so on. Three patients in each group were lost to follow up during treatment.

Conclusion

FOLFOX4 regimen showed good efficacy and an acceptable safety profile for patients with advanced gastric adenocarcinoma after curative gastrectomy compared with the control group. It may prove to be a suitable alterative regimen in this indication.     

Docetaxel and irinotecan as second-line therapy for advanced oesophagogastric cancer

Introduction

Systemic chemotherapy improves survival in oesophagogastric cancer however no standard second-line regimen exists due to a paucity of randomised data. Docetaxel combined with irinotecan (DI) provides a suitable option due to the lack of cross-reactivity with first-line therapeutics and a tolerable toxicity profile.

Methods

We retrospectively reviewed a cohort of patients with advanced oesophagogastric cancer in two institutions treated with the combination of docetaxel 35 mg/m² plus irinotecan 60 mg/m² day 1 and day 8 every 21 days, following progression with first-line platinum-based therapy.

Results

Between January 2000 and September 2009, 41 eligible patients were identified. Median age was 58 years, male:female 25:16, adenocarcinoma:squamous cell carcinoma 37:4, oesophageal:oesophagogastric junction:gastric 7:10:24. Locally advanced:metastatic disease 6:35. Previous radical surgery:radiotherapy:both 6:4:7. 27/41 had progressed within 90 days of receiving platinum-based therapy. Median number of chemotherapy cycles: 3 (range 1-12). Eight patients required dose reductions due to DI toxicity. 10/28 evaluable patients had a response, median progression-free survival (PFS) was 11 weeks (95% confidence intervals (CI): 9-13 weeks) with median overall survival 24 weeks (95%CI: 12-35 weeks). No significant prognostic factors were identified.

Conclusion

Weekly docetaxel combined with irinotecan has acceptable safety and modest efficacy in the second-line treatment of advanced oesophagogastric cancer. Further prospective evaluation of this regimen is warranted.     

Phase II study of dose-intense chemotherapy with sequential topoisomerase-targeting regimens with irinotecan/oxaliplatin followed by etoposide/carboplatin in chemotherapy naive patients with extensive small cell lung cancer

Introduction

Topoisomerase inhibitors are active agents in small cell lung cancer (SCLC), and preclinical models indicate that sequential administration of a topoisomerase I inhibitor followed by a topoisomerase II inhibitor can result in enhanced cytotoxicity.

Patients and methods

In this phase II study, patients with extensive SCLC were treated with two sequential topoisomerase-based regimens: irinotecan (150 mg/m²)/oxaliplatin (85 mg/m²) [regimen A] on day 1 followed by etoposide (100 mg/m² × 3)/carboplatin (AUC 6) [regimen B] on day 15. Regimen A was repeated 3 weeks later. The primary objective was objective response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS), toxicity, and exploratory correlative analysis of the tumor expression of the excision repair cross complementing (ERCC1) and topoisomerase II-α. Patients received a maximum of 5 cycles of sequential therapy of regimen A → B.

Results

The overall response rate was 96%, the 6-month PFS was 76.9%, the median PFS was 8.95 months, and OS was 12.9 months in 26 evaluable patients. Grade 4 neutropenia (23%) and thrombocytopenia (58%) were observed with regimen B; and grade 2/3 nausea-vomiting (54%) and diarrhea (46%) with regimen A. Seven patients required dose reductions in regimen A and 19 patients in regimen B. The dose intensity, delivered during the first three cycles was 89%. No significant correlations were observed between the tumor expression of the ERCC1 and topoisomerase II-α and clinical outcomes (PFS or OS).

Conclusions

Although cross-study comparisons are difficult to make, our data suggests that sequential topoisomerase-targeting regimens may enhance the efficacy of chemotherapy in newly diagnosed SCLC patients (Clinical Trial Registration Number, 9 NCT00240097; Clinical Trials.gov number, NCT00240097).