Hanspeter Honegger

Mediastinal Lymph Node Clearance After Docetaxel-Cisplatin Neoadjuvant Chemotherapy Is Prognostic of Survival in Patients With Stage IIIA pN2 Non–Small-Cell Lung Cancer: A Multicenter Phase II Trial

PURPOSE A multicenter, phase II trial investigated the efficacy and toxicity of neoadjuvant docetaxel-cisplatin in locally advanced non-small-cell lung cancer (NSCLC) and examined prognostic factors for patients not benefiting from surgery. PATIENTS AND METHODS Ninety patients with previously untreated, potentially operable stage IIIA (mediastinoscopically pN2) NSCLC received three cycles of docetaxel 85 mg/m2 day 1 plus cisplatin 40 mg/m2 days 1 and 2, with subsequent surgical resection. RESULTS Administered dose-intensities were docetaxel 85 mg/m2/3 weeks (range, 53 to 96) and cisplatin 95 mg/m2/3 weeks (range, 0 to 104). The 265 cycles were well tolerated, and the overall response rate was 66% (95% confidence interval [CI], 55% to 75%). Seventy-five patients underwent tumor resection with positive resection margin and involvement of the uppermost mediastinal lymph node in 16% and 35% of patients, respectively (perioperative mortality, 3%; morbidity, 17%). Pathologic complete response occurred in 19% of patients with tumor resection. In patients with tumor resection, downstaging to N0-1 at surgery was prognostic and significantly prolonged event-free survival (EFS) and overall survival (OS; P =.0001). At median follow-up of 32 months, the median EFS and OS were 14.8 months (range, 2.4 to 53.4) and 33 months (range, 2.4 to 53.4), respectively. Local relapse occurred in 27% of patients with tumor resection, with distant metastases in 37%. Multivariate analyses identified mediastinal clearance (hazard ratio, 0.22; P =.0003) and complete resection (hazard ratio, 0.26; P =.0006) as strongly prognostic for increased survival. CONCLUSION Neoadjuvant docetaxel-cisplatin is effective and tolerable in stage IIIA pN2 NSCLC. Resection is recommended only for patients with mediastinal downstaging after chemotherapy.

Docetaxel (Taxotere®)-cisplatin (TC): An effective drug combination in gastric carcinoma

PURPOSE A multi-centric trial was performed to explore the clinical activity, in terms of response and toxicity (primary objectives), duration of response and survival (secondary objectives), of docetaxel with cisplatin in advanced gastric cancer (AGC). PATIENTS AND METHODS Patients with measurable unresectable and/or metastatic gastric carcinoma, performance status < or = 1, normal hematological, hepatic and renal functions and not pretreated for advanced disease by chemotherapy received up to eight cycles of TC (docetaxel 85 mg/m2 dl, cisplatin 75 mg/m2 dl) q3w. Dose escalation to 100 mg/m2 was performed in five patients and was discontinued for excessive toxicity. RESULTS Forty-eight patients were accrued. A median of 5 cycles/patient was given. We observed 2 complete and 25 partial responses for an overall intent to treat response rate of 56% (95% CI: 41%-71%). Twelve patients had stable disease for > or = 9 weeks (3 cycles). The median time to progression and overall survival were 6.6 and 9 months, respectively. Grade > or = 3 toxicities were neutropenia 81%, anemia 32%, thrombocytopenia 4%, alopecia 36%, fatigue 9%, mucositis 9%, diarrhea 6%, nausea/vomiting 4%, neurologic 2%, and one anaphylaxis precluding treatment administration. We recorded nine episodes of non-fatal febrile neutropenia in eight patients, two of them with docetaxel at 100 mg/m2. There were no direct treatment-related deaths. CONCLUSIONS TC is active in AGC with a high response rate in a multicentric trial. Despite its hematotoxicity, this regimen is well tolerated and can be recycled as originally planned in 78% of the cases. These results may serve as basis for further developments of docetaxel containing regimens in this disease.

Phase II Study of Capecitabine and Oxaliplatin in First- and Second-Line Treatment of Advanced or Metastatic Colorectal Cancer

PURPOSE To determine the efficacy and tolerability of combining oxaliplatin with capecitabine in the treatment of advanced nonpretreated and pretreated colorectal cancer. PATIENTS AND METHODS Forty-three nonpretreated patients and 26 patients who had experienced one fluoropyrimidine-containing regimen for advanced colorectal cancer were treated with oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1,250 mg/m(2) bid on days 1 to 14 every 3 weeks. Patients with good performance status (World Health Organization grade 0 to 1) were accrued onto two nonrandomized parallel arms of a phase II study. RESULTS The objective response rate was 49% (95% confidence interval [CI], 33% to 65%) for nonpretreated and 15% (95% CI, 4% to 35%) for pretreated patients. The main toxicity of this combination was diarrhea, which occurred at grade 3 or 4 in 35% of the nonpretreated and 50% of the pretreated patients. Grade 3 or 4 sensory neuropathy, including laryngopharyngeal dysesthesia, occurred in 16% of patients on both cohorts. Capecitabine dose reductions were necessary in 26% of the nonpretreated and 45% of the pretreated patients in the second treatment cycle. The median overall survival was 17.1 months and 11.5 months, respectively. CONCLUSION Combining capecitabine and oxaliplatin yields promising activity in advanced colorectal cancer. The main toxicity is diarrhea, which is manageable with appropriate dose reductions. On the basis of our toxicity experience, we recommend use of capecitabine in combination with oxaliplatin 130 mg/m(2) at an initial dose of 1,250 mg/m(2) bid in nonpretreated patients and at a dose of 1,000 mg/m(2) bid in pretreated patients.

Prognostic factors affecting long-term outcomes in patients with resected stage IIIA pN2 non-small-cell lung cancer: 5-Year follow-up of a phase II study

The aim was to investigate the efficacy of neoadjuvant docetaxel–cisplatin and identify prognostic factors for outcome in locally advanced stage IIIA (pN2 by mediastinoscopy) non-small-cell lung cancer (NSCLC) patients. In all, 75 patients (from 90 enrolled) underwent tumour resection after three 3-week cycles of docetaxel 85 mg m−2 (day 1) plus cisplatin 40 or 50 mg m−2 (days 1 and 2). Therapy was well tolerated (overall grade 3 toxicity occurred in 48% patients; no grade 4 nonhaematological toxicity was reported), with no observed late toxicities. Median overall survival (OS) and event-free survival (EFS) times were 35 and 15 months, respectively, in the 75 patients who underwent surgery; corresponding figures for all 90 patients enrolled were 28 and 12 months. At 3 years after initiating trial therapy, 27 out of 75 patients (36%) were alive and tumour free. At 5-year follow-up, 60 and 65% of patients had local relapse and distant metastases, respectively. The most common sites of distant metastases were the lung (24%) and brain (17%). Factors associated with OS, EFS and risk of local relapse and distant metastases were complete tumour resection and chemotherapy activity (clinical response, pathologic response, mediastinal downstaging). Neoadjuvant docetaxel–cisplatin was effective and tolerable in stage IIIA pN2 NSCLC, with chemotherapy contributing significantly to outcomes.

Randomized study of recombinant human granulocyte colony-stimulating factor after high-dose chemotherapy and autologous bone marrow transplantation for high-risk lymphoid malignancies.

PURPOSE The aim of this prospective randomized trial was to examine the efficacy and safety of filgrastim after high-dose chemotherapy and autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS Patients with poor-risk non-Hodgkins lymphoma or relapsed Hodgkins disease were treated in a randomized, open-label trial to study the use of filgrastim as an adjunct to high-dose chemotherapy and ABMT. Of 43 assessable patients, 19 were randomized to receive filgrastim by continuous subcutaneous infusion at a dose of 10 micrograms/kg/d, 10 to filgrastim 20 micrograms/kg/d, and 14 to a parallel control group that received no filgrastim after ABMT. RESULTS For all filgrastim-treated patients analyzed together, the median time to neutrophil recovery > or = 0.5 x 10(9)/L after the day of ABMT was significantly accelerated to 10 days compared with 18 days in control patients (P = .0001). The median number of platelet transfusions was identical in both groups. Clinical parameters, including the median number of days with fever (1 v 4, P = .0418) and neutropenic fever (5 v 13.5, P = .0001) were significantly shorter in the filgrastim than in the control group. The number of days on intravenous antibiotics and duration of hospitalization were also shorter in the treated groups; however, the differences did not reach statistical significance. For patients treated with the two different dose levels of filgrastim, the neutrophil recovery and clinical results were similar. Filgrastim-associated toxicity appeared to be minimal, with five adverse events considered at least possibly related to filgrastim: two in the higher-dose group and three in the lower-dose group. All of these were rated moderate, except one case of severe bone pain that did not preclude continued filgrastim treatment at a lower dose. Survival and relapse-free survival were similar for control and filgrastim-treated patients. CONCLUSION Taken together, the results of this first randomized study support the role of filgrastim given as an adjunct to ABMT in accelerating neutrophil recovery, as well as in reducing treatment-related morbidity and overall duration of the treatment procedure.

Ototoxicity in patients with dose-intensive therapy for cisplatin-resistant germ cell tumors.

durable complete remission (rate, 57%) after dose-intense sequential, accelerated chemotherapy with paclitaxel ifosfamide and three cycles of high-dose carboplatin etoposide (mean target carboplatin area under the curve [AUC] of 24 [mg/mL] minute per cycle) followed by peripheral blood-derived stem-cell support in patients with cisplatin-resistant germ cell tumors. Hearing impairment or deafness were not reported as adverse effects. Carboplatin-induced ototoxicity in different high-dose combination regimens has been described by other investigators [2,3]. Between October 2000 and August 2002, we treated nine patients with resistant or recurrent germ cell tumors according to the regimen described by Motzer et al, with three cycles of high-dose carboplatin etoposide (carboplatin AUC of 24 [mg/mL] minute). All patients were pretreated with as many as four cycles of cisplatin-containing chemotherapy. At the beginning of the dose-intense therapy, none of the patients had a clinically obvious hearing impairment. During treatment, all of them started to suffer from hearing disorders and finally developed a clinically manifested hearing impairment. Audiometry revealed bilateral high-frequency sensorineural hearing loss (above 2,000 Hz), with tinnitus in six patients; three of them needed a hearing aid. Hearing impairment was apparent in the other three patients as well, though audiometry was not done. Our experience confirms the favorable results in this group of patients with poor prognosis (five of nine patients are in durable complete remission; complete remission rate, 56%), whereas the ototoxicity observed with this regimen is a considerable adverse effect. Ototoxicity seems to be strongly related to the cumulative carboplatin AUC [3]. High-dose carboplatin is thought to be important to obtain favorable results in patients with relapsed or resistant germ cell tumors. Clinicians should be aware of the possible severe ototoxicity with this regimen, and patients undergoing multiple cycles of carboplatin-containing high-dose chemotherapy should be informed about this relevant toxicity.

Treatment of advanced soft-tissue sarcomas using a combined strategy of high-dose ifosfamide, high-dose doxorubicin and salvage therapies

Having determined in a phase I study the maximum tolerated dose of high-dose ifosfamide combined with high-dose doxorubicin, we now report the long-term results of a phase II trial in advanced soft-tissue sarcomas. Forty-six patients with locally advanced or metastatic soft-tissue sarcomas were included, with age <60 years and all except one in good performance status (0 or 1). The chemotherapy treatment consisted of ifosfamide 10 g m−2 (continuous infusion for 5 days), doxorubicin 30 mg m−2 day−1 × 3 (total dose 90 mg m−2), mesna and granulocyte-colony stimulating factor. Cycles were repeated every 21 days. A median of 4 (1–6) cycles per patient was administered. Twenty-two patients responded to therapy, including three complete responders and 19 partial responders for an overall response rate of 48% (95% CI: 33–63%). The response rate was not different between localised and metastatic diseases or between histological types, but was higher in grade 3 tumours. Median overall survival was 19 months. Salvage therapies (surgery and/or radiotherapy) were performed in 43% of patients and found to be the most significant predictor for favourable survival (exploratory multivariate analysis). Haematological toxicity was severe, including grade ⩾3 neutropenia in 59%, thrombopenia in 39% and anaemia in 27% of cycles. Three patients experienced grade 3 neurotoxicity and one patient died of septic shock. This high-dose regimen is toxic but nonetheless feasible in multicentre settings in non elderly patients with good performance status. A high response rate was obtained. Prolonged survival was mainly a function of salvage therapies.

A prospective study of risk-adapted therapy for large cell non-Hodgkin's lymphoma with VACOP-B followed by high-dose CBV and autologous progenitor cell transplantation for high-risk patients in remission

Several centres reported a favourable outcome after high‐dose chemotherapy with autologous progenitor cell transplantation in selected patients with high‐risk large cell non‐Hodkgins lymphoma in first remission. Based on these observations, we wanted to prospectively determine the outcome of a risk‐adapted therapy for patients with large cell lymphoma. Patients aged 60 years or less received 12 weeks of VACOP‐B chemotherapy. For high‐risk patients in remission this was immediately followed by high‐dose chemotherapy with cyclophosphamide, carmustine and etoposide and autologous progenitor cell transplantation. High‐risk criteria were defined before the establishment of the International Index and included large cell lymphoma stage III or IV or mediastinal large lymphoma with sclerosis stage II or higher, and the presence of bulky tumours and/or an elevated LDH. 89 patients fulfilled the clinical selection criteria and were entered onto this multicentre study. 82 patients were evaluable after confirmation of large cell histology by pathology review. Of these, 51 were considered to be in the low‐risk group and 31 in the high‐risk group. The 3‐year event‐free survival for all patients was 68%. The 3‐year event‐free survival was 76% for the low‐risk and 55% for the high‐risk group (P = 0.061). Only 22/31 high‐risk patients were able to receive the high‐dose chemotherapy in first remission as intended. In conclusion, although our study demonstrated that a risk‐adapted therapy for large cell lymphoma could be safely administered, the potential impact on outcome of the strategy chosen here is likely to be small.

Validation of prognostic factors and survival of patients with multiple myeloma in a real-life autologous stem cell transplantation setting: a Swiss single centre experience

PRINCIPLES High-dose chemotherapy with subsequent autologous stem cell transplantation (ASCT) is an important treatment option in younger patients with multiple myeloma (MM). We analysed the outcome of patients treated at our institution outside the clinical trials framework and tried to identify risk factors prognostic for survival. METHODS Medical histories of the patients were screened for response, event-free survival (EFS) and overall survival (OS). Pre-transplant variables were analysed to identify possible prognostic risk factors. RESULTS Overall, 182 ASCT were performed in 120 patients with MM from 2002 to 2007. Treatment-related mortality (TRM) was 0.5%. Median EFS was 23.1 months (95% confidence interval [CI]: 19.4-28.4) and median OS was 49.8 months (95%CI: 43.7 - not reached) in the whole patient population. The median OS in patients who received one ASCT was 46.4 months (95%CI: 35.2 - not reached), and 63.7 months (95%CI: 48.9 - not reached) in patients who underwent double ASCT. Patients who already achieved a complete remission (CR) before ASCT had a longer EFS (p = 0.016) than patients without CR. Additionally, patients who achieved a CR after ASCT had a longer EFS (p = 0.0061) and OS (p = 0.0024) than patients without CR. ISS stage <III at first diagnosis strongly correlated with improved EFS (p = 0.0006) and OS (p <0.0001). CONCLUSIONS ASCT is a safe and effective treatment mode in eligible patients with MM. TRM was below average at our institution. Achievement of CR after transplantation was the most valuable predictor for improved overall survival.

Equivalence of Pegfilgrastim and Filgrastim in Lymphoma Patients Treated with BEAM Followed by Autologous Stem Cell Transplantation

Objective: To evaluate the impact of pegfilgrastim on engraftment, hospital stay and resources in patients with Hodgkin’s and non-Hodgkin’s lymphoma after conditioning with high-dose BEAM followed by autologous peripheral blood stem cell transplantation (APBSCT) compared with filgrastim. Methods: We reviewed patient charts and our prospective transplantation database for clinical data from the post-transplant period. An integrated cost analysis, including the use of blood products and length of hospital stay, was also performed. Results: Fourteen (26%) patients with Hodgkin’s lymphoma and 40 (74%) patients with non-Hodgkin’s lymphoma were analyzed. Thirty-four (68%) patients received single-dose pegfilgrastim (6 mg), and 20 (32%) patients received daily filgrastim (5 µg/kg) after APBSCT. No differences were observed regarding duration of neutropenia grade 4 (pegfilgrastim median 7 days/filgrastim median 8 days; p = 0.13), thrombocytopenia grade 4 (7/9.5 days, respectively; p = 0.21), fever (4.5/2 days; p = 0.057), intravenous antibiotic treatment (11/10 days; p = 0.75) or length of hospital stay (16.5/16 days; p = 0.27) between the groups. The use of pegfilgrastim resulted in 12% higher treatment-related costs when compared to filgrastim, without reaching statistical significance (p = 0.38). Conclusion: Pegfilgrastim appears to be equivalent to filgrastim after high-dose BEAM followed by APBSCT in the treatment of lymphoma patients.