Deciphering adenocarcinoma of lung and treatment

Case based discussion lung carcinoma

1. N Engl J Med 2022;387:1889-96. DOI: 10.1056/NEJMcpc2211354 A 60-Year-Old Man with Progressive Dyspnea , Neck Swelling, and a Lung Mass Jennifer S. Temel , M.D., David M. Dudzinski , M.D., Subba R. Digumarthy , M.D., Colleen M. Keyes, M.D., Florence K. Keane, M.D., and Daniel Shepherd, M.D., Ph.D. DR.MEENA R

2. A 60 year old man presented to massachusetts hospital with complaints of New onset dysponea Cough Neck swelling Lung mass

3. Before current admission , patient was transported to another hospital by ambulance, H/o progressive dysponea x 4 months while walking or lifting items at his job for past one year and at present he also has orthopnea with persistent non productive cough H/o sore throat x 5 days Swelling of neck and both arms His daughter a health care worker called EMS when she noticed patient had facial redness and flushing and swelling of neck and his arms

4. EVALUATION AT OTHER HOSPITAL Vitals Temperature - 35.6˚c Heart rate - 78 beats per minute Blood pressure - 121/57mmHg Respiratory rate - 19 breaths per minute Oxygen saturation - 96% room air

5. Clinical examination Face was flushed and neck was swollen Respiratory system – breath sounds were absent in right lung fields Amylase and troponin I - normal

6. INVESTIGATIONS

7. CECT OF CHEST A new mass in the hilar region of the right upper lobe that measured 9.2 cm in greatest dimension Evidence of mass effect on the right pulmonary artery and right main stem and right upper lobe bronchi Encasement of the right bronchus intermedius , occlusion of svc and narrowing of the right superior pulmonary vein Pulmonary emboli in pulmonary artery of left lower lobe , consolidation and atelectasis in right upper lobe Chest wall edema and extensive venous collateral vessels and B/L moderate sized pleural effusions

8. Patient was shifted to other hospital , Intravenous piperacilin – tazobactam and heparin were administered Next day, thoracentesis was performed , around 500ml of pleural fluid was drained PARAMETERS RESULT Appearance Cloudy yellow fluid Glucose level 98 mg / dl Protein level 3.4/dl pH 7.5 Gram staining Malignant cells No growth No

9. Usg of legs : no evidence of DVT CECT brain : no haemorrhage or infarct CT abdomen & pelvis : subcentimeter lucent areas in the iliac bones Next day , patient was transferred to the oncology unit of this hospital for further evaluation and care . On admission to this hospital , patient reported that during past 3 days ,he had progressive swelling of both upper arms with pain in right shoulder and arm

10. He had weight loss 10 kg in past 6 months Anorexia Hoarse voice Dizziness with changes in position (including bending forward) Dyspnea on exetion NEGATIVE HISTORY : Hemoptysis , chest pain , palpitations , nausea , changes in bowel habits , vomiting, abdominal pain, night sweats ,head ache and diplopia .

11. Medical history : No medications were taken and no past history of surgery to shoulder and leg. Occupational history : he was self employed and worked in plumbing and engineering Personal history : he had smoked two packs of cigarettes per days x 40 years. he drank five beers per day two times per week. Family history : Notable for pancreatic cancer in his mother

12. Vitals : Temperature – 37.1ºc Heart rate – 110bpm BP - 114/66 mmHg RR - 22cpm SpO2 - 94% @ room air Weight – 90 kg Height - 172cm BMI - 30.6

13. Neck swelling and erythema + JVP distended Edema and swelling of arms right more than the left was present Erythema on the chest and evidence of engorged veins in the chest wall Investigations were done and shown ECG: sinus tachycardia with premature atrial beats low precordial lead volatge and non specific ST segment and T wave changes

14. CECT chest : Revealed a persistent large central mass in the right upper lobe with occlusion of the right upper lobe bronchus and collapse of the right upper lobe Multiple enlarged right mediastinal and right hilar lymph nodes Brachiocephalic veins and SVC shows no opacifications Presence of extensive collateral veins in right chest wall was consistent with venous occlusion and SVC syndrome

15. Incidental cyst was noted in the upper lobe of the left kidney No evidence of pericardial effusion and no other evidence of cancer in the abdomen Differential diagnosis : non small cell lung cancer small cell lung cancer metastasis from extrathoracic lung cancer and lymphoma

16. Angiography : no opacification of the subclavian and brachiocephalic veins or the SVC Extensive collateral veins were present in the arms After removal of some of the clots multiple overlapping stents were placed in the internal jugular veins , brachiocephalic veins and SVC

17. On day 4 of hospitalization , Rigid bronchoscopy revealed diffusely friable mucosa and dynamic narrowing of the right main stem bronchus Airway narrowing appeared to be due to extrinsic compression Ballon dilation of airway was performed but failed , therefore endobronchial stenting was not placed Endobronchial USG : Revealed 1.5cm mass near the carina and transbronchial needle aspiration was performed

18. Hematoxylin and eosin staining : Clusters of large epithelioid cells Anisonucleosis Irregularly contoured nuclei Prominent nucleoli occasional binucleated forms no morphological forms of small cell carcinoma seen Immunohistochemical staining for neuroendocrine and PD-L1 was negative Pathological diagnosis : poorly differentiated adenocarcinoma of the lung

19. FINAL DIAGNOSIS POORLY DIFFERENTIATED ADENOCARCINOMA OF THE LUNG COMPLICATED BY SUPERIOR VENA CAVA SYNDROME

20. RADIATION ONCOLOGY MANAGEMENT Therapeutic radiation is ionizing , causing breaks in DNA and generation of free radicals from cell water that may damage cell membranes, proteins, and organelles. Radiation damage is augmented by oxygen; hypoxic cells are more resistant . Augmentation of oxygen presence is one basis for radiation sensitization . X-rays and gamma rays are the forms of ionizing radiation most commonly used to treat cancer.

21. Radiation is quantitated based on the amount of radiation absorbed by the tumor in the patient; it is not based on the amount of radiation generated by the machine. The International System (SI) unit for radiation absorbed is the Gray ( Gy ): 1 Gy refers to 1 J/kg of tissue. Radiation dose is measured by placing detectors at the body surface or based on radiating phantoms that resemble human form and substance, containing internal detectors.

22. Radiation effect is influenced by three determinants: total absorbed dose, number of fractions, and time of treatment. Thus , a typical course of radiation therapy should be described as 4500 cGy delivered to a particular target (e.g ., mediastinum) over 5 weeks in 180-cGy fractions. Most curative radiation treatment programs are delivered once a day, 5 days a week, in 150- to 200-cGy fractions. Nondividing cells are more resistant than dividing cells, and this is one rationale for delivering radiation in repeated fractions, to ultimately expose a larger number of tumor cells that have entered the division cycle.

23. Therapeutic radiation is delivered in three ways: ( 1) teletherapy , with focused beams of radiation generated at a distance and aimed at the tumor within the patient; ( 2) brachytherapy , with encapsulated sources of radiation implanted directly into or adjacent to tumor tissues; (3) systemic therapy , with radionuclides administered, for example, intravenously but targeted by some means to a tumor site. Teletherapy with x-ray or gamma-ray photons is the most commonly used form of radiation therapy.

24. This patient had poorly differentiated adenocarcinoma of the lung that was complicated by SVC syndrome. Radiotherapy plays a critical role in the treatment of patients with lung cancer, with more than 50% of patients receiving radiotherapy during their treatment course . For patients with metastatic lung cancer , radiotherapy is most often used for palliation of symptoms, including pain, bleeding, dyspnea , and neurologic symptoms.

25. Palliation of intrathoracic disease is particularly important, given the substantial effect on quality of life. This patient had clinically significant vascular ompression , an indication for urgent initiation of palliative radiotherapy. Radiotherapy is the primary method of treatment for this type of compression. The response to radiotherapy among patients with SVC syndrome is approximately 70%, with a reduction in symptoms typically seen within 72 hours after initiation of treatment

26. Palliative radiotherapy generally results in limited side effects and can be delivered over a short period of time. Treatment regimens including 30 Gy in 10 fractions, 20 Gy in 5 fractions , and 8 Gy in 1 fraction have been studied for palliation of symptoms. Although the initial response to radiotherapy is similar regardless of dose , the durability of response increases with larger doses and longer courses of radiotherapy.

27. Therefore, selection of the regimen is individualized and includes an assessment of symptoms, the site of treatment, available systemic therapy options , and the overall prognosis.

28. Owing to this patient’s clinically significant symptoms , radiotherapy was started immediately after stent placement, before the performance of staging PET-CT. His presentation at that time was consistent with NSCLC of at least stage III, or locally advanced disease . For patients such as this one with inoperable stage III NSCLC , treatment consists of curative-intent chemoradiotherapy followed by adjuvant immunotherapy.

29. The possibility that a curative course of radiotherapy would be needed in the absence of distant metastases influenced our selection of the radiotherapy dose and fractionation. This is because each normal organ, such as the spinal cord, lungs, esophagus , and heart, can endure only a certain dose of radiotherapy. The use of a traditional palliative regimen, such as 20 Gy in 5 fractions, would have limited our ability to deliver a curative dose of radiotherapy, such as 60 Gy in 30 fractions

30. Staging PET-CT, performed after the administration of intravenous 18F-fluorodeoxyglucose (FDG ) tracer, and diagnostic CT revealed that a stent in the right internal jugular vein had migrated into the right atrium. The PET-CT image showed increased FDG uptake in the mass located in the hilar region of the right upper lobe and in the right mediastinal nodes , as well as an additional focus of intense FDG uptake in a right adrenal nodule, findings that were suggestive of oligometastatic disease. There were no osseous lesions that were consistent with metastasis.

31. Given the FDG avidity in the right adrenal lesion, this patient had stage IV NSCLC with one site of metastasis. On the basis of the one site of metastasis, his presentation was suggestive of oligometastatic disease. Oligometastatic disease was historically defined by the presence of a surgically resectable primary lung tumor , with no evidence of nodal metastasis, and a solitary adrenal or brain metastasis.

32. In retrospective series, improved outcomes were reported when patients with oligometastatic disease were treated with curative-intent local therapies , such as surgical resection or radiotherapy, in addition to systemic therapy. However, as systemic therapy and local treatment options have improved, there has been interest in expanding the definition of oligometastatic disease to include multiple sites of metastasis. For example, a multidisciplinary consensus group suggested that patients with up to a total of five metastases in three organs could be considered considered to have synchronous oligometastatic disease .

33. In this cohort, randomized phase 2 trials have shown significant improvements in progression-free survival with the addition of radiotherapy to systemic therapy. Long-term results of these trials have also shown improvements in overall survival among patients receiving intensive local therapy. It should be noted that, although these trials allowed the enrollment of patients with three to five metastases, a majority of the patients had one or two metastases. Additional trials in which patients with larger numbers of metastatic sites are enrolled are ongoing .

34. This patient had unresectable intrathoracic disease , but given the presence of the isolated adrenal metastasis, we recommended delivery of a higher dose of radiotherapy to the right mediastinal and right hilar lymph nodes with the aim of more durable local control. This approach necessitated a revision of his radiotherapy plan. He had initially started treatment with threedimensional conformal radiotherapy — the standard technique for palliative radiotherapy because it can be planned quickly. However , in patients with lung cancer, this technique is associated with increased toxic effects when it is used to deliver curative doses of radiotherapy

35. Advances in radiotherapy planning and delivery techniques during the past 15 years have enabled the delivery of higher doses of radiotherapy over shorter time periods with fewer side effects. In this patient, a plan that continued to include the use of three-dimensional conformal radiotherapy would have resulted in an increased risk of both short- and long-term toxic effects, including pneumonitis and esophagitis.

36. Given his relatively young age, his improving clinical status, and the isolated site of metastasis, we transitioned to a treatment plan that used volumetricmodulated arc therapy. With this plan, the delivery of a higher dose of radiotherapy was feasible. The patient was ultimately treated with a hypo- fractionated course of radiotherapy at a dose of 50 Gy in 20 fractions. Local therapy for the adrenal lesion was deferred, with a plan to reassess after the administration of systemic therapy.

37. MEDICAL ONCOLOGY MANAGEMENT Care of patients with metastatic NSCLC, oncologists focus on variety of factors. These factors includes : Determining whether the patient needs local treatment such as surgery or radiotherapy Identifying an appropriate systemic therapy(oral or IV with the goal of treating all sites of disease) Assessing patient health status and co-existing conditions and to determine any contraindication to systemic therapy

38. Eliciting the patients goals and values to ensure that care is aligned with their priorities. Addressing the palliative and supportive care needs of the patient and family members. Systemic therapy with the goal of prolonging life is the main stay of treatment for patients with metastatic NSCLC Local therapy such as radiotherapy or surgery for sites of disease that warrant urgent management such as bone metastases with extensive cortical destruction or brain metastases

39. Systemic therapy that would have the highest likelihood of controlling the patient cancer growth and spread for as long as possible For choosing systemic therapy, somatic gene therapy to be assessed in metastatic NSCLC,since severe mutations have been identified and treated with oral targeted therapies which are highly effective with fewer side effects In this patient , no targetable mutations are identified Then patient was tested for the level of PD-L1 expression whether a patient is candidate for treatment with PD1 or PD-L1 inhibitor (immune check pint inhibitor) alone or combination with chemotherapy

40. PD-L1 expression is assessed by means immunohistochemical staining and reported as a tumor proportion score which is based on percentage of tumour cells with membranous staining for PDL1. Score was zero and best systemic option to treat his cancer was determined to be chemotherapy in combination with an immune checkpoint inhibitor. Patient had no coexisting health conditions or renal dysfunction or no pre existing cytopenia or no preexisting lung fibrosis or autoimmune disorder

41. Patient was considered to be a candidate for systemic therapy for NSCLC , adenocarcinoma subtype, which includes carboplatin , pemetrexed and pembrolizumab. After explaining the risks and benefits about above regimen to the patient and family members, we elicited the goals and values to ensure that proceeding with treatment was consistent with his preferences. Patient stated that , although his cancer was not curable , primary goal was to extend his life .

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