A very large number of clinical trials have been conducted in "pure" SCLC over the past several decades. As a result, evidence-based sets of guidelines for treating monophasic SCLC are available. While the current set of SCLC treatment guidelines recommend that c-SCLC be treated in the same manner as "pure" SCLC, they also note that the evidence supporting their recommendation is quite weak. It is likely, then, that the optimum treatment for patients with c-SCLC remains unknown.

The current generally accepted standard of care for all forms of SCLC is concurrent chemotherapy (CT) and thoracic radiation therapy (TRT) in LD, and CT only in ED. For complete responders (patients in whom all evidence of disease disappears), prophylactic cranial irradiation (PCI) is also given. TRT serves to increase the probability of total eradication of residual locoregional disease, while PCI aims to eliminate any micrometastases to the brain.

Surgery is not often considered as a treatment option in SCLC (including c-SCLC) due to the high probability of distant metastases at the time of diagnosis. This paradigm was driven by early studies showing that the administration of systemic therapies resulted in improved survival as compared to patients undergoing surgical resection. Recent studies, however, have suggested that surgery for highly selected, very early-stage c-SCLC patients may indeed improve outcomes. Other experts recommend resection for residual masses of NSCLC components after complete local tumor response to chemotherapy and/or radiotherapy in c-SCLC.

Although other combinations of drugs have occasionally been shown to be noninferior at various endpoints and in some subgroups of patients, the combination of cisplatin or carboplatin plus etoposide or irinotecan are considered comparable first-line regimens for SCLC. For patients who do not respond to first line therapy, or who relapse after complete remission, topotecan is the only agent which has been definitively shown to offer increased survival over best supportive care (BSC), although in Japan amirubicin is considered effective as salvage therapy.

Importantly, c-SCLC is usually much more resistant to CT and RT than "pure" SCLC. While the mechanisms for this increased resistance of c-SCLC to conventional cytotoxic treatments highly active in "pure" SCLC remain mostly unknown, recent studies suggest that the earlier in its biological history that a c-SCLC is treated, the more likely it is to resemble "pure" SCLC in its response to CT and RT.

The prognosis of patients with FA as a whole is considered to be better than that of most other forms of non-small cell carcinoma, including biphasic pulmonary blastoma.

NSCLCs are usually "not" very sensitive to chemotherapy and/or radiation, so surgery remains the treatment of choice if patients are diagnosed at an early stage. If patients have small, but inoperable tumors, they may undergo highly targeted, high intensity radiation therapy. New methods of giving radiation treatment allow doctors to be more accurate in treating lung cancers. This means less radiation affects nearby healthy tissues. New methods include Cyberknife and stereotactic body radiation therapy(SBRT). Certain patients deemed to be higher risk may also receive adjuvant (ancillary) chemotherapy after initial surgery or radiation therapy. There are a number of possible chemotherapy agents which can be selected however most will involve the platinum-based chemotherapy drug called cisplatin.

Other treatments include percutaneous ablation and chemoembolization. The most widely used ablation techniques for lung cancer are radiofrequency ablation, cryoablation, and microwave ablation. Ablation may be an option for patients whose tumors are near the outer edge of the lungs. Nodules less than 1 cm from the trachea, main bronchi, oesophagus and central vessels should be excluded from RFA given high risk of complications and frequent incomplete ablation. Additionally, lesions greater than 5 cm should be excluded and lesions 3 to 5 cm should be considered with caution given high risk of recurrence. As a minimally invasive procedure, it can be a safer alternative for patients who are poor candidates for surgery due to co-morbidities or limited lung function. A study comparing thermal ablation to sublobar resection as treatment for early stage NSCLC in older patients found no difference in overall survival of the patients. It is possible that RFA followed by radiation therapy has a survival benefit due to synergysm of the two mechanisms of cell destruction.

Because LCLC-RP is so rare, no clinical trials have ever been conducted that specifically address treatment of this lung cancer variant. Because LCLC-RP is considered a form of non-small cell lung carcinoma (NSCLC), most physicians adhere to published NSCLC treatment guidelines in rhabdoid carcinoma cases. When possible, radical surgical resection with curative intent is the primary treatment of choice in early stage NSCLC's, and can be administered with or without adjuvant, neoadjuvant, or palliative chemotherapy and/or radiotherapy, depending on the disease stage and performance status of the individual patient.

In numerous clinical trials conducted in NSCLC, several different platinum-based chemotherapy regimens have been shown to be more-or-less equally effective. LCLC's, as a subtype of NSCLC, have traditionally been included in many of these clinical trials, and have been treated like other NSCLC's. More recent trials, however, have shown that some newer agents may have particular effectiveness in prolonging survival of LCLC patients. Pemetrexed, in particular, has shown significant reduction in the hazard ratio for death when used in patients with LCLC. Taxane-based (paclitaxel, docetaxel) chemotherapy was shown to induce a complete and sustained response in a liver metastasis in a case of LCC-RP. A later-appearing metastasis within mediastinal lymph nodes in the same case also showed a durable response to a taxane alone.

There have also been reports of rhabdoid carcinomas expressing vascular endothelial growth factor (VEGF), suggesting that targeted molecular therapy with VEGF blocking monoclonal antibodies such as bevacizumab may be active in these variants. However, evidence suggests that caution must be used when treating a cavitated rhabdoid tumor, one that contains significant components of squamous cell differentiation, or large tumors with containing major blood vessels, due to the potential high risk of life-threatening pulmonary hemorrhage.

A recent study reported a case wherein 2 courses of adjuvant therapy with cisplatin and paclitaxel, followed by oral gefitinib, were used after complete resection. The patient had had no recurrence 34 months later.

As large-volume LCLC-RP may show significant central necrosis and cavitation, prudence dictates that oncologists use extreme caution if contemplating the therapeutic use of bevacizumab, other anti-VEGF compounds, or anti-angiogenesis agents in general, which have been associated with a greatly increased risk of severe hemorrhage and hemoptysis that may be quickly fatal in cavatated pulmonary squamous cell carcinomas. Similar elevated risks have also been noted in tumors located near, or containing, large blood vessels.,

When BAC recurs after surgery, the recurrences are local in about three-quarters of cases, a rate higher than other forms of NSCLC, which tends to recur distantly.

In ES-SCLC, combination chemotherapy is the standard of care, with radiotherapy added only to palliate symptoms such as dyspnea, pain from liver or bone metastases, or for treatment of brain metastases, which, in small-cell lung carcinoma, typically have a rapid, if temporary, response to whole brain radiotherapy.

Combination chemotherapy consists of a wide variety of agents, including cisplatin, cyclophosphamide, vincristine and carboplatin. Response rates are high even in extensive disease, with between 15% and 30% of subjects having a complete response to combination chemotherapy, and the vast majority having at least some objective response. Responses in ES-SCLC are often of short duration, however.

If complete response to chemotherapy occurs in a subject with SCLC, then prophylactic cranial irradiation (PCI) is often used in an attempt to prevent the emergence of brain metastases. Although this treatment is often effective, it can cause hair loss and fatigue. Prospective randomized trials with almost two years follow-up have not shown neurocognitive ill-effects. Meta-analyses of randomized trials confirm that PCI provides significant survival benefits.

NSCLC patients with advanced disease who are not found to have either EGFR or ALK mutations may receive bevacizumab which is a monoclonal antibody medication targeted against the vascular endothelial growth factor (VEGF). This is based on an Eastern Cooperative Oncology Group study which found that adding bevacizumab to carboplatin and paclitaxel chemotherapy for certain patients with recurrent or advanced non-small-cell lung cancer (stage IIIB or IV) may increase both overall survival and progression free survival.

In 2015 the US FDA approved the anti-PD-1 agent nivolumab for advanced or metastatic squamous cell carcinoma.

October 2, 2015, the FDA approved pembrolizumab for the treatment of metastatic non-small cell lung cancer (NSCLC) in patients whose tumors express PD-L1 and who have failed treatment with other chemotherapeutic agents.

October 2016, pembrolizumab became the first immunotherapy to be used first line in the treatment of NSCLC if the cancer overexpresses PDL1 and the cancer has no mutations in EGFR or in ALK; if chemotherapy has already been administered, then pembrolizumab can be used as a second line treatment but if the cancer has EGFR or ALK mutations, agents targeting those mutations should be used first. Assessment of PDL1 must be conducted with a validated and approved companion diagnostic.

The treatment of choice in any patient with BAC is complete surgical resection, typically via lobectomy or pneumonectomy, with concurrent ipsilateral lymphadenectomy.

Non-mucinous BACs are highly associated with classical EGFR mutations, and thus are often responsive to targeted chemotherapy with erlotinib and gefitinib. K-ras mutations are rare in nm-BAC.

Mucinous BAC, in contrast, is much more highly associated with K-ras mutations and wild-type EGFR, and are thus usually insensitive to the EGFR tyrosine kinase inhibitors. In fact, there is some evidence that suggests that the administration of EGFR-pathway inhibitors to patients with K-ras mutated BACs may even be harmful.

Because of its rarity, there have been no randomized clinical trials of treatment of GCCL, and all information available derives from small retrospective institutional series or multicenter metadata.

Complete radical surgical resection is the treatment of choice for EMECL, and in most cases, results in long-term survival or cure.

In recent years, several new types of "molecularly targeted" agents have been developed and used to treat lung cancer. While a very large number of agents targeting various molecular pathways are being developed and tested, the main classes and agents that are now being used in lung cancer treatment include:

- Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs):

- Erlotinib (Tarceva)

- Gefitinib (Iressa)

- Cetuximab (Erbitux)

- Inhibitors of vascular endothelial growth factor (VEGF)

- Bevacizumab (Avastin)

- Inhibitors of folate metabolism

- Pemetrexed (Alimta)

To date, most clinical trials of targeted agents, alone and in combination with previously tested treatment regimens, have either been ineffective in SCLC or no more effective than standard platinum-based doublets. While there have been no randomized clinical trials of targeted agents in c-SCLC, some small case series suggest that some may be useful in c-SCLC. Many targeted agents appear more active in certain NSCLC variants. Given that c-SCLC contains components of NSCLC, and that the chemoradioresistance of NSCLC components impact the effectiveness of c-SCLC treatment, these agents may permit the design of more rational treatment regimens for c-SCLC.

EGFR-TKI's have been found to be active against variants exhibiting certain mutations in the EGFR gene. While EGFR mutations are very rare (<5%) in "pure" SCLC, they are considerably more common (about 15–20%) in c-SCLC, particularly in non-smoking females whose c-SCLC tumors contain an adenocarcinoma component. These patients are much more likely to have classical EGFR mutations in the small cell component of their tumors as well, and their tumors seem to be more likely to respond to treatment with EGFR-TKI's. EGFR-targeted agents appear particularly effective in papillary adenocarcinoma, non-mucinous bronchioloalveolar carcinoma, and adenocarcinoma with mixed subtypes.

The role of VEGF inhibition and bevacizumab in treating SCLC remains unknown. Some studies suggest it may, when combined with other agents, improve some measures of survival in SCLC patients and in some non-squamous cell variants of NSCLC.

Pemetrexed has been shown to improve survival in non-squamous cell NSCLC, and is the first drug to reveal differential survival benefit in large cell lung carcinoma.

Interestingly, c-SCLC appear to express female hormone (i.e. estrogen and/or progesterone) receptors in a high (50–67%) proportion of cases, similar to breast carcinomas. However, it is at present unknown whether blockade of these receptors affects the growth of c-SCLC.

All in all, small-cell carcinoma is very responsive to chemotherapy and radiotherapy, and in particular, regimens based on platinum-containing agents. However, most people with the disease relapse, and median survival remains low.

In "limited-stage" disease, median survival with treatment is 14–20 months, and about 20% of patients with limited-stage small-cell lung carcinoma live 5 years or longer. Because of its predisposition for early metastasis, the prognosis of SCLC is poor, with only 10% to 15% of patients surviving 3 years.

The prognosis is far more grim in "extensive-stage" small-cell lung carcinoma; with treatment, median survival is 8–13 months; only 1–5% of patients with extensive-stage small-cell lung carcinoma treated with chemotherapy live 5 years or longer.

Because of its extreme rarity, there have been no controlled clinical trials of treatment regimens for FA and, as a result, there are no evidence-based treatment guidelines. Complete surgical resection is the treatment of choice in FA, as it is in nearly all forms of lung cancer.

Anecdotal reports suggest that FA is rarely highly sensitive to cytotoxic drugs or radiation. Case reports suggest that chemotherapy with UFT may be useful in FA.

MCACL has a much more favorable prognosis than most other forms of adenocarcinoma and most other NSCLC's. Cases have been documented of continued growth of these lesions over a period of 10 years without symptoms or metastasis. The overall mortality rate appears to be somewhere in the vicinity of 18% to 27%, depending on the criteria that are used to define this entity.

Early stage disease is treated surgically. Targeted therapy is available for lung adenocarcinomas with certain mutations. Crizotinib is effective in tumors with fusions involving ALK or ROS1, whereas gefitinib, erlotinib, and afatinib are used in patients whose tumors have mutations in EGFR.

The true incidence, prevalence, and mortality of GCCL is generally unknown due to a lack of accurate cancer data on a national level. It is known to be a very rare tumor variant in all populations examined, however. In an American study of a database of over 60,000 lung cancers, GCCL comprised between 0.3% and 0.4% of primary pulmonary malignancies, with an age-adjusted incidence rate of about 3 new cases per million persons per year. With approximately 220,000 total lung cancers diagnosed in the US each year, the proportion suggests that approximately 660 and 880 new cases are diagnosed in Americans annually.

However, in a more recent series of 4,212 consecutive lung cancer cases, only one (0.024%) lesion was determined to be a "pure" giant-cell carcinoma after complete sectioning of all available tumor tissue. While some evidence suggests GCCL may have been considerably more common several decades ago, with one series identifying 3.4% of all lung carcinomas as giant-cell malignancies, it is possible that this number reflect

Most published case series and reports on giant cell-containing lung cancers show that they are diagnosed much more frequently in men than they are in women, with some studies showing extremely high male-to-female ratios (12:1 or more). In a study of over 150,000 lung cancer victims in the US, however, the gender ratio was just over 2:1, with women actually having a higher relative proportion of giant-cell cancers (0.4%) than men (0.3%).

Giant-cell carcinomas have been reported to be diagnosed in a significantly younger population than all non-small-cell carcinomas considered as a group. Like nearly all lung carcinomas, however, GCCs are exceedingly rare in very young people: in the US SEER program, only 2 cases were recorded to occur in persons younger than 30 years of age between 1983 and 1987. The average age at diagnosis of these tumors has been estimated at 60 years.

The vast majority of individuals with GCCL are heavy smokers.

Although the definitions of "central" and "peripheral" can vary between studies, GCCL are consistently diagnosed much more frequently in the lung periphery. In a review of literature compiled by Kallenburg and co-workers, less than 30% of GCCLs arose in the hilum or other parts of the "central" pulmonary tree.

A significant predilection for genesis of GCCL in the upper lobes of victims has also been postulated.

Although reliable and comprehensive incidence statistics are nonexistent, LCLC-RP is a rare tumor, with only a few hundred cases described in the scientific literature to date. LCLC's made up about 10% of lung cancers in most historical series, equating to approximately 22,000 cases per year in the U.S. Of these LCLC cases, it is estimated that about 1% will eventually develop the rhabdoid phenotype during tumor evolution and progression. In one large series of 902 surgically resected lung cancers, only 3 cases (0.3%) were diagnosed as LCLC-RP. In another highly selected series of large-cell lung carcinoma cases, only 4 of 45 tumors (9%) were diagnosed as the rhabdoid phenotype using the 10% criterion, but another 10 (22%) had at least some rhabdoid cell formation. It appears likely, therefore, that LCLC-RP probably comprises between 0.1% and 1.0% of all lung malignancies.

Similar to nearly all variants of lung carcinoma, large cell lung carcinoma with rhabdoid phenotype appears to be highly related to tobacco smoking. It also appears to be significantly more common in males than in females.

For treatment purposes, MCACL has been traditionally considered a non-small cell lung carcinoma (NSCLC). Complete radical surgical resection is the treatment of choice.

There is virtually no data regarding new molecular targets or targeted therapy in the literature to date. Iwasaki and co-workers failed to find mutations of the epidermal growth factor receptor (EGFR) or the cellular Kirsten rat sarcoma virus oncogene "K-ras" in one reported case.

The prognosis of EMECL is relatively good, and considerably better than most other forms of NSCLC. The skull and dura are possible sites for metastasis from pulmonary EMC. The MIB-1 index is a predictive marker of malignant potential.

In most series, LCLC's comprise between 5% and 10% of all lung cancers.

According to the Nurses' Health Study, the risk of large cell lung carcinoma increases with a previous history of tobacco smoking, with a previous smoking duration of 30 to 40 years giving a relative risk of approximately 2.3 compared to never-smokers, and a duration of more than 40 years giving a relative risk of approximately 3.6.

Another study concluded that cigarette smoking is the predominant cause of large cell lung cancer. It estimated that the odds ratio associated with smoking two or more packs/day for current smokers is 37.0 in men and 72.9 in women.

This type of cancer occurs most often in Caucasians between 60 and 80 years of age, and its rate of incidence is about twice as high in males as in females. There are roughly 1,500 new cases of MCC diagnosed each year in the United States, as compared to around 60,000 new cases of melanoma and over 1 million new cases of nonmelanoma skin cancer. MCC is sometimes mistaken for other histological types of cancer, including basal cell carcinoma, squamous cell carcinoma, malignant melanoma, lymphoma, and small cell carcinoma, or as a benign cyst. Researchers believe that exposure to sunlight or ultraviolet light (such as in a tanning bed) may increase the risk of developing this disease. Similar to melanoma, the incidence of MCC in the US is increasing rapidly.

Immunosuppression can profoundly increase the odds of developing Merkel-cell carcinoma. Merkel-cell carcinoma occurs 30 times more often in people with chronic lymphocytic leukemia and 13.4 times more often in people with advanced HIV as compared to the general population; solid organ transplant recipients have a 10-fold increased risk compared to the general population.

Current research directions for lung cancer treatment include immunotherapy, which encourages the body's immune system to attack the tumor cells, epigenetics, and new combinations of chemotherapy and radiotherapy, both on their own and together. Many of these new treatments work through immune checkpoint blockade, disrupting cancer's ability to evade the immune system.

Ipilimumab blocks signaling through a receptor on T cells known as CTLA-4 which dampens down the immune system. It has been approved by the U.S. Food and Drug Administration (FDA) for treatment of melanoma and is undergoing clinical trials for both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

Other immunotherapy treatments interfere with the binding of programmed cell death 1 (PD-1) protein with its ligand PD-1 ligand 1 (PD-L1), and have been approved as first- and subsequent-line treatments for various subsets of lung cancers. Signaling through PD-1 inactivates T cells. Some cancer cells appear to exploit this by expressing PD-L1 in order to switch off T cells that might recognise them as a threat. Monoclonal antibodies targeting both PD-1 and PD-L1, such as pembrolizumab, nivolumab, atezolizumab, and durvalumab are currently in clinical trials for treatment for lung cancer.

Epigenetics is the study of small, usually heritable, molecular modifications—or "tags"—that bind DNA and modify gene expression levels. Targeting these tags with drugs can kill cancer cells. Early-stage research in NSCLC using drugs aimed at epigenetic modifications shows that blocking more than one of these tags can kill cancer cells with fewer side effects. Studies also show that giving patients these drugs before standard treatment can improve its effectiveness. Clinical trials are underway to evaluate how well these drugs kill lung cancer cells in humans. Several drugs that target epigenetic mechanisms are in development. Histone deacetylase inhibitors in development include valproic acid, vorinostat, belinostat, panobinostat, entinostat, and romidepsin. DNA methyltransferase inhibitors in development include decitabine, azacytidine, and hydralazine.

The TRACERx project is looking at how NSCLC develops and evolves, and how these tumors become resistant to treatment. The project will look at tumor samples from 850 NSCLC patients at various stages including diagnosis, after first treatment, post-treatment, and relapse. By studying samples at different points of tumor development, the researchers hope to identify the changes that drive tumor growth and resistance to treatment. The results of this project will help scientists and doctors gain a better understanding of NSCLC and potentially lead to the development of new treatments for the disease.

For lung cancer cases that develop resistance to epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors, new drugs are in development. New EGFR inhibitors include afatinib and dacomitinib. An alternative signaling pathway, c-Met, can be inhibited by tivantinib and onartuzumab. New ALK inhibitors include crizotinib and ceritinib.

Three membrane associated tyrosine kinase receptors are recurrently involved in rearrangements in adenocarcinomas: ALK, ROS1, and RET, and more than eighty other translocations have also been reported in adenocarcinomas of the lung.

Targeted therapies: ALK and ROS1 fusions proteins are both sensitive to treatment with the new ALK tyrosine kinase inhibitors (see the Atlas of Genetics and Cytogenetics in Oncology and Haematology,).

Radiotherapy is commonly used to treat Merkel-cell cancers. The radiotherapy fields used are usually very large so as to cover sufficient areas of skin. This is necessary because of MCC's aggressive local and regional metastatic behavior.

Adjuvant radiotherapy has been shown to be effective in reducing the rates of recurrence and in increasing the survival of patients with MCC. Patients who present with no distant metastases and a negative sentinel lymph node biopsy have a very good prognosis when treated with both surgery and radiotherapy (approximately 90% survival rate at five years).

Metastatic MCC may respond to treatment with chemotherapy and/or radiation, but current multimodal therapies are usually not curative. Intensive treatment can be effective in shrinking the tumor and improving operability when tumors are too large to be removed or located in a place where removal would be difficult or dangerous, or in palliation of signs and symptoms caused by metastatic tumors.

a) Surgical resection is mainstay of treatment, whenever possible. If tumor is completely removed, post-operative radiation therapy is typically not needed since acinic cell is considered a low-grade histology. Post-operative radiation therapy for acinic cell carcinoma is used if: 1) margins are positive, 2) incomplete resection, 3) tumor invades beyond gland, 4) positive lymph nodes.

b) Neutron beam radiation

c) Conventional radiation

d) Chemotherapy