Recent advances in the management of pancreatic adenocarcinoma

Introduction: Pancreatic cancer (PC) demonstrates very poor prognosis and its incidence continues to increase, despite developments in chemotherapy, radiotherapy, and targeted therapies. Surgical resection is currently the only curative approach for PC. The role of radiotherapy in adjuvant and locally advanced PC continues to be increasingly controversial. This review article aims to explore the current knowledge of pancreatic adenocarcinoma, focusing on diagnosis, treatment strategies, and the best supportive care.

Areas covered: The current literature on pancreatic adenocarcinoma treatment modalities has been summarized, with a focus on clinical trials and reviews. New treatment strategies and their impact on clinical practice have also been discussed.

Expert commentary: Despite many therapeutic developments, only modest improvements in survival rates have been achieved. There is an essential need to increase survival by developing more innovative treatment approaches for patients with PC.     

The safety and efficacy of Onivyde (irinotecan liposome injection) for the treatment of metastatic pancreatic cancer following gemcitabine-based therapy

Introduction: Patients with advanced and metastatic pancreatic cancer refractory to gemcitabine based therapy have a dismal prognosis and limited therapeutic options. Recently, the FDA approved nanoliposomal irinotecan combined with fluorouracil/folinic acid for such patients based upon results of the NAPOLI-1 study which showed this regimen compared to fluorouracil/folinic acid significantly prolonged progression free survival (3.1 vs. 1.5 months) and overall survival (6.2 vs. 4.1 months).

Areas covered: The pharmacokinetic and pharmacogenetic characteristics of this novel formulation of irinotecan, its safety profile, and use in a clinical context for patients with pancreatic cancer are reviewed.

Expert commentary: Nanoliposomal irinotecan, in combination with 5-FU/folinic acid, represents an important step forward in improving second line treatment options in patients with progression of metastatic pancreatic cancer. Furthermore, the novel drug formulation offers pharmacokinetic advantages which serve as a basis for further clinical testing in a various pancreatic cancer settings and other malignancies.     

Adjuvant therapy for resected colon cancer 2017, including the IDEA analysis

Introduction: Oxaliplatin-based adjuvant chemotherapy has been the standard of care for resected early colon cancer for over a decade. Recent results from the IDEA meta-analysis attempt to address the question of whether 3 or 6 months of adjuvant chemotherapy is preferable in Stage III colon cancer.

Areas covered: A review of the literature and recent conference presentations was undertaken on the topic of adjuvant therapy for resected early colon cancers. This article reviews the current evidence for adjuvant treatment of Stage II and III colon cancer, as well as up-to-date data regarding optimal duration of therapy. This article reviews the evidence for lifestyle modifications in the management of early colorectal cancer and other future directions for research in early colon cancer.

Expert commentary: In recent years, there have been no advances in the development of novel agents for adjuvant therapy in colorectal cancer. Although the IDEA meta-analysis was negative for its primary non-inferiority endpoint, the detailed results provide valuable information that allows personalisation of treatment regimen and duration.     

Renal cell cancer: overview of the current therapeutic landscape

Introduction: The last decade has witnessed dramatic improvements in the diagnosis, classification and treatment of renal cell cancer (RCC). Besides improvements in surgical techniques in early stages, introduction of novel targeted agents has resulted in improved outcomes in advanced RCC for which no effective treatment existed until recently.

Areas covered: This article reviews epidemiology, pathology and pathogenesis, diagnosis, clinical staging, prognostic factors and treatment modalities of early stage and advanced RCC.

Expert commentary: Although treatment options are expanding rapidly, practicing physicians face considerable challenges in the decision-making process. Therapeutic agents may have unique side effects and unexpected drug interactions. RCC represents one of the major success stories of clinical oncology in recent years and the progress appears to be far from having reached a plateau. We aim to present a comprehensive in-depth review of RCC in an attempt to provide evidence-based recommendations and future perspectives for practicing oncologists.     

Current challenges in optimizing systemic therapy for patients with pancreatic cancer: expert perspectives from the Australasian Gastrointestinal Trials Group (AGITG) with invited international faculty

Introduction: Despite recent progress, the outlook for most patients with pancreatic cancer remains poor. There is variation in how patients are managed globally due to differing interpretations of the evidence, partly because studies in this disease are challenging to undertake. This article collates the evidence upon which current best practice is based and offers an expert opinion from an international faculty on how latest developments should influence current treatment paradigms.

Areas covered: Optimal chemotherapy for first and subsequent lines of therapy; optimal management of locally advanced, non-metastatic cancer including the role of neoadjuvant chemo(radio)therapy, current evidence for adjuvant chemotherapy, major advances in pancreatic cancer genomics and challenges in supportive care particularly relevant to patients with pancreatic cancer. For each section, literature was reviewed by comprehensive search techniques, including clinical trial websites and abstracts from international cancer meetings.

Expert commentary: For each section, a commentary is provided. Overall the challenges identified were: difficulties in diagnosing pancreatic cancer early, challenges for performing randomised clinical trials in all stages of the disease, some progress in systemic therapy with new agents and in identifying molecular subtypes that may be clinically relevant and move towards personalized therapy, but still, pancreatic cancer remains a very poor prognosis cancer with significant palliative care needs.     

Hyperthermia-enhanced targeted drug delivery using magnetic resonance-guided focussed ultrasound: a pre-clinical study in a genetic model of pancreatic cancer

Purpose: The lack of effective treatment options for pancreatic cancer has led to a 5-year survival rate of just 8%. Here, we evaluate the ability to enhance targeted drug delivery using mild hyperthermia in combination with the systemic administration of a low-temperature sensitive liposomal formulation of doxorubicin (LTSL-Dox) using a relevant model for pancreas cancer.

Materials and methods: Experiments were performed in a genetically engineered mouse model of pancreatic cancer (KPC mice: LSL-Kras^G12D/+; LSL-Trp53^R172H/+; Pdx-1-Cre). LTSL-Dox or free doxorubicin (Dox) was administered via a tail vein catheter. A clinical magnetic resonance-guided high intensity focussed ultrasound (MR-HIFU) system was used to plan treatment, apply the HIFU-induce hyperthermia and monitor therapy. Post-therapy, total Dox concentration in tumour tissue was determined by HPLC and confirmed with fluorescence microscopy.

Results: Localized hyperthermia was successfully applied and monitored with a clinical MR-HIFU system. The mild hyperthermia heating algorithm administered by the MR-HIFU system resulted in homogenous heating within the region of interest. MR-HIFU, in combination with LTSL-Dox, resulted in a 23-fold increase in the localised drug concentration and nuclear uptake of doxorubicin within the tumour tissue of KPC mice compared to LTSL-Dox alone. Hyperthermia, in combination with free Dox, resulted in a 2-fold increase compared to Dox alone.

Conclusion: This study demonstrates that HIFU-induced hyperthermia in combination with LTSL-Dox can be a non-invasive and effective method in enhancing the localised delivery and penetration of doxorubicin into pancreatic tumours.     

Comparison of the effects of local treatment strategies in non-metastatic Ewing sarcoma of bone

Background: To investigate the optimal local treatment strategies for patients with non-metastatic Ewing sarcoma (ES) of bone.

Methods: Patients with ES of bone were identified using the Surveillance Epidemiology and End Results database. Kaplan-Meier log-rank test and Cox regression models were performed to assess the effect of the types of local treatment strategies on cause-specific survival and overall survival.

Results: 560 patients were included with a median age of 16 years. A total of 284, 162 and 114 patients received surgery alone, surgery and radiotherapy, and radiotherapy alone, respectively. The types of local treatment strategies had no effect on survival outcomes in multivariate analysis. In the subgroup analysis of patients with tumor diameter <8 cm, surgery ± radiotherapy had a significantly improved cause-specific survival (P = 0.039), and had potential to improve overall survival (P = 0.070) in multivariate analysis. The local treatment strategies had no effect on survival in patients with different tumor location.

Conclusion: There is no local treatment of choice for non-metastatic ES of bone in terms of survival. More well-designed studies are needed to confirm our findings and investigate the role of various local treatment strategies in relation to primary tumor diameter.     

Chemotherapy-induced neutropenia and the prognosis of colorectal cancer: a meta-analysis of cohort studies

Introduction: Recently, there has been a controversial discussion about the prognostic value of chemotherapy-induced neutropenia (CIN) in colorectal cancer patients. Thus, a meta-analysis was conducted to determine the relationship between CIN and the prognosis of colorectal cancer patients.

Methods: We searched the PubMed, EMBASE, and Cochrane library databases to identify studies evaluating the association between CIN and colorectal cancer prognosis. Pooled random/fixed effect models were used to calculate pooled hazard ratios (HRs) and 95% confidence intervals (CIs) to assess the association.

Results: Eight studies were selected for the meta-analysis, for a total of 2,745 patients. There was significant improved survival among colorectal cancer patients with CIN (HR = 0.62, 95% CI = 0.47–0.76). However, significant heterogeneity was found (p = 0.000, Ι² = 75.0%). Through subgroup analysis, we could greatly eliminate the heterogeneity and found that neutropenia was associated with better survival in stage IV colorectal cancer patients, no matter the HR calculated by overall survival (OS) or progression-free survival (PFS). Meanwhile, the prognostic value of neutropenia in stage II/III colorectal cancer can be found when the HR is calculated by disease-free survival (DFS). Additionally, we observed significant differences after stratification according to various tumor stages, endpoints, and the use of G-CSF.

Conclusions: Our results which, based on a cohort study, indicate that CIN is associated with improved survival in patients with colorectal cancer. However, further randomized controlled trials are warranted.     

Niraparib for the treatment of ovarian cancer

Introduction: Niraparib, an orally available selective inhibitor of poly(adenosine diphosphate-ribose) polymerase (PARP), is the first PARP inhibitor approved for use in patients with ovarian cancer who do not harbor a germ-line or somatic mutation in the breast cancer gene (BRCA). Overall, niraparib is well tolerated and its toxicities, primarily hematologic, are manageable especially with recently released initial dose modification guidelines based on weight and baseline platelet count. The role of niraparib as maintenance following frontline platinum-based chemotherapy as well as in the treatment of recurrent high-grade serous ovarian cancer is an active area of investigation.

Areas covered: This review focuses on niraparib, its pharmacology, clinical efficacy, and adverse effects as evidenced by prospective clinical trials, and licensed indications.

Expert commentary: Niraparib introduced the use of PARP inhibitors regardless of biomarker status. Recent studies highlight the critical need for more accurate biomarkers to identify patients most likely to benefit from treatment with PARP inhibitors. In the next 5 years, we anticipate further expansion of and elucidation regarding the optimal indication for use of niraparib in the treatment of ovarian cancer.     

Total pathological complete response versus breast pathological complete response in clinical trials of reference and biosimilar trastuzumab in the neoadjuvant treatment of breast cancer

Introduction: Trastuzumab is a key drug in the neoadjuvant treatment of breast cancers that overexpress the human epidermal growth factor receptor 2 (HER2). Pathological complete response (pCR) is commonly used as an endpoint in neoadjuvant clinical trials of trastuzumab as evidence suggests it may be a surrogate for long-term survival. Several biosimilar candidates of originator or ‘reference’ trastuzumab are in development and have used pCR as a primary endpoint to assess therapeutic equivalence between treatments. The exact definition of pCR has varied across studies.

Areas covered: Here we look at the clinical relevance of pCR and compare rates of total pCR (defined as ypT0/is ypN0) and breast pCR (defined as ypT0/is) in clinical trials of reference and biosimilar trastuzumab.

Expert commentary: In order to evaluate the efficacy of neoadjuvant systemic therapies in a uniform way, standardization of trial endpoints is necessary. Future studies in HER2-positive breast cancer should include full assessment of the breast and lymph node basin before and after neoadjuvant systemic therapy, and the use of total pCR as the primary outcome.     

Adjuvant trastuzumab: a 10-year overview of its benefit

Introduction: Anti-HER2 targeted therapy is one of the key advances in the treatment of breast cancer that have occurred in the last 20 years. In the adjuvant setting, the use of trastuzumab has led to prolonged and sustained survival benefit with very little toxicity as also confirmed by the 10-year follow-up results from the pivotal trials. Despite the survival improvement, several key issues are not entirely resolved in this field. These issues have led to multiple research efforts in de-escalating or escalating the standard treatment with chemotherapy and 1 year of adjuvant trastuzumab.

Areas covered: In this paper, we present an in depth overview on the state of the art on these key issues of refining decision-making in adjuvant anti-HER2 therapy.

Expert commentary: Despite many important research efforts in the field, chemotherapy plus trastuzumab for a total duration of 1 year remains the standard of care. However, recent data showed that besides standard anthracycline- and taxane-based cytotoxic therapy, alternative chemotherapy regimens can now be proposed to patients with small tumors without nodal involvement and to women at high-risk of developing cardiotoxicity. Of note, besides HER2 itself, biomarkers predicting patients who may truly benefit from anti-HER2 agents are still lacking.     

Fatigue,alopecia and stomatitis among patients with breast cancer receiving cyclin-dependent kinase 4 and 6 inhibitors: a systematic review and meta-analysis

Background: Cyclin-dependent kinase (CDK) inhibitors emerge as efficacious agents in hormone positive metastatic breast cancer with more acceptable toxicity profiles than cytotoxic chemotherapy. However, some adverse effects such as fatigue, alopecia and stomatitis, vastly concern patients.

Methods: The search was conducted in PubMed, American Society of Clinical Oncology meeting library, European Society for Medical Oncology meeting abstract, and the San Antonio meeting abstract databases. We identified phase 2 or 3 trials recruiting patients with breast cancer, randomized to receive hormonal treatment plus either CDK4/6 inhibitors or placebo. We considered studies providing incidence of fatigue, alopecia and stomatitis relevant.

Results: One thousand records were screened. 34 studies were considered relevant. Four studies were found to be eligible for meta-analysis with a total of 2007 patients. The relative risk for all grade fatigue was 1.34 [95% CI: 1.17–1.54, p < 0.0001], for all grade alopecia was 2.14 [95% CI: 1.23–3.73, p = 0.007], and for all grade stomatitis 4.87 [95% CI: 2.11–11.24, p = 0.0002]. In addition, the relative risk for high grade fatigue was 2.40 [95% CI: 1.10–5.26, p = 0.03].

Conclusion: CDK4/6 inhibitors were associated with an increased risk of fatigue, alopecia and stomatitis. Further studies with self-reported questionnaires may elucidate the impact of the increased risk of these selected adverse effects on the patients’ quality of life.     

Optimizing treatment in recurrent epithelial ovarian cancer

Introduction: Optimal management of recurrent ovarian cancer (ROC) remains an area of uncertainty. An estimated 85% of patients with epithelial ovarian cancer who achieve a full remission following first-line therapy will develop recurrent disease and median survival for these patients’ ranges from 12 months to 24 months. Many patients receive several lines of treatment following recurrence and, although each subsequent line of therapy is characterized by shorter disease-free intervals, decisions about the most appropriate treatment is complex.

Areas covered: This review focuses on chemotherapy, surgery and emerging biologic agents that present a therapeutic option for patients with ROC.

Expert commentary: Recurrent ovarian cancer is not curable. The goals of therapy should focus on palliation of cancer-related symptoms, extension of life, and maintenance of quality of life. Patients with platinum-sensitive ovarian cancer should have their recurrence treated with a platinum-based agent. For patients whose cancer progresses after platinum retreatment and for those with platinum-resistant disease, numerous other non-platinum combination and targeted therapies have been shown to be effective in palliating cancer-related symptoms and extending life.     

Risk of cardiac death among cancer survivors in the United States: a SEER database analysis

Background: Population-based data on the risk of cardiac death among cancer survivors are needed. This scenario was evaluated in cancer survivors (>5 years) registered within the Surveillance, Epidemiology and End Results (SEER) database.

Methods: The SEER database was queried using SEER*Stat to determine the frequency of cardiac death compared to other causes of death; and to determine heart disease-specific and cancer-specific survival rates in survivors of each of the 10 most common cancers in men and women in the SEER database.

Results: For cancer-specific survival rate, the highest rates were related to thyroid cancer survivors; while the lowest rates were related to lung cancer survivors. For heart disease-specific survival rate, the highest rates were related to thyroid cancer survivors; while the lowest rates were related to both lung cancer survivors and urinary bladder cancer survivors. The following factors were associated with a higher likelihood of cardiac death: male gender, old age at diagnosis, black race and local treatment with radiotherapy rather than surgery (P < 0.0001 for all parameters).

Conclusion: Among cancer survivors (>5 years), cardiac death is a significant cause of death and there is a wide variability among different cancers in the relative importance of cardiac death vs. cancer-related death.     

Recent advances in targeted advanced lung cancer therapy in the elderly

Introduction: With increasing life expectancy over the last several decades, the incidence of lung cancer is increasing in the elderly population too. In clinical practice about 50% of lung cancers were diagnosed in patients older than 65 years and about 30–40% of lung cancer patients are 70 years old or more. Treatment of elderly patients with non-small-cell lung cancer (NSCLC) represents a challenge in clinical practice, because these patients are not eligible for aggressive therapies for the age-related reduction of functional reserve of many organs and comorbidities.

Areas covered: The activity and safety of small molecules for the treatment of NSCLC harbouring EGFR mutations or ALK rearrangement are reviewed and discussed here, using evidence from clinical trials.

Expert commentary: Age alone should not dictate treatment-related decisions for elderly patients with advanced NSCLC. Some evidence has shown that the only relevant factor for survival outcome in the elderly is performance status and organ functions both with chemotherapy and targeted therapy too. Considering the toxicity profile of tyrosine kinase inhibitors, these small molecules are particularly attractive to treat elderly patients, who could experience potentially more toxicity from chemotherapy. Studies specifically addressed to evaluate the activity of targeted therapy are still more limited.     

Challenging a dogma: five-year survival does not equal cure in all colorectal cancer patients

Background: The current study tried to evaluate the factors affecting 10- to 20- years’ survival among long term survivors (>5 years) of colorectal cancer (CRC).

Methods: Surveillance, Epidemiology and End Results (SEER) database (1988-2008) was queried through SEER*Stat program.Univariate probability of overall and cancer-specific survival was determined and the difference between groups was examined. Multivariate analysis for factors affecting overall and cancer-specific survival was also conducted.

Results: Among node positive patients (Dukes C), 34% of the deaths beyond 5 years can be attributed to CRC; while among M1 patients, 63% of the deaths beyond 5 years can be attributed to CRC. The following factors were predictors of better overall survival in multivariate analysis: younger age, white race (versus black race), female gender, Right colon location (versus rectal location), earlier stage and surgery (P <0.0001 for all parameters). Similarly, the following factors were predictors of better cancer-specific survival in multivariate analysis: younger age, white race (versus black race), female gender, Right colon location (versus left colon and rectal locations), earlier stage and surgery (P <0.0001 for all parameters).

Conclusion: Among node positive long-term CRC survivors, more than one third of all deaths can be attributed to CRC.     

Rituximab plus reduced-dose cyclophosphamide,doxorubicin, vincristine and prednisone (RD R-CHOP) chemotherapy is feasible for very elderly patients (≥80 years) with B-cell lymphoma: analysis of treatment outcome

Objective: The aim of this trial was to evaluate the treatment outcome of reduced-dose (RD)R-CHOP treatment in very elderly patients with B-cell lymphoma.

Methods: This trial comprised 40 patients, aged ≥80 years, who were diagnosed with B-cell lymphoma and recruited at a single centre from 2007 to 2013. They received four to eight cycles of reduced-dose R-CHOP (rituximab 375 mg/m² Day 0, cyclophosphamide 400 mg/m² Day 1, epirubicin 35 mg/m² Day 1, vincristine 1 mg Day 1 and prednisone 50 mg/m² Days 1–5). The data of treatment responses and survival were collected and analysed comprehensively.

Results: The median age was 83 years old (range, 80–93 years old) and the median follow-up duration was 40.86 months. The overall response rate (ORR) was 87.5%. With a 40.9-month follow-up, 3-year overall survival (OS), 3-year progression free survival (PFS) and 3-year event-free survival (EFS) were 17.2, 46.5 and 39.1%, respectively. Using multivariate analysis, we concluded that age ≥85 years; LVEF ≤70%; M-CIRS score ≥6 and ECOG-PS ≥2 were predictive poor prognostic factors.

Conclusions: High response rate was concluded on very elderly B-cell lymphoma patients (≥80 years old) with reduced-dose R-CHOP. However, the very elderly patients with poor performance status and more complications benefit less from treatment.     

Response to afatinib in treatment-naïve patients with advanced mutant epidermal growth factor receptor lung adenocarcinoma with brain metastases

Background: Brain metastases are observable in 20–40% of non-small cell lung cancer patients, but standard treatments for such metastases may be intolerable to some. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were found to be effective against mutant-EGFR lung adenocarcinomas, but data regarding their effectiveness, especially for the second-generation EGFR-TKI afatinib, is limited. This study compared key outcomes for afatanib monotherapy versus afatinib combined with whole-brain radiotherapy (WBRT) in treatment-naïve lung adenocarcinoma patients harboring EGFR mutations.

Methods: A retrospective review of 28 brain metastatic lung adenocarcinoma patients treated between June 2014 and December 2016 was conducted; 17 were treated with WBRT and maintenance afatinib therapy, while 11 received afatinib monotherapy.

Results: The patients were predominantly female (n = 17, 60.7%) and non-smokers (78.6%). Almost all the patients (89.3%) had an Eastern Cooperative Oncology Group performance status of 0–2. The EGFR mutation type consisted of the del19 mutation in 57.1% of the patients (n = 16), while L858R mutations were found in 42.9% (n = 12). The mean number of brain metastases (6.1 ± 5.0) was higher among the patients treated with afatinib monotherapy, while the mean size of the largest brain metastasis (19.0 ± 10.5mm) was greater in the afatinib combined with WBRT group. The objective response rates for the afatinib monotherapy and combination therapy groups were 81.8% and 88.2%, respectively. However, the monotherapy group exhibited a significantly higher complete response rate for intracranial lesions (63.6% vs. 17.6%, p = 0.02), and there were no significant differences between the two treatment groups in overall survival or time to treatment failure.

Conclusion: Afatinib can provide therapeutic efficacy and a good response rate in treatment-naïve mutant-EGFR lung adenocarcinoma patients with brain metastases regardless of whether or not they also receive radiotherapy.     

Down-regulation of liver-intestine cadherin enhances noscapine-induced apoptosis in human colon cancer cells

Background: The aim of the present study was to explore the signaling pathway of noscapine which induces apoptosis by blocking liver-intestine cadherin (CDH17) gene in colon cancer SW480 cells.

Methods: Human colon cancer SW480 cells were transfected with CDH17 interference vector and treatment with 10 µmol/L noscapine. The proliferation and apoptosis of SW480 cells were detected by MTT assay and AnnexinV-FITC/PI flow cytometry kit (BD), respectively. Cell invasion were assessed by transwell assays. Apoptosis related proteins (Cyt-c, Bax, Bcl-2 and Bcl-xL) levels were evaluated by western blot.

Results: Compared to the noscapine group, the proliferation was decreased significantly and the apoptosis was increased significantly in SW480 cells of the siCDH17+noscapine group. Cyt-c and Bax protein levels in siCDH17+noscapine group was higher than that of the noscapine group, but Bcl-2 and Bcl-xL protein levels in siCDH17+noscapine group were lower than that of the noscapine group. Moreover, up-expression of CDH17 inhibited the efficacy of noscapine-induced apoptosis in SW480 cells.

Conclusions: We inferred that down-expression of extrinsic CDH17 gene can conspicuously promote apoptosis-inducing effects of noscapine on human colon cancer SW480 cells, which is a novel strategy to improve chemotherapeutic effects on colon cancer.