Patients with advanced NSCLC should have molecular testing of their tumor. Patients whose tumors contain an actionable mutation should then receive a targeted therapy. For example, first-line therapy with erlotinib significantly improves outcomes in advanced NSCLC patients with sensitizing EGFR mutations, which include exon 19 deletions or exon 21 (L858R) substitution mutations. Afatinib is a small molecule inhibitor of EGFR, HER2, and HER4, and it is approved for the first-line treatment of metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 mutations. Osimertinib is approved for the treatment of metastatic EGFR T790M-mutant NSCLC following progression on or after EGFR TKI therapy. This small molecule is important as it is able to overcome the resistance that arises from the emergence of the T790M gatekeeper mutation either de novo or following previous EGFR TKI therapy. In NSCLC that is ALK-positive, three new small molecules have been developed: crizotinib, ceritinib, and alectinib. Crizotinib is the first-generation ALK inhibitor, while ceritinib and alectinib have clinical efficacy in patients whose disease has progressed on or who have become intolerant to crizotinib.
Squamous cell NSCLC makes up approximately 30% of NSCLC. This form of NSCLC is responsive to platinum-based chemotherapy with either cisplatin or carboplatin in combination with gemcitabine. Recent studies have shown superior clinical activity when cisplatin and gemcitabine are combined with the anti-EGFR antibody necitumumab when compared to the cisplatin-gemcitabine combination in the first-line treatment of metastatic disease. In 2015, the immune checkpoint inhibitor nivolumab was approved to treat metastatic squamous cell NSCLC whose cancer has progressed during or after standard platinum-based chemotherapy. This agent binds to the PD-1 receptor and inhibits the PD-1 immune signaling pathway, which then leads to activation and proliferation of T cells as well as inhibition of T-regulatory cells.
Small cell lung cancer is the most aggressive form of lung cancer. It is usually exquisitely sensitive, at least initially, to platinum-based combination regimens, including cisplatin and etoposide or cisplatin and irinotecan. Unfortunately, drug resistance eventually develops in nearly all patients with extensive disease. When diagnosed at an early stage, this disease is potentially curable using combined chemotherapy and radiation therapy. Topotecan is used as second-line monotherapy in patients who have failed a platinum-based regimen.
In the majority of patients, ovarian cancer remains occult and becomes symptomatic only after it has already metastasized to the peritoneal cavity. At this stage, it usually presents with malignant ascites. It is important to accurately stage this cancer with laparoscopy, ultrasound, and CT scanning. Patients with stage I disease appear to benefit from whole-abdomen radiotherapy and may receive additional benefit from combination chemotherapy with cisplatin and cyclophosphamide.
Combination chemotherapy is the standard approach to stage III and stage IV disease. Randomized clinical studies have shown that the combination of paclitaxel and cisplatin provides survival benefit compared with the previous standard combination of cisplatin plus cyclophosphamide. More recently, carboplatin plus paclitaxel has become the treatment of choice. In patients who present with recurrent disease, topotecan, altretamine, or liposomal doxorubicin are used as single-agent monotherapy.