1. بنام خداوند جان و خرد

2. فوق تخصص هماتولوژی_ انکولوزژی
Systemic therapy in
lung cancer
دکتر زهرا مذهب
فوق تخصص هماتولوژی_ انکولوزژی

4.  Treatment of patients with lung cancer depends upon :
The tumor stage,
Histology (NSCLC versus small cell lung cancer, nonsquamous versus squamous lung cancer)
Molecular characteristics
An assessment of the patient's overall medical condition
Patient age
Tumor/metastatic location
May allow for more personalized treatment.

5. Systemic therapy is the standard approach for patients with advanced NSCLC, either at presentation or in patients with a recurrence after definitive therapy.
Molecular characterization of tumor — Therapy of advanced NSCLC should be individualized based upon the molecular features of the tumor.
Whenever possible, tumor tissue should be assessed for the presence of a somatic driver mutation (eg, mutated EGFR, ALK fusion oncogene, ROS1 which confers sensitivity to a specific inhibitor.
If no driver mutation is present, cytotoxic chemotherapy forms the backbone of therapy.
For those patients with a driver mutation, use of a specific inhibitor is indicated either as the initial or as therapy when progressive disease develops.

6. In some instances, adequate tissue may not be available for genotype testing or systemic treatment may be required before the results are available.
In this situation, systemic therapy is based upon the assumption that no driver mutation is present. When the results of molecular profiling become available, the treatment plan should be reassessed.
Even if a driver mutation is identified once chemotherapy has been started, we suggest continuing chemotherapy for four cycles as long as therapy is tolerated and there is no evidence of disease progression. Patients can then be switched to targeted therapy based upon the results of molecular studies.

7. Effect of histology 
Histology provides insight into the optimal agents to combine with a platinum compound.
Regimens containing pemetrexed are more effective in patients with adenocarcinoma and less effective than combinations without pemetrexed in patients with squamous cell carcinoma.
In addition, bevacizumab is often combined with the initial chemotherapy regimen for patients with nonsquamous histology.
For patients with squamous histology, there has been less progress in identifying driver mutations, but targeting the EGFR pathway may offer some benefit in combination with chemotherapy.

8. The impact of histology on the results with platinum based chemotherapy was illustrated by a phase III trial in which cisplatin plus pemetrexed was compared with cisplatin plus gemcitabine as initial therapy .
Survival in the 847 patients with adenocarcinoma was significantly prolonged with cisplatin plus pemetrexed compared with cisplatin plus gemcitabine (median versus 10.9 months).
Conversely, cisplatin plus gemcitabine was superior to cisplatin plus pemetrexed in the 473 patients with squamous cell carcinoma (median 10.8 versus 9.4 months).

9. Patient specific factors
The patient’s age, performance status, co- morbidities, and concerns and preferences regarding treatment all need to be integrated into the initial treatment approach.
In particular, elderly patients and those with a poor performance status may not tolerate treatment as well as younger patients with a good performance status and may not derive the same benefit from aggressive treatment.

10. APPROACH TO TREATMENT
For patients whose tumors do not contain a driver mutation or when information regarding the mutation status is unknown, combination therapy using a platinum based doublet is generally recommended.
Cytotoxic chemotherapy is generally limited to four to six cycles. For patients with non-squamous NSCLC, initial treatment also typically includes bevacizumab.

11.  'Maintenance therapy'
For patients who have an objective response following the initial cycles of platinum based chemotherapy, maintenance therapy is generally continued following the initial treatment.
Options include :
single agent chemotherapy,
bevacizumab,
or targeted therapy with an EGFR tyrosine kinase inhibitor.
An alternative approach might be close observation with initiation of second-line therapy at the earliest sign of progression for selected patients who are well informed about the risks and benefits of such an approach. 

12. INITIAL REGIMEN
Combination chemotherapy regimens using a platinum compound (cisplatin, carboplatin) plus a second active cytotoxic agent, potentially in combination with bevacizumab, are preferred as the initial treatment for younger patients with advanced non-small cell lung cancer (NSCLC) and a good performance status (PS).
Patients without progression after four to six cycles of treatment may benefit from continuation of treatment (maintenance) with a single agent (chemotherapy, biologic, targeted).
Multiple cytotoxic agents in addition to cisplatin and carboplatin have antitumor activity. These include pemetrexed, taxanes (docetaxel, paclitaxel, nanoparticle albumin bound paclitaxel), gemcitabine, vinorelbine, and camptothecins (irinotecan, topotecan).

13. Systemic therapy for advanced non-small cell lung cancer in elderly patients and patients with a poor performance status
For elderly or borderline performance status patients (ECOG PS) whose tumor does not contain an EGFR mutation or the ALK fusion oncogene and who are candidates for systemic therapy, we recommend cytotoxic chemotherapy.
General approach is to use a carboplatin-based doublet if the treating physician thinks that the doublet therapy will be tolerated. Single agent chemotherapy may be an alternative for patients who cannot tolerate combination chemotherapy.
For maintenance therapy in elderly, recommend approach is to treat these patients the same as younger or good performance status patients if they have an objective response or stable disease to their initial treatment regimen.
For elderly patients or poor performance status whose tumor contains an EGFR mutation, it is recommended to treat with an EGFR tyrosine kinase inhibitor (TKI) rather than chemotherapy.

14. prognosis
Systemic chemotherapy improved overall survival using a platinum- based regimen compared with best supportive care in multiple clinical trials. Despite the potential toxicities associated with chemotherapy, this can generally be achieved without impairing quality of life.
A systematic review of the literature and meta-analysis incorporated individual patient data from 2714 cases enrolled on 16 randomized trials. Chemotherapy was associated with an improved survival (one- year survival rate 29 versus 20%). This survival benefit was independent of histology, performance status, and age.
However, subsequent trials have shown that additional survival benefits may be derived from the addition of biologic agents such as bevacizumab with the chemotherapy, or from the use of single agent chemotherapy as maintenance therapy after the initial platinum doublet chemotherapy. In addition, better results have been observed with targeted agents in patients with a driver mutation.

15. MANAGEMENT OF SPECIFIC METASTATIC SITES
Occasional patients will present initially with an isolated metastasis combined with a potentially resectable primary tumor, or with a recurrence at a single site. In this situation, surgical resection or definitive radiation therapy (RT) of the metastatic disease may produce durable benefit.
The most frequent sites of such metastases are the brain, bone and the adrenal gland.

16. Bone metastases
  Bone metastases are a frequent complication in patients with metastatic NSCLC and can impair quality of life.
In addition to systemic therapy, treatment may include RT for localized painful lesions or surgical intervention to treat or prevent pathologic fractures.
Osteoclast inhibition with denosumab or zoledronic acid is recommended for patients with bone metastases to prevent skeletal-related complications.

17. Central nervous system metastases
 Brain metastases are a frequent complication in patients with metastatic NSCLC. The management of patients with brain metastases may include surgical resection, RT, or systemic therapy.
Leptomeningeal carcinomatosis from NSCLC is associated with a particularly poor prognosis, with a median survival of approximately three months.
Standard treatment with whole brain RT and/or intrathecal chemotherapy does not appear to have a significant effect on survival. There is anecdotal evidence that treatment with EGFR inhibitors may be beneficial in patients whose tumors contain an EGFR mutation.

18. SYMPTOM PALLIATION
 Short courses of radiation therapy (RT) are useful for patients who require palliation of symptoms (eg, dyspnea due to airway obstruction, dysphagia, or hemoptysis), either as part of their initial management or after other treatment has failed.

20. Extensive stage small cell lung cancer: Initial management
Small cell lung cancer (SCLC) is a neuroendocrine tumor that represents about 15 percent of all lung cancers. SCLC occurs predominantly in smokers.
SCLC is distinguished clinically from most types of non- small cell lung cancer (NSCLC) by its rapid doubling time, high growth fraction, and the early development of metastases.
Large cell neuroendocrine carcinoma, a rare form of lung cancer, and extrapulmonary small cell carcinomas are generally treated with the same chemotherapy regimens used for SCLC.

21. Extensive stage disease
 The majority of patients with SCLC have extensive stage disease, with tumor that includes distant metastases, malignant pericardial or pleural effusions, and/or contralateral supraclavicular or contralateral hilar lymph node involvement.
In this setting, the primary therapeutic modality is systemic chemotherapy.
For patients who respond well to initial systemic therapy, RT may provide additional benefit.
Prophylactic cranial irradiation decreases the incidence of symptomatic brain metastases in patients who have responded to systemic chemotherapy, although its impact on overall survival is uncertain.
For patients with a response to systemic chemotherapy, thoracic radiation may be of benefit in increasing the percentage of long-term survivors.

22. SCLC is highly responsive to multiple chemotherapeutic drugs, and chemotherapy dramatically prolongs survival compared with best supportive care.
From the time of original diagnosis, the median survival for patients with ES-SCLC is about 8 to 13 months. In most series, less than 5 percent of those with ES-SCLC survive beyond two years.

23. CHEMOTHERAPY
Active agents — Multiple chemotherapeutic agents have significant activity against SCLC either in the first or second line setting.
These agents include:
Platinum compounds (cisplatin, carboplatin)
Podophyllotoxins (etoposide, teniposide)
Camptothecins (irinotecan, topotecan)
Alkylating agents (ifosfamide, cyclophosphamide)
Anthracyclines (doxorubicin, epirubicin, amrubicin)
Taxanes (paclitaxel, docetaxel)
Vinca alkaloids (vincristine, vinorelbine)
Platinum-based combinations are generally preferred based upon efficacy and toxicity profiles.

24. Platinum-based combinations are generally preferred based upon efficacy and toxicity profiles.
The most frequently used combinations are cisplatin plus etoposide (PE) or carboplatin plus etoposide (CE), based upon their clinical activity and toxicity profile.
Because both cisplatin and etoposide possess little mucosal toxicity, limited risk for interstitial pneumonitis, and modest hematologic toxicity, PE is the regimen of choice to use with concurrent chest RT in patients with limited stage SCLC.
Most clinicians in the United States use carboplatin plus etoposide to treat patients with ES-SCLC based upon its better toxicity profile, while cisplatin plus etoposide is preferred for those with LS-SCLC because of the possibility of a higher response rate
Efforts to improve on the results with PE have substituted carboplatin for cisplatin or replaced etoposide with a camptothecin analogue (irinotecan or topotecan) or epirubicin.

25. Initial therapy is usually limited to four to six cycle of induction chemotherapy.
The use of maintenance chemotherapy, three- or four-drug combinations, and alternating or sequential non-cross-resistant regimens have not been shown to offer substantial benefits compared with a two- drug combination; thus, these approaches are not routinely utilized.

28.  Traditionally, a good offer to this patient is chemotherapy, maybe chemotherapy plus some antiangiogenic therapy.
More recently, anti-PD-1 agents, in particular nivolumab and pembrolizumab are recommended.
Particularly, there is a better chance of having even longer-term survival, particularly 2- or 3-year survival with immunotherapy compared with chemotherapy.
We still do not know how long survival is going to be because the data are still immature from those various trials. Also important for patients is that the toxicities with immunotherapies are more tolerable compared with those with chemotherapy.
Immunotherapy would be my favorite option for this particular patient. Of course, we should inform the patient and discuss the different possibilities, not only when they first present at diagnosis but also at the time of this progression and so on.

36. Thank you