Overview
SCLC accounts for 15% of all lung cancers, and approximately 98% of SCLC is associated with smoking. In 2004, there were an estimated 26,000 new cases of SCLC in the U.S. SCLC grows faster and metastasizes more extensively earlier than NSCLC, with approximately 67% of SCLC patients presenting with significant extrathoracic metastases and the remaining 33% with tumors confined to a single radiation field in the chest, referred to as the limited stage. SCLC is highly sensitive to radiotherapy and chemotherapy, but the vast majority of patients will eventually relapse. Almost all SCLC eventually progresses to the extensive stage, therefore, treatment is mainly combined with chemotherapy and, when the lesion is confined to the chest, radiotherapy. Combination chemoradiotherapy can cure some limited-stage SCLC, although the main means of curing NSCLC is surgical resection, but only for 2-5% of patients with limited-stage SCLC.
Pathology
SCLC is a malignant epithelial tumor. Cancer cells have little cytoplasm, poorly defined borders, fine granular chromatin, and often absent or small, pale nuclei. The cells are round, oval or spindle shaped, with distinct nuclear shape and high mitotic index. Histologically, there are small cell carcinomas and mixed SCLCs with squamous, adenocarcinoma and large cell carcinomas, and up to 30% of autopsies are found with non-small cell carcinoma differentiation, but this is rare in untreated specimens, suggesting that carcinogens may act on pluripotent stem cells that can differentiate in multiple directions.
Tumors that differentiate into small blue cells include SCLC, extrapulmonary small cell carcinoma, Merkel cell tumor, carcinoid tumor, atypical carcinoid tumor, large cell neuroendocrine carcinoma, lymphoma, small cell sarcoma, and other neuroendocrine tumors. Small cell carcinomas originating outside the lungs can occur in the nasopharynx, gastrointestinal tract, and genitourinary tract. Pulmonary and extrapulmonary small cell carcinomas have similar clinicobiological behavior and both are prone to severe and extensive metastasis, but extrapulmonary small cell carcinomas are not associated with 3P deficiency, suggesting the existence of different pathogenesis.
Almost all SCLC showed positive expression of keratin, epithelial membrane antigen and thyroid transcription factor (TTF-1) immunoreactivity, indicating the presence of differentiation to epithelial cells. At the same time, most tumors also differentiate toward neuroendocrine and neurological differentiation, showing positive immunoreactivity for chromogranin A, neurospecific enolase, neural cell adhesion molecule (NCAM), and synaptophysin. However, we cannot distinguish SCLC from NSCLC on this basis, because in more than 10% of NSCLC, at least one neuroendocrine marker is positive.
The paraneoplastic syndrome of SCLC manifests in various forms, including neurological and endocrine paraneoplastic syndromes. Common neurological syndromes include Lan-Y syndrome, cancer-associated encephalomyelitis, and sensory neuropathy. Lan-I syndrome is characterized by proximal leg weakness, which is caused by autoantibodies against “voltage-gated calcium channels. SCLC can also produce a variety of peptide hormones, including ACTH and pressor hormones, leading to Cushing’s syndrome and hyponatremia.
Clinical manifestations, staging and prognostic factors
The clinical manifestations of SCLC are mainly cough, dyspnea, weight loss and weakness with or without obstructive pneumonia, which are caused by large masses at the hilum and enlarged mediastinal lymph nodes. Sometimes they also present as small peripheral nodules, but rarely a single isolated peripheral nodule without enlarged mediastinal lymph nodes. Biopsy pathology by fine needle aspiration cannot distinguish SCLC from typical or atypical carcinoid tumors or neuroendocrine tumors, in which case surgical resection and staging based on mediastinal lymph nodes is recommended.
SCLC can be divided into two stages according to the extent of invasion: (1) confined stage: the lesion is confined to the same side of the chest and within a single tolerable and safe field of irradiation. (2) Extensive stage: tumor beyond one side of the chest cavity, malignant pleural effusion, pericardial effusion or hematogenous metastasis. Contralateral mediastinal and ipsilateral supraclavicular lymph node metastases are usually classified as limited stage, while contralateral hilar and supraclavicular lymph node metastases are classified as extensive stage. Approximately 2/3 of patients have significant hematogenous metastases, manifesting as contralateral lung, liver, adrenal and/or bone marrow metastases. Synchronized chemoradiotherapy is the standard treatment for limited-stage SCLC, while chemotherapy is the standard treatment for extensive stage. Thoracic radiotherapy has an important role for some patients in the limited stage, however, it is no longer indicated in the presence of contralateral hilar and supraclavicular lymph node metastases and pericardial or malignant pleural effusions. Approximately 67% of patients present with significant metastases, and the common metastatic organs are the liver, adrenal glands, bone, bone marrow, and brain.
All patients with SCLC, including those with limited stage, require systemic therapy. Staging includes chest X-ray, physical examination, CT scan of the chest and abdomen, MRI or CT of the head; bone scan; and unilateral or bilateral bone aspiration or biopsy when hematocrit or other metastases are present. Less than 5% of patients with extensive stage SCLC present with bone marrow invasion only. PET scan can be used for staging.
The extent of tumor invasion cannot be determined clinically based on symptoms or laboratory findings alone. About 30% of patients with normal alkaline phosphatase levels or asymptomatic patients have positive bone scans; 10% to 15% of newly seen patients have central nervous system metastases detected on cranial CT or MRI scans, of which about 30% are asymptomatic. Early treatment of brain metastases reduces the incidence of chronic neurological disease. SCLC grows very rapidly and most patients develop typical symptoms within 8 weeks, so do not delay treatment for more than 7 to 10 days to complete staging, as the disease can worsen significantly during this time.
Low PS score, extensive stage, weight loss, multiple sites of tumor invasion and oversized tumors are important poor prognostic factors. In the limited stage, women, under 70 years of age, stage I, and no elevated LDH levels have a better prognosis. In the extensive stage, those with normal LDH and a single metastasis have a good prognosis. The number of organs involved is negatively correlated with the prognosis, and the prognosis of liver metastasis is worse. The prognosis of those who present with endocrine paraneoplastic syndrome is mostly poor.
Initial evaluation
History and physical examination and pathology report are crucial. Staging should usually include chest radiography, CT scans of the chest and upper abdomen (including liver and adrenal glands), and MRI or CT of the head and its enhancement, with MRI preferred because of its higher sensitivity than CT. Bone scans are also recommended, and if abnormalities are found, X-rays of the abnormal areas are done.
Since most patients with SCLC are weak, routine blood and platelet counts, serum electrolytes, liver function tests, calcium, LDH, BUN and serum creatine are routinely checked. Pulmonary function, electrocardiogram and cardiac function tests should also be performed if clinically necessary, especially if chest radiotherapy is to be done.
Although controversial, unilateral bone marrow aspiration and biopsy are still performed in many treatment centers for patients with limited-stage SCLC, while bone aspiration is no longer performed for those with significant dissemination. Indications for bone marrow needle aspiration biopsy include the presence of nucleated erythrocytes, leukopenia or thrombocytopenia, or elevated LDH, or for the evaluation of comorbidities that can affect treatment. Approximately 5-10% of patients with limited-stage SCLC are classified as having extensive stage due to the discovery of bone marrow metastases, and the treatment plan is changed as a result. If chest x-ray reveals pleural fluid, thoracentesis is recommended. If the puncture is a malignant exudate or malignant cells are found then the patient is classified as having an extensive stage; if the pleural fluid is not bloody or non-exudative, the pleural fluid does not affect the clinical staging based on clinical exclusion of those whose pleural fluid is caused by a tumor.
Elderly patients
The world population is tending to age. Because the incidence of lung cancer increases with age, at least 25% of patients with SCLC are older than 70 years, but these patients constitute a very low percentage of participants in clinical trials, accounting for only 1% of participants. Some of the newer trials have looked at older patients. Although actual age affects treatment tolerability, physiological age and health status prior to the disease have a greater impact on the development of treatment strategies, and if an elderly patient has been in good health in daily life for several months prior to the diagnosis of SCLC, adequate chemotherapy (combined with radiotherapy if indicated) should be recommended. Severe myelosuppression and decreased organ reserve may be encountered during treatment, especially in the first chemotherapy cycle, where the toxicity of chemotherapy is often superimposed on the destruction of the disease itself.
In general, the prognosis of elderly patients is similar to that of younger individuals, but the needs of the disease and the ability to cover it accordingly must be well predicted in older patients. Randomized trials have shown that “mild” therapy (e.g., pedialyte glycosides alone) is inferior to combination chemotherapy with platinum/pedialyte glycosides regimens. There have been a number of attempts to develop chemotherapy strategies for older SCLC, notably a four-cycle regimen of cisplatin or carboplatin in combination with pegylated glycosides, with dosage and administration similar to those used to treat younger patients. The AUC (area under the curve) dose of carboplatin is selected taking into account the declining renal function in older patients. Some patients cannot tolerate carboplatin at AUC measures above 6. Murray et al. explored the feasibility of short-cycle, full-dose chemotherapy in elderly or frail patients, with promising near- and long-term results with only two cycles of chemotherapy, but these approaches have not been directly compared with standard therapy. Paclitaxel combined with carboplatin (AUC = 2) was effective in 38% (1 complete remission, 24 partial remission) of patients with extensive stage SCLC who were elderly (≥70 years) or in poor general condition (PS = 2), and neutropenia occurred in 22%.
Rescue therapy
The vast majority of SCLC patients relapse or progress after initial treatment, with a median survival of 4 to 5 months for patients who relapse. Second-line chemotherapy plays an obvious palliative role in most patients, but the efficacy depends mainly on the time between the last treatment and relapse; if this period is less than 2 to 3 months, then it will be insensitive to most drugs or regimens, suggesting refractory SCLC; if the interval is longer, the efficiency is about 20% to 50%. For example, if CAV (cyclophosphamide, adriamycin, vincristine) is used as first-line treatment with an interval of 6 months or longer between relapses, the efficiency of EP (VP-16 DDP) as second-line treatment can be 45% to 50%. Topotecan has similar efficiency and survival rates to the CAV regimen and is recommended as a second-line agent because of its low toxicity. In recurrent SCLC, second-line chemotherapy should be given for 4 full cycles until the patient has maximized benefit, is treatment resistant, or has experienced severe toxicity. For localized lesions with symptoms, such as painful bone metastases, bronchial obstruction or brain metastases, radiotherapy can have a better symptom reduction effect.
Radiotherapy
Thoracic radiotherapy
The addition of thoracic radiotherapy improved the survival of patients with limited stage, with a median survival of 14 to 18 months. Meta-analysis of more than 2,000 patients showed that chest radiotherapy reduced the failure rate of local control in limited-stage SCLC by 25% to 30%, and increased the 2-year survival rate by about 5% to 7%. Conventional chemoradiotherapy is difficult to control local tumors well, and local recurrence is more common. The reasons for this may include too large tumor load (109-1011 tumor cells), endogenous drug resistance, the presence of non-small cell components that are insensitive to chemotherapy, poor drug distribution due to ischemia and drug resistance associated with tumor tissue hypoxia. In addition, if high-dose chemotherapy improves systemic control rates, the chance of local control failure increases accordingly.
The specific implementation of thoracic radiotherapy includes the timing (simultaneous, sequential or alternate application), timing (early or late), extent of radiation field (initial tumor volume or reduced field after tumor regression), dose and its fractionation of chemotherapy and radiotherapy. A randomized study at the National Cancer Institute of Canada comparing the efficacy of radiotherapy administered in the 2nd or 6th cycle of chemotherapy showed that early radiotherapy improves local and systemic control rates and may prolong survival. For significant infiltration accompanying tracheal obstruction, chemotherapy followed by radiotherapy improves local control. A randomized trial by the Japanese Oncology Cooperative comparing EP regimens combined with early (synchronized with cycle 1) or late chest radiotherapy, respectively, found that early radiotherapy resulted in longer survival than those with delayed radiotherapy, suggesting that synchronized chest radiotherapy is superior to sequential radiotherapy.
Following Turrisiet’s phase II trial, the Eastern Cooperative Oncology Group/Radiotherapy Oncology Group (ECOG/RTOG) treated 412 patients with synchronized chemoradiotherapy at a total radiation dose of 45 Gy for 3 weeks or 5 weeks with 2 daily doses or 1 daily dose, respectively. The incidence of esophagitis was higher in the 2-times-daily radiotherapy group. The median survival for both was 23 and 19 months (P=0.04), respectively, and the 5-year survival rates were 26% and 16%, respectively.
These results are encouraging, but the drawback of this study is that there are technical difficulties in treating patients with bilateral mediastinal lymph node enlargement with 2 daily radiotherapy sessions. Therefore, only patients with relatively low lymph node enlargement were selected in this trial, and the smaller lymph node volume may be one of the factors for the better prognosis. In addition, the maximum tolerated dose was not reached with 1 treatment dose per day, so it is not clear whether split radiotherapy is superior. Patients receiving combination therapy must be in good physical condition and have good lung function.
Prophylactic cranial irradiation
Intracranial metastases occur in approximately up to 50% of SCLC patients, and radiotherapy is difficult to control completely after the onset of symptoms of brain metastatic cancer, with a high mortality rate. Randomized and non-randomized studies have shown that prophylactic cranial radiation therapy (PCI) is effective in preventing brain metastases (6% vs. 20%), but does not significantly prolong survival. Moreover, radiotherapy can cause late secondary neuropathy, especially at single radiotherapy doses exceeding 3 Gy and/or in combination with concurrent chemotherapy. Low-dose PCI after the end of chemotherapy is less neurotoxic.
A Meta-analysis including all randomized trials of PCI showed that PCI reduced the 3-year brain metastasis rate from 58.3% to 33.3%, a 25% reduction. 3-year survival improved from 15.3% to 20.7%, a 35.4% increase. This shows that PCI prevented rather than delayed brain metastasis. Although the number of extensive periods in the study was small, they also benefited from PCI.
It is necessary for physicians to inform patients about the value and adverse effects of PCI and to discuss the implementation of PCI prior to PCI. On the basis of meta-analysis, we strongly advocate whole-brain prophylactic irradiation for patients with limited stage who achieve complete remission (category 1) and may be considered for patients with extensive stage who achieve complete remission (category 2B). The recommended dose of PCI is 24Gy (in 8 fractions) to 36Gy (in 18 fractions), and low-dose fractionated radiotherapy (1.8-2Gy/dose) is recommended. PCI should not be used in conjunction with systemic chemotherapy to avoid increased neurotoxicity.
Surgical resection of early SCLC
Less than 5% of patients are diagnosed with early stage SCLC. SCLC with a clinical stage of (T1 ~ 2, N0) should be considered for surgical resection. Mediastinoscopic or postoperative surgical staging should also be performed if the lymph nodes or local tissues are not invaded. Routine postoperative chemotherapy is recommended for successful surgical procedures (lobectomy and mediastinal lymph node dissection). Adjuvant postoperative chemotherapy can result in a 5-year survival rate of 35% to 40%, compared with less than 5% for surgery alone. Those without lymph node metastasis are preferred to those with positive lymph nodes, who can be treated with chemotherapy alone. The prognosis of those with mediastinal invasion is generally poor, and postoperative chemotherapy plus chest radiotherapy should be recommended for these patients.
Those with staging beyond T1-2N0 do not benefit from surgery. A prospective randomized study conducted by the American Lung Cancer Research Organization evaluated the place of surgery in the management of SCLC. The study did not include patients with stage I (T1, N0 or T2, N0). All patients with limited stage received 5 cycles of CAV chemotherapy, and if effective, patients were randomized to either the surgery alone group or the surgery plus radiotherapy group. Survival curves were not separated between the two groups: median survival of 16 months and a 2-year survival rate of 20%.
A rare situation was the diagnosis of SCLC confirmed by intraoperative frozen section, which allowed lobectomy and lymph node dissection, but not total lung resection on one side because the tumor was too large, lest postoperative lung function be compromised by poor postoperative treatment.
Treatment of patients who do not participate in clinical trials
Clinical trials basically represent the current status of SCLC treatment, and although some progress has been made, the principles and standards of SCLC treatment based on previous trials have not achieved good results. Therefore, patients should be strongly encouraged to participate in clinical trials.
For patients in limited stage, simultaneous chemoradiotherapy with 4 cycles of chemotherapy with a platinum/podophyllin-based regimen is recommended (Class 1 recommendation), and chest radiotherapy should be started in cycle 1 or 2 at a dose of 1.8 Gy per day or higher (total dose of 45 Gy) (Class 1 recommendation). PCI is recommended for those in complete remission. follow-up examinations and chest radiology are recommended every 2 to 3 months for the first few years, and patients should also be encouraged to quit smoking, as continued smoking increases toxicity and has a shorter survival.
Patients with SCLC are prone to develop a second primary tumor, and if a new pulmonary nodule appears after 2 years, it should be considered a second primary site. Adequate chemotherapy with standard combination regimens is recommended for patients with extensive stage, and new therapies are eagerly awaited.
Treatment of small cell lung cancer (SCLC)
The following recommended treatment is based on the treatment principles proposed by the National Cancer Institute and the Mayo Clinical Center.
The stage and histologic classification of the tumor are very important factors in determining the treatment plan, as most patients have underlying and obvious metastases at the time of diagnosis. There is no significant difference in survival in less-differentiated staging; therefore, the actual treatment of patients with small cell lung cancer does not use the complex TNM staging system mentioned previously, but most often uses diffuse and limited stage staging, which is difficult to define by name. Currently, it is considered that limited stage small cell cancer refers to tumors confined to the organs of one side of the chest, the mediastinum and supraclavicular lymph nodes, while diffuse stage refers to tumors that are extensive and These patients often have distant metastases.
Limited Stage SCLC
Chemotherapy is the mainstay of treatment for limited-stage SCLC, as only 1/3 of patients are diagnosed with limited-stage SCLC.
Chemotherapy uses cytotoxic substances that act on different cell division cycles, such as vincristine to block the formation of microtubules and adriamycin to block the synthesis of DNA and RNA. These drugs, which target the process of cell division, therefore have a greater effect on rapidly dividing cells than other cells. side effects, such as chemotherapy-induced alopecia and bone marrow transplantation.
In patients in complete remission, 35% to 65% still have central nervous system (CNS) involvement 2 years after treatment, so prophylactic cranial radiotherapy (PCI) is often required for patients in remission, but further studies on the neurotoxic effects of PCI are needed to confirm its benefits in terms of survival.
Treatment options
1. Combination chemotherapy and chest radiotherapy with one of the following regimens may be used
o EC: cisplatin + cisplatin + 4000-4500 cGy of chest radiotherapy
o ECV: pedialyte + cisplatin + vincristine + 4500 cGy of chest radiotherapy
Patients in complete remission should also be given prophylactic cranial radiotherapy (PCI) to prevent CNS metastases.
1. Combination chemotherapy (with or without PCI) in patients with impaired pulmonary function or poor outcome.
In highly selective cases, surgical resection (with or without PCI) after chemotherapy or chemotherapy plus chest radiotherapy.
New drug regimens, different doses, surgical resection of the primary tumor, new radiotherapy regimens and techniques, and timing of radiotherapy are being investigated, which also includes the application of immunotherapy for NSCLC and SCLC, for which there are no valid findings. High-dose chemotherapy using autologous bone marrow transplantation has been studied for many years, but has hardly demonstrated prolonged survival. As the understanding of the biological properties of small cell carcinoma gradually increases, new factors will be discovered and the role of autocrine growth factors and their receptors, interferons, etc. will be further investigated.
The poor survival of lung cancer patients and the need for new treatment options have led to the enrollment of a large number of patients in clinical trials and the use of unproven drugs. In clinical studies, special attention should be paid to the following issues: ethical considerations when using unproven drugs for treatment and the potential for increased patient suffering before recommending experimental treatments.
Diffuse stage SCLC
Chemotherapy regimens for patients with diffuse stage are similar to those used for patients with limited stage, and chest radiotherapy is rarely used due to extensive metastases.