Clinical validation of a prognostic tool in a population of outpatients treated for incurable cancer undergoing anticancer therapy: PRONOPALL study.

BACKGROUND: In 2008, a study of the characteristics of hospitalised patients led to the development of a prognostic tool that distinguished three populations with significantly different 2-month survival rates. The goal of our study aimed at validating prospectively this prognostic tool in outpatients treated for cancer in terminal stage, based on four factors: performance status (ECOG) (PS), number of metastatic sites, serum albumin and lactate dehydrogenase. PATIENTS AND METHODS: PRONOPALL is a multicentre study of current care. About 302 adult patients who met one or more of the following criteria: life expectancy under 6 months, performance status ≥ 2 and disease progression during the previous chemotherapy regimen were included across 16 institutions between October 2009 and October 2010. Afterwards, in order to validate the prognostic tool, the score was ciphered and correlated to patient survival. RESULTS: Totally 262 patients (87%) were evaluable (27 patients excluded and 13 unknown score). Median age was 66 years [37-88], and women accounted for 59%. ECOG PS 0-1 (46%), PS 2 (37%) and PS 3-4 (17%). The primary tumours were: breast (29%), colorectal (28%), lung (13%), pancreas (12%), ovary (11%) and other (8%). About 32% of patients presented one metastatic site, 35% had two and 31% had more than two. The median lactate dehydrogenase level was 398 IU/l [118-4314]; median serum albumin was 35 g/l [13-54]. According to the PRONOPALL prognostic tool, the 2-month survival rate was 92% and the median survival rate was 301 days [209-348] for the 130 patients in population C, 66% and 79 days [71-114] for the 111 patients in population B, and 24% and 35 days for [14-56] the 21 patients in population A. These three populations survival were statistically different (P <0.0001). CONCLUSION: PRONOPALL study confirms the three prognostic profiles defined by the combination of four factors. This PRONOPALL score is a useful decision-making tool in daily practice.

Minor clone provides a reservoir for relapse in multiple myeloma.

Recent studies have provided direct evidence for genetic variegation in subclones for various cancer types. However, little is known about subclonal evolutionary processes according to treatment and subsequent relapse in multiple myeloma (MM). This issue was addressed in a cohort of 24 MM patients treated either with conventional chemotherapy or with the proteasome inhibitor, bortezomib. As MM is a highly heterogeneous disease associated with a large number of chromosomal abnormalities, a subset of secondary genetic events that seem to reflect progression, 1q21 gain, NF-κB-activating mutations, RB1 and TP53 deletions, was examined. By using high-resolution single-nucleotide polymorphism arrays, subclones were identified with nonlinear complex evolutionary histories. Such reordering of the spectrum of genetic lesions, identified in a third of MM patients during therapy, is likely to reflect the selection of genetically distinct subclones, not initially competitive against the dominant population but which survived chemotherapy, thrived and acquired new anomalies. In addition, the emergence of minor subclones at relapse appeared to be significantly associated with bortezomib treatment. These data support the idea that new strategies for future clinical trials in MM should combine targeted therapy and subpopulations' control to eradicate all myeloma subclones in order to obtain long-term remission.

Cisplatin alone or combined with gemcitabine in carcinomas of unknown primary: results of the randomised GEFCAPI 02 trial.

PURPOSE: To compare the overall survival rates of good-prognosis carcinomas of an unknown primary site (CUPS) patients treated with cisplatin alone (C) or in combination with gemcitabine (CG). PATIENTS AND METHODS: Good prognosis was defined according to the GEFCAPI (Groupe d'Etude Français des Carcinomes de site Primitif Inconnu) classification by PS (Performance Status) ≤ 1 and LDH (Lactate Deshydrogenase) within the normal range. Patients were randomly assigned to receive C or CG. Patients in the C arm received cisplatin 100 mg/m(2) repeated every 3 weeks. In the CG arm, chemotherapy consisted of gemcitabine 1250 mg/m(2) on days 1 and 8 and cisplatin 100 mg/m(2) IV on day 1, repeated every 3 weeks. The original plan was to accrue 192 patients in order to detect a 20% difference in overall survival. RESULTS: Fifty-two patients were enrolled (arm A: 25; arm B: 27). The trial was stopped early due to insufficient accrual. The median overall survival (OS) rate was 11 months [95% confidence interval: 9-20] and 8 months [95%CI: 6-12], in the CG arm and in the C arm, respectively. The 1-year survival rate was 46% [95%CI: 28-64] in the combination arm and 35% [95%CI: 19-56] in the C arm (log rank test: p=0.73). The median progression-free survival (PFS) rate was 5 [95%CI: 3-11] and 3 [95%CI: 1-8] months in the CG and in the C arm, respectively. The 1-year PFS rate was 29% [95%CI: 15-48] in the combination arm and 15% [95%CI: 5-35] in the C arm (log rank test: p=0.27). No toxic deaths occurred. Grade 3-4 neutropenia (63% versus 12%) and grade 3-4 thrombocytopenia (37% versus 4%) were more frequent in the CG arm than in the C arm. CONCLUSION: A non-significantly better outcome was observed with CG as compared to C in patients with CUP and a non-unfavourable prognosis. The toxicity profile of the combined arm was represented by haematologic toxicity with thrombocytopenia and leuconeutropenia. International collaboration is required to conduct phase III trials in patients with CUP.

Randomised phase II study of siltuximab (CNTO 328), an anti-IL-6 monoclonal antibody, in combination with mitoxantrone/prednisone versus mitoxantrone/prednisone alone in metastatic castration-resistant prostate cancer.

PURPOSE: This open-label phase II trial assessed mitoxantrone/prednisone (M/P) with and without siltuximab (CNTO 328), an anti-interleukin-6 chimeric monoclonal antibody, for patients with metastatic castration-resistant prostate cancer who received prior docetaxel-based chemotherapy. METHODS: Part 1 assessed the safety of biweekly siltuximab 6 mg/kg plus M 12 mg/m(2) every 3 weeks and P. Part 2 assessed efficacy and safety of siltuximab plus M/P versus M/P alone. The primary end-point was progression-free survival (PFS). Progression was defined as progressive disease per Response Evaluation Criteria in Solid Tumours (RECIST), or ≥ 3 new skeletal lesions with clinical deterioration or without deterioration confirmed by repeated bone scan. Rising prostate-specific antigen was not considered progression. RESULTS: Siltuximab plus M/P was well tolerated in Part 1 (n=9). In Part 2, 48 and 49 patients received siltuximab plus M/P or M/P alone, respectively. Enrolment was prematurely terminated by the Independent Data Monitoring Committee since an apparent imbalance in patient baseline characteristics (favoring the M/P only arm) made it unlikely that the study could achieve its primary efficacy end-point. Median PFS was 97 days with siltuximab combination and 228 days with M/P alone (hazard ratio, 1.72; P=0.043). Use of a novel non-validated PFS definition may have contributed to this result. Abnormal laboratory assessments were more frequent with the combination. Infection and febrile neutropenia rates were similar between groups. Greater C-reactive protein suppression was achieved during siltuximab combination treatment compared with M/P alone (P=0.0003). CONCLUSION: While siltuximab plus M/P appeared well tolerated, improvement in outcomes was not demonstrated.

Autologous transplantation in acute myeloid leukemia: peripheral blood stem cell harvest after mobilization in steady state by granulocyte colony-stimulating factor alone.

In order to determine whether granulocyte colony-stimulating factor (G-CSF) alone initiated during steady state was able to mobilize peripheral blood stem cells (PBSC) in acute myeloid leukemia (AML) and to assess predictive factors for engraftment after autologous PBSC transplantation, we studied 49 successive adult AML patients for whom autologous transplantation was planned between July 1994 and November 1998. G-CSF was used as priming agent and was initiated at least 4 weeks after the last day of chemotherapy, while neutrophil count was >0.5 x 10(9)/l and platelet count was >30 x 10(9)/l. A median of three aphereses was performed resulting in a median collection of 14.8 x 10(8) nucleated cells/kg containing 7.7 x 10(8) mononuclear cells/kg, 47.1 x 10(4) CFU-GM/kg, and 3.8 x 10(6) CD34+ cells/kg. A significant correlation was observed between nucleated cell, mononuclear cell, and CFU-GM yields, while no correlation was found with CD34+ cell yield. Recruitment was not significantly different in patients with CD34+ leukemic cells at the time of initial diagnosis when compared to that of those presenting with CD34- blastic cells. Thirty-three patients actually underwent transplantation. Reasons for not autografting were inadequate stem cell harvest (ten patients), early relapse (two patients), prolonged neutropenia (one patient), organ failure (two patients), or patient refusal (one patient). Median time to achieve a neutrophil count greater than 0.5 x 10(9)/l and platelet count >50 x 10(9)/l untransfused was 13 and 36 days, respectively. A predictive factor for a shorter period neutropenia and a shorter thrombopenia was a higher count of harvested nucleated cells (p < 0.01 and p = 0.02, respectively). A higher count of harvested cells was also a predictive factor for less red cell and platelet transfusions (p=0.03 and p=0.02, respectively). The number of CD34+ harvested PBSC was not predictive for engraftment. We conclude that PBSC mobilization with G-CSF alone initiated in steady state is a feasible, safe, and suitable procedure for harvesting cells in sight of autologous transplantation in adult acute myeloid leukemia.

A prospective study of the LMB regimen for diffuse large cell non Hodgkin's lymphoma in adults.

Although the CHOP regimen remains a standard first line chemotherapy for diffuse large cell lymphoma (DLCL) in adults, a majority of these patients will still experience disease progression after the completion of this treatment. The LMB protocol is an intensive chemotherapy regimen which yields high survival rates in Burkitt's lymphoma (BL) and diffuse large cell lymphoma (DLCL) in children, as well as in primary cerebral DLCL (PCL) of adults. Here, we report the long term results of this regimen in a prospective series of 22 adult patients with DLCL excluding PCL. Fifteen male and 7 female patients with a median age of 30 years (range: 20-55) were treated prospectively between 1988 and 1993. 16 (72%) patients had an age adjusted International Pronostic Index (IPI) > or = 1. The median duration of the treatment was 15 weeks (range 13-19). Nineteen of the 22 patients (87%) experienced an objective response (14 complete, and 5 partial responses) at the end of the protocol. The predominant toxicity was myelosuppression: 89% of the COPADEM courses were followed by grade IV neutropenia and 5% with grade IV infection. One patient died (4%) of treatment related toxicity. With a median follow-up of 94 months and a minimum follow-up of 65 months, 8-year overall and progression-free survival are 73% and 67% respectively. The 8 year overall survival were 100%, 78% and 42% in patients with an IPI 0, 1, and 2-3 respectively. This short intensive regimen yields promising long term survival rates in this monocentric prospective study and may deserve to be tested in a larger multicentric prospective study comparing it to the CHOP regimen.

Factors that predict chemotherapy-induced myelosuppression in lymphoma patients: role of the tumor necrosis factor ligand-receptor system.

PURPOSE: To analyze factors that predict the occurrence of chemotherapy-induced myelosuppression and, in particular, the role of the tumor necrosis factor (TNF) ligand-receptor system in lymphoma patients at the beginning of their treatment. PATIENTS AND METHODS: We investigated the predictive factors for myelosuppression after the first course of chemotherapy in a cohort of 101 consecutive, previously untreated lymphoma patients receiving regimens that include doxorubicin and cyclophosphamide. Plasma samples were tested at baseline by enzyme-linked immunosorbent assay for TNF and its soluble receptors. Univariate and multivariate analyses were performed with a forward regression procedure that included all of the parameters that were found to be significant in the univariate analysis. The dose of chemotherapy and the prophylactic treatment with granulocyte colony-stimulating factor were deliberately included in this model. RESULTS: Sixty-seven patients experienced World Health Organization (WHO) grade 4 neutropenia, and 37 patients experienced febrile neutropenia, which was responsible for WHO grade 2 through 4 infections in 23 patients. In multiparametric regression analysis, the occurrence of grade 4 neutropenia was associated with high doses of cyclophosphamide (odds ratio ¿OR, 19.8; P =.008) and high levels of soluble p75-R-TNF (OR, 8.52; P =.001). The duration of grade 4 neutropenia for more than 5 days was associated with the lack of hematopoietic growth factor administration (OR, 6.76; P =.004) and high levels of soluble p75-R-TNF (OR, 5.84; P =.0023). The occurrence of febrile neutropenia was associated with high doses of cyclophosphamide (OR, 4.7; P =.007), altered performance status (OR, 18.8; P <.0001) and high levels of soluble p75-R-TNF (OR, 3.49; P =.029). CONCLUSION: This study indicates that in addition to the dose of chemotherapy and the administration of hematopoietic growth factors, poor performance status and high p75-R-TNF levels can predict the occurrence of chemotherapy-induced myelosuppression in lymphoma patients. This model may help in selecting patients for prophylactic growth factor administration.

Multicentric phase II study of cisplatin and etoposide in patients with metastatic carcinoma of unknown primary.

The aim of this study was to determine the efficacy and toxicity of combination cisplatin and etoposide chemotherapy in patients with metastatic carcinoma of unknown primary. Patients were treated with cisplatin (100 mg/m2 iv day 1) followed by etoposide (100 mg/m2 iv days 1-3) every 3 weeks for a maximum of 6 cycles. Patients with progressive disease after two or four courses could receive FAC (fluorouracil, doxorubicin, and cyclophosphamide) until progression. Twenty-five patients were entered and were assessable for response and toxicity. Fifteen (60%) patients had adenocarcinomas. Patients received a median of four courses. Toxicity was mainly hematologic including grade III/IV neutropenia. The overall response rate was 32%. There was no complete response, 32% partial responses, 32% stable disease, and 36% disease progression. Median response duration was 4 months (range: 2-5 months). The median overall survival of the 25 patients was 8 months. No objective response could be obtained with FAC, but 33% of patients achieved stabilization of the disease for at least 3 months. This cisplatin-etoposide combination demonstrated some activity against an usually resistant disease.

PCR detection of Epstein-Barr virus, herpes simplex virus and human papillomavirus from the anal mucosa in HIV-seropositive and HIV-seronegative homosexual men.

This study aimed to examine the prevalence of the Epstein-Barr virus (EBV), herpes simplex virus (HSV) and human papillomavirus (HPV) in the anal and oral mucosa of homosexual men with and without HIV infection and to correlate these findings to CD4+ count and anal cytology. Anal and oral cell samples from 20 HIV-infected and 14 non-infected homosexual men attending the STD clinic at Sahlgrenska University Hospital, Goteborg were examined for EBV, HSV and HPV by the polymerase chain reaction (PCR) technique. Proctoscopy was performed in all patients and swabs for cytology were taken. EBV was demonstrated in 32% (6/19) of anal cell samples from the HIV-positive group but in none from 13 HIV-negative men. Asymptomatic shedding of HSV type 2 from the anus was detected in 3 of 19 HIV-positive men, all with low CD4+ counts and abnormal cytology. No patient in the HIV-negative group shed HSV from the anus. HPV was demonstrated in 16 of 17 anal cell samples in the HIV-infected group and in 7 of 13 HIV-negative men. More than one HPV type was detected in 7 HIV-infected men. Five (29%) of 17 HIV-positive patients exhibited abnormal cytology whereas none did so in the HIV-negative group. Those with abnormal cytology all had CD4+ counts below 0.35 and were infected with multiple HPV types including HPV 16/18. In conclusion, our results demonstrate an enhanced expression of HPV as well as EBV from the anus in HTV-infected homosexual men. In this small number of patients EBV was not related to low CD4+ count or to abnormal cytology.

[Merkel cell carcinoma: diagnostic and treatment]. / Le carcinome à cellules de Merkel: diagnostic, traitement de la maladie locorégionale et de la maladie en phase métastatique.

Merkel cell carcinoma (MCC) is an uncommon neuro-endocrine tumor of the sun-exposed skin predominantly observed in white patients in the sixth decade of the life. In electron microscopy MCC characteristically contains dense core secretory granules. This tumor expresses both epithelial (keratins of low molecular weight of the simple epithelial type, epithelial membrane antigen) and neuro-endocrine markers (neuron-specific enolase, chromogranin A). The analysis of available literature indicates that MCC has a propensity for involvement of regional lymphatics (12% of patients at the date of initial diagnosis and 50 to 66% afterwards) and for metastases to distant sites (20 to 52%). The prognosis of metastatic disease is poor. The overall survival from the diagnosis of metastases is 6 months. The optimal treatment of locoregional stages should include excision and post-operative radiation. The role of chemotherapy in this tumor is unclear but recent data suggest a high chemosensitivity.

Chemotherapy for patients with locally advanced or metastatic Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a highly malignant skin neoplasm. Regional lymph node and distant metastasis occur in 20-52% of patients. The role of chemotherapy in the treatment of patients with this rare tumor is unclear. METHODS: An exhaustive analysis of the literature (1980-1995) describing chemotherapy for patients with locally advanced or metastatic MCC was performed. All available published medical records (n = 101 patients) were entered in a database. In addition, data on six additional patients given chemotherapy during this time frame in Lyon, France, were included in the database. RESULTS: For the 107 patients, the overall objective response rate to first-line chemotherapy was 61% (61 of 101 evaluable patients). The response rate was 57 % (41 of 72) for patients with metastasis and 69% (20 of 29) for patients with locally advanced tumors. No clinical parameter was found to be correlated to response to chemotherapy. A high rate of toxic death during first-line treatment (n = 7.7%) was reported for these patients. The median overall survival from the date of chemotherapy initiation was 9 months for patients with metastasis and 24 months for patients with locally advanced tumors. The projected overall survival at 3 years was 17% for patients with metastasis and 35% for patients with locally advanced tumors. Progression after first-line chemotherapy was associated with significantly worse survival for patients with metastasis. Rates of response to second-line (n = 33) and third-line (n = 10) chemotherapy were 45% and 20%, respectively. CONCLUSIONS: MCC is chemosensitive but rarely chemocurable in patients with metastasis or locally advanced tumors. A high incidence of toxic death due to chemotherapy is reported in the literature.

[Do the prevention and treatment of deep venous thrombosis have specificity in the cancer patient?]. / La prévention et le traitement de la thrombose veineuse profonde ont-ils une spécificité chez le patient cancéreux?

An increased incidence of deep vein thrombosis is reported in cancer patients as compared with general population. Several risk factors for deep vein thrombosis have been identified: venous stasis, direct invasion of venous wall by tumor, and hypercoagulability state by inadequate secretion of procoagulant activities. Reports have suggested that chemotherapeutic agents and hormonal treatment may contribute to this risk. Few papers are available concerning the prophylaxis and curative treatment of deep vein thrombosis in cancer patients and no consensus has been reached yet. This predisposition for deep vein thrombosis should be taken into consideration for perioperative prophylaxis. Efficacy and safety of heparin and antivitamin K in the curative treatment of deep vein thrombosis are discussed but can not be accurately evaluated because of diversity of clinical presentations and mechanism of activation of coagulation. Prospective studies are necessary.

Are acetowhite lesions of the cervix correlated to the presence of Epstein-Barr virus DNA?

The purpose of this study was to investigate whether Epstein-Barr virus (EBV) is associated with acetowhite lesions of the portio cervix, demonstrating koilocytosis and/or cervical intraepithelial neoplasia (CIN) I-III. The study group comprised 37 women admitted to the Department of Gynaecology and Obstetrics, Sahlgrenska University Hospital, Göteborg because of pathological colposcopy or cytology of the portio cervix. Colposcopically, all exhibited acetowhite lesions of the portio cervix. Cells were sampled with a cytobrush for examination for EBV and human papillomavirus (HPV) DNA by polymerase chain reaction (PCR) and a biopsy was taken for histopathology. Biopsies from 5 patients positive for EBV by PCR in cervical cell samples were examined by an in situ hybridization technique for EBER (Epstein-Barr virus encoded RNA), RNAs expressed in latent EBV infection. The control group consisted of women attending the Department of Dermato-Venereology at the same hospital for STD check-up. These had a normal cytology and no signs of acetowhiteness of the portio cervix. In the study group, EBV DNA was found in 30% and HPV DNA in 51%. In the control group 57% exhibited EBV DNA and 23% HPV DNA. EBV was not found to be a predictive factor in the development of koilocytosis and/or CIN I-III. HPV was a predictive factor in acetowhite, koilocytotic lesions. No expression of EBER was found in the 5 biopsies examined by in situ hybridization.

Demonstration of Epstein-Barr virus DNA and human papillomavirus DNA in acetowhite lesions of the penile skin and the oral mucosa.

Oral hairy leukoplakia (OHL), thought to be caused by Epstein-Barr virus (EBV), shows similar histological and clinical features to human papillomavirus (HPV)-related acetowhite lesions of the vulva. We thus aimed to investigate the role of both HPV and EBV in men with acetowhite lesions of the penis. HPV but not EBV was significantly associated with penile acetowhite lesions showing koilocytosis compared with normal penile skin (12/20 versus 5/20, P < 0.02). HPV (5/20) and EBV (6/20) was detected in oral mucosa of some of these individuals. These results confirm an aetiological association between HPV and acetowhite penile lesions showing koilocytosis. HPV and EBV carriage in the oral mucosa is relatively common in young sexually active men.

Genital viral infections. Studies on human papillomavirus and Epstein-Barr virus.

The concept 'sexually transmitted diseases' (STD) was introduced in the nineteen sixties and comprises many diseases of varying importance from scabies to HIV infection. The STD family has grown wider and new members will probably join. The starting point of these studies was that patients with HPV infection, attending the STD clinic, appeared to increase in number in the late eighties. HPV was analysed with the Southern blot technique from portio cervix in a female population attending the STD clinic. In this population 8% were HPV-positive. If vulvar/vaginal HPV manifestations were present the figure increased to 34%. Abnormal cytology was found in 13% and if the woman harboured high-risk types of HPV there was also a greater risk of abnormal cytology (Paper I). Different clinical manifestations of HPV infection were examined in men with respect to different types of HPV. Macular lesions seemed mainly to be related to high-risk types to accuminate lesions. Histological dysplasia was correlated to high-risk HPV types (Paper II). The resemblance of acetowhite lesions of the vulva to oral hairy leukoplakia suggested the possibility of EBV as an etiological factor. EBV was demonstrated with PCR in 48% and HPV in 17%. In the group with no acetowhite reactions the correspondings figures were 11% and 42% (Paper III). As these results were unexpected, another group of women with the same clinical manifestations, as well as a control group, were examined. The tendency to find more EBV in the acetowhite lesions was confirmed. HPV was detected equally in both groups (Paper IV). The inclusion criterion was presence of acetowhite, koilocytotic lesions in routine histological examination. When all biopsies were reevaluated, only 8 of 20 demonstrated an evident koilocytosis (Paper IV). A male group with acetowhite penile lesions and a group with no acetowhite reactions were investigated with respect to EBV and HPV. HPV positivity was strongly correlated to acetowhite lesions but not EBV. All lesions demonstrated an evident koilocytosis (Paper IV). The oral mucosa of men with acetowhite, penile lesions more often harboured both EBV and HPV compared to the controls (Paper IV). The portio cervix was examined to detect EBV and HPV, irrespective of clinical manifestations. EBV and HPV was found in 38% and 33%, respectively (Paper V). In patients with acetowhite, koilocytotic and/or dysplastic lesions on the portio cervix EBV was found in 30% and HPV in 51%. EBV was not associated with either acetowhiteness or dysplasia (Paper VI). A group of HPV infected men was investigated concerning psychological complications in connection with their viral, genital infection. Half of the group were anxious about the risk of giving their partner an oncogenic virus, and a fifth of the group had feelings of "dirtiness" and reported a decrease in their sexual desire (paper VII). In view of this, it is concluded that acetowhite, koilocytotic lesions of the penis and the cervix are HPV related. On the vulva, however, HPV seems to have a minor role, whereas EBV might be associated with acetowhite lesions. These and other recent findings suggest EBV to be a possible STD related virus. The oncogenic potential of EBV underlines the importance of further studies. Koilocytosis as a pathognomonic sign of HPV infection has to be reconsidered. Finally, psychological aspects have to be kept in mind in the treatment of patients with HPV infection.