Balic, Marija; Hilbe, Wolfgang; Gusel, Sylvia; Fiegl, Michael; Ludwig, Heinz; Mayrbäurl, Beate; Thaler, Josef; Samonigg, Hellmut; Hegenbarth, Karin; Eisner, Florian; Mlineritsch, Brigitte; Greil, Richard; Schandl, Maria Johanna; Weltermann, Ansgar; Petzer, Andreas; Fuchs, David; Stangl, Wolfgang; Krippl, Peter; Stauder, Reinhard; Stöger, Herbert
The purpose of this observational study was to determine the prevalence of comorbid conditions in cancer patients with solid tumours selected for specific treatment at 12 divisions of medical oncology in Austria. Data from 1137 patients were collected using a standardized questionnaire; of these, 1036 datasets were evaluable for further analysis. Data were prospectively collected from patients during an in- or outpatient hospital visit over a 4-month period in 2011. Of these patients 42% had gastrointestinal cancer, 31% had breast cancer, 9% lung cancer and the remaining had urogenital cancer, sarcoma or other types of rare cancers. Around two-thirds of patients had metastatic disease (59%), confined to a single organ site in 55% of patients. A high proportion of patients had a good performance status (Eastern Cooperative Oncology Group [ECOG] 0, 1: 82%). Comorbid conditions were classified according to the Charlson scheme score and were present in 86% of patients with a median age of 64 years. The predominant conditions were cardiovascular diseases (57%), metabolic diseases (44%), endocrinological diseases (30%), gastrointestinal diseases (26%), neurological (23%) and respiratory diseases (23%). As has been reported by others we found a clear association between number of comorbid conditions and age. While 60% of the whole population had at least 2 comorbidities, most patients of the elderly population (89%) had more than three comorbidities. The high proportion of patients with comorbidities and accompanying medication represents a substantial challenge for medical oncologists in selecting the optimal cancer-specific treatment especially in the era of novel targeted and immunotherapies. Comorbid conditions and accompanying comedications require special precautions concerning potential interactions and unexpected adverse reactions from prescribed tumour-specific treatment.
During the last 30 years the developments in small cell lung cancer (SCLC) have been extremely scarce. Concurrent chemo-radiation associated with prophylactic cranial irradiation in case of complete clinical remission is standard in limited disease. In extensive disease, platinum/etoposide and topotecan remain the standard systemic approaches in the first- and second-line setting, respectively. The only notable improvement was communicated in the IMpower133 trial, by the addition of atezolizumab to the platinum/etoposide chemotherapy backbone. Against this background, the current article aims to review the most important abstracts presented at ASCO 2019 along with their potential impact for current clinical practice.
New targeted therapies for patients with non small cell lung cancer were presented at this year’s ASCO. EGFR exon 20 insertions might soon be treatable with TAK-788, which showed an objective response rate (ORR) of between 25 and 56% with a disease control rate (DCR) between 67 and 100% depending on the presence or absence of brain metastases at baseline. Capmatinib and tepotinib showed durable responses in MET exon 14 mutations as presented in the phase II GEOMETRY trial and the VISION trial. The median duration of response (DOR) was 9.7 months with a median progression free survival (PFS) of 5.42 months in pretreated patients and 11.14 months respective 9.6 months in those receiving capmatinib in the frontline setting. Tepotinib showed similar results with a median DOR of 12.4 months and a DCR of 66.7%. For RET-fusion lung cancer the well tolerated RET inhibitor BLU-667 has already been granted breakthrough therapy designation. Among previously treated patients an ORR of 58% and a DCR of 96% was reported. The median duration of response had not yet been reached, with many patients continuing to respond for longer than 24 months. For the large and hard-to-treat group of patients with KRAS-mutated lung cancer, early data on the covalent irreversible inhibitor of the KRASG12C-mutant kinase AMG 510 were presented. In pretreated patients AMG 510 achieved a 50% response rate, with a duration of treatment from 7.3 to 27.4 weeks. Furthermore, AMG 510 has been safe and well tolerated at dose levels tested in 35 patients in dose exploration.
This article intends to summarize personal highlights from the 2019 ASCO (American Society of Clinical Oncology) Annual meeting. The article does not aim to offer a comprehensive summary of the 1642 abstracts presented, but rather aims to highlight the abstracts that are the most relevant for the neo/adjuvant therapy of the HER2-negative, HR-positive breast cancer. By doing so, the article generates discussion on the practical implications, while portraying the rapidly changing landscape of the use of personalized treatment of early breast cancer in patients with HER2-negative, HR-positive disease.
At the 2019 ASCO (American Society of Clinical Oncology) Annual Meeting, several interesting trial results were presented in the field of HER2-positive metastatic breast cancer. The end-of-study analysis of the pivotal CLEOPATRA trial indicated an overall survival of 57.1 months in patients receiving pertuzumab in addition to trastuzumab and docetaxel in the first-line setting. SOPHIA was the first phase III trial comparing the Fc-engineered antibody margetuximab plus chemotherapy by physician’s choice with trastuzumab plus chemotherapy in heavily pretreated patients; the novel antibody yielded a statistically significant albeit short prolongation of progression-free survival (PFS) over standard treatment. The phase III NALA trial compared the second-generation tyrosine-kinase inhibitors neratinib with lapatinib; both drugs were combined with capecitabine. In this study a clinically meaningful prolongation of PFS by 2.2 months was observed. In addition, the time to intervention for brain metastases was prolonged in the neratinib group and the cumulative incidence of brain metastases was lower as well. On the downside a high rate of grade 2 and 3 diarrhoea was observed.
Early stage HER2-positive cancer outcomes have been substantially improved over the last two decades, but there is still some potential for improvement. Several studies on the preoperative/postoperative treatment of HER2-positive breast cancer were presented at the American Society of Clinical Oncology (ASCO) 2019 annual meeting.
A substantial increase in the number of elderly patients with muscle invasive bladder cancer (MIBC) is expected in upcoming years due to demographic changes and the peak incidence of bladder cancer in the 8th decade of life. The management of these patients is mainly driven by chronological age, comorbidities, tumor characteristics (unifocality, multifocality, concomitant carcinoma in situ, depth of invasion) and the presence of tumor-related symptoms (hematuria, pain, bladder dysfunction). A potential algorithm for the treatment of elderly patients with MIBC is presented. Ideally these patients are managed by a multidisciplinary team that includes an in-depth geriatric assessment and in centers experienced with MIBC to avoid any delay for—potentially—curative treatment.
To date, intravesical instillation of Bacillus Calmette–Guérin (BCG) is the standard adjuvant treatment for most intermediate- and all high-risk bladder nonmuscle invasive urothelial carcinomas (NMIBC) after complete transurethral resection. Although BCG immunotherapy successfully reduces both recurrence and progression rates in affected patients, there are certain limitations associated with its application. Major issues are the relatively high failure rate in up to 40% of patients, the adverse effects of the instillations, and the shortage in BCG supply, requiring concerted alternative strategies. Furthermore, radical cystectomy, the currently suggested salvage treatment for patients failing BCG therapy, is often an overtreatment for a significant proportion of patients. Checkpoint inhibitor (CKI) immunotherapy has proven to be highly effective in a subset of advanced bladder cancer patients and is currently tested in various clinical scenarios alone and in combination with BCG in the adjuvant setting. CKIs’ mechanism is to a large part similar to that reported for BCG—that is, activation of the immune system and elimination of cancer cells in the bladder. Furthermore, CKIs could synergistically enhance the effect of the immune system attracted by BCG and are generally associated with acceptable rates of adverse reactions. Thus, they may represent an ideal alternative to or partner for BCG immunotherapy in NMIBC. In case the recent encouraging results of currently ongoing trials translate into tangible improved outcomes, the combination of CKI and BCG immunotherapy can be expected to represent a valid treatment strategy for well-selected nonmuscle invasive bladder cancer patients in the future.
Three important oral presentations from the ASCO 2019 congress concerning advanced and metastatic urothelial carcinoma of the urinary bladder and the upper tract are highlighted and their potential clinical implications for the improvement of systemic therapies in respective patients are discussed. Enfortumab vedotin, an antibody-drug conjugate targeting nectin‑4, demonstrated a clinically meaningful objective response rate in patients with prior platinum-based chemotherapy and checkpoint inhibition, in a phase II trial. A high unmet need in this heavily pretreated patient population combined with good tolerability and manageable safety profile support a submission to the FDA (US Food and Drug Administration) for accelerated approval. The early use of an immunotherapeutic approach via pembrolizumab in patients with metastatic urothelial carcinoma as “switch maintenance” therapy achieved an objective response rate of 22% vs. 12% in the placebo arm in a phase II trial. Pembrolizumab was shown to potentially “deepen” responses achieved with first-line chemotherapy. Moreover, switch maintenance pembrolizumab was able to significantly delay disease progression, whereby a better characterized role of switch maintenance programmed death‑1 blockade will be refined by currently ongoing phase III trials. Based on data showing that angiogenesis plays an important role in urothelial carcinoma growth and progression, a randomized, placebo-controlled phase III trial tested whether the addition of bevacizumab to gemcitabine + cisplatin combination chemotherapy is able to improve overall survival in metastatic urothelial carcinoma patients in first-line therapy. This trial was negative regarding its primary endpoint; thus, currently the standard of care remains cisplatin-based chemotherapy without the addition of biologic agents in advanced or metastatic urothelial carcinoma.
Neoadjuvant cisplatin-based chemotherapy is standard treatment for muscle-invasive bladder cancer before radical cystectomy (RC). Despite level 1 evidence demonstrating an overall survival benefit for patients undergoing RC after neoadjuvant chemotherapy (NAC), acceptance rates are still low. In high-risk upper tract urothelial cancer (UTUC), cumulative evidence suggests that NAC for locally advanced UTUC can improve oncological outcome. Ongoing phase 3 trials will finally prove the benefit or futility of NAC in this tumor entity. Since urothelial cancer (UC) is a heterogeneous disease, predictive biomarkers are needed to select specific patient populations and potentially increase response rates to NAC. Novel targeting therapies, including immune checkpoint inhibitors, have been approved for metastatic UC. In combination with predictive biomarkers, these might have the potential to change systemic therapy for UC from a “one-fits-all” principle to a more individualized approach.
The introduction of immune checkpoint inhibitors has further improved response and survival rates in patients with metastatic renal cell carcinoma. In this context, the most promising trial results in the past 12 months include KEYNOTE 426 and the 30-month update of CheckMate 214. Both trials, similar to IMmotion 151 and JAVELIN Renal 101, reported improved survival and response data. CheckMate 214 reported an overall survival benefit in intermediate and poor risk patients, however, such benefit was observed irrespective of conventional risk groups in KEYNOTE 426. These results prompted the European Association of Urology (EAU) to update their guidelines on the treatment of metastatic renal cell carcinoma and to recommend the combinations pembrolizumab/axitinib and nivolumab/ipilimumab as standard of care in previously untreated intermediate and poor risk patients and the combination pembrolizumab/axitinib as standard of care in previously untreated favorable risk patients. Inflammatory and angiogenic markers profiles may have the potential to become a tool aiding to better individualize treatment regimens in the future. Exploratory analyses of the IMmotion 151 trial present first results supporting such approach. Sarcomatoid variant histology remains an unfavorable prognostic parameter. Subgroup analyses of CheckMate 214 revealed exceptional response in patients with sarcomatoid histology. Whereas conventional therapy was inferior in such patients, more than 50% of patients responded to combined checkpoint inhibitor therapy. Increasing evidence points towards a crucial role of the gut microbiome in the response of patients to modern immune therapies. Any antibiotic treatment prior to the inition of immune checkpoint therapy can have detrimental impact on the intestinal microbiome, thereby dramatically reducing response rate to checkpoint inhibitors.
The treatment landscape of metastatic renal cell cancer (mRCC) is rapidly evolving. To date in 2019 twelve drugs are licensed for this indication, two more drugs are awaited to be introduced into our portfolio of treatment options by the end of the year. First-line treatment has robust clinical trial data and is clearly stated by the consensus guidelines. It consists either of a tyrosine kinase inhibitor (TKI) monotherapy for favorable risk patients—defined by the Heng or IMDC (International mRCC Database Consortium) score—or the immuno-oncology (IO) combination of ipilimumab and nivolumab (Ipi/Nivo) for intermediate- and poor-risk patients who are eligible for this treatment. To date we have a clearly positive phase III trial of a TKI-IO combination that was superior to standard of care with sunitinib in untreated metastatic patients independent of the risk group. Pembrolizumab and axitinib will be most likely introduced to the treatment landscape by the end of the year. Despite all these very enthusiastic treatment options in first line, subsequent treatment recommendations are missing due to the lack of data. Only retrospective data can be used as a tool to make the right choice after the use of an IO drug in first line.
We have entered a new era for patients with mRCC with multiple treatment options including VEGF(Vascular Endothelial Growth Factor)-, MET(Mesenchymal-eptihelial Transition)-, AXL(AXL-Rezeptortyrosinkinase)-, mTOR(mechanistic Target of Rapamycin)-targeted TKIs (tyrosinekinaseinhibitors) as well as PD-1(programmed cell death protein 1)-, PD-L1(Programmed cell death 1 ligand)- and CTLA4(cytotoxic T-lymphocyte-associated Protein 4)-targeted IOs and their combinations, respectively. However, the possibility to select patients based on predictive biomarkers for the different treatment options is still lacking. The TCGA (Cancer Genome Atlas) consortium conducted comprehensive analyses of genomic and metabolic features of RCC (renal cell carcinoma) and these findings demonstrated significant differences between the major histological subtypes of RCC like differences in immune signatures and their course of disease. The increasing knowledge on the genomic landscape of RCC supports stratification of patients for targeted therapies. Biomarker development for future therapeutic approaches will require integration of multiple biologic components like PD-L1 expression, tumor-infiltrating lymphocytes and mutations in addition to the prognostic risk scores. However, no single molecular marker has been shown to improve the accuracy of MSKCC (Memorial Sloan Kettering Cancer Center) or IMDC (International Metastatic RCC Database Consortium) prognostic risk scores. Large-scale biomarker-driven prospective trials with consensus methodologies on biomarker assessment and scoring are needed to obtain clinically validated new prognostic and predictive biomarkers as described above. The integration of routinely available parameters and new biomarkers could hold the key for personalized treatment strategies of patients with RCC.
Surgical resection of RCC should be the aim for cure of localized or locally advanced RCC, either by partial or radical nephrectomy, depending on tumor size and patient’s performance status. In cT1 stages partial nephrectomy is recommended. In metastatic stage, immediate CN can be performed in patients with good performance status, who do not need systemic therapy because of oligometatastic disease with feasibility of complete resection.
Human papilloma virus (HPV) is a DNA virus consisting of approximately 8000 base pairs. HPV represents the most common sexually transmitted infection worldwide. Around 200 different genotypes exist. They are distinguished into low- and high-risk genotypes, depending on the risk of such HPV-associated lesions undergoing malignant transformation. The high-risk genotypes include HPV 16 and 18, which are responsible for a variety of human cancers. The most common malignancies that are associated with HPV infection are cervical cancer, oropharyngeal cancer and anal cancer. Screening for HPV precursor lesions in women has led to a drastic reduction in cervical cancer morbidity and mortality in the last 30 years. Unfortunately no such screening tests are available for other HPV-associated malignancies. With the advent of HPV vaccination programs a marked decrease in the prevalence of HPV was reached in vaccinated individuals. However, since these programs were initiated around 2009 the full effect on the incidence of HPV-associated cancers cannot be fully estimated yet.
Renal leiomyoma (RL) is a rare benign tumor, usually presenting as a small asymptomatic lesion, frequently found during autopsy with a higher incidence in women (2:1). However, larger RL can become symptomatic and show structural changes (such as hemorrhagic and cystic degeneration), thus posing a diagnostic challenge. A 49-year-old woman with a recent history of weight loss and left flank pain was referred to our institution. An ultrasound exam revealed the presence of a complex mass at the left kidney. Both CT and MRI scans were performed to characterize the renal mass, which appeared well circumscribed with no signs of local invasion. Moreover, CT and MRI provided valuable additional information such as the absence of both macroscopic and microscopic fat and the presence of calcifications, hemorrhagic areas, multiple cysts and delayed enhancement. A left nephrectomy was performed via laparoscopy. Histopathological evaluation confirmed the diagnosis of RL. Imaging techniques can aid in the identification of large RL and guide the differential diagnosis; however, histopathologic analysis is required for a definitive diagnosis.