Early market access of cancer drugs in the EU.

Patient access to new cancer drugs in the EU involves centralised licensing decisions by regulators as well as reimbursement recommendations in the context of national healthcare systems. Differences in assessment criteria and evidence requirements may result in divergent decisions at central and national levels, ultimately compromising effective access to patients. Early access decisions are particularly challenging due to the limited clinical evidence available to conclude on the benefit-risk and relative (cost-) effectiveness of new high-priced cancer drugs. We describe mechanisms to accelerate approval of promising anticancer drugs that fulfil an unmet medical need, review the experience from the European Medicines Agency, compare timelines and outcomes of reimbursement decisions in major EU markets, and discuss shortcomings of the current system, ongoing initiatives, and future steps to facilitate effective early access.

Dynamics of the time-resolved stimulated Raman scattering spectrum in presence of transient vibronic inversion of population on the example of optically excited trans-ß-apo-8'-carotenal.

We have studied the effect of transient vibrational inversion of population in trans-ß-apo-8(')-carotenal on the time-resolved femtosecond stimulated Raman scattering (TR-FSRS) signal. The experimental data are interpreted by applying a quantum mechanical approach, using the formalism of projection operators for constructing the theoretical model of TR-FSRS. Within this theoretical frame we explain the presence of transient Raman losses on the Stokes side of the TR-FSRS spectrum as the effect of vibrational inversion of population. In view of the obtained experimental and theoretical results, we conclude that the excited S2 electronic level of trans-ß-apo-8(')-carotenal relaxes towards the S0 ground state through a set of four vibrational sublevels of S1 state.

A multicenter phase III prospective randomized trial of high-dose epirubicin in combination with cyclophosphamide (EC) versus docetaxel followed by EC in node-positive breast cancer. GOIM (Gruppo Oncologico Italia Meridionale) 9902 study.

BACKGROUND: The Gruppo Oncologico Italia Meridionale 9902 trial compared four cycles of high-dose epirubicin plus cyclophosphamide (EC) with four cycles of docetaxel (Taxotere, D) followed by four cycles of EC as adjuvant treatment of node-positive breast cancer. PATIENTS AND METHODS: Patients were randomly assigned to EC (E 120 mg/m(2), C 600 mg/m(2), arm A) for four cycles or four cycles of D (100 mg/m(2)) followed by four cycles of EC (arm B), both regimens every 21 days. Hormone receptor-positive patients were given hormonal therapy for 5 years. Primary end point was 5-year disease-free survival (DFS). Secondary objectives were overall survival (OS) and safety. RESULTS: There were 750 patients enrolled. With a median follow-up of 64 months, 5-year DFS was 73.4% in both arms, and 5-year OS was 89.5% versus 90.7% in arm A and B [hazard ratio was 0.99 (95% confidence interval for DFS 0.75-1.31; P = 0.95)], respectively. Grade 3-4 toxicity was more common in arm B. CONCLUSIONS: This study did not show advantages from the addition of docetaxel to high-dose EC as adjuvant chemotherapy in node-positive breast cancer. The small sample size and low number of DFS events may have limited the ability to observe statistically significant difference between the two arms.

[Adjuvant chemotherapy in hormone-receptor positive HER2-negative early breast cancer]. / Chemioterapia adiuvante del carcinoma della mammella con recettori ormonali positivi HER2-negativo.

Adjuvant treatment in hormone-receptor positive, HER2-negative early breast cancer is controversial. Chemotherapy benefit in this subset of patients is generally small, and a wide variability exists among dif-ferent subgroups of patients, depending on various patient and tumor characteristics. To select subsets of patients who will really benefit from chemotherapy, one of the possible strategy is based on multigene expression analysis. This approach is providing deeper insights into the biological heterogeneity of breast cancer, allowing to further sub-divide hormone-receptor positive tumors into groups, with different clinical behavior and response to treatments. Among less expensive and better validated methods, high levels of Ki67, a routinely assessed immunohistochemical marker of cell proliferation, can suggest the use of chemotherapy in this subset of patients. Generally, regimen used should include a taxane. In fact, retrospective analyses of clinical trials suggest that anthracyclines may be less active in hormone-receptor positive HER2-negative patients, while several other trials and meta-analyses involving taxanes, showed a benefit in terms of risk of relapse and death reduction. Among taxanes, docetaxel should be preferred because of a better therapeutic index, and a higher activity in comparison to paclitaxel. At present, reliable and accurate evaluation of histopathological and immunohistochemical factors may allow the choice of omitting adjuvant chemotherapy in patients with low risk hormone receptor positive HER2-negative breast cancer. Uncertainty still exists about chemotherapy benefit for a substantial proportion of women of this subgroup. Nevertheless, the addition of taxanes, mainly docetaxel, to anthracyclines, seems to overcome the relative chemoresistance of hormone-receptor positive tumors, providing a benefit in disease free survival and overall survival.

[Role of adjuvant chemotherapy in the choice of chemotherapeutic treatment of metastatic breast cancer]. / Ruolo della chemioterapia adiuvante nella scelta del trattamento chemioterapico del carcinoma mammario metastatic

Adjuvant treatment of early breast cancer has changed considerably in recent years, and the majority of patients are currently treated with the most active single agents in this setting. As a result, the decisions regarding the treatment of patients with metastatic breast cancer have become more difficult. In patients who have not received chemotherapy for early-stage breast cancer or were treated with CMF, many choices are available, including regimens containing anthracyclines or taxanes. Patients who received anthracyclines in the adjuvant setting, may sometimes be re-treated with these agents, and the inclusion of a taxane is frequently the most reasonable choice. Among taxanes, docetaxel should be preferred because it is the most active single agent, and has a synergistic action with several other drugs, when used in combination. Taxanes can be used also in selected patients who had received these agents as adjuvant treatment. In particular, docetaxel did not show complete cross-resistance with paclitaxel, whereas weekly paclitaxel is only minimally effective in patients resistant to docetaxel. Retreatment with trastuzumab combined with chemotherapeutic agents might be a reasonable option in patients who had received adjuvant chemotherapy with trastuzumab. Nevertheless, another recent option is the combination of chemotherapy with lapatinib. Currently, novel target agents are being developed, with the potential to improve survival in patients with metastatic breast cancer. Arguably, the future for treatment of these patients appears to be the combination of effective single agents, such as docetaxel, with novel biologic therapies.

Docetaxel in the adjuvant therapy of HER-2 positive breast cancer patients.

Considering the clinical benefit of trastuzumab in advanced breast cancer, fi ve prospective adjuvant randomized trials have recently been completed and early results have been published. Two of them, (NSABP-B31 and NCCTG N9831), employed anthracycline-containing regimens with sequential paclitaxel, with or without trastuzumab. The third study, HERA trial, randomized patients after adjuvant chemotherapy into an observational arm, one or two years of trastuzumab. Results of these studies, after a median follow up of 2-3 years confirm a DFS and OS benefit for the experimental arms. The worst rate of cardiotoxicity, in terms of incidence of CHF, with the use of trastuzumab and anthracycline based regimens was 4.1% in the trastuzumab arm of the NSABP-B31 trial. Among the fi ve trastuzumab trials, two, BCIRG 006 and FinHer, employed docetaxel-based regimens. The innovative BCIRG 006 trial compared ACdocetaxel (T) with two trastuzumab-containing regimens, ACTH, and a non-anthracycline-containing regimens, TCH, with a clear advantage in DFS for both trastuzumab arms. Data from the second interim analysis indicate that, in the subgroup of patients without co-amplification of topoisomerase 2 (TOPO-2), the arm without trastuzumab (ACT) showed a DFS significantly poorer that in the other arms; moreover, if we consider the lower toxicity of TCH regimen in comparison with anthracycline-containing arms, the innovative statements offered by BCIRG 006 trial appear evident, and these findings opened an important question about the consolidated employment of anthracyclines in adjuvant setting.The FinHer trial was a small trial testing a short course of trastuzumab (9 weeks) concomitantly with a chemotherapy including docetaxel, and there was a significant advantage in DFS for the trastuzumab based arms, without relevant toxicity and without any cardiotoxicity. Although data from all trastuzumab adjuvant trials, and without particulary from BCIRG-006 and FinHer trials, appear very intriguing, further follow-up is required.

Optimal sequence of anthracyclines and taxanes as adjuvant breast cancer treatment.

Results from randomized trials evaluating taxane versus non-taxane containing regimens in adjuvant breast cancer treatment indicate an advantage in DFS and OS for the taxane-arms, but the best schedule of administration, in combination with anthracyclines or in sequence, is still a debated issue, even if the sequential strategy appears to be less toxic. Up to now, the majority of clinical trials employed the "standard" sequence, with anthracycline-based combinations fi rst, followed by taxanes. Few small phase II trials evaluated the reverse sequence, with taxanes administered fi rst, most of them in metastatic or neoadjuvant setting, suggesting efficacy and lower toxicity. An important issue to be considered is the hypothesized differences in the ability of the drugs to induce cross-resistance to each other, as suggested by data of a preclinical study, and from clinical study with a cross-over design; results of these trials suggest that the best strategy would be to administer a taxane prior to an anthracycline, also according to the Norton and Simon hypothesis. Moreover, trials evaluating the best sequence of anthracyclines and taxanes in adjuvant breast cancer setting are of small sample size, and an adequately powered randomized phase III trial is needed before definitive conclusions are reached.

[Optimal role of docetaxel in adjuvant chemotherapy for early stage HER2-negative breast cancer]. / Uso ottimale del docetaxel nella chemioterapia adiuvante delle pazienti con carcinoma mammario HER2-negativo.

The fundamental imperative of adjuvant treatment of early breast cancer is to improve long-term survival and minimize toxicity. The inclusion of docetaxel in adjuvant chemotherapy regimens has improved patient survival in comparison to anthracycline-containing regimens, even if the incidence of acute side effects has increased in some studies. However, late or persistent toxic effects are becoming more important due to an increasing proportion of patients remaining disease free after treatment for early breast cancer. Several studies have recently reported that docetaxel-containing regimens without anthracyclines are equally active, and have no apparent cardiotoxicity. At present, docetaxel-based combinations represent an appropriate choice in the adjuvant treatment of HER2-negative breast cancer, and several studies are ongoing aiming at a better evaluation of the efficacy of this agent in order to optimize its role.

[High-dose CEF (cyclophosphamide, epirubicin, fluorouracil) as primary chemotherapy in locally advanced breast cancer: long-term results]. / CEF (ciclofosfamide, epirubicina, fluorouracile) ad alte dosi come chemioterapia primaria nel trattamento del carcinoma mammario localmente avanzato: risultati a lungo termine.

PURPOSE: To determine wether primary CEF is effective in locally advanced breast cancer, as measured by response, local recurrences, disease free survival (DFS) and overall survival (OS). MATERIAL AND METHODS: From 1990 to 1998, 62 patients with stage III disease were enrolled into a prospective study at Regina Elena Institute for Cancer Research, Rome. Inflammatory breast cancer (IBC) was included. Patients received three 21 days cycles of chemotherapy that consisted in epirubicin 50 mg/m2, cyclophosphamide 400 mg/m2, and fluorouracil 500 mg/m2 i.v. on days 1 and 8. G-CSF (300 microg) was given subcutaneously every other day from day 5 to day 17. After primary chemotherapy, whenever possible, mastectomy or conservative surgery was performed. Subsequently responding patients received the same regimen, while non responders were given a non cross resistant chemotherapy. In case of conservative surgery or initial T4 tumor radiation therapy was performed at the end of adjuvant chemotherapy. ER positive patients received tamoxifen 20 mg/d for five years. RESULTS: Seven IIIA patients had a median OS of 43 months (C.I. 95%, 31-55) and DFS of 42 months (C.I. 95%, 16-68), while 15 IBC patients had a median OS of 52 months (C.I. 95%, 52-79) and DFS of 27 months (C.I. 95%, 14-39). Forty IIIB non inflammatory breast cancer patients had a median DFS of 87 months (C.I. 95%, 1-175); median OS was not reached. Ten-year OS was 28.6% for stage IIIA, 50.6% for stage IIIB and 36% for IBC. CONCLUSION: Primary CEF appear to be an effective treatment. In our study we obtained a good local control and interesting long term data of disease free and overall survival.

Irinotecan, docetaxel and oxaliplatin combination in metastatic gastric or gastroesophageal junction adenocarcinoma.

This phase II study was designed to evaluate the activity and safety of a combination of irinotecan, docetaxel and oxaliplatin in metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. Forty patients with measurable distant metastasis received irinotecan 150 mg m(-2) and docetaxel 60 mg m(-2) on day 1, and oxaliplatin 85 mg m(-2) on day 2. Cycles were repeated every 3 weeks. The primary end point was to demonstrate a 50% improvement in time-to-progression (TTP) over historical controls. All patients were evaluable. Median TTP was 6.5 months (95% confidence interval (CI) 5.6-7.4), the overall response rate was 50% (95% CI 35-65%) and the median overall survival was 11.5 months (95% CI 8.7-14.3). Grade 3/4 neutropaenia occurred in 47.5% of patients. There were four episodes of febrile neutropaenia in three patients. Other non-haematological grade 3 toxicities included diarrhoea in four patients (10%), vomiting in three patients (7.5%) and mucositis in two patients (5%). The irinotecan, docetaxel and oxaliplatin combination chemotherapy is an active and well-tolerated novel regimen for treating metastatic gastric or GEJ adenocarcinoma and deserves further evaluation in randomised trials and in combination with molecular targeting agents.

[New combination chemotherapy regimens in the primary treatment of operable breast cancer]. / Nuove combinazioni chemioterapiche nel trattamento primario del carcinoma mammario operabile.

Primary (neoadjuvant) systemic chemotherapy is the standard treatment for locally advanced breast cancer and a standard option for primary operable disease. Although survival results are similar, primary chemotherapy has the following advantages in comparison to adjuvant chemotherapy: it represents a chemosensitivity test in vivo and can be of value in determining the prognosis of the patient since pathologic complete responses are related to improved survival. Among a variety of primary chemotherapy regimens currently available, the most effective seem to be those containing both anthracyclines and taxanes, expecially when these agents are administered sequentially. There are also several ongoing studies evaluating primary hormonal therapy and the combination of cytotoxic chemotherapy and targeted agents. It is conceivable that in the future primary chemotherapy of breast cancer will be increasingly used. In fact, besides its clinical effectiveness, primary chemotherapy is extremely important to evaluate new agents and to find useful prognostic and predictive factors.

High activity of salvage treatment with biweekly paclitaxel-gemcitabine combination in heavily pretreated breast cancer patients.

The treatment of refractory metastatic breast cancer is primarily palliative, without a significant impact on overall survival. Among the innovative combinations in this unfavourable setting, paclitaxel and gemcitabine showed a possible synergistic action and an encouraging activity in some clinical trials. This phase II study was carried out to evaluate paclitaxel-gemcitabine combination in very heavily pretreated advanced breast cancer on a bi-weekly schedule.Thirty-nine women with advanced breast cancer were treated with paclitaxel 150 mg/m2 as 3 hrs infusion, and gemcitabine 1,500 mg/m2 as 30 mins infusion, both drugs administered on days 1, 15, with cycles repeated every 28 days. All but two patients received granulocyte colony stimulating factor (G-CSF) on days 7 to 9 and 20 to 22 of every cycle. More than two third (71%) of the patients had previously received two or more chemotherapy regimens for advanced disease, including almost all active agents in this disease. Objective responses were observed in 18 out of 34 evaluable patients (53%; 95% CI, 36% to 70%). Disease remained stable in 7 patients (21%). Responses by sites were 67% in soft tissue and in bone, and 48% in visceral disease. Median time to progression and overall survival were 9 and 20 months, respectively. Treatment was well tolerated, with G3-4 neutropenia in 8%, and G 1-2 thrombocytopenia in 13% of the patients; non-hematological toxicities were mild, with G3 hepatotoxicity in 5% of the patients, and G3 peripheral neurotoxicity in 10% of the patients. Biweekly paclitaxel/gemcitabine combination with G-CSF support appears to be very active as salvage therapy in heavily pretreated breast cancer patients, with a very favourable safety profile.

Cost-minimisation analysis comparing gemcitabine/cisplatin, paclitaxel/carboplatin and vinorelbine/cisplatin in the treatment of advanced non-small cell lung cancer in Italy.

A retrospective cost-minimisation analysis was conducted comparing novel chemotherapies for the treatment of chemo-naive patients with locally advanced, recurrent, and/or metastatic non-small cell lung cancer (NSCLC). Resource use information was obtained from a Phase III randomised trial investigating the efficacy and toxicity of gemcitabine/cisplatin (Gem/Cis), paclitaxel/carboplatin (Pac/Carbo) and vinorelbine/cisplatin (Vin/Cis) combination regimens in 612 patients with advanced NSCLC. Since there were no statistically significant differences between the three treatments in terms of progression-free or overall survival in this trial, a cost-minimisation analysis was considered to be the appropriate type of economic evaluation. The perspective was that of the national healthcare provider in Italy. Medical resource use was obtained from the clinical trial database, from which mean cost streams were calculated for each treatment group. The mean total treatment costs per patient were 8094 euros, 11,203 euros and 9320 euros for the Gem/Cis, Pac/Carbo and Vin/Cis regimens, respectively. Based on resource consumption in a clinical trial, Gem/Cis had the lowest overall mean costs of the three chemotherapy regimens. Gem/Cis therefore has the potential to save costs in the treatment of advanced NSCLC in Italy.

[Molecular therapy of breast carcinoma in the advanced phase]. / Terapia molecolare del carcinoma della mammella in fase avanzata.

Conventional chemotherapy regimens for the treatment of breast cancer have limited efficacy and are associated with significant toxicity, highlighting the need for novel targeted therapies. Increased expression and activation of receptor tyrosine kinases frequently occurs in human breast carcinomas and, therefore, several clinical trials are currently evaluating therapies targeting these receptors. Therapeutic strategies include blockade of individual receptors with monoclonal antibodies (e.g., trastuzumab) and inhibition of tyrosine kinase function (e.g., gefitinib). Trastuzumab is the first agent that has been approved for patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer. Other growth-factor targeted drugs are in clinical development such as STI-571, farnesyl-transferase inhibitors and antibodies directed at the insulin-like growth factor.

Docetaxel in patients with anthracycline-resistant advanced breast cancer.

OBJECTIVE: To better determine docetaxel activity in patients with well-defined anthracycline-resistant breast cancer. METHODS: From October 1996, we carried out a phase II trial in 69 heavily pretreated patients with advanced breast cancer with docetaxel 100 mg/m(2) by a 1-hour infusion on day 1, with cycles repeated every 3 weeks. Patients were classified as having primary anthracycline resistance (n = 32), secondary anthracycline resistance (n = 7), anthracycline pretreatment (n = 22) or no anthracycline pretreatment (n = 8). RESULTS: Among 68 evaluable patients, we observed 6 (9%) complete responses and 27 (40%) partial responses, for an overall response rate of 49% (95% confidence interval 37-61%); the disease remained stable in 17 patients (25%). Responses according to the above subgroups were as follows: primary anthracycline resistance 41%, secondary anthracycline resistance 43%, anthracycline pretreatment 64% and no anthracycline pretreatment 43%. The median time to response, median time to progression and median overall survival were 2, 7 and 10 months, respectively. Myelosuppression was the dose-limiting toxicity, with grade 4 neutropenia occurring in 47% of the patients and neutropenic fever in 12%. G-CSF was added in the case of grade 4 febrile neutropenia; a 25% reduction in the dose of docetaxel was required in 4 patients. Other side effects were mild. CONCLUSIONS: The results of the present trial confirm the high activity of docetaxel in heavily pretreated patients with advanced breast cancer, including those with strictly defined anthracycline resistance.

The photochemical behavior of colchicone and thiocolchicone.

The irradiation of colchicone 5 led to the formation of lumicolchicone 7. The same reaction cannot be obtained by using thiocolchicone 6 as substrate. Transient absorption spectroscopy of colchicone and beta-lumicolchicone showed that probably the photoisomerization occurred on colchicone in its first excited singlet state. The spectroscopic data are in agreement with the hypothesis that lumicolchicone was generated in the ground state from the S1 state of colchicone without the presence of any intermediate. Semiempirical calculations on colchicone and thiocolchicone showed that the highest single occupied molecular orbital and the lowest unoccupied molecular orbital of the singlet excited colchicone can give a disrotatory ring closure to 7, while thiocolchicone cannot give the same type of process.

[Treatment of malignant pleural effusion by pleurodesis with talc]. / Trattamento del versamento pleurico maligno mediante pleurodesi con talco.

In some types of cancer (breast, lung) a malignant pleural effusion may be present during the evolution of the neoplastic disease in more than 50% of cases. The main therapeutic option for palliative purposes in these cases is chemical pleurodesis with talc. The aims of this study were to report on our experience with the use of pleurodesis with talc in the treatment of patients affected by malignant pleural effusions and to analyse the results in the short and mean term. Over the period from January 1998 to December 1999, 16 patients were included in the study. The causes of the pleural effusion were a pleural mesothelioma in 1 patient and pleural metastases in 15 patients (from lung and breast cancers in 62%). We treated 14 of these patients with talc poudrage and 2 patients with talc slurry. The talc was applied under video-assisted thorascopic management in 15 patients, while in 1 patient the talc was injected via the thoracic drainage tube. Two patients died within the first month as a result of progression of the neoplastic disease and one patient was withdrawn from the study owing to failure to collaborate. Of the other 13 patients, 11 (84%) had a total or partial response to the pleurodesis; in 9 of these patients (69.2%) the response remained stable until death, while in 2 patients the pleural effusion reappeared after 3 and 5 months, respectively. Failure of the pleurodesis occurred in 2/13 patients owing to reappearance of the pleural effusion within the first month.

[Cancer of unknown primary site]. / Neoplasie a sede primitiva ignota.

INTRODUCTION: Patients with cancer of unknown primary site represent 0.5 to 9 percent of all cancer patients with a major incidence in people aged 50 to 70 years. The most common histological diagnosis is adenocarcinoma. The vast majority of patients have at least two different metastatic sites involved at the moment of the diagnosis. Among the identified occult primaries lung and pancreas constitute the majority. Histological diagnosis, age, sex, performance status, tumor burden and organs involved are the most important prognostic factors. DIAGNOSIS: Complete medical history and physical examination are able to reveal symptoms and signs in more than 90 percent of patients. Routine laboratory tests, serum tumor markers, imaging studies and endoscopies will complete the diagnostic approach. The pathologic assessment of biopsied material is usually initiated by light microscopic examination: additional pathologic studies, including histochemistry, electron microscopy and genetic analysis are frequently and productively employed. THERAPEUTIC APPROACH: Locoregional treatment can be curative in a few and selected cases and is more often offered with a palliative intent. The elective treatment for metastatic disease is represented, in the vast majority of cases, by systemic chemotherapy with different schedules according to pathological diagnosis. Best supportive care is sometimes the best choice. CONCLUSIONS: It is recommended to treat such patients in the context of clinical trials.