Weekly docetaxel in metastatic breast cancer patients: no superior benefits compared to three-weekly docetaxel

Background

In anthracycline-pretreated metastatic breast cancer (MBC) patients, it is unknown whether weekly single-agent docetaxel is preferable to 3-weekly docetaxel regarding its toxicity and efficacy profile.

Patients and methods

In this multicenter, randomised, open-label phase III trial, 162 patients were randomised to weekly docetaxel (group A) or 3-weekly docetaxel (group B). The primary end-point was tolerability; secondary end-points were efficacy and quality of life (QoL).

Results

Group A (weekly docetaxel, n = 79) experienced less haematological toxicity, with just 1.3% versus 16.9% febrile neutropenia in group B (3-weekly docetaxel, n = 77) (p = 0.001). Not this difference, but fatigue and general malaise foremost led to more patient withdrawals in group A (24 versus 12 patients, p = 0.032), less patients completing treatment (29 versus 43 patients, p = 0.014) and reduced dose-intensity (15.6 versus 26 mg/m²/week, 58% versus 70% of projected dose, p = 0.017). As a result, 3-weekly docetaxel was related to better overall survival in multivariate analysis (hazard ratio 0.70, p = 0.036), although in univariate analysis efficacy was similar in both groups. Reported QoL was similar in both groups, but less effective treatment with more general toxicity led to less completed QoL forms in group A (65.4% versus 50%, p=0.049).

Conclusion

Weekly docetaxel is less well tolerated than a 3-weekly schedule, due to more non-haematological toxicity, despite less febrile neutropenia. Also, no efficacy benefits can be demonstrated for weekly docetaxel, which may even be inferior based on multivariate analysis. Therefore, a 3-weekly schedule should be preferred in the setting of MBC.     

Randomised phase II trial of 4 dose levels of single agent docetaxel in performance status (PS) 2 patients with advanced non-small cell lung cancer (NSCLC): DOC PS2 trial. Manchester lung cancer group

Background

The role of chemotherapy for advanced NSCLC patients and ECOG PS2 remains controversial. We evaluated 4 doses of 3-weekly docetaxel to identify a less toxic, clinically effective dose.

Methods

Seventy-three patients with stage III (22%) (unsuitable for radical surgery/radiotherapy) and IV (78%) NSCLC were randomized to receive 4 doses of 3-weekly docetaxel, for 4 cycles: arm (A) 40 mg/m² (n = 17), arm (B) 50 mg/m² (n = 17), arm (C) 60 mg/m² (n = 19), arm (D) 50 mg/m² escalated by 10 mg/m² to a maximum of 70 mg/m² (n = 19). Primary endpoints: maximum tolerated dose, RR, duration of response, symptom improvement, toxicity and QoL. Secondary endpoint: overall survival (OS). Patients and disease characteristics were well balanced. Median age was 67 (range 45-81), there were 32 male and 41 female, histology subtype: squamous/adenocarcinoma/mixed/NOS = 42%/49%/4%/5%.

Results

Seven patients did not receive any treatment because of deterioration in PS or death. 50% of patients in arm D, who received more than one cycle, received dose escalation. There was no statistical difference in the number of cycles administered (arms A, B and D: median 2 cycles and arm C: median 3 cycles) and no difference in RR: arm A = 6%, arm B = 6%, arm C = 10%, and arm D = 0%. There was no statistically significant difference in grade 3/4 neutropenia and thrombocytopenia between the four arms. No difference was observed in hospitalization rate, blood transfusions, antibiotics administration and non-haematological toxicity. QoL: no difference in total scores between baseline and cycles 1-4. There was a significant decrease in pain scores from baseline to post cycles 2 and 3 (p = 0.025 and p = 0.002, respectively). There was no difference in OS (p = 0.992). Median survival and 6-month survival were 61, 86, 88 and 97 days and 29%, 33%, 21% and 26% for arms A, B, C, and D, respectively.

Conclusions

Clinical efficacy of docetaxel was observed at all dose levels. Higher dose levels were not associated with increased toxicities, use of IV antibiotics or hospitalization rates. However, the median survival observed is shorter than historical data and do not support further evaluation of these doses of single agent docetaxel in this population.     

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.     

Multicentre phase I-II trial of capecitabine and oxaliplatin in combination with radiotherapy for unresectable pancreatic and biliary tract cancer: The CORGI-U study

Background and Purpose

In this multicentre phase I-II trial we evaluated the feasibility and efficacy of capecitabine and oxaliplatin followed by the combination of these two drugs with radiotherapy in patients with locally advanced pancreatic or biliary tract cancer.

Material and methods

Thirty-nine patients with inextirpable adenocarcinoma of the pancreas, gallbladder or extrahepatic bile ducts were included. Two cycles of XELOX (capecitabine 1000 mg/m² bid d1-14 + oxaliplatin 130 mg/m² d1, q3w) were followed by XELOX-RT (radiotherapy (50.4 Gy), combined with capecitabine 750-675 mg/m² bid every radiotherapy day and oxaliplatin 40-30 mg/m² once weekly). Primary end-points were tolerance (phase I) and objective response (phase II).

Results

The maximum tolerated doses of oxaliplatin and capecitabine to combine with irradiation were 30 mg/m² and 675 mg/m², respectively. Twenty-one percent (95% CI: 9-38%) of evaluable patients achieved partial response. Five patients went through surgery (three R0 resections). Two-year survival was 28%, and estimated local tumour control rate at 2 years was 72%. The most common grade 3-4 toxicity was nausea and vomiting.

Conclusions

XELOX-RT (30 mg/m² oxaliplatin/675 mg/m² capecitabine in combination with 50.4 Gy/28 fractions) was well tolerated and effective for locally advanced pancreatic and biliary tract cancer.     

Phase I safety and pharmacokinetic study of SU-014813 in combination with docetaxel in patients with advanced solid tumours

Background

In pre-clinical models enhanced anti-tumour activity was observed when SU-014813, an oral multi-targeted tyrosine kinase inhibitor was combined with docetaxel. This synergy might be explained by improvement of the penetration of cytotoxic agents into tumours as a result of both VEGFR and PDGFR inhibition. We assessed the maximal tolerated dose (MTD), evaluated the pharmacokinetics and preliminary anti-tumour efficacy of oral SU-014813 administered continuously in combination with docetaxel to patients with advanced solid tumours.

Methods

In this phase I study successive patient cohorts received docetaxel 60 or 75 mg/m² every 3 weeks in combination with chronic daily dosing of SU-014813. Dose limiting toxicity was assessed both in the first and second treatment cycle.

Results

Twenty-five patients were entered on study of which 24 started treatment. Dose limiting toxicities were prolonged neutropenia, neutropenic fever, fatigue and diarrhoea. Other toxicities included fatigue, alopecia, nausea, vomiting, anorexia, rash, hypertension and hair discolouration. The recommended phase II dose was determined to be docetaxel 75 mg/m² in combination with SU-014813 50 mg/day. There was no clinically relevant pharmacokinetic drug-drug interaction. Two patients (8%) achieved a partial response (PR) and 7 patients (29%) had stabilisation of their disease (SD) >6 months, for a clinical benefit rate of 37.5%. The activity observed in patients with melanoma and sunitinib refractory gastrointestinal stromal tumours (GIST) was particularly noteworthy.

Conclusions

Oral SU-014813 50 mg/day with docetaxel 75 mg/m² is a clinically feasible regimen with a manageable safety profile and anti-tumour activity. Further development is warranted in patients with melanoma and GIST.     

A phase I/II trial of non-pegylated liposomal doxorubicin, docetaxel and trastuzumab as first-line treatment in HER-2-positive locally advanced or metastatic breast cancer

Aim

To assess the activity and safety of non-pegylated liposomal doxorubicin (Myocet®) in combination with docetaxel and trastuzumab as first-line treatment of patients with HER-2/neu-positive metastatic breast cancer (MBC).

Patients and methods

The maximum tolerated dose of the combination was defined in the phase I part of the study. In the phase II part, 45 HER-2/neu-positive MBC patients were enrolled to receive 6-8 cycles of Myocet® 50 mg/m² (day 1), docetaxel 30 mg/m² (days 2 and 9) plus trastuzumab (day 2, 4 mg/kg followed by 2 mg/kg/week) every 21 d until unacceptable toxicity or progression occurred. Objective response (primary end-point) and treatment tolerability were assessed according to World Health Organisation criteria. Cardiotoxicity was defined as signs and/or symptoms of congestive heart failure and/or a decrease in left ventricular ejection fraction (LVEF).

Results

The overall response rate was 55.6% (complete response 8.9%, partial response 46.7%), with a median time-to-progression of 10.9 months (C.I. 8.7-15.0). Median overall survival was not reached. The most frequent grade 3-4 adverse events were granulocytopaenia (60.0%), leukocytopenia (43.2%) and alopecia (35.6%). Grade 3-4 diarrhoea, pain, oral and skin toxicity (4.4%, each) and nausea/vomiting, thrombocytopenia and elevated alkaline phosphatase (2.2%, each) were also reported. In 2 patients LVEF fell to <50%, with a decrease from baseline >15%. LVEF median values remained stable from baseline to the end of the study (60%).

Conclusions

The combination of Myocet®, docetaxel and trastuzumab is safe and shows promising activity as first-line treatment of HER-2-positive MBC.     

Weekly docetaxel and bortezomib as first-line treatment for patients with hormone-refractory prostate cancer: a Minnie Pearl Cancer Research Network phase II trial

Background

Docetaxel is currently the standard first-line treatment in patients with hormone-refractory prostate cancer (HRPC). Bortezomib, the first proteasome inhibitor in clinical use, demonstrated activity against prostate cancer in phase I trials. For this reason, we evaluated the efficacy of docetaxel plus bortezomib in the first-line treatment of patients with HRPC.

Patients and Methods

Between February 2004 and May 2005, 63 eligible patients entered this phase II trial. All patients had metastatic adenocarcinoma of the prostate that had progressed on hormonal therapy. All patients received docetaxel 30 mg/m² and bortezomib 1.6 mg/m² on days 1, 8, and 15 of a 28-day cycle. Patients were reevaluated after 8 weeks of treatment; responding and stable patients continued treatment until tumor progression.

Results

Sixty patients (95%) received ≤ 2 courses of treatment and were evaluable for response. Fifteen patients (25%; 95% confidence interval, 15%-38%) had a > 50% decrease in serum prostate-specific antigen level with treatment; the median response duration was 8 months. The median progression-free and overall survival times for the entire group were 4.1 months and 13.8 months, respectively; 20% of patients were alive at 2 years. The regimen was well tolerated, with uncommon grade 3/4 toxicity.

Conclusion

Treatment with this combination of weekly docetaxel and bortezomib showed no suggestion of improved efficacy versus previous results with docetaxel alone. Bortezomib has minimal activity in patients with HRPC and is unlikely to make any impact on treatment efficacy.     

Wnt3 gene expression promotes tumor progression in non-small cell lung cancer

Background

Recent studies have shown that human copper transporter 1 (hCtr1), the major copper influx transporter, is involved in the transport of platinum-based antitumor agents. We investigated the predictive and prognostic values of hCtr1, and copper efflux transporters ATP7A and ATP7B, in patients with locally advanced non-small cell lung cancer (NSCLC) receiving first-line platinum-based chemotherapy.

Methods

From 2004 to 2009, we identified 54 consecutive stage III NSCLC patients who underwent first-line platinum-based doublet chemotherapy. Immunohistochemical studies of hCtr1, ATP7A and ATP7B on the paraffin-embedded pre-treatment tumor samples were performed and correlated with chemotherapy response and survival.

Results

Overexpression of hCtr1, ATP7A and ATP7B were observed in 68%, 48% and 74% of the participants, respectively. hCtr1 overexpression was associated with better chemotherapy responses (P < 0.01); whereas ATP7A and ATP7B were not. Patients with hCtr1 overexpressing tumors had better progression-free survival (PFS) and overall survival (OS) (P = 0.01 and 0.047, respectively). In multivariate analyses for chemotherapy response and PFS, only hCtr1 overexpression emerged as a favorable independent predictive and prognostic factor (all P < 0.01).

Conclusion

This is the first report to state that hCtr1 is not only an independent predictor of platinum-based chemotherapy response but also a prognostic factor in stage III NSCLC.     

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.     

Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group

Background

Gemcitabine usually given until progressive disease (PD) is the main first-line treatment option for patients with inoperable advanced pancreatic cancer (APC). Currently there is no accepted active regimen for second-line chemotherapy. Previous phase II studies suggest clinical relevant activity of oxaliplatin, folinic acid and 5-FU (OFF). We initiated a phase III multicentre study comparing OFF versus best supportive care (BSC) in patients with APC progressing while on gemcitabine therapy.

Methods

In this open randomized study, patients with CT and/or MRI confirmed progressive disease while on gemcitabine therapy were randomized 1:1 to OFF or BSC. Stratification included duration of first-line therapy (<3, 3 to 6 and >6 months), performance status (KPS 70-80%; 90-100%) and tumour stage (M1/M0). OFF consisted of folinic acid 200 mg/m² followed by 5-fluorouracil 2 g/m² (24 h) on d1, d8, d15, d22 and oxaliplatin 85 mg/m² on days 8 and 22. After a rest of 3 weeks the next cycle was started on d43. A total of 165 patients were calculated to demonstrate a doubling of survival time after progression on first-line therapy.

Results

After inclusion of forty six patients the trial was terminated according to predefined protocol regulations due to insufficient accrual (lack of acceptance of BSC by patients and physicians. Patient characteristics were well balanced between both study arms. The OFF regimen was well tolerated with more patients with grade I/II paraesthesia and grade II/III nausea/emesis and diarrhoea. Median second-line survival was 4.82 [95% Confidence Interval; 4.29-5.35] months for OFF treatment and 2.30 [95% CI; 1.76-2.83] months with BSC alone (0.45 [95% CI: 0.24-0.83], p = 0.008). Median overall survival for the sequence GEM-OFF was 9.09 [95% CI: 6.97-11.21] and 7.90 [95% CI: 4.95-10.84] months for GEM-BSC (0.50 [95% CI: 0.27-0.95], p = 0.031) respectively.

Interpretation

Although stopped prematurely, this randomized trial provides at first time evidence for the benefit of second-line chemotherapy as compared to BSC alone for patients with APC. OFF significantly prolonged survival time compared to BSC alone after failure of first-line therapy with gemcitabine.     

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.     

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.     

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.     

Promoter methylation of BRMS1 correlates with smoking history and poor survival in non-small cell lung cancer patients

Purpose

To investigate whether methylation of BRMS1 is associated with clinical outcomes in patients with NSCLC.

Methods

Methylation status of BRMS1 was examined in 325 NSCLC patients who were treated with surgery. We analyzed associations between the methylation of BRMS1 genes separately and available epidemiologic and clinical information including smoking status, gender, age, and histological type, or the stage of the tumor.

Results

In the cohort of 325 NSCLC cases, 152 samples were identified as methylated (46.77%). Promoter methylation of BRMS1 was present only in 6 specimens (8.42%) in adjacent non-cancerous tissues (P = 2.257 × 10⁻¹⁴). Patient smoking history had a positive correlation with methylation rate of BRMS1 (OR = 2.508, 95%CI(1.516, 4.151)). Compared with unmethylated group, methylated group showed the lower level of BRMS1 mRNA (P = 0.013). And patients with a high level of BRMS1 mRNA expression had significantly better overall survival than those with low expression (P = 0.002). Multivariate Cox proportional hazard regression analysis also showed that promoter methylation of BRMS1 was significantly unfavorable prognostic factors (hazard ratio, 1.912; 95% CI, and 1.341-2.726).

Conclusions

These results provide clinical evidence to support the notion that BRMS1 is a NSCLC metastasis suppressor gene. Measuring methylation status of BRMS1 promotor is a useful marker for identifying NSCLC patients with worse disease-free survival.     

Phase II trial of docetaxel/capecitabine in hormone-refractory prostate cancer

Background

Docetaxel is the most active single agent in the treatment of hormone-refractory prostate cancer (HRPC). Because of the preclinical and clinical evidence of synergy of capecitabine and docetaxel, it was hypothesized that this combination would be active and tolerable in HRPC.

Patient and Methods

Patients received docetaxel 60 mg/m² intravenously over 60 minutes on day 1 of each 21-day cycle and capecitabine 1000 mg/m² administered orally twice daily on days 1-14 of each cycle for a maximum of 8 cycles or until disease progression or intolerable toxicity. Seventy-seven patients were enrolled at 43 US Oncology sites. The median age was 69.3 years (range, 48-86 years); 86% were white, and the Eastern Cooperative Oncology Group performance status scores of 0 and 1 were 49% and 51%, respectively. Sixty-nine (90%) patients were evaluable for prostate-specific antigen response.

Results

Overall, 41% of patients had a decreased prostate-specific antigen level ≥ 50%. There were 4 complete responses (6%), 24 partial responses (35%), 29 incidences of stable disease (43%), and 11 incidences of progressive disease (16%). Nine patients had stable disease ≥ 6 months, and the clinical benefit rate was 54%. The median time to response was 1.5 months (range, 1-6 months), and the median duration of response was 5.2 months (range, 1-16.9 months). The estimated survival at 12 and 24 months was 65% and 22%, respectively, with a median survival of 17 months (range, < 1-27 months). There were no treatment-related deaths. Grade 3/4 toxicities included neutropenia (50%), leukopenia (22%), hand-foot syndrome (17%), fatigue (11%), and nausea (11%).

Conclusion

Docetaxel/capecitabine is an active and tolerable combination in HRPC. Toxicity was acceptable and anticipated. Response rate and survival are comparable with other docetaxel combinations.     

Outcomes of stereotactic ablative radiotherapy following a clinical diagnosis of stage I NSCLC: Comparison with a contemporaneous cohort with pathologically proven disease

Introduction

As a finding of benign disease is uncommon in Dutch patients undergoing surgery after a clinical diagnosis of stage I NSCLC, patients are also accepted for stereotactic ablative radiotherapy (SABR) without pathology. We studied outcomes in patients who underwent SABR after either a pathological (n = 209) or clinical diagnosis (N = 382).

Materials and methods

Five hundred and ninety-one patients with a single pulmonary lesion underwent SABR after either a pathological- or a clinical diagnosis of stage I NSCLC based on a ¹⁸FDG-PET positive lesion with CT features of malignancy. SABR was delivered to a total dose of 60 Gy in 3, 5 or 8 fractions, and outcomes were compared between groups with and without pathological diagnosis.

Results

Patients with pathology had significantly larger tumor diameters (p < .001) and higher predicted FEV1% values (p = .025). No significant differences were observed between both groups in overall survival (p = .99) or local control (p = .98). Regional and distant recurrence rates were also similar.

Conclusions

In a population with a low incidence of benign ¹⁸FDG-PET positive lung nodules, clinical SABR outcomes were similar in large groups of patients with or without pathology. The survival benefits reported after the introduction of SABR are unlikely to be biased by inclusion of benign lesions.     

Stereotactic radiotherapy of histologically proven inoperable stage I non-small cell lung cancer: Patterns of failure

Background and purpose

To report patterns of failure of stereotactic body radiation therapy (SBRT) in inoperable patients with histologically confirmed stage I NSCLC.

Materials and methods

Ninety-two inoperable patients (median age: 75 years) with clinically staged, histologically proven T1 (n = 31) or T2 (n = 61), N0, M0 non-small cell lung cancer (NSCLC) were included in this study. Treatment consisted of 3-5 fractions with 7-15 Gy per fraction prescribed to the 60% isodose.

Results

Freedom from local recurrence at 1, 3 and 5 years was 89%, 83% and 83%, respectively. All 10 local failures were observed in patients with T2 tumors. Isolated regional recurrence was observed in 7.6%. The crude rate of distant progression was 20.7%. Overall survival at 1, 3, and 5 years was 79%, 38% and 17% with a median survival of 29 months. Disease specific survival at 1, 3, and 5 years was 93%, 64% and 48%. Karnofsky performance status, T stage, gross tumor volume and tumor location had no significant impact on overall and disease specific survival. SBRT was generally well tolerated and all patients completed therapy as planned.

Conclusion

SBRT for stage I lung cancer is very well tolerated in this patient cohort with significant cardiopulmonal comorbidity and results in excellent local control rates, although a considerable portion develops regional and distant metastases.     

Chemotherapy/chemoradiation in anal cancer: a systematic review

Introduction

Results from recent phase III trials in anal cancer failed to show any benefit for neoadjuvant chemotherapy (NACT) with cisplatin, or cisplatin-based consolidation chemotherapy compared to chemoradiation alone for loco-regional control, disease-free survival (DFS) and overall survival (OS).

Aims

This systematic review examines evidence for efficacy and toxicity of chemotherapy and chemoradiotherapy in anal cancer.

Results

In total, for chemoradiation, 103 retrospective/observational studies, four phase I/II studies, 16 phase II prospective studies, two randomised phase II studies, and six phase III trials of chemoradiation in anal cancer were identified. Only three phase II chemotherapy studies in metastatic disease were identified. Few retrospective studies were consistent in their use of chemotherapy or radiation doses, and long-term follow-up (>3 years) was rare.

Conclusions

In anal cancer T3/T4 lesions fare badly (3 year DFS 40-68%). Cisplatin appears an effective drug, but novel strategies have not allowed progress from the schedule of chemoradiation using MMC, infusional 5FU and radiotherapy - the paradigm developed by Nigro over 30 years ago. Different cytotoxic agents such as capecitabine, oxaliplatin and docetaxel, and biologically targeted agents - either an EGFR monoclonal antibody or an oral tyrosine kinase inhibitor, which exploits this pathway, might offer an alternative. In particular, the role of EGFR inhibition following chemoradiation should be explored.     

Limited prognostic value of dual time point F-18 FDG PET/CT in patients with early stage (stage I & II) non-small cell lung cancer (NSCLC)

Objective

The aim of the current study was to investigate the prognostic value of dual time point F-18 FDG PET/CT in patients with early stage (stage I & II) NSCLC.

Methods

A retrospective review identified 66 patients with surgically resected early (stage I & II) NSCLC who received dual time point F-18 FDG PET/CT at diagnosis of cancer. Survival analysis was conducted using Kaplan-Meier analysis, and survival curves stratified by age, sex, mediastinal lymph node involvement, TNM staging, SUV_maxE, SUV_maxD, and %ΔSUV_max were generated for estimation of overall survival and disease-free survival (DFS). Independent predictive factors for survival were determined using Cox proportional hazard model.

Results

The overall survival and DFS were better in patients with tumor SUV_maxE ? 5.75 than the patients with tumor SUV_maxE ? 5.75. Seventeen patients (18.2%) with a tumor SUV_maxD ? 6.8 and 4 of 33 patients with tumor SUV_maxD ? 6.8 recurred during follow-up period. The median disease-free survival of the patients with tumor SUV_maxD ? 6.8 was 31.7 months and was significantly worse than the patients with tumor SUV_maxD ? 6.8 (Log rank test, Χ² = 10.45, p = 0.0012). The %ΔSUV_max did not have prognostic values for overall survival and disease-free survival. The SUV_maxE and SUV_maxD were the potent predictors for overall survival. Also, the potent predictor of DFS was the SUV_maxE.

Conclusion

In conclusion, %ΔSUV_max measured by dual time point F-18 FDG PET/CT might not have a prognostic value for overall survival and DFS in surgically resected early stage (stage I & II) NSCLC.     

Under usage of zoledronic acid in non-small cell lung cancer patients with metastatic bone disease--a short communication

Background and aim

The use of zoledronic acid (ZA) is now recommended for patients with NSCLC and metastatic bone disease (MBD). We thus examined the rates of ZA administration in NSCLC looking specifically at the use of this drug with systemic chemotherapy (ZCt) and comparing overall survival between patients who had ZCt from diagnosis to those who had chemotherapy (Ct) alone.

Method

In this retrospective audit, we analysed the data of 114 consecutive patients with stage IV NSCLC and MBD at presentation. Forty-three of these patients had received zoledronic acid and chemotherapy (ZCt) and 71 had received chemotherapy alone (Ct).

Results

Forty-three (37.7%, 43/114) of NSCLC patients diagnosed with MBD received ZA with their first chemotherapy (ZCt). Patients on ZCt, after adjustment for the planned prognostic factors (sites of disease, histology and PS), had better overall survival (OS), with a median of 34 weeks, compared to those who received chemotherapy alone, who had a median of 19 weeks (p = 0.03), HR = 0.60 (95%CI: 0.38-0.96). After adjusting for prognostic factors (sex, age. single versus doublet chemotherapy), ZCt patients still maintained a trend to better OS (p = 0.06) HR 0.63 (95%CI: 0.39-1.02) 34 versus 21 weeks.

Conclusions

The percentage of patients with MBD treated with ZA at first chemotherapy (37.7%) is low. The addition of ZA increased OS in NSCLC patients with MBD in this audit. More formal policies and dedicated trials on the treatment of MBD in NSCLC patients need to be put in place.