Impact of modern systemic therapies and clinical markers on treatment outcome for metastatic melanoma in a real-world setting.

BACKGROUND: The survival in metastatic melanoma has dramatically improved after the introduction of immune checkpoint- (ICIs) and MAPKinase inhibitors (MAPKis). OBJECTIVE: Our aim was to describe therapy response and survival in a real-world population as well as to assess the associations between clinical variables and therapy outcome for patients with metastatic melanoma receiving first-line ICIs or MAPKis. METHODS: A total of 252 patients with metastatic (stage IV) melanoma were prospectively followed between 1 January 2010 and 3 December 2017 with follow-up until 31 March 2019, at the Karolinska University Hospital, Sweden. Hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were analysed with Cox regression, and logistic regression was used to estimate odds ratios (ORs) for therapy response. RESULTS: Patients receiving ICIs (n = 138) experienced longer PFS compared to patients that received MAPKis (n = 114; median PFS for ICIs was 6.8 months, and median PFS for MAPKis was 5.3 months). In the multivariable analyses of clinical markers, increasing M-stage (OR 0.65; 95% CI 0.45-0.94; P = 0.022) and male sex (OR 0.41; 95% CI 0.19-0.90; P = 0.027) were significantly associated with lower response to ICIs. Lower baseline albumin levels (OR 0.90; 95% CI 0.83-0.98; P = 0.019) and male sex (OR 0.33; 95% CI 0.12-0.93; P = 0.036) were related with lower response to MAPKis. For ICIs, increasing M-stage (HR 1.34; 95% CI 1.07-1.68; P = 0.010), increasing LDH (HR 1.73; 95% CI 1.19-2.50; P = 0.004) and decreasing albumin (HR 1.06; 95% CI 1.01-1.10; P = 0.011) were significantly associated lower PFS in the adjusted model. The corresponding markers for MAPKis were increasing LDH (HR 1.44; 95% CI 1.08-1.92; P = 0.013) and decreasing albumin (HR 1.05; 95% CI 1.02-1.09; P = 0.005) for PFS. CONCLUSION: ICIs and MAPKis were effective in this real-world population, and we could confirm the importance of previously reported clinical prognostic markers. Albumin values may be associated with therapy outcome but need further validation.

Supportive care organisation in France: an in depth study by the French speaking association for supportive care in cancer (AFSOS).

BACKGROUND: Supportive care in cancer (SCC) was further enhanced in the Second National Cancer Act decreed in December 2009. The aim of our study was to assess current SCC efficacy. PATIENTS AND METHODS: The French speaking association for supportive care in cancer (AFSOS) conducted an observational study to evaluate practices, organisations and information given to patients. A specific 32 point questionnaire was sent to 1621 French physicians (MDs) caring for cancer patients. RESULTS: Three different organisations were evaluated: the individual MDs, the transversal team and its particular structure specialised in global patient care specifically developed at comprehensive cancer centres - CCC. During their disease, 68% of patients received SCC, which was more available during the palliative period (90%) than at the diagnosis (44%). Our results found that 71% of cancer departments had a specific interdisciplinary cross-team to provide SCC, particularly in CCC (62%; p=0.01) while 37% had specific inpatient units. A specific organisation dedicated to home care was greater in CCC than in public or private centres (69%, 45%, 20% respectively; p=0.01). Adverse event information was performed more by an oncologist than other specialists (p=0.01). CONCLUSION: Our results suggest that the specific SCC organisation could be a useful management tool to improve supportive care for cancer patients.

[Practice guidelines of the use of bisphosphonates in solid tumours with bone metastases and in multiple myeloma]. / Guide de recommandations d'utilisation des bisphosphonates dans les lésions osseuses malignes des tumeurs solides et du myélome multiple.

Bisphosphonates are indicated for the treatment of bone lesions in patients with solid tumours or multiple myeloma. Bisphosphonates have proven their effectiveness in reducing the number of bone complications (hypercalcemia, pain, disease-related fractures, spinal cord compression) and delaying their occurrence in patients with bone tumours; they have also been shown to reduce the need for bone surgery and palliative or pain-relieving radiotherapy in these patients. International recommendations for the treatment of bone lesions related to malignant solid tumours and multiple myeloma have been established. We have elaborated clinical practice guidelines on the use of bisphosphonates to assist treatment decision-making in bone oncology. The guide contains decision trees and tables with information to guide pre-treatment evaluation and patient follow-up, as well as indications and conditions of use of bisphosphonates. In 2007, the regional cancer network of Rhône-Alpes, ONCORA, formed a working group (GIP ONCORA) to elaborate the guideline. The final version was then discussed and adopted at a plenary session in July 2009, during a collaborative workshop on supportive care recommendations organized by ONCORA and the regional cancer network of Lorraine.

[Initial management in oncology: results of CPRIM surveys on 2,583 patient's perceptions and expectations (outside Anticancer Centers)]. / Prise en charge initiale: résultats des enquêtes CPRIM sur le ressenti et les attentes de 2,583 patients (hors centres de lutte contre le cancer).

During the initial phase of management, the caregivers' role is particularly difficult. These two consecutive surveys have been conducted to cover three main aspects: 1) How the initial management took place; 2) What the perceived deficits were; 3) What improvements could be made. A self administered and anonymous questionnaire was given to the patients by physicians. Surveys were conducted in numerous institutions representative of all kinds of practice except for Anticancer Centres. Two thousand five hundred and eighty three adult patients have completed the questionnaire (1366 and 1217 respectively in the first and subsequent survey): women (55%), age under 70 years (76%), breast cancer (32%). Results were rather encouraging. About sixty per cent of the patients are entirely satisfied by the given information and 95% are confident with the department of care. The mean level of global aid is 8.2/10 in the first survey and 8.6/10 in the second one. However, improvements remain needed, particularly for the 8% dissatisfied patients. In spite of the classical bias for these studies, this work gives several concrete responses for improving initial management, particularly for the first consultation in the centre, which has a major impact on the patient satisfaction.

[Radiofrequency ablation for palliation of soft tissue tumor pain]. / La radiofréquence dans le traitement palliatif à visée antalgique des tumeurs des parties molles.

PURPOSE: To assess the efficacy of radiofrequency (RF) ablation for palliation of soft tissue tumor pain. MATERIALS AND METHODS: Retrospective study of 12 patients receiving palliative treatment for soft tissue tumors (5 primary tumors including 4 sarcomas and 1 PEComa and 7 metastatic tumors) with pain refractory to standard management. RF ablation was performed under CT or ultrasound guidance. RESULTS: The efficacy was determined by using pain scores and treatment regimen modifications after RF ablation. Response was graded as absent, partial or complete. Short term symptomatic relief was observed in 100% of cases, with complete response in 43% of cases ; Mid term and long term symptomatic relief was observed in 70% and 83% of cases respectively. We also observed dosage reduction for narcotics with corresponding reduction in related side-effects and functional improvement in some patients. A single case of complication with serosanguinous collection within a region of necrosis was observed. CONCLUSION: Radiofrequency ablation for palliation of soft tissue tumor pain may be a useful complement to standard management. It results in symptomatic improvement with few complications.

[Observational study of the initial prescription of level 3 analgesics in cancer patients.]. / Enquête observationnelle sur la primoprescription d'antalgiques de palier 3 chez les patients cancéreux.

To evaluate pain management in cancer patients, a study was conducted examining the treatment circumstances and modalities of initial prescription level 3 analgesics used by 122 French cancer specialists. The rationale for moving to level 3, the implementation and the follow-up were evaluated in 1,038 patients. The reasons underlying the initial prescription were in line with recommendations for clinical practice (WHO, SOR) and the professionals generally preferred molecules with which they were already familiar. Though pain intensity was reduced in 67% of patients, treatment follow-up could have been improved in a number of cases. In particular, titration was not systematically performed, and the interruption of the prescribed treatment (owing to inefficacy or negative side-effects) was not sufficiently timely. The awareness-raising campaigns performed over the past few years should be continued, underlining the importance of early follow-up, notably during the titration phase of level 3 analgesic initiation.

[Setting up supportive care in oncology: reflexions and suggestions.]. / A propos de la mise en place des soins de support en cancérologie : pistes de réflexions et propositions.

A group of 19 health professionals implicated in supportive care wanted to suggest some reflexions for organization, setting and evaluation of the supportive care in institutions and health territories. The suggested organization must be applicable to any cancer patient and the place of the care whatever the age, the stage of the disease; in the future, must be applicable to any patient with serious chronic illness. This organization must allow to optimize the accompaniment and the care of the patients and their close relations by 1) precise and regular analysis of their needs; 2) the respect of the continuity of the health care; 3) the setting of collaborative practice and transversality in the care. It is not a new medical speciality but a coordination of competences for patients and their families.

[Nociceptive cancer pain in adult patients: statement about guidelines related to the use of antinociceptive medicine]. / Douleurs cancéreuses par excès de nociception chez l'adulte: mise au point sur les recommandations concernant les traitements antalgiques médicamenteux.

OBJECTIVE: The World Health Organization (WHO) published guidelines to improve cancer pain control which allow to relieve noceptive cancer pain in 80% of adult patients. Nevertheless WHO recommendations do not include: various ways to start morphine treatment, how to manage opioids adverse effects, severe cancer pain management, postoperative pain and procedure-relatived pain. The goal of this review is to discuss these issues. DATA SOURCES: The data were retrieved from PubMed years 2001 to 2006 (keywords used alone or in combination were: opioids, cancer, pain, pain killers, rotation, intraspinal, ketamine, side effects), the "Standard, Options and Recommendations on cancer nociceptive pain treatments for adult patients" published by the French Union of Comprehensive Cancer Centers (FNCLCC; Fédération nationale des centres de lutte contre le cancer) and the European Association for Palliative Care (EAPC) recommendations on morphine and alternative opioids in cancer pain. Data also include an analysis of studies before 2001 which give information about the pharmacokinetic data of transdermal and transmucosal fentanyl. STUDY SELECTION: Studies written in English or French related to the medical treatments (commercialized in France) for nociceptive cancer pain for adult patients were analyzed. Analyzed articles were clinical or experimental studies or metaanalyses. Studies on neuropathic cancer pain, editorials and letters to the editor were discarded. RESULTS: Nociceptive cancer pain is characterized by its frequent instability. More than 50% of patients have paroxystic painful accesses (PPA), either spontaneous or induced by care or mobilizations. Morphine is the main treatment but the prescription of controlled-release morphine must be associated with the prescription of immediate-release morphine to treat the PPA or to transmucosal fentanyl which has a faster onset of action than immediate-release morphine. Morphine treatment can be introduced either by immediate-release morphine or by controlled-release morphine. The introduction of immediate-release morphine is recommended for old or fragile patients, patients with denutrition, hepatic or renal failure. For patients suffering unbearable side effects under morphine or morphine resistant pain, opioid rotation or intravenous morphine or fentanyl are recommended. Spinal opioids administration (by epidural or intrathecal routes) is most often indicated in patients with very severe and resistant pain in terminal disease. In the postoperative period, previous pain treatment must be maintained or increased. Pain bounded to care procedures must be prevented with various and associated treatments: for example, mixed topics lidocaïne-prilocaine for venous or arterial punctures; infiltration of local anaesthetics and inhalation of an oxygen - nitrous oxide mixture for medullary biopsies. CONCLUSION: Oral immediate or controlled release morphine is the most common and effective pain treatment for most patients with nociceptive cancer pain but rotation with other opioids or alternative routes of administration must be discussed quickly if pain persits or if adverse effects occur.

Gemcitabine combined with cisplatin as first-line treatment in patients with epithelial ovarian cancer: a phase II study.

OBJECTIVE: This phase II study was performed to evaluate the activity and toxicity of gemcitabine plus cisplatin as first-line treatment of advanced epithelial ovarian cancer. METHODS: Chemonaive patients with histologically or cytologically confirmed FIGO stage III or IV epithelial ovarian carcinoma were enrolled. Patients received cisplatin 75 mg/m(2) on Day 1 and gemcitabine 1250 mg/m(2) on Days 1 (after cisplatin) and 8 of a 21-day cycle. RESULTS: Of the 42 female patients (median age 60 years) enrolled, 81% had a Zubrod performance status of 0 or 1. Among the 37 response-evaluable patients, there were 5 (13.5%) pathological complete responses (CRs), 16 (43.2%) pathological partial responses (PRs), and 3 (8.1%) clinical PRs, for an overall response rate of 64.9% (95% CI: 47.4-79.8%) and a pathological response rate of 56.8%. Per an intent-to-treat analysis, the overall response rate was 57.1% (95% CI: 41.0-72.3%). After a median follow-up time of 15.8 months, the median survival was 24.0 months and median progression-free survival was 13.4 months. Grade 3/4 neutropenia and thrombocytopenia occurred in 69.0 and 33.3% of patients, respectively, with no febrile neutropenia or hemorrhage. Grade 3/4 nausea and vomiting occurred in 35.7% and grade 3 alopecia in 21.4% of the patients. One patient died due to a toxicity-related death (dyspnea). CONCLUSIONS: Gemcitabine plus cisplatin is active and feasible as first-line treatment of advanced epithelial ovarian cancer. Further clinical trials adding gemcitabine to first-line treatment seem warranted.

[Coordinated organization of symptoms management and support in all the stages of cancer disease: putting in place pluridisciplinary structures of supportive oncological care]. / Organisation coordonnée de la prise en charge des symptômes et du soutien à toutes les phases de la maladie cancéreuse: vers la mise en place de structures pluridisciplinaires de soins oncologiques de support.

The organization of the management of pain and other symptoms all along the cancer disease, of psychological support and palliative care is a complex question that does not correspond to any perfectly established model, both in France and abroad. Different structures are implied in there care and coexist with an insufficient coordination: cancerology structures, structures of chronic pain management, structures of psycho-oncology, structures of palliative care. Some other assistances are more or less isolated inside the hospital: nutritional support, social assistance, action against tobacco and other addictions, volunteer work. Because of the evolution of practices and mentalities over the last ten years, the highlights of evident interfaces and complementary activities, the notions of "continuous care" and "integrated care" inside conventional departments, the budgetary and organizational restraints, it is now possible to propose a model of hospital structure adapted to the problem of supportive care. The creation is proposed from preexisting structures, consultations, units, departments of supportive oncological care according to the size of the institution. The structure should comply with some specifications, sometimes regulations, and to coordinate at best different competencies in the interest of the patients and medical teams : pain and symptoms management (of which palliative care is an important part), psycho-oncology, rehabilitation (functional rehabilitation, nutrition, social work, fights against addictions). A pooling of technology settings is one of its interest. The model can be applied in other domains than cancerology and in most health institutions.

Verapamil increases the survival of patients with anthracycline-resistant metastatic breast carcinoma.

BACKGROUND: Verapamil (VER), a potent calcium channel blocker, has been found to overcome P-gp-mediated multi-drug resistance (MDR) and to increase sensitivity to cytotoxic anticancer drugs in refractory myeloma and non-Hodgkin lymphoma. The value of VER for treating solid tumors is still a matter for debate. PATIENTS AND METHODS: We performed a prospective study in 99 patients with anthracycline-resistant metastatic breast carcinoma (MBC), to assess the clinical effect of oral VER given in association with chemotherapy. Instead of retreating patients with anthracycline, we used a partially noncross-resistant regimen (VF), combining vindesine (VDS) and 5-fluorouracil given as a continuous infusion (5-FU CI). Patients were randomly assigned to two cohorts. One cohort (47 patients) was treated in 28-day cycles, each involving the administration of VDS (3 mg/m2 i.v. bolus on days 1 and 10) and 5-FU CI, (400 mg/m2/day i.v. from day 1 to day 10). The other cohort (52 patients) received the same VDS and 5-FU treatment and an additional oral VER treatment (240 mg/day divided in 2 doses), from day 1 to day 28 of each cycle. Patients were treated until progression. RESULTS: The treatment was well tolerated and no side effects that could be attributed to VER were detected. Patients treated with VER had longer overall survival (OS) (median OS: 323 vs. 209 days, P = 0.036) and a higher response rate (27% vs. 11%, P = 0.04) than those not given VER. Progression-free survival (PFS) was also longer but the difference was not statistically significant (median PFS: 4.6 and 2.7 months for the VER and non-VER groups respectively, P = 0.6). CONCLUSIONS: This clinical trial demonstrates that a chemosensitizer, such as VER, can increase the survival of MBC patients with acquired anthracycline resistance.

High-dose methotrexate and HELP [Holoxan (ifosfamide), eldesine (vindesine), platinum]--doxorubicin in non-metastatic osteosarcoma of the extremity: a French multicentre pilot study. Fédération Nationale des Centres de Lutte contre le Cancer and Société Française d'Oncologie Pédiatrique.

UNLABELLED: This study evaluates histological response, long-term outcome, and toxicity in an intensive chemotherapy program given before surgery. PATIENTS AND METHODS: Sixty-two patients (39 males, 23 females: median age 14) with biopsy, chest computerised-tomography, technetium bone-scan and magnetic resonance imaging, were enrolled. Primary localisations were femur (44%) and tibia (26%). Induction chemotherapy involved seven courses of high-dose methotrexate and two courses of HELP (ifosfamide, eldesine (vindesine), cisplatin (platinum)-doxorubicin. After surgery, patients received six courses of high-dose methotrexate and two courses of HELP-doxorubicin. RESULTS: Pre- and postoperative toxicities were similar. Fifty-nine patients underwent surgery; histological response was good in thirty-eight patients (64%) and poor in twenty-one (36%). Median follow-up is 57 months (range 30-80), with 77% overall survival and 59% progression-free survival. In a multivariate analysis, age under 10 years is the only prognostic factor that significantly correlates with outcome. CONCLUSIONS: This regimen appears to increase histological necrosis, but associates with severe toxicity. Results for patients with less necrosis at surgery are encouraging. Future trials should determine the minimum effective doses to reduce toxicity. New drugs should be added.

Phase I-II trial of intensification of the MAID regimen with support of lenograstim (rHuG-CSF) in patients with advanced soft-tissue sarcoma (STS).

This study was conducted to determine the maximum tolerated dose of an intensified MAID (mesna, adriamycin, ifosfamide, dacarbazine) regimen with the support of lenograstim in patients with advanced soft tissue sarcomas. Following 1 cycle of MAID at the standard dose, four patients were to be treated at each of five dosage levels: +25%, +45%, +65%, +85%, +100%. Sixteen patients were treated. Because there were no significant differences in hematologic toxicity between patients receiving lenograstim 5 or 10 microg/kg/day (levels 1-5 and 1-10), the data were pooled for comparison with level 2. The median duration of absolute neutrophil count < 0.5 x 10(9)/l was 3 days at level 1 and 7 days at level 2 (p < 0.01). The median platelet nadir was 25 x 10(9)/l at level 1 and 10 x 10(9)/l at level 2 (p < 0.01). The median duration of toxicity-related hospitalization was 3.5 days and 11 days at levels 1 and 2, respectively, (p < 0.001). Mucositis > or = grade III occurred after 3/29 cycles at level 1 and 10/15 cycles at level 2 (p < 0.001). After 4 cycles at level 1, 8/8 patients still had performance status scores < or = 2, and only 4/8 had performance status scores < or = 2 after the second cycle at level 2. Lenograstim enabled an increase of 25% of the MAID regimen. At higher dose levels, severe mucositis and deterioration in performance status were dose limiting.

Outpatient treatment with subcutaneous interleukin-2 and interferon alfa administration in combination with fluorouracil in patients with metastatic renal cell carcinoma: results of a sequential nonrandomized phase II study. Subcutaneous Administration Propeukin Program Cooperative Group.

PURPOSE: We report the results of the Subcutaneous Administration Propeukin Program (SCAPP) II trial of an outpatient treatment in renal cell carcinoma using interleukin-2 (IL-2) and interferon alfa-2a (IFN-alpha) administered subcutaneously in combination with fluorouracil (5-FU). The objective of this multicenter trial was to confirm that the combination of IL-2, IFN-alpha, and 5-FU leads to a response rate greater than 20%. PATIENTS AND METHODS: Patients with metastatic renal cell carcinoma were included in this study. During the induction phase of the treatment, which lasted 10 weeks, IL-2 and IFN-alpha were administered subcutaneously three times a week for 8 weeks at doses of 18 MIU and 9 MIU, respectively. During these 8 weeks, every Monday, 5-FU was administered at a dose of 750 mg by intravenous infusion over 30 minutes. After evaluation, responding patients or patients with stable disease (SD) were given maintenance treatment, until disease progression (PD) or the appearance of unacceptable toxicity. Each maintenance cycle consisted of a 2-week treatment followed by a three-week rest period. During treatment, IL-2 and IFN-alpha were administered subcutaneously three times a week at doses of 18 MIU and 9 MIU, respectively. Every Monday, 5-FU was administered at a dose of 750 mg by intravenous infusion over 30 minutes. RESULTS: This trial was closed when the sixth sequential analysis showed the lack of benefit from this combination. At the end of the induction period, of 62 patients, 12 (19%; 95% confidence interval [CI], 10% to 31%) reached an objective response, including one complete response (CR), 16 presented with SD, and 27 showed PD. Twenty-seven patients (43%) developed severe toxicity that required reduction of the planned doses (13 patients), delayed treatment (eight patients), or treatment termination (six patients). Seventeen patients were given maintenance treatment. One- and 2-year survival rates were estimated at 55% and 33%, respectively. The 2-year survival rate was 15% in 11 patients who presented with three poor-prognosis factors and 41% in 51 patients who initially presented with no, one, or two poor-prognosis factors (P = .04). CONCLUSION: As in other recently published studies that used 5-FU, IL-2, and IFN-alpha, the multicenter SCAPP II trial in patients with metastatic renal cell carcinoma generated severe toxicity. This sequential trial failed to confirm the favorable results previously obtained by Atzpodien and Sella with this combination of three drugs. Its efficacy, assessed on the response and survival rates, is near to the results observed in programs that used IL-2 alone given subcutaneously.

Results of a phase II trial with second-line cystemustine at 60 mg/m2 in advanced soft tissue sarcoma: a trial of the EORTC Early Clinical Studies Group.

The aim of this phase II trial was to examine the efficacy of a new nitrosourea, cystemustine, in soft tissue sarcoma. Between January 1990 and March 1991, 32 pretreated patients with advanced soft tissue sarcoma were enrolled. Cystemustine was given every 2 weeks at 60 mg/m2 via a 15-min i.v. infusion. All eligible patients were considered evaluable for response and toxicity (WHO criteria). Of the 32 enrolled patients, 4 were ineligible, leaving 28 evaluable patients. All but 1 had been pretreated: 6 with adjuvant chemotherapy, 18 patients with first-line palliative chemotherapy without nitrosourea, 3 with both treatments, and 18 had received radiotherapy. Median age was 54 years (range 20-73) and median performance status was 1 (0-2). One partial response (PR, duration 12 weeks), 2 stable disease and 25 progressions were observed, giving an overall response rate of 3.57% (confidence interval: 0.1-18.4%). Toxicity was mild, and was mainly neutropenia (no grade 3 or 4), thrombocytopenia (3.57% grade 3 and grade 4) and nausea-vomiting (no grade 3 or 4). It should be noted that the treatment for the patient who obtained a PR was third line with no previous response. Cystemustine with this schedule appears to have a low clinical activity and toxicity in advanced soft tissue sarcoma.