Hypofractionated radiotherapy for the palliation of advanced head and neck cancer in patients unsuitable for curative treatment--"Hypo Trial".

BACKGROUND AND PURPOSE: The primary purpose of the trial was to assess rate of tumour response to a hypofractionated course of radiotherapy in patients with incurable squamous cell carcinoma of the head and neck (HNSCC). Secondary objectives included radiation toxicity, symptom control, quality of life (QoL) and progression-free and overall survival. PATIENTS AND METHODS: Patients were planned to receive 30 Gy in 5 fractions at 2/week, at least 3 days apart, with an additional boost of 6 Gy for small volume disease (< or =3 cm) in suitable patients. Thirty-seven patients were enrolled between August 2004 and March 2006. Median age was 68 (43-87) years, 81% were male and the predominant primary site was oropharynx (32%). The majority (73%) presented with Stage III-IV disease. RESULTS: Thirty-five patients received radiotherapy, 1 died prior to treatment and one refused treatment. Of the 35 patients receiving radiotherapy, 31 (88%) received > or =30 Gy. Of the 35 patients who received treatment the overall objective response was 80%. Grade 3 mucositis and dysphagia were experienced in 9/35 (26%) and 4/35 (11%), respectively. QoL and symptom control were assessable in 21 patients. Thirteen (62%) reported an overall improvement in QoL and 14 (67%) experienced an improvement in pain. The median time to progression and death was 3.9 and 6.1 months, respectively. CONCLUSION: The "Hypo Trial" regimen provided effective palliative treatment in HNSCC unsuitable for curative treatment. Compliance was excellent and resulted in high response rates, symptom control and improvement in QoL with acceptable toxicity. However, progression free and overall survival was short.     

Efficient palliation in patients with small-cell lung cancer by a combination of paclitaxel, etoposide and carboplatin: quality of life and 6-years'-follow-up results from a randomised phase III trial

PURPOSE: Based on the promising activity of paclitaxel in small-cell lung cancer (SCLC) we conducted a randomized phase III trial to evaluate whether a combination of paclitaxel, carboplatin and etoposide phosphate (TEC) improves survival and time to progression as well as tolerability and quality of life (QoL) compared to a regimen of carboplatin, etoposide phosphate and vincristine (CEV) in SCLC patients. PATIENTS AND METHODS: Six hundred and fourteen patients with stages I-IV SCLC were randomly assigned between January 1998 and December 1999 to both treatment arms. All patients were evaluated for response rate, survival, side effects and quality of life with overall survival (OS) serving as primary endpoint. A final analysis was done after a six-year follow-up. Survival curves were estimated using Kaplan-Meier curves and tested with the log-rank test. Quality of life data were assessed in using the EORTC QLQ-C30 questionnaire and evaluated by calculating and comparing the mean scores as well as applying longitudinal techniques. RESULTS: Six hundred and eight patients were evaluable for efficacy and toxicity. The long-term follow-up confirms the significant survival benefit for the paclitaxel, etoposide, carboplatin (TEC) regimen with a median OS of 12.5 months compared to 11.7 months for the CEV arm (HR, 1.21; 95% CI, 1.02-1.43; P=.030). The 5-year survival rates were 14% for the experimental versus 6 % for the CEV arm. Significant survival prolongation was also observed in the subgroup of patients with stage IV disease (HR, 1.27; 95% CI, 1.00-1.60; P=.047). The previously reported clinical benefit in form of an overall reduction of grade 3/4 toxicity was backed by the results of the comprehensive QoL analysis we report hereby. TEC significantly improves the relevant QoL parameters like global overall QoL or physical functioning. CONCLUSION: When administered in combination with etoposide and carboplatin, paclitaxel is able to offer in SCLC patients with extensive disease a survival benefit without additional toxicities, but with gains in patient-reported quality of life. In terms of efficient palliative care, TEC might be seen as an alternative to standard cisplatin plus etoposide in patients requesting a powerful palliative regimen not compromising any survival benefit.     

Hypofractionated radiotherapy for the palliation of advanced head and neck cancer in patients unsuitable for curative treatment – “Hypo Trial”

Background and purposeThe primary purpose of the trial was to assess rate of tumour response to a hypofractionated course of radiotherapy in patients with incurable squamous cell carcinoma of the head and neck (HNSCC). Secondary objectives included radiation toxicity, symptom control, quality of life (QoL) and progression-free and overall survival.Patients and methodsPatients were planned to receive 30 Gy in 5 fractions at 2/week, at least 3 days apart, with an additional boost of 6 Gy for small volume disease (⩽3 cm) in suitable patients. Thirty-seven patients were enrolled between August 2004 and March 2006. Median age was 68 (43–87) years, 81% were male and the predominant primary site was oropharynx (32%). The majority (73%) presented with Stage III–IV disease.ResultsThirty-five patients received radiotherapy, 1 died prior to treatment and one refused treatment. Of the 35 patients receiving radiotherapy, 31 (88%) received ⩾30 Gy. Of the 35 patients who received treatment the overall objective response was 80%.Grade 3 mucositis and dysphagia were experienced in 9/35 (26%) and 4/35 (11%), respectively. QoL and symptom control were assessable in 21 patients. Thirteen (62%) reported an overall improvement in QoL and 14 (67%) experienced an improvement in pain. The median time to progression and death was 3.9 and 6.1 months, respectively.ConclusionThe “Hypo Trial” regimen provided effective palliative treatment in HNSCC unsuitable for curative treatment. Compliance was excellent and resulted in high response rates, symptom control and improvement in QoL with acceptable toxicity. However, progression free and overall survival was short.     

Second-line chemotherapy of metastatic malignant melanoma with intravenous treosulfan: a phase II multicentre trial

The purpose of this multicentre phase II trial was to evaluate time to progression, survival time, rate of objective tumour response and toxicity of second-line intravenous treosulfan chemotherapy in stage IV melanoma patients. Thirty-one patients with measurable stage IV malignant melanoma and prior chemotherapy with a dacarbazine-containing regimen were included. Of this group, 26 patients were evaluable. All patients received treosulfan (8 g/m intravenously on day 1; cycle repeated every 28 days up to six courses). Patients were evaluated for tumour response, survival time and toxicity. No objective responses (complete or partial) were observed. Five patients (19%) showed no change and 21 had progressive disease after treosulfan treatment. Four patients experienced a minor or mixed response. The median time to progression was 1.8 months (95% confidence interval [CI] 1.6-2.1 months) and the median overall survival was 6.5 months (95% CI 3.1-10 months). The 1 year survival rate was 33.9% (95% CI 15.4-52.3%). Leukocytopenia and thrombocytopenia (Common Toxicity Criteria grades 3 and 4) occurred in 15% and 18% of cases, respectively. The non-haematological toxicity of this outpatient regimen was mild. In conclusion, intravenous treosulfan treatment does not induce objective response rates when used as a second-line treatment of metastatic malignant melanoma.     

Weekly systemic cisplatin plus locoregional hyperthermia: an effective treatment for patients with recurrent cervical carcinoma in a previously irradiated area.

PURPOSE: Patients with recurrent cervical carcinoma within a previously irradiated area respond poorly to chemotherapy. We have treated these patients with simultaneous cisplatin and hyperthermia (CDDP + HT) and investigated response, toxicity, palliative effect and survival. MATERIALS AND METHODS: Between 1992 and 2005 47 patients received CDDP + HT. Response was evaluated by gynaecologic examination and CT-scan. The Common Toxicity Criteria (CTC) were used for evaluation of toxicity and palliative effect. The Kaplan-Meier method was used to estimate survival, and Cox regression analysis to evaluate the influence of prognostic factors. RESULTS: The objective response rate was 55%, palliation was achieved in 74% and operability in 19% of patients. Two patients are currently disease free at 9 years and 18 + months following treatment and 2 remained disease free until death by other causes. The median survival was 8 months and was influenced by duration of disease free interval and tumour diameter. Grade 3-4 haematological toxicity was observed in 36% of patients and renal toxicity was maximum grade 2. CONCLUSION: CDDP + HT results in a high response rate and acceptable toxicity in patients with recurrent cervical cancer.     

Cisplatin versus carboplatin in combination with mitomycin and vinblastine in advanced non small cell lung cancer. A multicenter, randomized phase III trial

BACKGROUND: In advanced not selected NSCLC chemotherapy achieved an advantage of approximately 1-2 months on median survival versus best supportive care. Chemotherapy seems to improve symptoms control, even if randomised studies with quality of life as first endpoint are lacking and often chemotherapy toxicity compromises the frail cost/benefit ratio. The aim of the present study is to evaluate the impact on QoL, substituting cisplatin, a pivot drug in NSCLC therapy, with carboplatin, an analogue with an improved toxicity profile. The combination of cisplatin with Mitomycin and Vinblastine was one of the most frequently used in the palliative setting at the time of design of our study. METHODS: Patients were randomized to receive MVP regimen (Mitomycin-C 8 mg/m2 d1, Vinblastine 4 mg/m2 d 1-8, Cisplatin 100 mg/m2 d1) or MVC regimen (Mitomycin-C 8 mg/m2 d1, Vinblastine 4 mg/m2 d 1-8, Carboplatin 300 mg/m2 d1) every 3 weeks. The QoL was evaluated by the Spitzer QL-Index and by the EORTC QLQ-C30+LC 13 questionnaires before chemotherapy, after one cycle, after three cycles, and then every 6 weeks in the first 6 months and every 3 months thenafter. RESULTS: From September 1994 to July 1997, 153 consecutive patients were randomized to MVP (75 patients) or MVC arm (78 patients). Despite difficulties in carrying out and analysing QoL items in such patients, the global QoL evaluated by the Spitzer's questionnaire suggested an advantage for MVC regimen (P=0.05) and a significant difference was observed in global health subdomain (P=0.04). The disease-related symptoms improved with time, and the benefits lasted for the entire treatment period. When evaluated with the EORTC questionnaire there was significantly less nausea and vomiting (P=0.0001), appetite loss (P=0.01), insomnia (P=0.03), constipation (P=0.01) and peripheral neuropathy (P=0.01) in favour of MVC, and a trend for less hair loss (P=0.05). The advantage lasted for all the duration of chemotherapy. No differences were observed in global quality of life subdomain (P=0.40) between the two regimen. QoL was the first endpoint and the statistical power was inadequate to assess other parameters. However, we reported a response rate of 43.1 and 38.6%, respectively, in MVP and MVC arm (P=0.59) and a median survival of 10.2 and 7.2 months, respectively, for cisplatin and carboplatin arm (P=0.39). CONCLUSIONS: The carboplatin containing regimen (MVC) has a significant better toxicity profile than the cisplatin containing (MVP) regimen as proven both by the EORTC questionnaires and by the WHO toxicity data reported by physicians. No significant differences in terms of response rate, time to progression and overall survival were observed between the two regimen. The two chemotherapy regimen showed a similar effectiveness in symptom palliation when evaluated with C30 addendum of EORTC QOL questionnaire. With the Spitzer's questionnaires a trend towards an improved quality of life index was observed during treatment with the carboplatin combination in comparison to the cisplatin combination. This difference, however, was not observed when the global quality of life was evaluated with the EORTC patients compiled questionnaires. A carboplatin containing regimen with better toxicity profile and a similar potentiality for symptoms control offers an option in comparison to similar cisplatin containing combinations in the palliative treatment of advanced NSCLC.     

Randomized phase II trial of carboplatin versus paclitaxel and carboplatin in platinum-sensitive recurrent advanced ovarian carcinoma: a GEICO (Grupo Espanol de Investigacion en Cancer de Ovario) study.

BACKGROUND: The aim of this study was to determine whether the response rate for the paclitaxel-carboplatin combination is superior to carboplatin alone in the treatment of patients with platinum-sensitive recurrent ovarian carcinoma. PATIENTS AND METHODS: Patients with recurrent ovarian carcinoma, 6 months after treatment with a platinum-based regimen and with no more than two previous chemotherapy lines, were randomized to receive carboplatin area under the curve (AUC) 5 (arm A) or paclitaxel 175 mg/m(2) + carboplatin AUC 5 (arm B). The primary end point was objective response, following a 'pick up the winner' design. Secondary end points included time to progression (TTP), overall survival, tolerability and quality of life (QoL). RESULTS: Eighty-one patients were randomized and included in the intention-to-treat analysis. The response rate in arm B was 75.6% [26.8% complete response (CR) + 48.8% partial response (PR)] [95% confidence interval (CI) 59.7% to 87.6%] and 50% in arm A (20% CR + 30% PR) (95% CI 33.8% to 66.2%). No significant differences were observed in grade 3-4 hematological toxicity. Conversely, mucositis, myalgia/arthralgia and peripheral neurophaty were more frequent in arm B. Median TTP was 49.1 weeks in arm B (95% CI 36.9-61.3) and 33.7 weeks in arm A (95% CI 25.8-41.5). No significant differences were found in the QoL analysis. CONCLUSIONS: Paclitaxel-carboplatin combination is a tolerable regimen with a higher response rate than carboplatin monotherapy in platinum-sensitive recurrent ovarian carcinoma.     

Phase II study of gemcitabine in combination with docetaxel in patients with advanced pancreatic carcinoma (E1298). A trial of the eastern cooperative oncology group

BACKGROUND: Responses have been observed in several studies of docetaxel as treatment for advanced pancreatic carcinoma. This trial was designed to determine if the addition of docetaxel to gemcitabine therapy produced responses in >/=25% of patients with chemonaive advanced pancreatic cancer. PATIENTS AND METHODS: This trial involved patients with biopsy-proven, advanced carcinoma of the pancreas not amenable to surgical resection. Patients received docetaxel 75 mg/m(2) i.v. over 1 h followed by gemcitabine 2,000 mg/m(2) biweekly until progression or intolerable toxicity. The primary endpoint of the trial was to determine the objective response rate with secondary endpoints of progression-free survival and overall survival. RESULTS: Out of the 32 eligible patients, 2 patients had a complete response and 2 patients had a partial response for an observed objective response rate of 12.5% (90% CI: 4.4, 26.4%). Median survival was 4.7 months. Most toxicities were hematologic, with 48% of patients experiencing grade 4 toxicity. CONCLUSIONS: The confirmed complete response rate of 6% and partial response rate of 6% is encouraging, but the toxicity of this regimen appears significant. Based upon these results, this combination of gemcitabine and docetaxel is not worthy of further study. Different schedules and dosages may be more promising.     

Trimetrexate as biochemical modulator of 5-fluorouracil/leucovorin in advanced colorectal cancer: final results of a randomised European study.

BACKGROUND: Trimetrexate (TMTX) is a biochemical modulator of 5-fluorouracil (5-FU) and leucovorin (LV). Phase II trials have shown promising activity of 5-FU/LV/TMTX in patients with advanced colorectal cancer (ACC). This trial evaluated the effect of TMTX in combination with 5-FU/LV as first-line treatment in ACC. PATIENTS AND METHODS: Patients with ACC were randomised to receive either intravenous LV 200 mg/m2/5-FU 600 mg/m2 or TMTX 110 mg/m2 followed 24 h later by LV 200 mg/m2/5-FU 500 mg/m2 plus oral LV rescue. Both schedules were given weekly for 6 weeks every 8 weeks. Patients were evaluated for progression-free survival (PFS), overall survival (OS), tumour response, quality of life (QoL) and toxicity. RESULTS: A total of 365 patients were randomised. A statistically significant prolongation of median PFS was seen in patients treated with TMTX/5-FU/LV compared with 5-FU/LV (5.4 months versus 4.1 months, respectively; P = 0.03), and a trend towards a significant benefit for OS (13.4 months versus 10.5 months, respectively; P = 0.08). Tumour response, QoL and toxicity were comparable between the two arms. Diarrhoea was the most frequently occurring grade 3 or 4 toxicity (22% and 30%, respectively). CONCLUSIONS: The addition of TMTX to a weekly regimen of 5-FU/LV results in a small but significant improvement in PFS without adding toxicity or worsening QoL in patients with ACC.     

Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non-small-cell lung cancer: A randomized phase III study of the Italian Lung Cancer Project.

PURPOSE: To compare gemcitabine and cisplatin (GC) with mitomycin, ifosfamide, and cisplatin (MIC) chemotherapy in patients with stage IIIB (limited to T4 for pleural effusion and N3 for supraclavicular lymph nodes) or stage IV non-small-cell lung cancer (NSCLC). The end points were the evaluation of quality of life (QoL), response rates, survival, and toxicity. PATIENTS AND METHODS: Three hundred seven patients were randomized to receive either gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 plus cisplatin 100 mg/m(2) on day 2, every 28 days, or mitomycin 6 mg/m(2), ifosfamide 3,000 mg/m(2), and mesna on day 1 plus cisplatin 100 mg/m(2) on day 2, every 28 days. The whole-blood cell count was repeated on day 1 in both arms and weekly in the GC arm before each gemcitabine administration. RESULTS: No major differences in changes in QoL were observed between the two treatment arms. The objective response rate was 38% in the GC arm compared with 26% in the MIC arm (P =.029). The median survival time was 8.6 months in the GC arm and 9.6 months in the MIC arm (P =.877, log-rank test). Grade 3 and 4 thrombocytopenia was significantly worse in the GC arm (64% v 28%, P <.001), whereas grade 3 and 4 alopecia was reported more commonly in the MIC arm (39% v 12%, P <. 001). CONCLUSION: We report an increased response rate without changes in QoL and a similar overall survival, time to progression, and time to treatment failure for the GC when compared with the MIC regimen in the treatment of advanced NSCLC.     

Docetaxel is effective in heavily pretreated patients with disseminated nasopharyngeal carcinoma

BackgroundTo evaluate the efficacy and toxicity of single-agent docetaxel (Taxotere) as therapy in patients with disseminated nasopharyngeal carcinoma (NPC).Patients and methodsPatients with histologically confirmed metastatic or recurrent NPC who have failed at least one line of palliative chemotherapy regimen but no prior docetaxel were eligible. Patients received weekly docetaxel every 28 days (docetaxel 30 mg/m² on days 1, 8 and 15) and were evaluated every two cycles of treatment of response assessment. Quality-of-life (QoL) assessments during the treatment period were done using the European Organization for Research and Treatment of Cancer QoL questionnaire QLQ-C30; version 3.0.ResultsThirty patients were assessable for toxicity and response. The median age of the patients was 47 years (range 25–68 years) and the majority of patients had good performance status (Eastern Cooperative Oncology Group 0–1). Grade 3 or 4 toxicity included fatigue (13%), anemia (10%) and diarrhea (3%) of patients. Eleven (37%) and four (13.3%) patients achieved partial response and stable disease, respectively. The median progression-free survival was 5.3 months and median overall survival of 12.8 months. The partial responders had a mean duration of response of 4.1 months. Docetaxel caused a significant decline in QoL scores during treatment of patients responding or progressing with the treatment.ConclusionsOur findings suggest that weekly docetaxel is well tolerated and is an active agent in patients with disseminated NPC who were previously exposed and largely refractory to platinum-based chemotherapy but can cause a significant decline in QoL during treatment.     

Mitomycin C and Vinorelbine for second-line chemotherapy in NSCLC--a phase II trial

Single-agent therapy with Docetaxel or Pemetrexed is the current therapy of choice for second-line treatment in advanced non-small-cell lung cancer (NSCLC). The role of older agents was underattended over the last years. This study presents the combination of Mitomycin C and Vinorelbine in pretreated patients. Forty-two patients (stage IIIB and IV, pretreated with platinum-based chemotherapy) received 8 mg m(-2) Mitomycin C on day 1 and 25 mg m(-2) Vinorelbine on days 1 and 8 of a 28-day cycle. End points were objective tumour response, survival, and toxicity. Additionally, quality of life (QoL) was assessed. Five patients (11.9 %) achieved partial responses and 13 patients (31.9%) stable disease. Progression-free survival was 16 weeks. The median overall survival was 8.5 month. Eleven patients (26.2 %) suffered from grade 3 or 4 neutropenia and four patients (9.52%) from grade 3 or 4 anaemia. Evaluation of QoL showed that some items ameliorated during therapy. The therapeutic concept including Mitomycin C and Vinorelbine offers an efficacious and well-tolerated regimen, with relatively low toxicity. Objective response and survival data correlate with other second-line studies using different medication. As costs of Mitomycin C and Vinorelbine are lower compared with current drugs of choice, this regimen is likely to be cost-saving.     

Paclitaxel and mitoxantrone in metastatic breast cancer: a phase II trial of the Italian Oncology Group for Cancer Research

Background: In a previous dose-finding trial, in previously treated patients with metastatic breast cancer (MBC), we showed that the combination of Mitoxantrone (M) and Paclitaxel (P) may be an interesting (response rate: 69%) and well-tolerated regimen. On the basis of these results, our group started a new trial in chemotherapy-naive patients with MBC. Patients and Method: Forty-six women entered in this trial, and all patients were evaluated for response and toxicity. Schedule of treatment was P 175 mg/m² over 3 hr day 1 and M 12 mg/m² day 1, every 3 weeks. Patients were reevaluated every 3 months and chemotherapy was continued unless tumor progression or unacceptable toxicity occurred. Result: The intent-to-treat objective response was 61% (95% confidence interval: 49%-78%). Five patients (11%) obtained complete response and 23 (50%) partial response with a median time to failure of 14 months. The median survival was 22 months (range 1-39). The principal toxicity was hematological: 38 (82%) patients had grade 3 to 4 leukopenia; only 2 patients had grade 4 anemia and one grade 4 thrombocytopenia. Nonhematological toxicity (grade 3-4) was mild and cardiotoxicity was infrequent. Conclusion: This trial suggests the combination of M and P is an active palliative regimen for patients with MBC. Toxicity was moderate. The infrequent development of cardiotoxicity suggests this combination may not share the problems reported with P plus doxorubicin combinations.     

Hypofractionated intensity-modulated radiotherapy for primary glioblastoma multiforme

PURPOSE: A pilot study was designed to evaluate the safety and efficacy of a novel regimen of hypofractionated intensity-modulated radiotherapy (RT) in the adjuvant treatment of primary glioblastoma multiforme (GBM). The rationale of the study was to combine the potential radiobiologic advantage of hypofractionation to GBM with a highly conformal radiotherapeutic technique. The study was designed to measure the acute and chronic morbidity of patients treated with this regimen, response of GBM to the treatment, overall survival, and time to disease progression after therapy completion. METHODS AND MATERIALS: Twenty eligible patients were accrued between February 1999 and May 2000 for the study. All patients had Karnofsky performance scores of >/=70. All patients were treated with intensity-modulated RT using the NOMOS Peacock system. A dose of 50 Gy was delivered in 5-Gy daily fractions within 2 weeks to enhancing primary disease, residual tumor, or surgical cavity. Simultaneously, 30 Gy was prescribed in 3-Gy daily fractions to surrounding edema. The time to progression was measured with serial neurologic examinations and MRI or CT scans after RT completion. Acute and late toxicity was graded using Radiation Therapy Oncology Group neurotoxicity scores. RESULTS: Of the 20 patients, 18 were evaluated for outcome. The median time to disease progression was 6 months after RT completion. The median overall survival was 7 months after treatment completion. All recurrences were within 2 cm of the operative bed. Neurotoxicity during therapy was minimal, with all patients experiencing Grade 0 or 1 toxicity. Late toxicity included 10 patients with Grade 0, 2 patients with Grade 2, and 3 patients with Grade 4 toxicity, manifesting as brain necrosis requiring surgical reexcision. The survival of the 3 patients with brain necrosis was 23, 20, and 9 months. Mortality in all cases was the result of tumor recurrence, with no mortality resulting from brain necrosis. CONCLUSION: This regimen of hypofractionated intensity-modulated RT did not improve the time to disease progression or overall survival compared with historical experience using conventional fractionation. However, the treatment duration was reduced from 6 weeks to 2 weeks, which may be of palliative benefit in certain subsets of patients. This treatment regimen demonstrated a greater incidence of brain necrosis requiring surgical intervention; however, the 3 patients experiencing this toxicity had longer survival times. Future investigation may be useful to determine which fraction size may be optimal for GBM when highly conformal RT is used in the adjuvant setting.     

Assessment of quality of life during chemotherapy.

Increasingly more aggressive chemotherapy together with expected small differences between treatments with respect to objective endpoints has heightened awareness about the importance of addressing how patients experience and value the impact that treatment has had on their overall life situation. Assessment of a patient's quality of life (QoL) is now conceptually viewed as an important complement to traditional objective evaluation measures. It was therefore considered important to review the basis for the assessment of this endpoint when The Swedish Council of Technology Assessment in Health Care (SBU) performed a systematic overview of chemotherapy effects in several tumour types. The group came to the following conclusions: QoL assessments, mostly by patient self-reporting in questionnaires, have come increasingly into use during the past decade. A number of general, cancer-specific and cancer diagnosis-specific instruments have been developed. There is at present little need for development of new cancer instruments, although specific treatment modalities and tumour types may need new additional modules. A predefined hypothesis should determine the instrument to be used. Since the selection of a QoL instrument in a specific study influences both the results and the conclusions, it is essential to carefully select the instrument or instruments that have the greatest likelihood of identifying relevant differences between treatment alternatives. Interpretation of QoL data is more difficult than interpretation of objective endpoints such as survival time, objective response rates or toxicity. Despite these difficulties, QoL analyses have provided new insights into the advantages and disadvantages of various treatments not provided by traditional end-points. Some palliative treatments seemingly increase patients' QoL despite side-effects or the lack of, or marginal, increases in survival. When using potentially curative chemotherapy, it is not a matter of when the treatment should be started, but rather when it should be concluded. When using less active chemotherapy, the expected small therapeutic gains must be weighed against the QoL costs of using the therapy: does the toxicity and/or the inconvenience of the proposed treatment justify the expected gain? When it is found that the strain on the patient is greater than the effects of the cancer, treatment must be discontinued. It is not possible to determine whether or not the advantages of palliative chemotherapy are worth their costs without knowledge about patients' personal values regarding the influence on factors of relevance for QoL. The mostly used QoL questionnaires do not consider individual preferences, which therefore need to be addressed in the dialogue with the patient. QoL assessment is clearly in need of further methodological improvement before this endpoint can be regarded as fully established with respect to ability to provide unequivocally useful data in clinical trials. The multitude of questionnaires, missing data, lack of pre-study hypotheses of relevant differences between treatments and data multiplicity giving a risk for chance findings are examples of serious methodological problems. Patient response-shifts over time further complicate the interpretation of the data. Thus, QoL data, also from seemingly well-performed clinical trials, have to be interpreted cautiously. The international development during recent years has aimed at creating increased standardization of QoL measures. This has created greater possibilities to compare results from different trials. Hopefully, this also implies that it will be possible to draw firmer conclusions from QoL measurements in recently completed or ongoing trials than has been the case previously. QoL assessments are resource demanding even when short standardized questionnaires are used. Since cancer patients also generally give priority to anticancer effects over toxicity and convenience, QoL assessments in clinical trials are motivated mainly in study settings comparing treatments without expected major differences of outcome in objective endpoints.     

Efficacy of a chemotherapy combination for the treatment of metastatic neuroendocrine tumours.

OBJECTIVES: Neuroendocrine tumours (NETs) are heterogeneous neoplasms for which there is no standard treatment. We have previously proposed an effective polychemotherapy (5-fluorouracil, dacarbazine and epirubicin), which only produced objective responses of brief duration. The present study aimed to assess in a multidisciplinary manner the efficacy of the same regimen at intensified doses in patients with advanced NETs. PATIENTS AND METHODS: Eighty-two consecutive patients entered the study, of whom 21 had inoperable, locally advanced disease and 61 had metastatic disease. Seventy-two patients were evaluated for objective, biochemical and subjective responses. Response rate, time to progression (TTP) and overall survival (OS) were evaluated based on histotype. RESULTS: An objective response was observed in 20 patients (intention-to-treat and standard analysis 24.4% and 27.8%, respectively). Complete biochemical and subjective responses were obtained in 25.1% and 38.9% of the cases. The median duration of treatment was 4 months and the objective responses had a median duration of 38 months. After a 60-month follow-up the median TTP and OS were 21 and 38 months, respectively. CONCLUSIONS: Our polychemotherapy regimen is effective, with long duration, and is well tolerated both for gastroenteropancreatic and lung NETs, as well as for tumours with a more aggressive clinical behaviour. The new WHO endocrine tumour histotyping, examining also the tumour biology, may give additional information for selecting patients to chemotherapy.     

Gemcitabine plus CI-994 offers no advantage over gemcitabine alone in the treatment of patients with advanced pancreatic cancer: results of a phase II randomized, double-blind, placebo-controlled, multicenter study.

BACKGROUND: CI-994, an oral histone deacetylase inhibitor, has antineoplastic activity and synergism with gemcitabine preclinically. This randomized phase II trial explored whether CI-994 plus gemcitabine improves overall survival, objective response, duration of response, time to treatment failure and change in quality of life (QoL) or pain compared with gemcitabine alone. PATIENTS AND METHODS: A total of 174 patients received CG (CI-994 6 mg/m(2)/day days 1-21 plus gemcitabine 1000 mg/m(2) days 1, 8 and 15 each 28-day cycle) or PG (placebo plus gemcitabine 1000 mg/m(2) days 1, 8 and 15 of each 28-day cycle days 1-21). RESULTS: Median survival was 194 days (CG) versus 214 days (PG) (P = 0.908). The objective response rate with CG was 12% versus 14% with PG when investigator-assessed and 1% versus 6%, respectively, when assessed centrally. Time to treatment failure did not differ between the two arms (P = 0.304). QoL scores at 2 months were worse with CG than with PG. Pain response rates were similar between the two groups. There was an increased incidence of neutropenia and thrombocytopenia with CG. CONCLUSIONS: Adding CI-994 to gemcitabine in advanced pancreatic carcinoma does not improve overall survival, response rate or time to progression; CG produced decreased QoL and increased hematological toxicity and appears inferior to single-agent gemcitabine.     

Response of global quality of life to high-dose palliative radiotherapy for non-small-cell lung cancer

PURPOSE: To estimate the impact of high-dose palliative radiotherapy treatment (RT) for inoperable non-small cell lung cancer (NSCLC) on the patient's quality of life (QoL) over the remaining survival period, and to compute the number of quality adjusted life days (QALDs) gained. METHODS AND MATERIALS: The QoL of an NSCLC patient is modelled as a function of the days left to live, the days since the start of treatment, a patient specific intercept, and a random error term. Least squares regression analysis is used to fit this model to 376 monthly QoL observations supplied by 42 prospectively enrolled high-dose palliative RT patients with NSCLC. Prediction analysis, based on the regression results and on previously published estimates of the survival response to high-dose palliative RT, is used to compute QALDs gained as a result of treatment. RESULTS: QoL improves steadily over the first 86 days after the start of treatment. This improvement then dissipates to 0 over the subsequent 140 days. Median survival after entry (266 days) yields 158.5 QALDs, of which 56.9 can be attributed treatment: 12.6 as a result of a higher daily QoL and 44.3 as a result of longer survival. CONCLUSION: Patients with inoperable NSCLC who received high-dose palliative RT, and survived the median 266 days after entry into the study, can attribute about one-third of their 158.5 QALDs to the QoL and survival responses to treatment.     

Lack of activity of stealth liposomal doxorubicin in the treatment of patients with anthracycline-resistant breast cancer

PURPOSE: We conducted a single-institution phase II clinical trial to determine the objective response rate, duration of response, time to progression, and overall survival in patients with anthracycline-resistant breast cancer treated with Doxil. PATIENTS AND METHODS: Patients with metastatic breast cancer were eligible if they had disease progression while receiving an anthracycline-containing regimen or developed evidence of metastatic disease during or within 6 months after the last cycle of an anthracycline-containing adjuvant regimen. Prior treatment with liposomal doxorubicin was not allowed. Patients received a dose of 50 mg/m(2) infused every 4 weeks via a peripheral vein or central line. Doxil was administered for a total of six cycles or until disease progression. RESULTS: We treated 11 patients with stage IV breast cancer of whom two had never received chemotherapy for their metastatic disease. Most had a performance status of 1 and had visceral involvement as their dominant site of disease. All patients had received prior therapy with doxorubicin. No clinical evidence of congestive heart failure or cardiac toxicity was observed. The most common toxicities were nonhematologic and were mostly grade 1/2. These included fatigue, nausea, vomiting, and stomatitis. Significant myelosuppression was only observed in one patient. No complete or partial response was observed. There were two patients who had a minimal response and two other patients who had evidence of stable disease. CONCLUSION: Doxil was well tolerated with minimal toxicity. However, the lack of antitumor activity in anthracycline-resistant breast cancer patients indicates that further evaluation in this patient population is not warranted.     

Gemcitabine monotherapy as second-line treatment in cisplatin-refractory transitional cell carcinoma - prognostic factors for response and improvement of quality of life

OBJECTIVES: i) To evaluate objective response, toxicity, and quality of life (QoL) of gemcitabine monotherapy as second-line treatment in patients with cisplatin-refractory, metastatic transitional cell carcinoma (TCC). ii) To assess prognostic parameters for response to treatment and for improvement of QoL parameters. PATIENTS AND METHODS: 30 patients were prospectively enrolled in this open-label, nonrandomized multicenter phase II trial. Patients received up to 6 courses of gemcitabine monotherapy (1,250 mg/m(2) on day 1 and 8 of a 21-day course). 28 of 30 patients were available for response evaluation. RESULTS: Objective response (OR) was seen in 3/28 (11%) of patients (2 complete remissions, 1 partial remission). The mean time to progression (TTP) was 4.9 +/- 3.5 months and mean disease-specific survival time was 8.7 +/- 4.7 months. 13 of 28 patients did not progress (OR + 10 stable diseases), and TTP (8.0 +/- 2.7 months, p < 0.001) as well as survival time (10.2 +/- 3.8 months, p < 0.05) differed significantly from those who showed progressive disease within 18 weeks of treatment. Pain values significantly improved in the group of responders from 4.3 +/- 1.9 to 5.8 +/- 1.3 points (p < 0.05). Response to cisplatin pretreatment was the best prognosticator for the response to gemcitabine. CONCLUSIONS: Gemcitabine monotherapy as second-line treatment is justified in patients with metastatic TCC who are refractory to cisplatin treatment. Patients with initially OR to cisplatin benefit most from second-line treatment. QoL remains stable during treatment, and pain improves especially in patients with bone metastases.