According to American Cancer Society (ACS) , in US, lung cancer is a high incidence cancer type of which incidence rate ranks the third among all cancers in 2011-2015 and has a tendency to ascend to the second in recent years, and it’s the number one leading cause of cancer death all these years.
With advancement in tumor biology and pathogenesis, lung cancer classification correlates tumor morphology with biological characteristics, which now by facilitating therapeutic decision-making and prognostic prediction leads to the personalized medicine era.
Which can be observed from changes in some important guidance over time, as mentioned in the WHO Classification of Lung Tumors released in 2015 , the classification of lung cancer is constantly developed. Along with the traditional pathologic tissue biopsy or cytology to more expanded use of immunochemistry (IHC) and molecular testing for specific genetic alterations, the more and more comprehensive classification intends to offer more accurate information for therapeutic decision-making.
Generally, lung cancers have been classified into small cell lung carcinomas (SCLCs), which accounts for 20% of the cases, and the rest, non-small cell lung carcinomas (NSCLCs)2. The former behaves aggressively and is treated nonsurgically in most cases, while the latter is usually treated by combinations of surgery and adjuvant therapy. Previously, there was no clinical need for further classifying NSCLCs, however, with discovery of new effective targets, for example epidermal growth factor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements, along with development of EGFR tyrosine kinase inhibition or ALK inhibition strategies, it’s now imperative for pathologists to distinguish between squamous cell carcinoma and adenocarcinoma by molecular testing3, under the primary category of NSCLCs.
Therefore, it’s also noticeable that newer classification starts to provide standardized criteria and terminology for small biopsies and cytology. Because clinically, more patients are diagnosed based on small specimens (bronchoscopic, needle, or core biopsies) rather than resection specimens. And for eligibility to personalized medicine, based on accurate histologic diagnosis and genetic alterations, the small samples are needed not only for pathologic classification but also further molecular testing, so they need to be managed more carefully.
As mentioned above, SCLCs are highly aggressive, characterized by a high proliferation rate and early metastasis.
Surgery may only be recommended in limited early stage SCLCs which correspond to T1-2N0M0 tumors in the TNM primary tumor staging system (limited tumor size, no lymph-node involved, no existence of distant metastases, see Table 1), and postoperative chemotherapy(PORT) is required. For any higher stage, surgery is not recommended.
In most cases, patients with stages I, II and III diseases receive the combination of chemotherapy and thoracic irradiation. Chemotherapy is based on cisplatin. Following prophylactic cerebral irradiation (PCI) can diminish the relapses or metastases to central nervous system.
For stage IV, the standard treatment will be chemotherapy as the only treatment modality, usually with cisplatin or carboplatin plus etoposide.
Though SCLCs sensitively respond to initial treatment, most patients relapse with relatively resistant disease. If the original first-line platinum-based regimen no longer works for the patients when relapses occur, then second-line chemotherapy can provide palliation of symptoms in many patients. Topotecan is one agent commonly used for second-line therapy in many countries and is approved by FDA in US, whereas there are also other drugs in clinical trials, including paclitaxel, docetaxel, irinotecan, vinorelbine, gemcitabine, ifosfamide, temozolomide and oral etoposide.
Besides, seeing the recent successes in immunotherapy for other cancer types, it’s now introduced to the clinical treatment of SCLCs and is included in some guidelines.
Treatment for NSCLCs is usually the combination of resection and chemotherapy, and the chemotherapy can also be platinum-based just like in SCLCs.
However, differently from SCLCs, there has been more advanced molecular targeted therapy for subtypes of NSCLCs, as varied genetic alterations in each subtype cause different characteristics in chemotherapy response. It’s been observed that EGFR mutations and rearrangements of ALK and ROS1 are found primarily in adenocarcinoma, that pemetrexed is effective in patients with advanced lung adenocarcinoma rather than squamous cell carcinoma, and that bevacizumab is contraindicated in patients with squamous cell carcinoma, whereas Nivolumab (a programmed death-ligand [PDL] antibody) was most recently approved in patients with advanced lung squamous cell carcinoma. With molecular testing for biomarkers, besides those mentioned above, we may also test ROS1 Rearrangements and BRAF V600E Mutations, clinicians make therapy-decision more accurately according to NSCLCs subtype classification.
For second-line therapy, there are some well established agents, for example docetaxel, pemetrexed and erlotinib.
Also, in NSCLCs, immunotherapy, mainly targeting PD-1/PD-L1, seems promising in improving progression-free survival (PFS) and overall survival (OS).
The term maintenance therapy may sound similar to second-line therapy, however, in cancer therapy, second-line therapy mostly relies upon disease progression, while maintenance therapy may be taken immediately following the completion of initial treatment, prior to progression.
Conventionally, we believed in that extended regimens would cause more side effects instead of benefit in survival. However, in recent years, it’s been challenged in some trials in which the progression-free survival and overall survival were improved by using the established second-line drugs as maintenance therapy in NSCLCs.
In past decades, besides trials comparing maintenance therapy with placebo9, many trials in more comprehensive conditions have been carried out, taking expanded initial regimens, switching to a new non-cross resistant chemotherapy, taking molecular targeted therapy or immunotherapy following first-line chemotherapy, in which comparing cohorts taking the maintenance therapy immediately or delayed after the initial treatments10, . Partial results were summarized in Table 2 which have shown maintenance therapy benefited patients in PFS and/or OS, yet maintenance therapies won’t benefit all patients, patients’ response varied between agents and timeframes of therapy.
It’s noticeable that immunotherapy in lung cancer may have better prognosis than conventional chemotherapy itself, but the combination of immunotherapy with established chemotherapies or targeted therapies may not have a better outcome, as it’s observed alterations or deficiency in immune functions may occur after the initial treatment, which may affect the immunotherapy.
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