Advanced oesophago-gastric adenocarcinoma in older patients in the era of immunotherapy. A review of the literature.

Gastric (G) and gastro-esophageal junction (GEJ) adenocarcinomas are of the most common and deadly cancers worldwide and affect mainly patients over 70 years at diagnosis. Older age has been associated in gastric cancers with distal tumour location, well-differentiated adenocarcinoma and microsatellite instability and is not identified itself as an independent prognostic factor. As immune checkpoint inhibitors recently changed the landmark of advanced G and GEJ adenocarcinomas treatment, we decided to perform a literature review to define the evidence-level of clinical data in older patients. This work underlined the lasting low -inclusion rate of older patients and -implementation rate of frailty screening tools in clinical trials in G/GEJ carcinomas. In the first-line metastatic setting, two prospective randomized phase III studies have specifically assessed the efficacy of chemotherapy in older patients with HER2-negative gastric cancers, demonstrating the feasibility of reduced dose oxaliplatin-based chemotherapy regimen in this population. Only few data are available in HER2-positive tumors, or in the second-line setting. Furthermore, no specific trial with immune checkpoint inhibitors was performed in older frail patients whereas their benefit/adverse events ratio make them attractive candidates in this patient's population. We conclude that older fit patients can be treated in the same way as younger ones and included in clinical trials. Improving the outcome of older frail patients should be the oncology community next focus by implementing targeted interventions before initiating cancer therapy and designing specific clinical trials. Frailty screening tools and geriatric data collection have to be implemented in routine-practice and clinical trials.

Updated recommendations of the International Society of Geriatric Oncology on prostate cancer management in older patients.

BACKGROUND: The median age of prostate cancer diagnosis is 66 years, and the median age of men who die of the disease is eighty years. The public health impact of prostate cancer is already substantial and, given the rapidly ageing world population, can only increase. In this context, the International Society of Geriatric Oncology (SIOG) Task Forces have, since 2010, been developing guidelines for the management of senior adults with prostate cancer. MATERIAL AND METHODS: Since prostate cancer and geriatric oncology are both rapidly evolving fields, a new multidisciplinary Task Force was formed in 2018 to update SIOG recommendations, principally on health status screening tools and treatment. The task force reviewed pertinent articles published between June 2016 and June 2018 and abstracts from European Association of Urology (EAU), European Society for Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO) and American Society of Clinical Oncology Genito-urinary (ASCO GU) meetings over the same period, using search terms relevant to prostate cancer, the elderly, geriatric evaluation, local treatments and advanced disease. Each member of the group proposed modifications to the previous guidelines. These were collated and circulated. The final manuscript reflects the expert consensus. RESULTS: The 2019 consensus is that men aged 75 years and older with prostate cancer should be managed according to their individual health status, and not according to age. Based on available rapid health screening tools, geriatric evaluation and geriatric interventions, the Task Force recommends that patients are classified according to health status into three groups: (1) 'healthy' or 'fit' patients should have the same treatment options as younger patients; (2) 'vulnerable' patients are candidates for geriatric interventions which-if successful-may make it appropriate for them to receive standard treatment and (3) 'frail' patients with major impairments who should receive adapted or palliative treatment. The 2019 SIOG Task Force recommendations also discuss prospects and unmet needs for health status evaluation in everyday practice in older patients with prostate cancer.

Actinomycin D, cisplatin, and etoposide regimen is associated with almost universal cure in patients with high-risk gestational trophoblastic neoplasia.

BACKGROUND: Patients with high-risk gestational trophoblastic neoplasia (GTN) need multi-agent chemotherapy to be cured. The most common regimen is etoposide (E), methotrexate (M) and actinomycin D (A), alternating weekly with cyclophosphamide (C) plus vincristine (O) (EMA/CO). Cisplatin (P) is a very active drug, but it is usually restricted to second-line therapies. Herein, we report the results of a cisplatin-based therapy: APE (actinomycin D, cisplatin, and etoposide). PATIENTS AND METHODS: The efficacy and safety of APE for high-risk GTN (defined by Institut Gustave-Roussy (IGR) criteria and/or an International Federation of Gynaecology and Obstetrics (FIGO) score >6) are reported. Patients with brain metastasis or placental-site trophoblastic tumour were excluded. RESULTS: Between 1985 and 2013, 95 patients were treated with APE for high-risk GTN: 59 patients as first-line, 36 as ⩾ 2nd-line therapy. There was 94.7% complete remission, though five patients relapsed. One patient died from GTN after multiple lines of chemotherapy. The five-year overall survival rate (median follow-up 5.7 years) was 97% (95% confidence interval (CI): 91-99%). No death from toxicity occurred. Long-term, six grade-1 neuro-toxicities, three grade-1 and two grade-2 oto-toxicities, and one grade-1 renal toxicity were recorded. One patient developed AML-M4 after APE and EMA/CO. Thirty-four of 35 women, who wished to become pregnant, succeeded and all had at least one live birth. CONCLUSION: With a 97% long-term overall survival rate, limited long-term toxicity, and an excellent reproductive outcome, APE could be regarded as an alternative option to EMA/CO as a standard therapy for high-risk GTN.

Occupational exposures in rare cancers: A critical review of the literature.

The contribution of occupational exposures to rare cancers, which represent 22% of all cancers diagnosed annually in Europe, remains insufficiently considered. We conducted a comprehensive review of occupational risk factors in 67 rare cancers (annual incidence <6/100,000). An examination of relevant articles in PubMed (1960-2012) and the International Agency for Research on Cancer (IARC) monographs revealed that 26 cancer sites, such as mesothelioma, nasal, larynx, liver, ovarian cancer, bone sarcoma, and hematopoietic malignancies were consistently linked to occupational factors. Main exposures included asbestos, wood dust, metals/metalloids, formaldehyde, benzene, vinyl chloride, and radiation. There was inconsistent evidence regarding 22 rare malignancies. We did not identify relevant data for 19 rare cancers. Despite limitations of published evidence, our review provides useful information that can facilitate the identification of work-related factors that contribute to rare cancers. International collaborations, development of improved exposure assessment methods, and molecular approaches can improve future studies.

Management of brain metastases from germ cell tumors: a single center experience.

BACKGROUND: Brain metastases from germ cell tumors (GCT) are rare and treatment has not yet been standardized. METHODS: The clinical data of men with brain metastases from GCT treated in a single cancer hospital from January 1993 to September 2007 were reviewed. Patients with primary central nervous system GCT were excluded. RESULTS: Thirteen patients had brain metastases at initial diagnosis. All patients received cisplatin-based chemotherapy. Three also received radiotherapy and 1 underwent surgery. Eight of the patients died. Median survival was 19 months (95% CI 0.84-not reached). Twenty-two patients developed brain metastases at recurrence. Median time from initial diagnosis to brain metastases was 8.25 months (3-17.5 months). Five patients received radiotherapy alone, 3 received chemotherapy alone and 3 received supportive care only. Nine patients were operated on: 6 received postoperative chemotherapy and 1 received postoperative radiotherapy. Only 1 patient is still alive. Median survival was 5.1 months (95% CI: 2.2-10.5 months). CONCLUSIONS: Patients with GCT who present with brain metastases at diagnosis tend to do better than patients who develop them at relapse. Chemotherapy can be adequate treatment for initial brain metastases. Treatment for patients with brain metastases at relapse is still not optimal.

[Primary mucinous carcinoma of the eyelid. Case report]. / Carcinome mucineux primitif palpébral. À propos d'un cas.

Primary cutaneous mucinous carcinoma, a tumor of the sweat glands, is a rare tumor localized to the eyelid in 40% of cases. We report a case of a primary cutaneous mucinous carcinoma of the upper eyelid in a 53-year-old Caucasian male who appeared to have a chalazion. Histology showed rows and lobules of epithelial cells with discretely anisonucleotic nuclei and few mitotic figures scattered throughout the tumor cells, surrounded by a mucoid substance. Immunohistochemical analysis was cytokeratin 7 positive and cytokeratin 20 negative, and imaging and endoscopic screening were negative for metastasis, favoring the diagnosis of primary cutaneous mucinous carcinoma. Despite a high recurrence rate of about 35%, this type of tumor displays an indolent course, and metastatic spread is very rare.

Tumor marker kinetics predict outcome in patients with relapsed disseminated non-seminomatous germ-cell tumors.

BACKGROUND: An early serum tumor marker (TM) decline during chemotherapy was shown to independently predict survival in patients with poor-prognosis disseminated non-seminomatous germ-cell tumors (NSGCTs). The aim of this study was to assess whether a TM decline (TMD) also correlates with the outcome in the salvage setting. PATIENTS AND METHODS: Data regarding 400 patients with progressive or relapsed disseminated NSGCTs after first-line chemotherapy prospectively accrued onto two phase III clinical trials were obtained. Serum alpha-fetoprotein (AFP) and/or human chorionic gonadotropin (hCG) were assessed at baseline and after 6 weeks of chemotherapy. A total of 297 patients, 185 and 112 in the training and validation sets, with initially abnormal TMs for whom a change from baseline could be established were used for this analysis. RESULTS: An unfavorable decline in either AFP or hCG was predictive of progression-free survival (PFS) [hazard ratio, HR = 2.15, (95% CI 1.48-3.11); P < 0.001; 2-year PFS rate: 50% versus 26%] as was the Lorch prognostic score (LPS). In the multivariate analysis, an unfavorable TMD, stratified based on the LPS, was an independent adverse prognostic factor for PFS and OS. CONCLUSION: An unfavorable TMD during the first 6 weeks after chemotherapy is associated with a poorer outcome in patients with relapsed disseminated NSGCTs.

Treatment of uncommon malignant tumours of the bladder.

PURPOSE OF REVIEW: Urothelial carcinoma is the most common histological type of bladder tumours. Nevertheless, its variants and less common types represent 20% of all bladder cancers. The objective was to update the recent publications on these rare diseases and to draw conclusions for clinical management. RECENT FINDINGS: Recent retrospective studies have been published. They refine the description of histological patterns and of immunochemistry diagnosis. Taking into account the heterogeneity of these pathologies, several groups have benefited of increased knowledge such as sarcomas and lymphomas. The need of international collaboration to study prospectively some subgroups of tumours is crucial. SUMMARY: Rare bladder cancers have generally poor outcome and in a majority of the cases surgery, namely cystectomy remains the most important curative treatment. Specific subgroups, as lymphoma, sarcoma and dedifferentiated epithelial tumours may benefit of molecular characterization and trials with targeted drugs.

[The role of chemotherapy in the management of bladder cancer]. / Rôle de la chimiothérapie dans la prise en charge du cancer de la vessie.

Bladder cancer represents for man the second genitourinary cancer after prostate cancer. Urothelial carcinoma is the most predominant histological type. In up to 70% of the cases, the diagnosis of bladder cancer is performed at early stages (Ta-T1). In this situation, the treatment of the disease is the transurethral resection with or without intravesical treatment (BCG, Amiticyne). In advanced disease, treatment is essentially palliative with chemotherapy based on cisplatin type MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) or gemcitabine-cisplatin. In invasive stages (T2-T3-T4), the radical cystoprostatectomy combined with urinary diversion for man, and the pelvectomy for woman are the gold standard. However, over 50% of these patients experienced metastatic recurrence during their evolution, which prompted investigators last 10 years to assess the value of néoadjuvant chemotherapy in their management. Indeed, neoadjuvant chemotherapy is now recognized as a standard by numerous American and European institutions. However, adjuvant chemotherapy remains controversial even for patients with lymph node involvement. The purpose of this literature review is to highlight the role of chemotherapy in the management of urothelial carcinoma of bladder with locally advanced and metastatic disease. The role of targeted therapies alone, in combination with chemotherapy, and in maintenance, is being evaluated.

Phase II study of carboplatin and etoposide in patients with anaplastic progressive metastatic castration-resistant prostate cancer (mCRPC) with or without neuroendocrine differentiation: results of the French Genito-Urinary Tumor Group (GETUG) P01 trial.

BACKGROUND: In the evolution of metastatic castration-resistant prostate cancer (mCRPC), patients present visceral metastases with or without neuroendocrine differentiation in 20% of cases. PATIENTS AND METHODS: We assessed the efficacy and toxicity of a platinum-based chemotherapy regimen in mCRPC patients with either neuroendocrine differentiation defined by high serum levels of chromogranin A (CgA) and neuron-specific enolase (NSE) or visceral metastases. Patients received the combination of carboplatin and etoposide every 3 weeks. Efficacy end points included prostate-specific antigen (PSA) and neuroendocrine marker response, objective response and toxicity. RESULTS: Of the 60 patients included from April 2005 to January 2008, 78.6% had bone metastases, 46.4% had lymph node involvement and 57.1% had liver and/or lung localizations. The objective response rate was 8.9% in the 46 patients with measurable disease. A neuroendocrine response was observed in 31% of cases for NSE and 7% for CgA. The PSA response rate was 8%. The most common grade 3-4 treatment-related toxic effects were neutropenia (65.5%), thrombocytopenia (32.7%) and anemia (27.3%). There was 7.2% febrile neutropenia, with one toxicity-related death. The median follow-up was 9.3 months [95% confidence interval (CI) 0.2-27.1] and the median overall survival 9.6 months (95% CI 8.7-12.7). CONCLUSION: The benefit-risk ratio of this regimen seems unfavorable due to poor response and high toxicity.

Potential drug interactions in elderly cancer patients.

INTRODUCTION: Drug interaction constitutes a major challenge in elderly cancer patients. This study investigated the number and types of medications patients and potential drug interactions in these patients. METHODS: Treatments received by 105 cancer outpatients aged ≥70 years were analyzed using the French Thesaurus to identify drug-drug interactions according to four levels: contraindication, concomitant use not recommended, concomitant medications requiring precautions and concomitant medications to be taken into account. RESULTS: The mean number of medications per patient was 4.7 (range: 0-14). Among 97 patients taking ≥2 drugs, 45 potential interactions were identified, occurring in 32 patients. No contraindication, 2 cases of concomitant use not recommended, 9 cases requiring precautions (20%) and 34 cases of concomitant medications to be taken into account were identified. Drug interactions caused respiratory distress and increased bleeding risk. CONCLUSION: Drug interactions are common in the elderly, but almost half of interactions were moderate.

[Rare tumours: a new heading in Bulletin du cancer]. / Problématique des tumeurs rares : une nouvelle rubrique du Bulletin du cancer.

Rare cancers are defined by an incidence less than 5/100,000, which means in France less than 3,000 new cases a year. They are difficult to diagnose, their physiopathology has led to new knowledge in cancer medicine. There is no large experience for their management, and they are not generally the subject of randomized trials to establish treatment strategy. Therefore they are often managed by suboptimal cares. Even individually rare cancers do not concern large populations, the number of patients suffering of rare cancer is important. This is the reason why the "Bulletin du cancer" will open a new section on rare cancers. This article aims to draw the context of such a decision, based on an effort to allow these patients to receive optimal management.

[Uncommon bladder tumours]. / Tumeurs rares de la vessie.

Bladder tumours are frequent with around 10,000 new cases each year in France. Less than 500 of these cases are not transitional cell carcinoma, the most frequent pathological aspect. The identification of these pathological patterns requires an initial biopsy through transurethral resection. Sarcomatoid, squamous and some adenocarcinomatous types are often pathological variants of the transitional pattern. These tumours are possibly secondary to alkylating drug metabolites or pelvic radiotherapy and they have often a poor prognostic outcome. This is also the case of spindle cell carcinoma, an endocrine variant of rare bladder cancers. The treatment is generally based on an aggressive approach combining chemotherapy and a radical cystectomy. Other tumours have a more locally invasive pattern, as have urachal adenocarcinomas, sarcomas. The treatment is based on aggressive surgical exeresis of the tumour and surrounding structures. The outcome may be more favourable. Primary non Hodgkin lymphomas are rare, secondary involvement more frequent. All histological subtypes could be encountered. The treatment is the same as this of lymphomas of other location and of the same histology. Attention must be drawn on a precise evaluation of the pathological pattern and of the disease extension.

[Recommendations for the treatment of prostate cancer in the elderly man: A study by the oncology committee of the French association of urology]. / Recommandations pour la prise en charge du cancer de la prostate chez l'homme âgé : un travail du comité de cancérologie de l'association française d'urologie.

The increase in life expectancy combined with the increase in the global incidence of cancers will probably results in an increase in the number of cancers observed in the elderly. The increase in the incidence of prostate cancers in geriatric patients (45% of prostate cancers are diagnosed after 75 years old) is in sharp contrast with the lack of strong scientific data on the topic. By the meantime, oncogeriatrics has been developing for some years now under the guidance of the International Society of Oncogeriatrics. Such an approach aims at palliating the low quality of care of cancers in geriatric patients. The reasons for the low quality of care come from the characteristics of these patients and from the training of the care providers. The authors recall the principles of oncogeriatric evaluation and the classification of patients as it is actually proposed. They describe the main treatments and their results in the geriatric population and they describe the decision process concerning the choice of the treatment. They also suggest some guidelines on the diagnosis of prostate cancer, evaluation of the patients and the treatments of the disease in the elderly. Prostate cancer is almost the perfect model for oncogeriatrics. Urologists should remain the corner stone of its management, whatever the age of their patient.

Small cell cancer of the bladder: pathology, diagnosis, treatment and prognosis.

Small cell carcinoma of the bladder (SCCB) is rare, highly aggressive and diagnosed mainly at advanced stages. In addition, coexistence of SCCB with other types of carcinoma is common. Hematuria is the main symptom of this malignancy. Histological tests show a tumour, which is indistinguishable from small cell lung carcinoma (SCLC). Then immunohistochemistry tests may be helpful for a more precise diagnosis. Pathogenesis is uncertain; however the multipotent stem cell theory applies best to this case. The most common staging system used is the two-stage system (limited-extensive). Because of the rarity of the disease, the management is extrapolated from that of SCLC. Limited-stage disease should be treated with etoposide-cisplatin chemotherapy in combination either with radiotherapy, or surgery or both. Extensive-stage disease should be managed by combined chemotherapy. Further research programmes are needed to improve the diagnosis and the treatment of SCCB tumour. This paper would provide a comprehensive review of the epidemiology, clinical features, diagnosis, pathologic features, histogenesis, molecular genetics, staging, treatment, and prognosis of SCCB.

[Definition and outline on geriatric oncology]. / Définition et présentation de la cancérologie du sujet âgé.

Geriatric oncology is the concept for management of elderly cancer patients. It is an equal approach of the health status problems and of cancer in a patient considered as a whole. Therefore it is not a subspecialty but a practice which can be translated in the elderly cancer patient's care. The treatment of cancer is based on the same principles than this of younger patients; recommendations used are those of the scientific oncological societies. Health problems of elderly patients are screened by specific tools. Patients without major health problems are managed by the oncological team in the routine; those for whom screening have demonstrated problems are first evaluated in the geriatrics setting and then oncological decisions are adapted to the patient situation. Decisions are made in specific geriatric oncology conferences. Specific clinical trials are required to build an Evidence Based Medicine background. Geriatric oncology teaching programs are warranted.

[Testis germ cell tumours: which chemotherapy, for which patients?]. / Cancer du testicule: quelle chimiothérapie, pour quels malades?

Germ cell tumours of the testis are curable disease. Two different pathological subtypes are observed: seminoma and non-seminoma. Two tumour stages have been defined: the disease limited to the testis and the advanced disease. In the latter group, the prognosis is established by a specific classification based on the level of serum tumour marker and the location of the metastases. The most active first line chemotherapy is a combination of bleomycine, etoposide and cisplatine. Patients with good prognostic factors receive three cycles of this regimen; patients with poor-risk characteristics receive four cycles of the same regimen. The strategy in non-seminoma patients is to give a first-line chemotherapy adapted to the risk factors, then to complete surgical exeresis of all residual disease. Patients with stage I disease may receive two cycles of the same regimen. The strategy for advanced seminoma is to give first-line good-risk chemotherapy followed by a close observation and in several selected cases a surgical removal of all residual disease. Patients with stage I disease may receive one cycle of carboplatin. Salvage chemotherapy is based on the combination of ifosfamide, cisplatine and either vinblastine or paclitaxel.

Refining the optimal chemotherapy regimen for good-risk metastatic nonseminomatous germ-cell tumors: a randomized trial of the Genito-Urinary Group of the French Federation of Cancer Centers (GETUG T93BP).

BACKGROUND: High cure rates are expected in good-risk metastatic nonseminomatous germ-cell tumor (NSGCT) patients with bleomycin, etoposide and cisplatin. PATIENTS AND METHODS: Patients received either three cycles of BE500P or four cycles of E500P every 3 weeks. Disease was defined according to the Institut Gustave Roussy prognostic model. Patients were retrospectively assigned into the International Germ Cell Cancer Collaborative Group (IGCCCG) classification. A sample size of 250 patients was necessary for an expected favorable response rate (primary end point) of 90% and not more than a 10% difference between the two arms. RESULTS: Among 257 assessable patients, 124 and 122 patients achieved a favorable response in the 3BE500P and 4E500P arms, respectively (P = 0.34). Median follow-up was 53 months. The 4-year event-free survival rates were 91% and 86%, respectively (P = 0.135). The 4-year overall survival rates were not significantly different [five deaths versus 12 deaths, respectively (P = 0.096)]. Similar nonsignificant trends were observed in good IGCCCG prognosis patients. CONCLUSIONS: Both regimens produced similar results in terms of favorable response rates. As the trial was underpowered for survival analyses, conclusive data would require a larger randomized trial. Unless such a study is done, 3BE500P is the treatment of choice for metastatic NSGCT patients.

Organization of the clinical activity of geriatric oncology: report of a SIOG (International Society of Geriatric Oncology) task force.

Management for elderly cancer patients world wide is far from being optimal and few older patients are entering clinical trials. A SIOG Task Force was therefore activated to analyze how the clinical activity of Geriatric Oncology is organized. A structured questionnaire was circulated among the SIOG Members. Fifty eight answers were received. All respondents identified Geriatric Oncology, as an area of specialization, however the organization of the clinical activity was variable. Comprehensive Geriatric Assessment (CGA) was performed in 60% of cases. A Geriatric Oncology Program (GOP) was identified in 21 centers, 85% located in Oncology and 15% in Geriatric Departments. In the majority of GOP scheduled case discussion conferences dedicated to elderly cancer patients took regular place, the composition of the multidisciplinary team involved in the GOP activity included Medical Oncologists, Geriatricians, Nurses, Pharmacists, Social Workers. Fellowships in Geriatric Oncology were present in almost half of GOPs. Over 60% of respondents were willing to recruit patients over 70 years in clinical trials, while the proportion of cases included was only 20%. Enrolment in clinical trials was perceived as more difficult by 52% and much more difficult in 12% of the respondents. In conclusion, a better organization of the clinical activity in Geriatric Oncology allows a better clinical practice and an optimal clinical research. The GOP which can be set up in the oncological as well as in the geriatric environment thought a multidisciplinary coordinator effort. Future plans should also concentrate on divisions, units or departments of Geriatric Oncology.