Hana Faltová, Tomáš Haruštiak, Alexandr Pazdro, Martin Šnajdauf, Jiří Tvrdoň, Robert Lischke
Stanislav Hloušek, Milada Zemanová
Josef Dvořák, Igor Richter, Jan Prokš, Aneta Rozsypalová, Jana Grimová
Benefits and risks of neoadjuvant therapy of esophageal and gastroesophageal junction tumors from the perspective of surgeon
Esophageal cancer is highly malignant disease and at the time of diagnosis it is operable in only 30-40% of patients. The operation is questioned as monotherapy mainly in locally advanced stages because of worse results of long-term survival.12 Oncological therapy alone, but also does not lead to satisfactory results without surgery. Studies on induction therapy protocols have not yet achieved a clear consensus in either adenocarcinomas or squamous cell carcinomas. One of the promising ways to move forward is to work with surgeons to determine the degree of tumor regression or lymph node involvement from the definitive resection. For surgeons, the benefits of cancer therapy are clearly noted in the form of increased microscopically radical resections and regressive tumor changes, which increases the locally operable findings and hence patient survival. However, the question remains the complications that neoadjuvant treatment may cause perioperatively.
There are two main types of esophageal cancer - adenocarcinoma and more aggressive squamous cell carcinoma. While squamous cell carcinoma was previously more frequently diagnosed, now the incidence of both types is comparable in developed countries, in some cases the incidence of adenocarcinoma is even more frequent. In the past, most esophageal cancers were indicated for surgery if it was a surgically solvable finding and the patient was not an unsuitable candidate for resection, e.g. due to comorbidities. Due to the fact that esophagectomy, compared to other procedures, represents an operation with a considerable risk of morbidity and mortality, a considerable number of operated patients died or were treated for a long time due to complications. Medicine has also undergone a fundamental change in this area - early carcinomas (defined as tumors with infiltration of the mucosa and submucosa) can be treated endoscopically, often radically and therefore curatively. Mortality from endoscopic treatment is practically zero and morbidity is minimal. The quality of life after endoscopic treatment is excellent thanks to the preserved organ. As a result, the established practice is beginning to change, when patients with early esophageal cancer used to be sent for surgery, nowadays these patients are increasingly referred to the assessment of endoscopic treatment. However, not every patient is resolved endoscopically, some still have to undergo surgery or possibly oncological treatment. Therefore, the treatment of early esophageal carcinomas should be discussed in a multidisciplinary team.
The treatment of locally and regionally advanced gastroesophageal junction adenocarcinomas is a very controversial topic. The therapeutic approach may include preoperative chemoradiotherapy, which is commonly used in esophageal cancer, as well as perioperative chemotherapy, eventually postoperative chemoradiotherapy, which are treatment alternatives used in gastric cancer. Due to the non-uniform approach in the treatment of gastroesophageal junction tumors, the benefit of radiotherapy is not clearly defined in these tumors, although it seems that the addition of radiation may be associated with some benefit over chemotherapy alone.
The goals of the treatment of the gastric and gastroesophageal junction adenocarcinoma is the quality of life, symptoms palliation and improvement in the overall survival. The generally recommended regimen in the first line setting is the chemotherapy combination based on platinum derivates (cisplatin or oxaliplatin) eventually with trastuzumab in tumors with HER2 overexpression. Nowadays, pembrolizumab is also the treatment of choice in the first line. The standard regimen in the second and later lines is much less defined. For patients in good performance status paclitaxel with ramucirumab remains generally recommended treatment of choice eventually monotherapy with taxane, irinotecan or capecitabine. In patients with MSI-H (microsatellite instability-high) or dMMR (deficient mismatch repair) tumors pembrolizumab is the treatment of choice. In third line of the treatment trifluridine/tipiracil is the new treatment standard. The aim of this article is to summarize the current treatment strategy of the locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma.
The case report presents a patient with locally advanced carcinoma of the distal esophagus, clinical stage IIIB. Due to the stage of the disease a neoadjuvant concomitant chemoradiotherapy was indicated. During the treatment the patient developed complications for which he had to be hospitalized. For the aphagia the patient was provided with parenteral nutrition and nutritional jejunostomy was indicated to adjust nutritional parameters. After improvement of the general condition, the patient was able to undergo a radical procedure, after which the disease remission lasts so far. Thus, the case presents the potential benefits and complications of combination therapy in a patient with locally advanced esophageal cancer.
Lung cancer leads to death within 5 years in 85-90% of newly diagnosed cases. Lung carcinomas with high mutation load belong to tumors with a good response to antitumor immunotherapy using checkpoint inhibitors. Monoclonal antibodies against the PD-1 receptor (nivolumab, pembrolizumab) or against the PD-L1 ligand (atezolizumab, durvalumab) have been registered for clinical use in lung tumors. The breakthrough in the second (and the next) line of treatment for advanced non-small cell lung cancer (NSCLC) is previously unattained survival median of over 12 months, benefit is particularly relevant for patients with high PD-L1 expression. A major breakthrough in the treatment of advanced NSCLC in patients with high PD-L1 (TPS > 50%) is the significantly higher potent efficacy of monotherapy with pembrolizumab compared to chemotherapy with median survival over 20 months. In patients with low or totally negative PD-L1 expression, the combination of chemotherapy + immunotherapy is significantly better than chemotherapy alone, with median survival rates in various evaluations of 15.2-23.7 months. A breakthrough in inoperable NSCLC is a significant prolongation of two and three-year survival, a 50% longer survival median, doubling the percentage of potentially cured patients after 20 years of treatment stagnation. Breakthrough in extensive stage small cell carcinoma is a significant prolongation of survival and achievement of significantly more long-term remissions by adding atezolizumab to standard chemotherapy including carboplatin and etoposide.
Immunotherapy is already an integral part of lung cancer treatment. The results of a number of studies with checkpoint inhibitors have shown an improvement in overall survival first in higher treatment lines in advanced non-small cell lung cancer (NSCLC), results are now available in combination with chemotherapy in first-line treatment regardless of PD-L1 (programmed cell death protein ligand) expression, including small cell lung cancer (SCLC). Atezolizumab is approved by the European Medicines Agency as monotherapy for the second-line therapy of advanced NSCLC, in combination with bevacizumab, paclitaxel and carboplatin for the first-line treatment of metastatic non-squamous NSCLC, including patients with evidence of EGFR (epidermal growth factor receptor) mutation or ALK rearrangement after failure of target therapy, in combination with nab-paclitaxel and carboplatin in the first line of non-squamous NSCLC without evidence of EGFR mutation or ALK gene rearrangement, and in combination with etoposide and carboplatin as the first checkpoint inhibitor for extensive first-line SCLC treatment.
A prospective randomized phase III clinical trial, GOG 240, demonstrated a statistically significant increase in progression-free survival and overall survival in the first-line treatment of metastatic or locally advanced inoperable cervical cancer. Bevacizumab in combination with paclitaxel and cisplatin or alternatively in patients who cannot be treated with platinum, paclitaxel and topotecan, may be indicated for the treatment of adult patients with persistent, recurrent or metastatic cervical cancer.
This article reviews the efficacy panitumumab (Vectibix) in the treatment of metastatic colorectal carcinoma. Fist study published was PRIME in which panitumumab plus FOLFOX compared to chemotherapy alone prolonged overall survival in patients with non-resectable metastatic colorectal cancer (mCRC), furthermore it showed trend towards higher resection rate in patients with liver limited disease (LLD). The PEAK trial was comparing panitumumab and bevacizumab with chemotherapy backbone. Both overall survival and progression-free survival favored panitumumab compared to bevacizumab. PLANET trial was exploring potential of panitumumab to enhance overall response rate and allow for more curative resections in LLD population of mCRC patients. PLANET trial provided evidence high resectability and long overall survival. VOLFI trial represents a reasoned step in searching for more potent combination therapy. In randomized manner it compared FOLFOXIRI alone to FOLFOXIRI plus panitumumab. This study met its primary point, which was ORR, furthermore it showed greatly increased resectability in panitumumab arm and suggested better overall survival. Panitumumab plus FOLFOXIRI pose viable and efficient option for patients with mCRC, where deep tumor response could open way to surgical resection. VALENTINO study shed light on different maintenance strategies in 1st line mCRC after induction FOLFOX + panitumumab. Fluorouracil + leucovorin + panitumumab yielded better results in terms of 10-month PFS compared to panitumumab monotherapy.
More than 80 % of patients with pancreatic cancer are diagnosed in locally advanced or metastatic disease not amenable to potentially curative surgical resection. In patients with resectable tumor, resection followed by adjuvant chemotherapy is currently the standard of treatment. Adjuvant systemic therapy improves the prognosis of patients after curative resection. Up to a half of patients, however, cannot profit from adjuvant therapy due to postoperative complications, comorbidities or early metastases development. Neoadjuvant therapy has become the standard in majority of gastrointestinal malignancies (esophageal, gastric, rectal cancer). In recent years, it has emerged as an alternative treatment especially for patients with borderline resectable and resectable pancreatic cancer. However, randomized controlled trials of neoadjuvant treatment compared with upfront surgery are lacking. Results of recent meta-analyses suggest positive effect of neoadjuvant treatment and indicate better tolerance compared to adjuvant therapy, increased R0 resection rates and improved overall survival. Nevertheless, this positive effect as well as optimal type of neoadjuvant chemotherapy or chemoradiotherapy has to be elucidated in larger randomized trials.
Combination of nivolumab + ipilimumab – a new perspective in the treatment of metastatic renal carcinoma
For patients with advanced renal cell carcinoma intermediateor poor-risk disease without prior exposure to systemic therapy, the combination of nivolumab plus ipilimumab improves overall survival and progression free survival compared with sunitinib.
Larotrectinib is a registered anticancer drug for antitumor therapy for tumors with NTRK gene fusions. A published analysis of 159 adult and pediatric patients with solid NTRK fusion tumors treated with larotrectinib showed a median duration of response of 35.2 months and a median time to disease progression of 28.3 months. These were highly heterogeneous groups of advanced pretreated tumors. Larotrectinib has a good safety profile; the dose was reduced in 8% of patient, in 2% due to side effects.
We describe the case of a 41-year-old patient with breast cancer, where there was primarily surgical liver dissemination and then bone dissemination. The immunoprofile of the hormone-dependent primary tumor was different from the metastasis, which was triplet negative. The patient was treated systemically with hormone therapy with tamoxifen and a combination of cyclin-dependent kinase inhibitors and letrozole. Cyclin-dependent kinase inhibitors were varied according to the adverse event profile. The best tolerated treatment was the combination of abemaciclib with letrozole. Treatment with the combination with denosumab was effective, we achieved partial remission of lung metastases and stabilization of bone.
Trifluridine/tipiracil therapy with long‑term effect in the patient with primarily metastatic colorectal cancer – case report
A 71-year-old physician-surgeon in excellent condition, working full-time, with multiple locally advanced colon cancer and synchronous metastatic liver disease, was treated with subtotal colectomy and microwave ablation of liver lesions in 2015. Subsequent systemic therapy was difficult to tolerate, bevacizumab monotherapy only. He was treated with radiotherapy for progression in the liver 2016. Further progression in the liver in 2017 was solved by systemic therapy (irinotecan, cetuximab). For further progression in liver in February 2018, we have used trifluridine/tipiracil therapy, which the patient is still on (February 2020 - 28th cycle). Process stabilization with excellent tolerance has been achieved. The patient is without any problems, still working full-time.