The Relationship between a New Biomarker of Vagal Neuroimmunomodulation and Survival in Two Fatal Cancers.

BACKGROUND: The vagus nerve may slow tumor progression because it inhibits inflammation. This study examined the relationship between a new vagal neuroimmunomodulation (NIM) index and survival in fatal cancers. METHOD: We retroactively derived markers of vagal nerve activity indexed by heart rate variability (HRV), specifically the root mean square of successive differences (RMSSD), from patients' electrocardiograms near diagnosis. The NIM index was the ratio of RMSSD to C-reactive protein levels (RMSSD/CRP). Sample 1 included 202 Belgian patients with advanced pancreatic cancer (PC), while sample 2 included 71 Belgian patients with non-small cell lung cancer (NSCLC). In both samples, we examined the overall survival, while in sample 2, we additionally examined the survival time in deceased patients. RESULTS: In PC patients, in a multivariate Cox regression controlling for confounders, the NIM index had a protective relative risk (RR) of 0.68 and 95% confidence interval (95% CI) of 0.51-0.92. In NSCLC patients, the NIM index also had a protective RR of 0.53 and 95% CI of 0.32-0.88. Finally, in NSCLC, patients with a higher NIM index survived more days (475.2) than those with lower NIM (285.1) (p < 0.05). CONCLUSIONS: The NIM index, reflecting vagal modulation of inflammation, may be a new independent prognostic biomarker in fatal cancers.

Geriatric Assessment and Functional Decline in Older Patients with Lung Cancer.

PURPOSE: Older patients with lung cancer are a heterogeneous population making treatment decisions complex. This study aims to evaluate the value of geriatric assessment (GA) as well as the evolution of functional status (FS) in older patients with lung cancer, and to identify predictors associated with functional decline and overall survival (OS). METHODS: At baseline, GA was performed in patients ≥70 years with newly diagnosed lung cancer. FS measured by activities of daily living (ADL) and instrumental activities of daily living (IADL) was reassessed at follow-up to define functional decline and OS was collected. Predictors for functional decline and OS were determined. RESULTS: Two hundred and forty-five patients were included in this study. At baseline, GA deficiencies were present in all domains and ADL and IADL were impaired in 51 and 63% of patients, respectively. At follow-up, functional decline in ADL was observed in 23% and in IADL in 45% of patients. In multivariable analysis, radiotherapy was predictive for ADL decline. No other predictors for ADL or IADL decline were identified. Stage and baseline performance status were predictive for OS. CONCLUSIONS: Older patients with lung cancer present with multiple deficiencies covering all geriatric domains. During treatment, functional decline is observed in almost half of the patients. None of the specific domains of the GA were predictive for functional decline or survival, probably because of the high impact of the aggressiveness of this tumor type leading to a poor prognosis.

Phase II study of stereotactic body radiotherapy to primary tumor and metastatic locations in oligometastatic nonsmall-cell lung cancer patients.

BACKGROUND: Stereotactic body radiotherapy (SBRT) has emerged as a treatment modality in patients presenting with oligometastatic nonsmall-cell lung cancer (NSCLC). SBRT is used as a local consolidative treatment to metastatic disease sites. The majority of patients included in SBRT trials for oligometastatic NSCLC have controlled primary tumors and brain metastases. PATIENTS AND METHODS: Oligometastatic NSCLC patients with ≤5 metastatic lesions were included in a prospective phase II trial to evaluate efficacy and toxicity of SBRT to all disease sites, primary tumor and metastatic locations. SBRT to a dose of 50 Gy in 10 fractions was delivered. Positron emission tomography-computed tomography (PET-CT) was carried out at baseline and 3 months after SBRT to evaluate the metabolic response rate according to PET Response Criteria in Solid Tumors (PERCIST). The progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier method from start of chemotherapy or radiotherapy. Side-effects were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. RESULTS: Twenty-six patients received SBRT after induction chemotherapy (n = 17) or as a primary treatment (n = 9). Median follow-up was 16.4 months. Overall metabolic response rate was 60% with seven patients (30%) achieving a complete metabolic remission and 7 (30%) a partial metabolic response. Any acute grade 2 toxicity was observed in four patients (15%) and grade 3 pulmonary toxicity in two patients (8%). Median PFS and OS were 11.2 and 23 months. The 1-year PFS and 1-year OS rate were 45% and 67%, respectively. CONCLUSION: SBRT to all disease sites, primary tumor and metastatic locations, in oligometastatic NSCLC patients produced an acceptable median PFS of 11.2 months.

Prospective non-interventional multicentre observational trial of first-line anti-cancer treatment in patients with metastatic renal cell cancer in Belgium.

OBJECTIVES: Renal cell carcinoma (RCC) accounts for 2·4% of all new cancers in Belgium. Over the past decade, the armamentarium for systemic therapy of metastatic RCC (mRCC) has undergone important changes with implementation of targeted therapies directed against pathways involved in the pathogenesis of RCC. We describe first-line treatment choice of a group of patients in 9 Belgian oncology centres between October 2009 and November 2012. METHODS: A clinical report form was established to assess patient characteristics, Karnofsky performance score, Memorial Sloan-Kettering Cancer Center risk criteria (MSKCC) and first-line therapy of mRCC patients. Choice of therapy and starting dose was analyzed before and after reimbursement of pazopanib in Belgium. RESULTS: Ninety-six patients were eligible for the study. Non-smokers accounted for 53% of the patients. Seventy-three per cent of the patients had 0 or 1 MSKCC criteria in the group of patients that started treatment more than 1 year after initial diagnosis. In the group of patients that started therapy less than 1 year after diagnosis, 85% had 2 or more MSKCC criteria. This difference was statistically significant (P<0·0001). Overall distribution of the first-line therapies consisted of 43% sunitinib, 33% pazopanib, 14% temsirolimus, 7% everolimus and 3% sorafenib. Seventeen (18%) out of 96 patients started at a reduced dose level. CONCLUSION: This report shows that the guidelines for the start of first-line treatment in mRCC in 9 centres in Belgium were applied most of the time: a tyrosine kinase inhibitor was the first treatment choice for most patients while temsirolimus was an option for poor prognosis patients. In the majority of patients standard dose levels were initiated, although in some patients adaptation of dosage/treatment schedule was recorded.

Zoledronic acid in patients with stage IIIA/B NSCLC: results of a randomized, phase III study.

BACKGROUND: Bone metastases are common in patients with advanced non-small-cell lung cancer (NSCLC) and can have devastating consequences. Preventing or delaying bone metastases may improve outcomes. PATIENTS AND METHODS: This study evaluated whether zoledronic acid (ZOL) delayed disease progression or recurrence in patients with controlled stage IIIA/B NSCLC after first-line therapy. Patients received vitamin D and calcium supplementation and were randomized to i.v. ZOL (every 3-4 weeks) or no treatment (control). The primary end point was progression-free survival (PFS). RESULTS: No significant intergroup differences were observed in PFS or overall survival (OS). Median PFS was 9.0 months with ZOL versus 11.3 months for control. Fifteen ZOL-treated (6.6%) and 19 control patients (9.0%) developed bone metastases. Estimated 1-year OS was 81.8% for each group. ZOL safety profile was consistent with previous clinical data, but with higher discontinuations versus control. Fifteen ZOL-treated (6.6%) and five control patients (2.3%) had renal adverse events. Two cases of osteonecrosis of the jaw were reported. CONCLUSIONS: ZOL did not significantly affect PFS or OS in stage IIIA/B NSCLC patients with controlled disease, with a trend toward worsening PFS in the longer-term follow-up. Few patients experienced bone metastases, possibly limiting the potential ZOL impact on disease course.

Clinical activity of afatinib (BIBW 2992) in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu.

Human epidermal growth factor receptor (HER)2/neu kinase domain mutations are found in approximately 1-4% of lung adenocarcinomas with a similar phenotype to tumors with epidermal growth factor receptor (EGFR) mutations. Afatinib is a potent irreversible ErbB family blocker. We determined the tumor genomic status of the EGFR and HER2 genes in non- or light smokers with lung adenocarcinoma in patients who were entered into an exploratory Phase II study with afatinib. Five patients with a non-smoking history and metastatic lung adenocarcinomas bearing mutations in the kinase domain of HER2 gene were identified, three of which were evaluable for response. Objective response was observed in all three patients, even after failure of other EGFR- and/or HER2-targeted treatments; the case histories of these patients are described in this report. These findings suggest that afatinib is a potential novel treatment option for this subgroup of patients, even when other EGFR and HER2 targeting treatments have failed.

Docetaxel in the treatment of metastatic castration-resistant prostate cancer (mCRPC): an observational study in a single institution.

BACKGROUND: Treatment with docetaxel in combination with prednisone is the standard first-line treatment in patients with metastatic castration-resistant prostate cancer (mCRPC). For patients failing first-line docetaxel no standard has emerged. OBJECTIVES: The outcome in routine daily clinical practice of a cohort of unselected chemotherapy-naïve mCRPC patients treated with docetaxel plus methylprednisolone as first- and further-line treatment in a single institution was investigated. PATIENTS AND METHODS: Data from the medical records of patients treated with docetaxel plus methylprednisolone either in a three-weekly (75 mg/m(2)) (D3) or a three-of-four-weekly (35 mg/m(2))(D1) schedule as first- or further-line treatment were analysed with respect to clinical and prostate-specific antigen (PSA) response, time-on-treatment (TOT), treatment-free interval (TFI), overall survival time (OS) and toxicity and were compared to the results of the registration study TAX 327. RESULTS: Out of 41 patients, 28 and 13 received first-line docetaxel according to the D3 and the D1 schedules respectively. An overall PSA response ≥50% was achieved in thirty patients (73%). In ten patients (24%) the PSA level was normalised. The median OS of the total population was 18.7 months. No significant differences were observed between the D3 and the D1 regimens with respect to PSA response, duration of PSA response, TOT, TFI and OS. Patients obtaining a normalisation of PSA level achieved a significantly superior OS, TOT and TFI compared to those without normalisation of PSA. Second-line treatment with docetaxel in nine patients induced a normalisation in PSA level in two (22%). The TOT and TFI from the start of second-line treatment, was significantly superior in docetaxel compared to non-docetaxel treated patients. Treatment with docetaxel was well-tolerated and only two patients were withdrawn for non-haematological toxicity during first- and further-line treatment. There were no differences in either subjective or objective side-effects between both treatment schedules. CONCLUSION: The results of the retrospective analysis of non-selected patients with mCRPC treated with docetaxel chemotherapy are in line with the data from TAX 327. Normalisation of PSA during first-line treatment with docetaxel is associated with a better survival irrespective of second- or further-line treatment used. Retreatment with docetaxel in second- or further-line remains a treatment option in docetaxel-sensitive patients.

Changing preferences for information and participation in the last phase of life: a longitudinal study among newly diagnosed advanced lung cancer patients.

PURPOSE: The objective is to explore changes over time in the information and participation preferences of newly diagnosed stage IIIb/IV non-small-cell lung cancer patients. METHODS: Patients were recruited by physicians in 13 hospitals and interviewed every 2 months until the fourth and every 4 months until the sixth interview. RESULTS: Sixty-seven patients were interviewed three times. Over a period of 4 months from diagnosis, half of patients changed their information preferences for palliative care and end-of-life decisions with a possible or certain life-shortening effect (ELDs, e.g., non-treatment decisions) in both directions, from not wanting to wanting the information, but also--and as much--from wanting to no longer wanting it. The latter were more likely to be in a better physical condition. Preferences for participation in medical decision making also changed: 50% to 78%, depending on the type of decision (general, treatment, transfer or ELD), changed their preference towards wanting more or less participation. Pain seemed to be a trigger for patients wanting more involvement, which contrasts with studies suggesting that patients who are more ill tend to give up more control. CONCLUSIONS: Doctors should regularly ask their advanced lung cancer patients how much information and participation they want because preferences do change in unexpected ways.

Pemetrexed-induced hyperpigmentation of the skin.

Pemetrexed (Alimta™) is used frequently for the treatment of lung cancer and is associated with various types and grades of cutaneous side-effects. We report here one patient who presented with asymptomatic hyperpigmentation of the skin, localized on the palms of the hands and the soles of the feet after administration of pemetrexed for lung cancer despite receiving standard pre-medication. This type of skin toxicity was completely reversible after withdrawal of the drug (without pharmacologic intervention) and has to our knowledge not been reported before.

Langerhans cell histiocytosis: two case reports in adults and review of the literature.

Langerhans Cell histiocytosis is a rare proliferative histiocytic disorder in which pathologic Langerhans cells accumulate in a variety of organs. The clinical presentation, evolution and therapeutic options are highly variable. Because of its relative rarity and the broad clinical spectrum, the diagnosis of Langerhans cell histiocytosis is often delayed or missed. At present, many questions with respect to aetiology, pathogenesis and treatment remain unanswered. In the present article we want to raise the awareness of this rare disease in adults and its diversity by the means of two case reports. In addition, the clinical manifestations, diagnosis and the current management are reviewed.

Pemetrexed-induced eyelid edema: incidence and clinical manifestations.

BACKGROUND: Pemetrexed-induced eyelid edema is a rare side-effect of pemetrexed treatment. PATIENTS AND METHODS: Retrospective analysis of the incidence and severity of eyelid edema was conducted in patients treated with pemetrexed in a single institution. RESULTS: Eighty-six patients received pemetrexed-containing chemotherapy either as a single agent (45 patients) or in combination with cis- or carboplatin (41 patients). Two patients (2.3%) with stage IV non-small cell lung cancer (NSCLC) presented the edema typically localized in the lower eyelid after first-line treatment with carboplatin-pemetrexed. The edema remained identical in both patients during treatment and regressed in one patient in whom treatment was withdrawn. No other localizations of edema were observed in these patients. CONCLUSION: Pemetrexed-induced eyelid edema may be more frequent than originally reported. The physiopathological mechanism and, as a consequence, the treatment and/or prevention of this apparently benign side-effect remains unknown.

Tyrosine kinase inhibitor-induced macrocytosis.

BACKGROUND: The tyrosine kinase inhibitors (TKI) sunitinib and imatinib were shown to induce macrocytosis in patients with renal cell cancer (RCC) and gastrointestinal stromal tumors (GIST), presumably through inhibition of the c-KIT dependent signaling pathway of erythroid progenitor cells of the bone marrow. PATIENTS AND METHODS: Hematology charts of patients with RCC, breast cancer (BC), GIST, non-small cell lung cancer (NSCLC) and hepatocellular cancer (HCC), receiving single-agent sunitinib, imatinib, sorafenib, erlotinib and BI 2992 (Tovok) at the recommended dose for at least 3 months were reviewed retrospectively for the occurrence of macrocytosis. RESULTS: Macrocytosis occurred in all patients with RCC and BC treated with sunitinib and in all patients with GIST treated with imatinib. The percentage increase of the mean corpuscular volume (MCV) of peripheral red blood cells (RBC) compared with baseline at 3, 6, 9 and 12 months was 12.4%, 16.8%, 16.6%, 12.7% and 0.7%, 5.6%, 5.9%, 5% with sunitinib and imatinib respectively. The values at 3, 6 and 9 months between both groups were significantly different. Sorafenib, erlotinib and BI 2992 did not induce macrocytosis. CONCLUSION: Sunitinib-induced macrocytosis was not confined to patients with RCC alone but also occurred in patients with BC. Imatinib also induced macrocytosis in patients with GIST but to a significantly lower degree. Because both drugs were used at an effective pharmacodynamic dose inhibiting c-KIT, these data strongly suggest that pathways in addition to c-KIT and not common to both agents are involved in the TKI-induced macrocytosis.

Tolerance of adjuvant letrozole outside of clinical trials.

Recently aromatase inhibitors have become a standard care as an adjuvant treatment for many postmenopausal patients with hormone receptor positive early breast cancer. Adjuvant letrozole was made available either immediately postoperative, after 2-3 years of tamoxifen, or as an extended treatment after 5 years of tamoxifen. Between October 2003 and October 2005, we analyzed the subjective tolerance in 185 postoperative early breast cancer patients receiving letrozole outside of a clinical trial. The most prominent toxicity was musculoskeletal pain. In addition hot flushes, increased fatigue, nausea, vomiting, anorexia, mood disturbances, vaginal dryness, hair loss and rash were also recorded. In contrast to the prospective randomized clinical trials, a high drop-out rate of 20% was documented, mainly due to aromatase inhibitor-associated arthralgia syndrome interfering significantly with the daily life of our patients. Although adjuvant aromatase inhibitors have proven to be generally superior to tamoxifen in the adjuvant setting, it is important to focus attention on the tolerance during the adjuvant therapy and to balance this against the potential benefit in individual patients. Alternative options including switching to tamoxifen remain available.

Complete metabolic tumour response, assessed by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET), after induction chemotherapy predicts a favourable outcome in patients with locally advanced non-small cell lung cancer (NSCLC).

BACKGROUND: 18FDG-PET and multislice computerized axial tomography (CT) scan are used for diagnosis, staging and response evaluation in NSCLC patients. The correlation between the response assessment by both imaging techniques and survival was assessed in patients with unresectable stage III NSCLC treated with induction chemotherapy followed by consolidation radiotherapy. METHODS: Thirty-one patients, enrolled in a phase II study evaluating the efficacy and toxicity of a novel triplet induction chemotherapy (paclitaxel, carboplatin and gemcitabine) (PACCAGE) before consolidation radiotherapy, were evaluated by CT and 18FDG-PET at baseline and after three cycles of chemotherapy. The correlation between CT and 18FDG-PET response and time to progression and overall survival was analyzed using the Kaplan-Meier estimates of survival and the log rank test. RESULTS: Ten patients with a complete response (CR) on 18FDG-PET had a significantly longer time to progression and overall survival than patients with a non-CR (median 19.9 months versus 9.8 months, p=0.026, and median >49 months versus 14.4 months, p=0.004, respectively). Twenty patients with a partial CT response (PR) had a significantly longer time to progression (median 15 months versus 9.4 months, p=0.001) than patients with a non-PR but the difference in overall survival only showed a trend (23.3 months versus 14.4 months, p=0.093). CONCLUSIONS: A CR on 18FDG-PET following induction chemotherapy for locally advanced, unresectable NSCLC seems to be a more powerful prognostic marker for survival compared to PR on CT.

A Belgian registry of interleukin-2 administration for treatment of metastatic renal cell cancer and confrontation with literature data.

In an effort to map the use of interleukin-2 (IL-2) treatment in patients with clear cell renal cell cancer (RCC) in Belgian hospitals, 44 cases were registered from 9 hospitals between February 2003 and June 2006. It was demonstrated that the majority of these patients were treated with subcutaneous (SC) IL-2. Other methods such as the inhalation of the drug in case of intrathoracic disease or high dose intravenous (IV) administration were much less frequent (3 and 0 cases in this registry, respectively). The results of antitumour activity (around 16% partial response-absence of complete responses) and toxicity of this drug correlate with observations from the literature with the SC administration. In view of the poor results and tolerance with the currently used cytokines (IL-2 or interferon-alfa), much hope is directed towards the development of the novel targeted drugs like sunitinib or sorafenib used alone or in combination with cytokines in this disease.

A novel triplet regimen with paclitaxel, carboplatin and gemcitabine (PACCAGE) as induction chemotherapy for locally advanced unresectable non small cell lung cancer (NSCLC).

UNLABELLED: Phase II study of 3 cycles of triplet induction chemotherapy (response, toxicity) followed by radiotherapy in locally advanced non small cell lung cancer (NSCLC). BACKGROUND: Patients with locally advanced inoperable non-small cell lung cancer are currently treated with concomitant or sequential chemotherapy and radiotherapy. However, the outcome of existing treatment modalities is unsatisfactory. Development of new strategies including more efficient systemic chemotherapy is warranted. OBJECTIVE: To study the antitumour activity and toxicity of a triplet combination of paclitaxel, carboplatin and gemcitabine as induction chemotherapy before radiotherapy, in locally advanced NSCLC and to evaluate time to progression and survival. METHODS: Three cycles of paclitaxel (175 mg/m(2) by 3h infusion on day 1), carboplatin (AUC 5mg/(mlmin) by IV bolus on day 1) and gemcitabine (1000 mg/m(2) by IV bolus on day 1 and 8) were administered every 3 weeks in reasonably fit patients. Fractionated radiotherapy with curative intent was initiated 4 weeks after the last chemotherapy administration. Toxicity was assessed weekly during cycle 1 and on day 1 and 8 in cycles 2 and 3. Response evaluation was performed at the end of cycle 3. RESULTS: Forty-eight patients (20 stage IIIA and 28 stage IIIB) received a total of 134 cycles of chemotherapy. Forty-two patients received the intended 3 cycles. Thirty patients obtained an objective response (1 complete and 29 partial response) or 62.5% on the intent to treat analysis (95% confidence interval: 49-76%). None of the responders became eligible for surgery. The median time to progression and survival for all patients was 10.1 and 15.7 month, respectively. A significant difference was observed in survival parameters between stage IIIA and stage IIIB patients. Haematological toxicity grade 3/4, mainly neutropenia and thrombocytopenia, was most prominent on day 15 of the treatment cycles. Haematological support by means of recombinant erythropoietin, red blood cell or platelet transfusion, filgrastim administration or a combination was needed in 21 patients. None of the patients discontinued chemotherapy because of haematotoxicity. Grade 3/4 non-haematological toxicity leading to chemotherapy withdrawal occurred early during induction (2 and 1 in cycles 1 and 2, respectively). CONCLUSION: Three cycles of the novel triplet combination of paclitaxel, carboplatin and gemcitabine (PACCAGE) is an active and feasible induction regimen for patients with locally advanced inoperable NSCLC. Neutropenia and to a lesser extent thrombocytopenia represent the main haematological toxicity. Whether this triplet regimen can improve outcome when compared to specific cisplatin doublet regimens should be evaluated in a phase III study.

Gefitinib monotherapy in advanced nonsmall cell lung cancer: a large Western community implementation study.

Epidermal growth factor receptor tyrosine kinase inhibitors represent a new treatment option for patients with advanced nonsmall cell lung cancer (NSCLC). This retrospective study examined to what extent previous clinical trial experience matches large-scale Western community implementation of this treatment. In the Belgian expanded access programme, the data from 513 patients with advanced or metastatic NSCLC, not suitable for further chemotherapy and receiving oral gefitinib 250 mg.day(-1) until disease progression, death or unacceptable toxicity, were analysed. The median (range) duration of gefitinib treatment was 2.3 months (0.0-32.7). Its use was predominantly in second- or third-line treatment. The overall response and disease control rates were 8.9 and 41.2%, respectively. In univariate analysis, response was more common in females and never-smokers. In multivariate analysis, female sex was the only significant predictive factor (odds ratio (OR) (95% confidence interval (CI)) 0.329 (0.129-0.839)). Symptom improvement was reported in 108 patients of whom 32 (29.6%) had an objective response, 66 (61.1%) experienced disease stabilisation and 10 (9.3%) progressed. Gefitinib was well tolerated; only 7.8% of the patients reported grade 3 or 4 toxicity. The overall median survival was 4.7 months, with a 1-yr survival rate of 21%. Survival was strongly influenced by a better performance status (PS) (good PS: hazard ratio (HR) (95%CI) 0.110 (0.077-0.157)) and adenocarcinoma with bronchioloalveolar carcinoma features histology (HR (95%CI) 0.483 (0.279-0.834)). In conclusion, the activity of gefitinib was confirmed in the present large Western community implementation study. Response, present in a small subgroup, led to a rewarding survival and could be predicted by sex only. Baseline performance status and adenocarcinoma with bronchioloalveolar carcinoma features histology were significant factors for survival.

Sequential administration of epirubicin and paclitaxel for advanced breast cancer. A phase I randomised trial.

Forty-six previously untreated patients with advanced breast cancer were eligible for the present randomised phase I study. It aimed to evaluate the toxicity and activity of a therapeutic sequence with epirubicin on day 1 followed by paclitaxel on day 2 (sequence A) or the reverse sequence, ie., paclitaxel on day 1 followed by epirubicin on day 2 (sequence B). The starting doses of epirubicin and paclitaxel, administered either according to sequence A or B, (level 1 cohort) were 90 mg/m2 and 175 mg/m2, respectively. Per cohort of 3 patients, the dose of paclitaxel was increased by 25 mg/m2 (levels 2 and 4) and of epirubicin by 10 mg/m2 (levels 3 and 5). Treatment was repeated with 3-week intervals. The maximal tolerated dose (MTD) was achieved at level 1 in sequence B (paclitaxel first) and level 3 (epirubicin 100 mg/m2 followed by paclitaxel 200 mg m2) in sequence A. Dose limiting toxicity (DLT) was neutropenia (+/- febrile) in both sequences. Cardiac events occurred in 28% of the patients; significant decrease in left ventricular ejection function (LVEF) was observed in 8/33 and in 2/13 patients in sequence A and B, respectively. This was associated with 5 and 1 cardiac heart failure (CHF), respectively. In 43 evaluable patients, 10 CR and 25 PR were observed (overall response rate 81%). In the 20 patients with locally advanced disease (LABC), the respective numbers were 7 CR and 11 PR; in the 23 metastatic (MBC) patients, 3 CR and 14 PR were recorded. The median survival of the both groups was not reached at 33 + months. In conclusion , the combination of epirubicin and paclitaxel has significant activity in breast cancer. The recommended sequence of both drugs in combination therapy, mainly to avoid neutropenia, is epirubicin day 1 followed by paclitaxel on day 2. Cardiac toxicity remains problematic in either sequence of administration.

Multi-center study of two dose levels of paclitaxel with carboplatin in locally advanced and metastatic non-small cell lung cancer (NSCLC).

BACKGROUND: The efficacy and toxicity of the combination of two cytotoxic compounds that are active as single agents in non-small cell lung cancer (NSCLC), paclitaxel (Taxol) and carboplatin (Paraplatin) was investigated in a multicenter, community-based setting. MATERIALS AND METHODS: Two consecutive cohorts of chemonaive patients with stages IIIA/B and IV NSCLC received two dose levels of paclitaxel. The first cohort received 200 mg/m2 over 3 hours (HD) and the second cohort 175 mg/m2 over 3 hours (LD) in combination with a fixed dose of carboplatin. The dose of carboplatin was calculated according to the Calvert formula with an area under the concentration versus time curve (AUC) value of 6 mg/ml/minute. The carboplatin clearance, calculated by the Chatelut formula rather than the glomerulation filtration rate (GFR) +25, was introduced into the Calvert formula. The eligibility criteria were identical for both cohorts throughout the study. Treatment was administered every three weeks. The study endpoints were response rate (RR), toxicity, time to progression (TTP) and survival (S). RESULTS: One hundred and thirty consecutive eligible patients from 36 Belgian institutions were fully evaluable for all study parameters (99 in the HD and 31 in the LD cohort). Myelosuppression was the most prominent side-effect of treatment with comparable results for both cohorts. The worst grade 3-4 leucopenia and neutropenia per patient in the HD versus LD cohort was 34.4 vs 19.3% and 59.2 vs 51.6%, respectively. 10.4% of patients in the HD cohort required hospitalisation for febrile neutropenia (6.2% with and 4.2% without documented bacterial infection), while in the LD cohort the respective figures were 13.7, 10.3 and 3.4%. The most prominent non-hematologic toxicities were alopecia and polyneuropathy, with no major difference between the HD and LD cohort (grade 2 alopecia in 78.1 vs. 83.9% and grade 3 neuropathy in 14.3 vs. 9.7%, respectively). The overall best clinical RR was 31 out of 130 (23.8%) with one complete (CR) and 30 partial responses (PR). The respective RR in the HD and LD cohort was 23.2 and 25.8%. Median TTP and S for all patients was 120 and 248 days, with no apparent difference between the HD and the LD cohort (119 and 254 versus 128 and 222, respectively). The one year survival was 34% in the HD cohort. The 95% confidence intervals for efficacy and toxicity parameters overlapped in both cohorts. CONCLUSION: In this multicenter study, the combination of paclitaxel and carboplatin produced a moderate RR of 23.8% in stages IIIA/B & IV NSCLC. The therapy was generally well tolerated at both doses of paclitaxel. Myelosuppression, neurotoxicity and alopecia were the major therapy-related side-effects. The differences between the two paclitaxel dose cohorts with respect to activity and toxicity were minimal. The use of the Chatelut formula to calculate the carboplatin clearance is feasible, but might have lead to the apparent excess in myelotoxicity in our study compared to other studies which used other methods for estimating renal function.