Almost a steady state
James Fleck: Anticancerweb, 12(05), 2020
Small-Cell Lung Cancer (SCLC) is a very aggressive disease, showing a fast-diameter doubling-time (D-DT) and a fast-volume doubling-time (V-DT). The mean D-DT is 59.6 days and the mean V-DT is 50.5 days. Interestingly, both D-DT and V-DT are higher in primary tumor than in nodal disease and higher in extensive stage (ES) than in limited stage (LS) SCLC. Rapidly cell growth in lymph nodes may be responsible for the locally advanced thoracic disease presentation in the ironically called limited stage. SCLC is only incidentally diagnosed as N0 disease. Sometimes, it is a result of lung cancer low-dose CT screening, performed in high-risk population. Although SCLC was not included in the Cancer Genome Atlas, somatic mutations have been well-described. Whole exome-sequencing of surgical resected samples have shown a high prevalence of inactivating mutations in tumor suppressor genes (TP53 and RB1), amplification of MYC-family member and histone modifiers. SCLC has a high-mutation rate, reflecting the effects of tobacco smoke carcinogens on DNA. SCLC represents 15% of all cases of lung cancer, and is predominantly diagnosed as ES (70%). Despite the recommendation of the International Association for the Study of Lung Cancer (IASLC) to use the AJCC staging system, SCLC continues to be classified for treatment purposes as LS and ES. Based on this concept, LS is defined as a disease limited to ipsilateral hemithorax and regional lymph nodes, which could be encompassed in a safe radiotherapy field.
Unfortunately, the outcomes of SCLC have remained close to a steady state for the past 30 years. However, some small but important advances have been made, leading to a slight increase in overall survival or a reduction in adverse treatment events. A metanalysis comparing the two most used chemotherapy doublets (cisplatin + etoposide versus carboplatin + etoposide) showed no difference in efficacy, sustaining a treatment managed according to a personal toxicity profile. Although CNS metastases are seen as solitary metastatic site in only 4% of post-mortem analyzes, prophylactic cranial irradiation (PCI) has shown improved survival for SCLC patient, both in LS and in complete remission ES. Anecdotal diagnosis of very early-stage SCLC (T1, T2, N0) favors surgical treatment, followed by adjuvant chemotherapy (in pN0) or adjuvant combined chemoradiation therapy (in pN+). Due to late toxicity, PCI should never be administered concurrently with systemic chemotherapy, being used after completion of all induction or adjuvant treatment. Recent trials in SCLC-ES have shown slight improve in overall survival when induction chemotherapy is combined with humanized monoclonal anti-programed death-ligand 1 (anti-PDL1) atezolizumab or durvalumab followed by anti-PDL1 maintenance therapy. Currently, there is no mature date of combined chemo-immunotherapy in SCLC-LS. Patients with SCLC-LS should be ideally staged using PET-CT and treated with involved-field RT after the first cycle of chemotherapy, avoiding major toxicity. Second-line treatment would be based on platinum resistance. Surveillance, Epidemiology, and End Results (SEER) registries have showed a decrease in SCLC incidence, over the last three decades and a slight improve in 5-year overall survival. But, we are still too far away from ideal treatment. This is a very unstable tumor, showing early drug-resistance, and future will be determined by a better understanding of its biological behavior.
References:
1. Mood Syahizul, Nuhairy Mohd Sharial, Min Yuen Teo, et all: Modern imaging technique assessment of small cell lung cancer doubling time, Journal of Clinical Oncology 30, no. 15 supplement e17561, 2017
2. Shigeki Umemura, Katsuya Tsuchihara, Koichi Goto: Genomic profiling of small-cell lung cancer: the era of targeted therapies, Japanese Journal of Clinical Oncology, 45 (6): 513–519, 2015
3. Fleck JF, Einhorn, LH, Lauer, RC, et al: Is Prophylactic Cranial Irradiation Indicated in Small Cell Lung Cancer, 8: 209 – 214, 1990
4. Shuncong Wang, Jianjun Tang, Tiantian Sun, et all: Survival changes in patients with small cell lung cancer and disparities between different sexes, socioeconomic statuses and ages, Sci Rep, 1339 (7), 2017
5. Title: Bible reading. Date: 1831. Institution: Rijksmuseum. Provider: Rijksmuseum. Providing Country: Netherlands. Public Domain
Considering the high mortality rates associated with all lung cancer types, the Small-Cell Lung Cancer may play a specially important role in this scenario. It's hard to imagine we could stand good chances against this enemy when diagnosis occurs 70% at extensive stage disease. We look for new advances in the field of early diagnostics, such as in imaging and biochemical markers.
The advancements in immunotherapy and biological research on the last years represent new perspectives on the prognosis and treatment of many diseases, including lung cancer. It's important to keep investing in those areas and try to find new options of early diagnosis to achieve the hard goal of lower the mortality rate.
SCLC is a very aggressive cancer with high mortality that urges for innovations in its treatment. Unfortunately, the standard therapy has been the same for approximately 30 years, resulting in virtually stable (and extremely low) 12-month relative survival rates. This scenario contrasts with that of NSCLC, in which the use of targeted therapies has improved the survival rate. However, some good news is arriving: the use of PCI and anti-PDL1 has shown positive results. Nevertheless, there is still much to learn, and a lot of progress needs to be made in the development of new therapies.
SCLC is one of the greatest challenges for medicine since the 90s. It is the tumor that presents the highest growth rate among the cancers with the highest incidence. It grows so fast that diagnosis is rarely made before infiltration into a lymph node or becoming invasive of adjacent structures. Due to this particularity, this tumor is often classified as a non-resectable lesion. Despite the positive results of the trial using chemotherapy combined with anti-PDL1, this type of cancer is very unstable and the medical challenge still goes on.
Small-Cell Lung Cancer (SCLC) is a sort of lung cancer which has a rapid growth rate. Also, there has been demonstrated through genome sequencing that this type of cancer has a high mutation rate, evidencing the association between SCLC and the effects of tobacco use on DNA, mostly. Despite the progress in the studies on SCLC, the advances in outcomes did not followed the same rhythm. A few accomplishments over the last 30 years include a slight increase in overall survival and reduction in treatment adverse effects. In the future, we must know the SCLC biological behavior better to give the patient the ideal treatment.
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