includes management of lung cancer, mainly based on harrison's 20th edition

1. Management of lung cancer:
recent advances
Dr Laxmi Raj Bhatta
Resident,Internal Medicine
KMCTH

2. Staging Lung Cancer
• Anatomic Staging : the location of the tumor and
possible metastatic sites
• Physiologic Staging : assessment of a patient's
ability to withstand various antitumor treatments
• The most significant dividing line is between
those patients who are candidates for surgical
resection and those who are inoperable but will
benefit from chemotherapy, radiation therapy, or
both.

3. • Non-small cell lung cancer.(NSCLC)- TNM
classification.
• Small cell lung cancer has often metastasized
at the time of diagnosis.TNM staging is not
suited to small cell lung cancer.
• Small cell lung cancer(SCLC) : limited and
extensive stage disease.

4. Staging Of NSCLC

10. • All patients with NSCLC should undergo initial radiographic
imaging with CT scan, positron emission tomography (PET), or
preferably CT-PET.
• PET scanning attempts to identify sites of malignancy based
on glucose metabolism by measuring the uptake of
fluorodeoxyglucose F18.
• Rapidly dividing cells, presumably in the lung tumors (primary
or metastatic) will preferentially take up 18F-FDG and appear
as a "hot spot."
• False negatives : diabetes
lesions <8 mm
slow-growing tumors
concurrent infections such as tuberculosis.
• False positives : infections
granulomatous disease.

11. One of three pulmonary nodules demonstrates marked FDG uptake.

12. • Combined 18F-FDG PET-CT imaging has been
shown to improve the accuracy of staging in
NSCLC compared to visual correlation of PET
and CT or either study alone.
• CT-PET has been found to be superior in
identifying pathologically enlarged mediastinal
lymph nodes and extrathoracic metastases.
• For brain metastases, MRI is the most
effective method.

13. Major contraindications to potential
curative resection in NSCLC
– Extrathoracic metastases
– Superior vena cava syndrome
– Vocal cord and phrenic nerve paralysis
– Malignant pleural effusion
– Cardiac tamponade
– Tumor within 2 cm of the carina
– Metastasis to the contralateral lung
– Metastases to supraclavicular lymph nodes
– Contralateral mediastinal node metastases
– Involvement of the main pulmonary artery.

14. The Staging System for Small Cell Lung
Cancer
• Limited-stage disease (LD) have cancer that is confined to the
ipsilateral hemithorax and can be encompassed within a tolerable
radiation port. Thus, contralateral supraclavicular nodes, recurrent
laryngeal nerve involvement, and superior vena caval obstruction can all
be part of limited-stage disease.
• Extensive-stage disease (ED) have overt metastatic disease by
imaging or physical examination. Cardiac tamponade, malignant pleural
effusion, and bilateral pulmonary parenchymal involvement generally
qualify disease as extensive-stage, because the involved organs cannot be
encompassed safely or effectively within a single radiation therapy port.
• 60 to 70% of patients are diagnosed with extensive disease at
presentation.

15. Physiologic staging
• Pneumonectomy : FEV1 (forced expiratory volume in 1 s) of greater than 2 L or greater
than 80% of predicted
• Lobectomy. : FEV1 greater than 1.5 L
• Wedge or anatomic segmental resection : unable to tolerate lobectomy or
pneumonectomy from a pulmonary functional standpoint
• Cardiopulmonary exercise testing- In patients with borderline lung function but a
resectable tumor,. This test allows an estimate of the maximal oxygen consumption (Vo2max).
A Vo2max <15 mL/(kg·min) predicts for a higher risk of postoperative complications.
• A myocardial infarction within the past 3 months is a contraindication to thoracic surgery
because 20% of patients will die of reinfarction.
• An infarction in the past 6 months is a relative contraindication.
• Other major contraindications
– uncontrolled arrhythmias,
– an FEV1 of less than 1 L, CO2 retention (resting PCO2 >45 mmHg),
– DLCO <40%,
– severe pulmonary hypertension.

17. Management of Stages I and II NSCLC
• A clinical trial in patients with stage IA NSCLC found that lobectomy
was superior to wedge resection in reducing the rate of local
recurrence and overall survival.
• A limited resection, wedge resection, and segmentectomy
[potentially by video-assisted thoracic surgery (VATS)] may be more
appropriate in patients with comorbidities, including compromised
pulmonary reserve and small peripheral lesions.
• Pneumonectomy is reserved for patients with very central tumors
and excellent pulmonary reserve.
• The 5-year survival rates are 60–80% for patients with stage I
NSCLC and 40–50% for patients with stage II NSCLC

18. Radiation Therapy in Stages I and II
NSCLC
• There is currently no role for adjuvant radiation
therapy in patients following resection of stage I or II
NSCLC.
• Patients with stage I or II disease who refuse or are not
candidates for pulmonary resection.
• 5-year survival rates of 13–39% in patients with stage I
or II NSCLC treated with radical radiotherapy.

19. Chemotherapy in Stages I and II NSCLC
• Harmful effect of chemotherapy in patients with stage IA
disease, with questionable benefit in patients with stage IB
disease.
• Recommendation for adjuvant chemotherapy only in
patients with stage II or III NSCLC.
• Chemotherapy should start 6 to 8 weeks after surgery, if
the patient has recovered, and should be administered for
four cycles.
• The effect of cisplatin plus vinorelbine appeared marginally
better than other cisplatin-based doublet regimens

20. Recurrence and Screening
• All patients with resected NSCLC are at high risk
of recurrence or developing a second primary
lung cancer.
• Given that the majority of patients recur within
the first 2 years after therapy, CECT every 6
months for the first 2 years after surgery,
followed by yearly CT scans of the chest without
contrast thereafter.

21. Complications
– Febrile neutropenia or bleeding may result from
bone marrow suppression.
– Hyponatremia or hypomagnesemia may result
from cisplatin nephrotoxicity.
– Renal failure or ototoxicity may result from
cisplatin.
– Peripheral neuropathy may result from cisplatin,
paclitaxel, and vinorel

22. Management of Stage III NSCLC
• Surgery followed by adjuvant chemotherapy is the treatment of choice for
patients with stage IIIA disease due to hilar nodal involvement (T3N1).
• Surgery for N2 disease is more controversial.
A randomized phase III trial demonstrated an improvement in progression-
free survival but no improvement in overall survival when patients with
pathologically staged N2 NSCLC were treated with concurrent
chemoradiotherapy (cisplatin and etoposide) and 45 Gy of radiation
followed by surgery compared to chemotherapy and 61 Gy of radiotherapy
without surgery.
• Treatment-related mortality rate greater in the surgery arm (8% vs 2%)
• Chemotherapy plus radiation therapy is the treatment of choice for
patients with N3 nodal involvement or bulky stage IIIA disease.

23. Treatment of Metastatic Non-Small
Cell Lung Cancer
• The judicious use of pain medications, and the
appropriate use of radiotherapy and
chemotherapy form the cornerstone of
management.
• Chemotherapy in patients with stage IV NSCLC
– palliates symptoms
– improves the quality of life
– improves survival.

24. • Standard medical management, the judicious use of
pain medications, and the appropriate use of
radiotherapy and systemic therapy—which may
compromise of traditional cytotoxic chemotherapy,
targeted therapy, and immunotherapy depending on
the specific diagnosis and molecular subtype—form
the cornerstone of management.
• Systemic therapy palliates symptoms, improves the
quality of life, and improves survival in patients with
stage advanced NSCLC, particularly in patients with
good performance status.

25. First-Line Chemotherapy for Metastatic or
Recurrent Non-Small Cell Lung Cancer
• The first indication of the benefit of chemotherapy in
patients with advanced NSCLC came from a meta-
analysis published in 1995 that reported a survival
advantage in patients treated with cisplatin-based
chemotherapy compared to those receiving supportive
care alone (HR = 0.73, p < .0001).
• Several different platinum “doublet” regimens have
been used—combining platinum (cisplatin or
carboplatin) with another type of chemotherapy (for
example, paclitaxel, docetaxel, pemetrexed,
gemcitabine, or vinorelbine).

27. Second line therapy
• At present only three drugs are FDA-approved
for second-line therapy of NSCLC in the United
States, i.e., docetaxel, pemetrexed, and
erlotinib.
• Hematologic toxicity including febrile
neutropenia is greater for docetaxel compared
with pemetrexed and erlotinib, whereas
nonhematologic toxicity, namely rash and
diarrhea, is greater with erlotinib.

28. • Ramucirumab is a recombinant human IgG1
monoclonal antibody that targets VEGFR-2.
• A phase III trial demonstrated a significant
improvement in progression-free survival and
overall survival when ramucirumab was
combined with docetaxel as second-line therapy
in patients who had progressed on platinum-
based chemotherapy

29. Maintenance Therapy for Metastatic
NSCLC
• Maintenance chemotherapy in nonprogressing patients
(patients with a complete response, partial response, or
stable disease) is divided into two types of maintenance
strategies:
• (1) switch maintenance therapy, where patients receive
four to six cycles of platinum-based chemotherapy and are
switched to an entirely different regimen; and
• (2) continuation maintenance therapy, where patients
receive four to six cycles of platinum-based chemotherapy
and then the platinum agent is discontinued but the agent
it is paired with is continued

31. Agents that Inhibit Angiogenesis
• Bevacizumab was the first antiangiogenic
agent approved for the treatment of patients
with advanced NSCLC in the United States.
• This drug primarily acts by sponging up VEGF
and blocking the growth of new blood vessels,
which are required for tumor viability.

32. • Bevacizumab, a monoclonal antibody against VEGF, has
been shown to improve response rate, progression-
free survival, and overall survival in patients with
advanced disease when combined with chemotherapy.
• Maintenance erlotinib is only approved in patients with
EGFR mutations (see below). It should be noted that
there are no approved maintenance regimens for
patients with squamous cell histology.

33. • Currently, carboplatin/ paclitaxel and
bevacizumab or carboplatin/pemetrexed and
bevacizumab are appropriate regimens for first-
line treatment for stage IV nonsquamous NSCLC
patients followed by maintenance bevacizumab
or maintenance pemetrexed/bevacizumab
respectively.
• Currently, maintenance pemetrexed following
platinum-based chemotherapy in patients with
advanced NSCLC is also approved by the U.S. FDA.

34. Immunotherapy
• Several large randomized phase III trials demonstrated
superior overall survival for both the anti-PD1
antibodies, nivolumab and pembrolizumab and the
anti-PD-L1 antibody atezolizumab compared to second-
line docetaxel in patients with NSCLC who have
progressed on platinum-based chemotherapy.
• Pembrolizumab is approved as first-line therapy in
patients with tumors that are positive for PD-L1
expression in ≥50% of tumor cells.

36. Targeted Therapies for Select
Molecular Cohorts of NSCLC

37. Agents that Inhibit the Epidermal
Growth Factor Receptor
• Erlotinib, gefitinib and afatinib are oral small-
molecule Tyrosine kinase inhibitors that
inhibit signaling via EGFR.
• Osimertinib, a third generation mutant-
selective EGFR TKI received approval in 2015
for patients who progress on erlotinib,
gefitinib, or afatinib and whose tumors harbor
the T790M mutation.

38. • first ALK inhibitor, crizotinib, received FDA
approval for patients with lung tumors
harboring ALK rearrangements.
• Two additional ALK inhibitors, ceritinib and
alectinib, are currently approved in patients
who progress on crizotinib.

39. • Crizotinib, which inhibits both ALK and ROS1
kinases, was recently FDA approved for patients
whose tumors harbor a ROS1 fusion.
• In addition to EGFR, ALK, and ROS1 other driver
mutations have been discovered with varying
frequencies in NSCLC, including KRAS, BRAF,
PIK3CA, NRAS, AKT1, MET, MEK1 (MAP2K1),
NTRK, and RET.

41. Treatment of Small Cell Lung Cancer
Surgery
• SCLC is a highly aggressive disease
characterized by its rapid doubling time, high
growth fraction, early development of
disseminated disease.
• Surgical resection is not routinely
recommended for patients because even
those patients with LD-SCLC still have occult
micrometastases.

42. • American College of Chest Physicians Evidence-Based
Clinical Practice Guidelines recommend surgical resection
over nonsurgical treatment in SCLC patients with clinical
stage I disease after a thorough evaluation for distant
metastases and invasive mediastinal stage evaluation
(grade 2C).
• After resection, these patients should receive platinum-
based adjuvant chemotherapy (grade 1C).
• If the histologic diagnosis of SCLC is made in patients on
review of a resected surgical specimen, such patients
should receive standard SCLC chemotherapy as well.

43. Chemotherapy
• Chemotherapy significantly prolongs survival in patients with
SCLC.
• Combination chemotherapy with a platinum agent (cisplatin
or carboplatin) and etoposide or irinotecan for four to six
cycles is the mainstay of treatment
• Cyclophosphamide, doxorubicin (Adriamycin), and vincristine
(CAV) may be an alternative for patients who are unable to
tolerate a platinum-based regimen.
• Regardless of disease extent, the majority of patients relapse
and develop chemotherapy-resistant disease.

44. Chemotherapy
• Despite response rates to first-line therapy as high as 80%, the
median survival ranges from 12 to 20 months for patients with LD
and from 7 to 11 months for patients with ED.
• Only 6–12% of patients with LD- and 2% of patients with ED-SCLC
live beyond 5 years.
• PLATINUM-RESISTANT DISEASE :
– relapse within the first 3 months of therapy
– prognosis is especially poor
• PLATINUM-SENSITIVE DISEASE :
– relapse more than 3 months after their initial therapy
– somewhat better overall survival.

45. • Chemo-sensitive disease also benefit from
second line chemo-therapy- Topotecan
• Other agents that can be used but with low
level of activity include irinotecan, paclitaxel,
docetaxel, vinorelbine, oral etoposide, and
gemcitabine.

46. Radiation Therapy
• Patients with LD-SCLC are treated with combined
modality therapy with cisplatin and etoposide
chemotherapy and radiation therapy.
• The addition of radiation therapy early on is
preferred.
• Twice-daily fractionated radiation has been
shown to improve survival in patients with LD-
SCLC but is associated with higher rates of grade
3 esophagitis and pulmonary toxicity.

47. • The role of radiotherapy in ED-SCLC is largely
restricted to palliation of tumor-related
symptoms such as bone pain and bronchial
obstruction.

48. Prophylactic Cranial Irradiation
• Prophylactic cranial irradiation (PCI) should be considered in all
patients with LD- and ED-SCLC who have responded to initial
therapy.
• A meta-analysis including 7 trials and 987 patients with LD-SCLC
who had achieved a complete remission following primary
chemotherapy reported a 5.4% improvement in overall survival for
patients treated with PCI.
• In patients with ED-SCLC who had responded to first-line
chemotherapy, PCI reduced the occurrence of symptomatic brain
metastases and prolonged disease-free and overall survival
compared to no radiation therapy.
• Long-term toxicities including deficits in cognition have been
reported following PCI and are difficult to sort out from the effects
of chemotherapy or normal aging.

49. • Harrison’s Principles of Internal Medicine
(20th Edition)
• Davidson’s Principles and Practise of Medicine
(21st Edition)
• Medscape

50. THANK YOU