ESMO / ASCO Recommendations for a Global Curriculum in Medical Oncology Edition 2016.

The European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) are publishing a new edition of the ESMO/ASCO Global Curriculum (GC) thanks to contribution of 64 ESMO-appointed and 32 ASCO-appointed authors. First published in 2004 and updated in 2010, the GC edition 2016 answers to the need for updated recommendations for the training of physicians in medical oncology by defining the standard to be fulfilled to qualify as medical oncologists. At times of internationalisation of healthcare and increased mobility of patients and physicians, the GC aims to provide state-of-the-art cancer care to all patients wherever they live. Recent progress in the field of cancer research has indeed resulted in diagnostic and therapeutic innovations such as targeted therapies as a standard therapeutic approach or personalised cancer medicine apart from the revival of immunotherapy, requiring specialised training for medical oncology trainees. Thus, several new chapters on technical contents such as molecular pathology, translational research or molecular imaging and on conceptual attitudes towards human principles like genetic counselling or survivorship have been integrated in the GC. The GC edition 2016 consists of 12 sections with 17 subsections, 44 chapters and 35 subchapters, respectively. Besides renewal in its contents, the GC underwent a principal formal change taking into consideration modern didactic principles. It is presented in a template-based format that subcategorises the detailed outcome requirements into learning objectives, awareness, knowledge and skills. Consecutive steps will be those of harmonising and implementing teaching and assessment strategies.

A Phase I Protocol of Hydralazine and Valproic Acid in Advanced, Previously Treated Solid Cancers.

Smokers experience aberrant gene promoter methylation in their bronchial cells, which may predispose to the development of neoplasia. Hydralazine is a DNA demethylating agent, and valproic acid is a histone deacetylase inhibitor, and both have modest but synergistic anticancer activity in vitro. We conducted a phase I trial combining valproic acid and hydralazine to determine the maximally tolerated dose (MTD) of hydralazine in combination with a therapeutic dose of valproic acid in patients with advanced, unresectable, and previously treated solid cancers. Twenty females and nine males were enrolled, with a median age of 57 years and a median ECOG performance status of 0. Grade 1 lymphopenia and fatigue were the most common adverse effects. Three subjects withdrew for treatment-related toxicities occurring after the DLT observation period, including testicular edema, rash, and an increase in serum lipase accompanied by hyponatremia in one subject each. A true MTD of hydralazine in combination with therapeutic doses of valproic acid was not reached in this trial, and the planned upper limit of hydralazine investigated in this combination was 400 mg/day without grade 3 or 4 toxicities. A median number of two treatment cycles were delivered. One partial response by Response Evaluation Criteria In Solid Tumors criteria was observed, and five subjects experienced stable disease for 3 to 6 months. The combination of hydralazine and valproic acid is simple, nontoxic, and might be appropriate for chemoprevention or combination with other cancer treatments. This trial supports further investigation of epigenetic modification as a new therapeutic strategy.

Nicotine induces the up-regulation of the α7-nicotinic receptor (α7-nAChR) in human squamous cell lung cancer cells via the Sp1/GATA protein pathway.

Nicotine, the addictive component of cigarettes, promotes lung cancer proliferation via the α7-nicotinic acetylcholine receptor (α7-nAChR) subtype. The present manuscript explores the effect of nicotine exposure on α7-nAChR levels in squamous cell carcinoma of the lung (SCC-L) in vitro and in vivo. Nicotine (at concentrations present in the plasma of average smokers) increased α7-nAChR levels in human SCC-L cell lines. Nicotine-induced up-regulation of α7-nAChR was confirmed in vivo by chicken chorioallantoic membrane models. We also observed that the levels of α7-nAChR in human SCC-L tumors (isolated from patients who are active smokers) correlated with their smoking history. Nicotine increased the levels of α7-nAChR mRNA and α7-nAChR transcription in human SCC-L cell lines and SCC-L tumors. Nicotine-induced up-regulation of α7-nAChR required GATA4 and GATA6. ChIP assays showed that nicotine induced the binding of GATA4 or GATA6 to Sp1 on the α7-nAChR promoter, thereby inducing its transcription and increasing its levels in human SCC-L. Our data are clinically relevant because SCC-L patients smoked for decades before being diagnosed with cancer. It may be envisaged that continuous exposure to nicotine (in such SCC-L patients) causes up-regulation of α7-nAChRs, which facilitates tumor growth and progression. Our results will also be relevant to many SCC-L patients exposed to nicotine via second-hand smoke, electronic cigarettes, and patches or gums to quit smoking.

A phase II study of temsirolimus and erlotinib in patients with recurrent and/or metastatic, platinum-refractory head and neck squamous cell carcinoma.

OBJECTIVES: The epidermal growth factor receptor (EGFR) is a validated target in head and neck squamous cell carcinoma (HNSCC). In recurrent and/or metastatic (R/M) HNSCC, resistance to anti-EGFR therapy inevitably occurs. Downstream activation of the PI3K/Akt/mTOR pathway is an established resistance mechanism. Concurrent mTOR blockade may improve efficacy of anti-EGFR therapy. MATERIALS AND METHODS: Erlotinib 150 mg daily and temsirolimus 15 mg weekly were administered to patients with platinum-refractory R/M HNSCC and ECOG performance status 0-2. The primary endpoint was progression-free survival (PFS). Correlative studies determined PIK3CA and HRAS mutation status; p16, EGFR, pS6K, pAkt and PTEN expression; and pre- and post-treatment plasma levels of 20 immunomodulatory cytokines. RESULTS: Twelve patients enrolled; six withdrew within 6 weeks due to toxicity or death, prompting early closure of the trial. Grade ≥ 3 toxicities included fatigue, diarrhea, gastrostomy tube infection, peritonitis, pneumonia, dyspnea, and HN edema. Median PFS was 1.9 months. Median overall survival was 4.0 months. Six/12 tumors were p16(+), 9/11 lacked measurable PTEN expression, and 1/12 harbored a PIK3CA mutation. On exploratory analysis, high baseline plasma VEGF and interferon-gamma levels marginally associated with tumor progression. CONCLUSIONS: The combination of erlotinib and temsirolimus was poorly tolerated. Low prevalence of PTEN expression and 8% incidence of PIK3CA mutations indicate biological relevance of this pathway in R/M disease. Investigation of more tolerable combinations of EGFR and PI3K/Akt/mTOR pathway inhibitors in selected HNSCC patients is warranted.

A Phase II study of pulse dose imatinib mesylate and weekly paclitaxel in patients aged 70 and over with advanced non-small cell lung cancer.

BACKGROUND: In non-small cell lung cancer (NSCLC), interstitial hypertension is a barrier to chemotherapy delivery, and is mediated by platelet derived growth factor receptor (PDGFR). Antagonizing PDGFR with imatinib may improve intra-tumoral delivery of paclitaxel, increasing response rate (RR). METHODS: This single-stage, open-label phase II study evaluated pulse dose imatinib and weekly paclitaxel in elderly patients with advanced NSCLC. Eligible patients were aged ≥ 70 with untreated, stage IIIB-IV NSCLC and ECOG performance status 0-2. Primary endpoint was RR. Secondary endpoints included median progression free and overall survival (PFS, OS) and correlatives of PDGFR pathway activation. Baseline Charlson Comorbidity Index (CCI) and Vulnerable Elder Survey-13 (VES-13) were correlated with outcomes. RESULTS: Thirty-four patients with median age 75 enrolled. Eleven of 29 (38%) were frail by VES-13 score. Overall RR was 11/34 (32%; 95% CI 17%-51%), meeting the primary endpoint. Median PFS and OS were 3.6 and 7.3 months, respectively. High tumoral PDGF-B expression predicted inferior PFS. Frail patients by VES-13 had significantly worse median PFS (3.2 vs. 4.5 months; p=0.02) and OS (4.8 vs. 12 months; p=0.02) than non-frail. CONCLUSIONS: The combination of imatinib and paclitaxel had encouraging activity as measured by the primary endpoint of RR. However, PFS and OS were typical for elderly patients treated with single agent chemotherapy and the regimen is not recommended for further study. Adjunct imatinib did not overcome the established association of tumoral PDGF-B expression with inferior PFS. VES-13 was a powerful predictor of poor survival outcomes. Frailty should be further studied as a predictor of non-benefit from chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT01011075.

Development of bronchiolitis obliterans organizing pneumonia with platinum-based chemotherapy for metastatic rectal cancer.

Bronchiolitis obliterans organizing pneumonia (BOOP) is an adverse event known to occur after cancer chemotherapy and radiotherapy. We present a case of a 47-year-old patient who was diagnosed with BOOP after treatment for metastatic rectal cancer with oxaliplatin/capecitabine/bevacizumab. Removal of oxaliplatin from the regimen and replacement with irinotecan resulted in a resolution of his pulmonary symptoms.

Gastric cancer: standards for the 21st century.

Although the incidence of gastric cancer has been decreasing in the United States, it remains a leading cause of cancer death in the world, only lung cancer causes more deaths worldwide. The combination of relatively low prevalence, lack of pathognomonic symptoms, and lack of defined risk factors are associated with a delay in diagnosis leading to a dismal prognosis. For localized disease, surgery remains a cornerstone of treatment but much controversy remains regarding optimal peri-operative therapy. For advanced disease, several new agents and new combination chemotherapies have offered encouraging results. This paper seeks to review the major topics surrounding gastric cancer and cover the results of recently reported and ongoing trials.

Effectiveness of adjuvant chemotherapy for node-positive operable breast cancer in older women.

BACKGROUND: Randomized clinical trials have shown the efficacy of adjuvant chemotherapy in treating node-positive operable breast cancer in women aged < or = 69 years, but the benefit of chemotherapy in women aged > or = 70 is questionable. This study was to examine if adjuvant chemotherapy is effective for these women with breast cancer. METHODS: We studied a cohort of 5464 women diagnosed with node-positive operable breast cancer at age > or = 65 in 1992 through 1996 with last follow-up of December 31, 1999 in five states and six metropolitan areas. Hazard ratio (HR) for all-cause mortality was used for survival analysis with adjustment for patient and tumor characteristics; propensity analysis was used to control for observed factors; and sensitivity analysis was used to estimate potential effects of unmeasured confounders. RESULTS: After adjusting for propensity to receive chemotherapy, the chemotherapy-treated and untreated groups were not statistically significantly different for covariates except for age and hormone receptor status. Mortality was significantly reduced in women aged 65-69 who received adjuvant chemotherapy compared to those who did not, after adjusting for patient and tumor characteristics (HR = 0.70, 95% confidence interval [CI], 0.57-0.88) or after adjusting for propensity scores (HR = 0.76, 95% CI, 0.62-0.94). HR did not significantly differ between the treated and untreated women aged > or = 70 (HR = 0.96, 95% CI = 0.83-1.09, and HR = 0.99, 95% CI, 0.87-1.14). These results were relatively insensitive to changes in unmeasured confounders. CONCLUSIONS: Adjuvant chemotherapy is associated with improved survival in women with node-positive operable breast cancer aged 65-69 living in the community, but not in women aged > or = 70. These findings are consistent with those found in randomized controlled trials.

CYP2E1 polymorphism, cigarette smoking, p53 expression, and survival in non-small cell lung cancer: a long term follow-up study.

The expression of selected gene products involved in cell differentiation and cell growth and genetic polymorphism of detoxifying genes was examined in 105 surgically resected nonsmall cell lung cancer (NSCLC) patients, and the relationship of these factors was correlated with cigarette smoking and patient survival. Genotyping of peripheral blood lymphocytes from 87 patients was performed for CYP2E1, GSTM1, GSTT1, mEH, and MPO detoxifying genes using polymerase chain reaction. Formalin-fixed, paraffin-embedded tissue was immunostained with antibodies to p53, p27, phospho-AKT, and bcl-2 using the avidin-biotin-peroxidase method and tissue microarray technique. Tumors were assigned a positive or negative score based on more than 10% of tumor cells staining positive with the antibody. The subtypes of NSCLC included 48 adenocarcinomas, 47 squamous cell carcinomas, and 10 large cell undifferentiated carcinomas. A total of 54 tumors were pathologic stage I, 23 were stage II, and 26 were stage III. All subjects smoked (range, 10-175 pack-years; mean, 60 pack-years). The mean overall survival was 112 weeks (median, 129 weeks). Patients with p53-positive tumors had significantly fewer pack-years of smoking (52 pack-years vs 72 pack-years; P = 0.021), smoked fewer years (34 years vs 40 years; P = 0.018), and had significantly better survival compared with those with p53-negative tumors (P = 0.045). When smoking history was further analyzed, the authors found that p53 expression was associated with the number of years smoked and not the number of packs smoked per day. Patients with squamous cell carcinoma had smoked longer compared with those with adenocarcinoma (P = 0.011). Significant association was seen between the CYP2E1 wild-type allele and better survival (P = 0.016). Patients with stage I tumors had better survival compared with stages II and III (P = 0.032). No association was found between survival and tumor type; tumor differentiation; expression of phospho-AKT, p27, and bcl-2; and polymorphic metabolizing genes other than CYP2E1. The significant association of long duration of smoking (>40 years) with loss of p53 expression and poor survival suggests inactivation of the protective p53 pathway in those who had a history of more than 40 years of smoking.

The value of a complete blood count in predicting cancer of the colon.

Mortality from colon cancer could be reduced with routine screening, yet screening rates are low. Current screening tools are limited by expense and suboptimal acceptance. A retrospective case-control study of all cases of colon cancer diagnosed at our institution over a 5-year period was performed to determine the frequency of blood count abnormalities in these patients upon presentation. One hundred twenty-seven patients had right-sided colon cancer: 107 (84%) had an elevated red cell distribution width (RDW); 87 (69%) had anemia; and 70 (55%) had a low mean corpuscular volume (MCV). Ninety-eight patients had left-sided colon cancer: 49 (50%) had an elevated red cell distribution width; 43 (44%) had anemia; and 22 (22%) had a low mean corpuscular volume. The red cell distribution width was 84% sensitive and 88% specific for right-sided colon cancer. An elevated red cell distribution width may help better identify those patients who should be referred for full colonoscopy.

A case of radiation recall mucositis associated with docetaxel.

BACKGROUND: Radiation recall reactions, in particular dermatitis, are well documented in the literature. However, radiation recall mucositis is a rare clinical phenomenon. METHODS: We report a case of a 45-year-old man diagnosed with squamous cell carcinoma of the base of tongue. He was treated with surgery followed by chemotherapy and radiation therapy. Several months after completing treatment, he had a recurrence develop outside of the previously irradiated field. He was offered radiation therapy concurrent with docetaxel as salvage therapy. RESULTS: During salvage therapy, acute recall mucositis developed corresponding to his previously irradiated fields. His chemotherapy with docetaxel was withheld, and his symptoms rapidly improved. CONCLUSIONS: This case describes radiation recall mucositis associated with docetaxel, a rare but potentially serious clinical situation. Given the potential severity of the reaction and increasing use of docetaxel as second-line treatment of recurrent head and neck cancers, it is important to be aware of this phenomenon.

Recent advances in cell biology, diagnosis, and therapy of gastrointestinal stromal tumor (GIST).

The understanding of mesenchymal neoplasms of the gastrointestinal tract has evolved dramatically over the last two decades since gastrointestinal stromal tumor (GIST) was described as the most common stromal tumor arising anywhere from the esophagus to the ano-rectum. Although morphologically similar to other benign and malignant smooth muscle and neural stromal neoplasms, GIST constitutes a distinct group of rare gastrointestinal tract tumors that originate from the interstitial cells of Cajal, regulators of gut peristalsis that normally express CD117, which is the product of the c-KIT proto-oncogene that encodes a tyrosine kinase receptor that regulates cellular proliferation in GISTs. Virtually all GISTs occur from mutations of the c-KIT oncogene and exhibit consistent expression of c-KIT (CD117), which is considered the most specific criterion for a diagnosis of GIST. Gastrointestinal stromal tumors vary in their behavior and several features have to be considered to assess their malignant potential. The advent of sophisticated imaging techniques for the evaluation and sampling of stromal tumors of the gastrointestinal tract has resulted in improved detection of GISTs. The identification of a novel tumor-specific target in c-KIT resulted in the development of a tyrosine kinase-inhibitor (imatinib mesylate) that provides an encouraging option for treating GISTs. This article reviews recent advances in the understanding of the cell biology, diagnosis, and therapy of GISTS.

Recombinant human thrombopoietin augments mobilization of peripheral blood progenitor cells for autologous transplantation.

This study assessed the ability of various schedules of recombinant human thrombopoietin (rhTPO) to enhance mobilization of peripheral blood progenitor cells (PBPCs) in 134 patients with cancer undergoing high-dose chemotherapy and autologous PBPC transplantation. Patients received the study drug on days 1, 3, and 5 before initiation of granulocyte colony-stimulating factor (G-CSF) 10 microg/kg/day on day 5 and pheresis starting on day 9. Randomly assigned treatments on days 1, 3, and 5 were: group 1 (n=27) placebo, placebo, rhTPO 1.5 microg/kg; group 2 (n=27) rhTPO 1.5 microg/kg, placebo, placebo; groups 3 (n=28) and 4 (n=22) rhTPO 0.5 microg/kg on all 3 treatment days; and group 5 (n=30) placebo on all 3 treatment days. After high-dose chemotherapy and PBPC transplantation, groups 1 through 4 received rhTPO 1.5 microg/kg days 0, +2, +4, and +6 with either G-CSF 5 microg/kg/day (groups 1-3) or granulocyte-macrophage colony-stimulating factor 250 microg/m(2)/day (group 4). Group 5 received placebo plus G-CSF 5 microg/kg/day. The addition of rhTPO to G-CSF increased median CD34+ cell yield/pheresis in cohorts in which rhTPO was started before day 5, with higher yields in groups 2 (2.67 x 10(6)/kg) and groups 3 and 4 (3.10 x 10(6)/kg) than in group 1 (1.86 x 10(6)/kg) or group 5 (1.65 x 10(6)/kg) (P=.006 across groups). Comparing rhTPO to placebo, higher percentages of patients achieved the minimum yield of CD34+ > or =2 x 10(6)/kg (92% v 75%; P=.050) as well as the target yield of CD34+ > or =5 x 10(6)/kg (73% v 46%; P= .041). rhTPO-treated patients required fewer phereses to achieve minimum (P= .011) and target (P= .015) CD34+ cell values. rhTPO given after transplantation did not speed platelet recovery. No neutralizing antibodies were observed. We conclude that rhTPO can safely enhance mobilization of PBPC, reduce the number of leukapheresis, and allow more patients to meet minimal cell yield requirements to receive high-dose chemotherapy with PBPC transplantation.

SYT-SSX2 variant of primary pulmonary synovial sarcoma with focal expression of CD117 (c-Kit) protein and a poor clinical outcome.

Pulmonary synovial sarcoma is a rare neoplasm recently recognized as a distinct entity and characterized by t(X;18) translocation and production of at least 2 fusion genes, SYT-SSX1 and SYT-SSX2. We report a case of primary pulmonary synovial sarcoma with the SYT-SSX2 phenotype and a rapidly progressive downhill course. Previous reports have suggested that the soft tissue synovial sarcomas with SYT-SSX2 phenotype have a favorable clinical outcome. To the best of our knowledge, this is also the first report of CD117 (c-Kit) expression in a pulmonary synovial sarcoma. A 45-year-old woman presented with left chest pain and was found to have a left lower lobe tumor that was originally diagnosed as a sarcomatoid carcinoma. After the patient underwent chemotherapy and brachytherapy, the specimen from a left pneumonectomy showed a large spindle cell tumor, which was reclassified as a synovial sarcoma based on the results of immunophenotyping and molecular genetic studies. Differentiation between sarcoma and carcinosarcoma is crucial for implementing appropriate therapy. Furthermore, if the tumor expresses c-Kit, it may respond to target-based therapy.

Translocation (15;17) and trisomy 21 in the microgranular variant of acute promyelocytic leukemia.

Cytogenetic abnormalities in acute myelogenous leukemia have been identified as one of the most important prognostic factors. Favorable chromosomal changes such as inv(16), t(8;21), and t(15;17) are associated with higher rates of complete remission and event-free survival. Translocation t(15;17) characterizes acute promyelocytic leukemia (APL) (French-American-British [FAB] class M3) in almost all patients. Secondary chromosomal abnormalities are also present in approximately one-third of patients with newly diagnosed APL. We present a 26-year-old Hispanic man diagnosed with the microgranular variant of APL (FAB class M3v) whose initial cytogenetics included t(15;17) and trisomy 21. The prognostic implications of trisomy 21 and other secondary cytogenetic aberrations in APL are reviewed. To our knowledge, this is the first reported case of trisomy 21 with t(15;17) in the microgranular variant of APL.