New patients with limited-stage small cell lung cancer (SCLC) are always tough to treat. It's an aggressive cancer, with studies showing that our best therapy with concurrent cisplatin-etoposide and thoracic radiation still yield a five-year survival rate of only about 20 to 26 percent. Major advances in clinical outcomes remain slow, despite significant efforts by trial investigators.
SCLC is identified by positive immunohistochemistry staining for chromagranin, synaptophysin, and CD56, and on occasion may be positive for neuron-specific enolase and keratin. Although several genetic mutations have been identified in SCLC, none have been developed into validated predictive or prognostic biomarkers, and therefore are not incorporated into diagnostic evaluations.
Staging for SCLC is extremely critical. Approximately one third of SCLC patients will have limited-stage disease on initial presentation. The definition of limited-stage disease is evidence of disease confined to a single hemithorax that can be encompassed within a single tolerable radiation port, excluding the presence of pleural or pericardial effusion.
The staging workup for SCLC patients needs to be extensive, as roughly 30 percent of patients with brain metastases will be asymptomatic. Approximately 5% of patients are upstaged to extensive disease with bone marrow findings of disease involvement. I usually perform a PET-CT scan, brain MRI, and laboratory studies (including calcium, alkaline phosphatase).
I highly recommend initiating therapy within seven to 10 days of diagnosing the patient as these patients can develop disease progression and/or symptoms with debilitation quickly. In general, if the patient has extremely bulky limited-stage disease, I usually proceed with neoadjuvant chemotherapy first and bring in the radiation therapy by cycle 2 of treatment.
In the rare instance where a patient whose tumor is initially resected and presumed to be NSCLC is found incidentally to have SCLC, adjuvant chemotherapy with four cycles of cisplatin-etoposide is recommended.
Chemotherapy in Limited-Stage SCLC Disease
The recommended chemotherapy treatment plan for limited-stage SCLC consists of a platinum-etoposide regimen. A prior meta-analysis of 13 randomized trials found that combined modality therapies conferred better survival benefits than chemotherapy alone.
There have subsequently been extensive studies conducted to determine which chemotherapy regimen is optimal to be given concurrently with radiation. Originally, in the 1970s, the cyclophosphamide-doxorubicin-vincristine (CAV) regimen was the established standard treatment. This evolved in the mid-1980s to establishing that platinum-etoposide regimens had a complete response rate of 40% and a median survival time of 14 months.
Platinum-etoposide also appeared to be more tolerable with concurrent thoracic radiation as it is a relatively non-myelosuppressive regimen and is less aggressive on the mucosa compared with older regimens. Since then, no other regimens have shown superiority over platinum-etoposide given concurrent with radiotherapy for limited-stage SCLC patients; and the addition of supplemental chemotherapy agents has not led to improvements in survival outcomes.
The current recommended chemotherapy dosing to be administered concurrent with thoracic radiotherapy is cisplatin 60 mg/m2 day 1 and etoposide 120 mg/m2 on days 1–3. If the patients cannot tolerate this regimen, then carboplatin AUC 5 or 6 day 1 and etoposide 100 mg/m2 on days 1–3 is recommended. Alternatively, when giving cisplatin-etoposide as neoadjuvant (not during concurrent thoracic radiation) the dosing of cisplatin at 80 mg/m2 on day 1 and etoposide 100 mg/m2 on days 1–3 can be done. No growth factors are recommended or advisable during administration of concurrent chemotherapy and radiation.
Thoracic radiation should be delivered as either 1.5 Gy BID to 45 Gy or 2 Gy once daily to 60 to 70 Gy. XRT should be started during cycle 1 or 2 of chemo.
Radiation target volumes are defined by pretreatment PET-CT scans. Usually 3-D conformal or IMRT is recommended. Normal tissue restraints are advised to follow the CALGB 30610/RTOG 0538 protocol: If BID accelerated hyperfractionation (i.e., 45 Gy/30 BID treatments), maximum spinal cord dose is limited to 41 Gy (including scatter irradiation).
If once daily irradiation is used, the maximum spinal cord dose needs to be 50 Gy (including scatter irradiation). The volume of both lungs that receive 20 Gy (V20) needs to be less than 40% or the mean dose to the total lung volume should be 20 Gy.
For the esophagus, the mean dose should be less than 34 Gy, and the exposure to the heart should have less than one third of the organ affected with 60 Gy and less than two thirds affected for 45 Gy.
Prophylactic Cranial Irradiation (PCI)
If the patient's cancer demonstrates a complete response or if there is just radiation scarring on the chest images, prophylactic cranial radiation is strongly recommended in limited-stage SCLC. PCI is proven to be effective in decreasing the rate of brain metastasis in SCLC and increasing the overall survival rate five to six percent at three years.
In patients whose limited-stage cancer has only a partial response, PCI is not recommended. PCI should be administered as 25 Gy in 10 fractions or 30 Gy in 15 fractions. This is different than in extensive-stage SCLC patients who receive a complete response to systemic therapy; these patients are recommended to receive 20 Gy in five fractions.
Current recommendations for patients definitively treated for limited-stage SCLC should continue with follow-up physical exams and radiographic imaging every two to three months for the first several years.
I usually perform chest to adrenal CT scans every three months for two years. During surveillance, if a new pulmonary nodule arises after two years, it should be assessed as it may be a possible second primary tumor versus recurrent disease.
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