Phase II study of preoperative chemoradiotherapy (CRT) with irinotecan plus S-1 in locally advanced rectal cancer

Background and purpose

The aim of this study is to evaluate the efficacy and safety of preoperative radiation therapy combined with S-1 and irinotecan (SI) in LARC.

Materials and methods

Patients were considered LARC if they had a T3/T4 lesion or node positive. Weekly doses of 40 mg/m² irinotecan were intravenously administered once per week during weeks 1-5 of radiotherapy. S-1 (70 mg/m²) was given from Monday to Friday in all weeks of radiotherapy. 3-D conformal radiotherapy was given at daily fractions of 1.8 Gy for 5 days for a total dose of 50.4 (45 + 5.4) Gy. Surgery was performed 4-6 weeks following the completion of chemoradiation.

Results

Between June 2006 and November 2007, 43 pts were enrolled. The stage was: cT3 24 patients, cT4 6 patients; 28 patients were cN+. Forty-one patients completed the chemoradiation and 42 patients underwent operation: a low anterior resection was performed in 36 patients, a total colectomy in 1 patient, and an abdominal perineal resection in 5 patients. T downstaging was observed in 50%; 23 N+ patients became N− (55%). The complete pathological response was observed in 9 patients (21%). The 3-year locoregional failure rate, distant failure rate, disease-free survival, and overall survival were 9.5%, 18.6%, 72.1%, and 94.3%, respectively. Only three patients experienced G3 diarrhea; one had G3 sepsis and two had septic shock. Hematological toxicity (G3-G4) was observed in five patients.

Conclusions

This study demonstrated the efficacy of preoperative CRT with S-1 and irinotecan with 21% of complete response. However, prompt recognition and management of infection is needed to use it in patients with locally advanced rectal cancer.     

Long-term results of full-dose gemcitabine with radiation therapy compared to 5-fluorouracil with radiation therapy for locally advanced pancreas cancer

Purpose

To retrospectively compare the efficacy and toxicity of full-dose gemcitabine based chemoradiotherapy (GemRT) versus 5-fluorouracil (5-FU) based chemoradiotherapy (5FURT) for locally advanced pancreas cancer (LAPC).

Methods

From January 1998 to December 2008, 93 patients with LAPC were treated either with 5FURT (n = 38) or GemRT (n = 55). 5FURT consisted of standard-field radiotherapy given concurrently with infusional 5-FU or capecitabine. GemRT consisted of involved-field radiotherapy given concurrently with full-dose gemcitabine (1000 mg/m² weekly) with or without erlotinib. The follow-up time was calculated from the time of diagnosis to the date of death or last contact.

Results

Patient characteristics were not significantly different between treatment groups. The overall survival (OS) was significantly better for GemRT compared to 5FURT (median 12.5 months versus 10.2 months; 51% versus 34% at 1 year; 12% versus 0% at 3 years; 7% versus 0% at 5 years, respectively; all P = 0.04). The OS benefit of GemRT was maintained on subset analysis without concurrent erlotinib or with sequential gemcitabine (all P < 0.05). The rates of distant metastasis, subsequent hospitalization, acute and late grade 3-5 gastrointestinal toxicities were not significantly different between the GemRT and 5FURT groups.

Conclusions

GemRT was associated with an improved OS compared to standard 5FURT. This approach yielded long-term survivors and was not associated with increased hospitalization or severe gastrointestinal toxicity.     

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.     

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.     

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.     

Effect of omeprazole on the pharmacokinetics and toxicities of irinotecan in cancer patients: a prospective cross-over drug-drug interaction study

Background

Omeprazole is one of the most prescribed medications worldwide and within the class of proton pump inhibitors, it is most frequently associated with drug interactions. In vitro studies have shown that omeprazole can alter the function of metabolic enzymes and transporters that are involved in the metabolism of irinotecan, such as uridine diphosphate glucuronosyltransferase subfamily 1A1 (UGT1A1), cytochrome P-450 enzymes subfamily 3A (CYP3A) and ATP-binding cassette drug-transporter G2 (ABCG2). In this open-label cross-over study we investigated the effects of omeprazole on the pharmacokinetics and toxicities of irinotecan.

Methods

Fourteen patients were treated with single agent irinotecan (600 mg i.v., 90 min) followed 3 weeks later by a second cycle with concurrent use of omeprazole 40 mg once daily, which was started 2 weeks prior to the second cycle. Plasma samples were obtained up to 55 h after infusion and analysed for irinotecan and its metabolites 7-ethyl-10-hydroxycampothecin (SN-38), SN-38-glucuronide (SN-38G), 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin (NPC) and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC) by high-performance liquid chromatography (HPLC). Non-compartmental modelling was performed. Toxicities were monitored during both cycles. Paired statistical tests were performed with SPSS.

Results

The exposure to irinotecan and its metabolites was not significantly different between both cycles. Neither were there significant differences in the absolute nadir and percentage decrease of WBC and ANC, nor on the incidence and severity of neutropenia, febrile neutropenia, diarrhoea, nausea and vomiting when irinotecan was combined with omeprazole.

Conclusion

Omeprazole 40 mg did not alter the pharmacokinetics and toxicities of irinotecan. This widely used drug can, therefore, be safely administered during a 3-weekly single agent irinotecan schedule.     

Is concurrent radiation therapy required in patients receiving preoperative chemotherapy for adenocarcinoma of the oesophagus? A randomised phase II trial

Introduction

Preoperative chemotherapy (CT) and preoperative chemoradiation therapy (CRT) for resectable oesophageal cancer have been shown to improve overall survival in meta-analyses. There are limited data comparing these preoperative therapies. We report the outcomes of a randomised phase II trial comparing preoperative CT and CRT for resectable adenocarcinoma of the oesophagus and gastro-oesophageal junction.

Methods

Patients were randomised to receive preoperative CT with cisplatin (80 mg/m²) and infusional 5 fluorouracil (1000 mg/m²/d) on days 1 and 21, or preoperative CRT with the same drugs accompanied by concurrent radiation therapy commencing on day 21 of chemotherapy and the 5 fluorouracil reduced to 800 mg/m²/d. The radiation dose was 35 Gy in 15 fractions over 3 weeks. The endpoints were toxicity, response rates, resection (R) status, progression-free survival (PFS), overall survival (OS) and quality of life.

Results

Seventy-five patients were enroled on the study: 36 received preoperative CT and 39 preoperative CRT. Toxicity was similar for CT and CRT. Eight patients (11%) did not proceed to resection. The histopathological response rate (CRT 31% versus CT 8%, p = 0.01) and R1 resection rate (CRT 0% versus CT 11%, p = 0.04) favoured those receiving CRT. The median PFS was 14 and 26 months for CT and CRT respectively (p = 0.37). The median OS was 29 months for CT compared with 32 months for CRT (p = 0.83).

Conclusions

Despite no difference in survival, the improvement from preoperative CRT with respect to margin involvement makes this treatment a reasonable option for bulky, locally advanced resectable adenocarcinoma of the oesophagus.     

Peritumoural vascular invasion: a major determinant of triple-negative breast cancer outcome

Purpose

Triple-negative breast cancers (TNBC) have the worst outcome of all breast cancer subtypes. Nevertheless TNBC are heterogeneous in terms of pathological, biological and prognostic behaviours. We explored clinical and pathological factors correlated with outcome in this phenotype.

Methods

We retrospectively studied clinical and pathological factors correlated with prognosis in a series of 344 early TNBC. Staining for blood (CD31) and lymphatic (Podoplanin) vascular endothelium markers was performed to best characterise peritumoural vascular invasion (PVI) in 108 cases available for pathological reviewing.

Results

Univariate and multivariate analyses performed on our whole cohort underlined PVI as an independent predictive factor of distant metastasis (p = 0.00012, HR = 2.72 [1.63-4.52]). Standardised pathological reviewing of 101 histologically confirmed TNBC showed that PVI, observed in 41% (28% by haematoxylin and eosin staining plus 13% by immunohistochemistry), was confirmed as the first prognostic factor in TNBC, particularly in node-negative tumours. Five-year metastasis-free survival in this subset was 87.5% and 50.8% without and with PVI, respectively (p = 0.003).

Conclusions

Vascular invasion diagnosis is improved by the combination of HES and IHC. Moreover it is a major prognostic feature and must take a greater part in therapeutic management of early TNBC with the possibility to adapt the adjuvant treatment according to the predicted relapse risk.     

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.     

Survival after trimodality therapy for malignant pleural mesothelioma: Radical Pleurectomy, chemotherapy with Cisplatin/Pemetrexed and radiotherapy

Introduction

The role of surgery in the management of malignant pleural mesothelioma (MPM) is controversial and there are no established guidelines. We describe the feasibility and long-term outcomes associated with Radical Pleurectomy (RP) as surgical therapy modality in a standardized trimodality therapy concept of MPM.

Methods

From November 2002 to October 2007, 35 out of 102 consecutive patients with MPM were enrolled in our prospective database. They underwent trimodality therapy, including RP followed by 4 cycles of chemotherapy with Cisplatin (75 mg/m²)/Pemetrexed (500 mg/m²) and radiotherapy 4-6 weeks after operation.

Results

Median age was 65 years. Nineteen patients were in advanced stages III and IV (54.3%). Tumor histology was epithelial in 27 patients (77.1%). Macroscopic complete resection could be achieved in 18 patients (51.4%). Surgical morbidity/mortality and trimodality treatment-related mortality were 20.0%, 2.9% and 5.8%, respectively. Thirty-three patients completed the trimodality therapy. Median follow-up was 21.7 months. Overall median survival was 30.0 months. One-, 2-, and 3-year-survival were 69%, 50% and 31%, respectively. Advanced stages III/IV (p = 0.06), macroscopic incomplete resections (p = 0.001), non-epithelial histology (p = 0.55) and nodal metastases (p = 0.19) were associated with poorer survival.

Conclusions

The trimodality therapy concept with RP demonstrates promising results in terms of long-term survival, morbidity and mortality. We propose that a surgical philosophy of limiting the procedure related morbidity while achieving comparable cytoreductive results allows patients to maintain physiological reserve to be eligible for multimodality treatment options in the long-term. The observed and theoretical benefits of this trimodality treatment approach warrant confirmation in larger RCT.     

Efficacy and safety of maintenance pemetrexed in patients with advanced nonsquamous non-small cell lung cancer following pemetrexed plus cisplatin induction treatment: A cross-trial comparison of two phase III trials

Objectives

Two phase III trials of advanced NSCLC patients were compared to examine relative efficacy and safety of differing treatment regimens. The JMDB trial investigated first-line pemetrexed–cisplatin (pemetrexed 500 mg/m² plus cisplatin 75 mg/m² every 21 days; maximum: 6 cycles). The PARAMOUNT phase III trial compared maintenance pemetrexed versus placebo after patients with nonsquamous NSCLC completed 4 cycles of first-line pemetrexed–cisplatin without disease progression.

Methods

Overall survival (OS) and progression-free survival (PFS), analyzed by Kaplan–Meier and Cox methods, and toxicity rates were compared between the PARAMOUNT arms and a selected homogeneous population from JMDB: 346 patients with disease and prior treatment characteristics matching the PARAMOUNT population.

Results

Outcomes for the PARAMOUNT placebo arm were similar to the JMDB homogeneous group (median PFS: 5.6 versus 6.2 months, p = 0.117, HR = 1.16; median OS: 14.0 versus 14.2 months, p = 0.979, HR = 1.00). The PARAMOUNT maintenance pemetrexed group had statistically superior efficacy compared with the JMDB homogeneous group (median PFS: 7.5 versus 6.2 months, p < 0.00001, HR = 0.66; median OS: 16.9 versus 14.2 months, p = 0.003, HR = 0.75). Patients who received pemetrexed maintenance (median 4 cycles, range 1–44) following 4 cycles of pemetrexed–cisplatin exhibited a higher incidence of drug-related serious adverse events compared with JMDB patients (median 6 cycles of pemetrexed–cisplatin) (10.6% versus 2.9%); grade 3/4 fatigue and renal toxicity were also higher in the pemetrexed arm of PARAMOUNT.

Conclusions

The across-trial comparison of a relevant JMDB study population with the two arms of the PARAMOUNT study supported the efficacy of the pemetrexed continuation maintenance strategy and suggested the results are not influenced by limiting the pemetrexed–cisplatin induction treatment to four cycles. Although longer exposure to pemetrexed–cisplatin or maintenance pemetrexed increased some toxicities, the overall incidence remained low, underscoring the relative safety of these treatment regimens.     

Radiosensitivity of squamous cell carcinoma metastases to the neck assessed by immunocytochemical profiling of fine-needle aspiration biopsy cell specimens: A pilot study

Purpose

To assess radiosensitivity of neck metastases of squamous cell carcinoma of the head and neck (SCCHN) by immunocytochemical profiling of fine-needle aspiration biopsy (FNAB) cell specimens.

Patients and methods

Immunocytochemical reactions to p53, cyclin D1, stefin A and Ki-67 were determined in FNAB cell samples of neck metastases from 21 patients treated with concomitant chemoradiotherapy and correlated to clinical characteristics and response to therapy.

Results

Six (28.6%), eight (38.1%), 15 (71.4%) and nine (42.9%) FNAB cell samples were classified as p53, cyclin D1, stefin A and Ki-67 positive, respectively. Statistically significant predictors of favorable nodal response to chemoradiation were p53 (P = 0.025) and cyclin D1 (cytoplasmic fraction, P = 0.048) negativity and Ki-67 positivity (P = 0.045). Regional recurrence correlated with low Ki-67 immunoreactivity. A favorable profile of cyclin D1 and Ki-67 (one or both of the two) further improved the predictive strength of these markers.

Conclusions

FNAB is a non-invasive, simple and cheap procedure, which could serve simultaneously for diagnostic purposes and for radiosensitivity testing. Immunocytochemical determination of cyclin D1 and Ki-67 in FNAB cell samples from neck metastases of SCCHN seems to be a valuable marker for predicting regional response to radiotherapy and might assist when deciding on appropriate primary therapy.     

Feasibility of metronomic oral cyclophosphamide plus prednisolone in elderly patients with inoperable or metastatic soft tissue sarcoma

Background

The number of elderly people with soft tissue sarcoma (STS) is increasing. A sizeable population of elderly patients with STS is unfit for conventional doxorubicin- or ifosfamide-based chemotherapy. We assessed the feasibility of metronomic oral cyclophosphamide (CPM) in this population.

Patients and methods

Patients aged 65 years or older with unresectable STS received CPM 100 mg twice daily plus prednisolone 20 mg daily, the first week of a 2-week cycle in the outpatient setting. Main evaluation criterion was safety. Secondary evaluation criteria were objective response rate and progression-free survival.

Results

Twenty-six patients (median age: 72, range 66-88) received a total of 330 cycles (median per patient: 10, range 2-41) as first (n = 19) or second-line chemotherapy (n = 7). The most frequent histological subtypes were poorly differenciated sarcoma (n = 8), leiomyosarcoma and liposarcoma (n = 5 each) and angiosarcoma (n = 3). Grade ?3 lymphopenia was observed in 81% of pts but no opportunist infection occurred. Grade 3 anaemia and thrombocytopenia occurred in 2 pts (8%) each. No other grade 3-4 toxicity was seen. The response rate was 26.9% (95%CI: 9.9-44.0) and the disease control rate (responses and stable disease >12 weeks) was 69.2% (95%CI: 51.5-87.0). One complete (hepatic epithelioid haemangio-endothelioma) and 6 partial responses (including 5 pts with radiation-induced sarcomas) were seen. Progression-free survival ranged from 0 to 20.6 months (median: 6.8 months) and was significantly longer in patients with radiation-induced sarcomas (median: 7.8 versus 5.2 months, p = 0.02).

Conclusion

Metronomic CPM showed good safety results for this frail population, with promising activity in patients with radiation-induced sarcoma. Toxicity profile was favourable, allowing prolonged home staying and rare treatment discontinuations. A larger prospective study is warranted to confirm these encouraging results in elderly with STS.     

Malignant mucosal melanoma treated with carbon ion radiotherapy with concurrent chemotherapy: Prognostic value of pretreatment apparent diffusion coefficient (ADC)

Background and purpose

To evaluate the potential of apparent diffusion coefficient (ADC) value before carbon ion radiotherapy (C-ion RT) for malignant mucosal melanoma (MMM) to predict prognosis.

Materials and methods

We recruited 37 patients with MMM in the head and neck treated by C-ion RT with concomitant chemotherapy. Univariate and multivariate analyses of minimum ADC, mean ADC, tumor volume, age, PS, and gender were performed to identify prognostic factors.

Results

The 3-year local control rate, distant metastasis-free survival rate and overall survival rate of all patients were 81.1%, 37.6% and 65.3%, respectively, with a median follow-up period of 19.0 months. In univariate analyses, lower minimum ADC (?0.6380 × 10⁻³ mm²/s) and lower mean ADC (?1.1523 × 10⁻³ mm²/s) were unfavorable prognostic factors for distant metastasis (p = 0.029 and p = 0.014, respectively), and lower minimum ADC was an unfavorable prognostic factor for overall survival (p = 0.019). However, there was no significant prognostic factor of local control including ADC value. In multivariate analyses, only minimum ADC was selected as a prognostic factor of distant metastasis-free survival and overall survival (p = 0.015 and p = 0.006, respectively).

Conclusion

Minimum ADC can be a prognostic factor of MMM in the head and neck after C-ion RT.     

Sensitivity to previous irinotecan treatment does not predict the efficacy of combination chemotherapy with cetuximab plus irinotecan for wild-type KRAS metastatic colorectal cancer

The aim of this study was to evaluate the association of sensitivity to previous irinotecan-based chemotherapy with efficacy of cetuximab plus irinotecan therapy in metastatic colorectal cancer (MCRC) patients with wild-type KRAS. We analysed a pooled data set consisting of data from 87 MCRC patients from two previous phase II studies (n = 60) and a group given off-protocol treatment (n = 27) following irinotecan-, oxaliplatin-, and fluoropyrimidine-based chemotherapy. Overall objective response rate to cetuximab plus irinotecan was 28.7%, median progression-free survival (PFS) was 5.3 months, and median overall survival was 12.2 months. Objective response rate did not significantly differ between patients with a favourable response to previous irinotecan (n = 23), stable disease (n = 38), or progressive disease (n = 26), with observed rates of 29.2%, 31.6%, and 23.1%, respectively. Additionally, the non-parametric Spearman rank correlation coefficients (ρ) between the PFS of previous irinotecan-based chemotherapy and that of cetuximab plus irinotecan were quite low (ρ = 0.067 and 0.057 in patients with previous irinotecan as first- and second-line therapies, respectively). Although exploratory nature and small sample size may be limitations of this study, these findings indicate that the efficacy of irinotecan plus cetuximab in MCRC patients with wild-type KRAS did not differ by previous sensitivity to irinotecan.     

Phase II trial of the combination of carboplatin and irinotecan in elderly patients with small-cell lung cancer

Aim

The aim of the present phase II study was to assess the antitumour activity and safety of the combination of irinotecan and carboplatin in elderly patients with small-cell lung cancer (SCLC).

Material and methods

Patients with previously untreated SCLC were eligible if they had a performance status of 0-2, were 70 years or older, and had adequate organ function. Patients were treated with carboplatin at an area under the plasma concentration versus time curve of 5 min/ml on day 1 and with irinotecan at 50 mg/m² on days 1 and 8 every 3 weeks.

Results

Thirty patients (26 men and 4 women; median age, 76 years; age range, 70-86 years) were enrolled. Eight patients had limited disease (LD) and 22 patients had extensive disease (ED). The overall response rate was 83.3% (95% confidence interval: 65.3-94.4%). Response rates did not differ significantly between patients with LD (87.5%) and those with ED (81.8%; p = 0.71). The median survival time was 14 months overall and was significantly longer in patients with LD (26 months) than in patients with ED (11 months; p = 0.025). The median progression free survival time was 6 months overall and was significantly longer in patients with LD (12 months) than in patients with ED (6 months; p = 0.016). Grade 3-4 toxicities included neutropenia in 83% of patients, thrombocytopenia in 47%, anaemia in 60%, infection in 23%, and diarrhoea in 20%. There were no treatment-related deaths.

Conclusions

This chemotherapy is safe and effective for elderly patients with SCLC.     

Double-scattered proton-based stereotactic body radiotherapy for stage I lung cancer: A dosimetric comparison with photon-based stereotactic body radiotherapy

Purpose

Stereotactic body radiotherapy (SBRT) has gained popularity in the treatment of early-stage non-small-cell lung cancer (NSCLC) because of its ability to deliver conformal radiation doses to small targets. However, photon-based SBRT (xSBRT) is associated with significant grade 3+ toxicities. In this study, we compare xSBRT treatment plans with proton-based SBRT (pSBRT) to determine whether dose to normal structures could be reduced if SBRT was delivered with protons.

Materials and methods

Eight patients with medically inoperable, peripherally located stage I NSCLC were treated with xSBRT to 48 Gy in 4 12-Gy fractions. These patients were retrospectively re-planned using the same treatment volumes with 3-dimensional conformal double-scatter proton therapy. A Wilcoxon paired test compared dosimetric parameters between the plans for each patient.

Results

Compared with xSBRT there was a dosimetric improvement with pSBRT for these volumes: lung V5 (median difference [MD] = 10.4%, p = 0.01); V10 (MD = 6.4%, p = 0.01); V20 (MD = 2.1%, p = 0.01); V40 (MD = 1.5%, p = 0.05); and mean lung dose (MD = 2.17 Gy, p = 0.01). There were also benefits (p = <0.05) in D0.1cm3 and D5cm3 with pSBRT to the heart, esophagus, and bronchus.

Conclusions

In a dosimetric comparison between photon and proton-based SBRT, protons resulted in lower doses to critical organs at risk and a smaller volume of non-targeted normal lung exposed to radiation (V5, V10, V20, and V40). The clinical significance and relevance of these dosimetric improvements remain unknown.     

A phase II study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in relapsed small cell lung cancer

Introduction

We previously reported data on the safety, tolerability, and recommended phase II dose of obatoclax mesylate in conjunction with topotecan in patients with advanced solid tumor malignancies. Preliminary efficacy data suggested activity in patients with recurrent small cell lung cancer (SCLC). Based on these data, we performed a phase II study of obatoclax mesylate plus topotecan in patients with relapsed SCLC to assess efficacy.

Methods

This was an open-label, single-arm, phase II extension of obatoclax mesylate plus topotecan in patients with relapsed SCLC. Obatoclax mesylate was given intravenously (IV) at a dose of 14 mg/m² on days 1 and 3 with IV topotecan at 1.25 mg/m² on days 1-5 of an every 3-week cycle. The primary end-point of this study was overall response rate.

Results

Nine patients with recurrent SCLC were enrolled into the first stage of the study. Patients received a median of 2 cycles of treatment. All patients were evaluable for the primary end-point of overall response. There were no partial or complete responses. Five patients (56%) had stable disease. The remaining four patients (44%) developed progressive disease. The most common grade 3 or 4 adverse events included thrombocytopenia (22%), anemia (11%), neutropenia (11%), and ataxia (11%).

Conclusion

Obatoclax mesylate added to topotecan does not exceed the historic response rate seen with topotecan alone in patients with relapsed SCLC following the first-line platinum-based therapy.     

Assessment of lung-cancer mortality reduction from CT Screening

Background

CT screening has been shown to increase lung cancer curability and we now assess the corresponding reduction in lung cancer mortality.

Methods

Lung-cancer mortality in a cohort of 7995 smokers who underwent CT screening for lung cancer in New York State (NYS) was compared with two unscreened cohorts (CPS-II and CARET). The standardized mortality ratio (SMR) of observed to expected lung cancer deaths for NYS was jointly adjusted for age, sex, and smoking history. As more current NYS smokers might have quit as a result of the screening, thus reducing deaths from lung cancer, another analysis was restricted to those participants smoking at entry and still smoking 6 years later.

Results

The SMR was 64/99.8 = 0.64 (P = 0.84 × 10⁻⁴) and 28/77.6 = 0.36 (P = 0.83 × 10⁻¹⁰), showing a significant reduction in deaths from lung cancer of 36% and 64% for CPS-II and CARET, respectively. Considering participants who were smoking at entry and still smoking 6 years later, the SMR using CPS-II rates was 29/49.1 = 0.59 (P = 0.001) and using CARET rates it was 21/57.4 = 0.37 (P = 0.31 × 10⁻⁷).

Conclusions

CT screening significantly reduces lung-cancer mortality.