|Year : 2010 | Volume
| Issue : 3 | Page : 362-364
Dramatic responses to gefitinib when used as front line therapy in two cases of metastatic lung adenocarcinoma with poor performance status
Ajay Gupta1, Vinod Raina1, Priyam Garg2, Rakesh Kumar3
1 Department of Medical Oncology, Institute Rotary Cancer Hospital, New Delhi, India
2 Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
3 Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||29-Nov-2010|
P-41, South Extension-2, New Delhi - 110 049
Source of Support: None, Conflict of Interest: None
A 54-year-old man, a non-smoker, suffering from metastatic lung adenocarcinoma presented with extensive bilateral pulmonary infiltrates. He was dyspneic at rest. Performance status (PS) was 4. Institution of gefitinib resulted in relief from dyspnea within two weeks. Positron emission tomography done after 10 months revealed only a 2 cm residual lesion. However, the patient stopped therapy on his own and died two months later.
An 80-year-old female, a non smoker, presented with metastatic lung adenocarcinoma and right sided pleural effusion. Her PS was 4. She was started on gefitinib. Within four weeks, she showed marked improvement. At six months, she was radiologically documented to be in partial remission. She continues to be asymptomatic at one year follow-up. These are the first reports of dramatic responses to gefitinib when used as front-line therapy in patients with poor performance status from India.
Keywords: Gefitinib, lung cancer, non-smokers
|How to cite this article:|
Gupta A, Raina V, Garg P, Kumar R. Dramatic responses to gefitinib when used as front line therapy in two cases of metastatic lung adenocarcinoma with poor performance status. J Can Res Ther 2010;6:362-4
|How to cite this URL:|
Gupta A, Raina V, Garg P, Kumar R. Dramatic responses to gefitinib when used as front line therapy in two cases of metastatic lung adenocarcinoma with poor performance status. J Can Res Ther [serial online] 2010 [cited 2021 Jan 26];6:362-4. Available from: https://www.cancerjournal.net/text.asp?2010/6/3/362/73372
| > Introduction|| |
Gefitinib is an EGFR tyrosine kinase inhibitor with a very favorable toxicity profile. It is particularly efficacious in patients who are non smokers and suffer from adenocarcinomas. Our case reports are the first such reports of dramatic responses to gefitinib when used as front line therapy in patients with poor performance status (PS) from India. We wish to stress upon the efficacy of gefitinib in this patient subgroup.
| > Case Reports|| |
The patient, a 54-year-old male automobile engineer and a non-smoker presented with a six month history of non productive cough and swelling over the left shoulder along with progressive dyspnea. Since the last one month, the cough had worsened and the swelling over the shoulder had become large (10×10 cm) and painful causing restriction of overhead abduction.
He was mildly cyanotic. His PS was 4 and he was dyspneic at rest. Auscultation revealed bilateral coarse crepitations and rhonchii.
Radiological investigations including chest X-ray and contrast enhanced computerized tomography (CECT) of the chest revealed an irregular spiculated mass, 3×2 cm in size, in the apical segment of right upper lobe without pleural or mediastinal invasion. Extensive alveolar and interstitial ground glass opacities were seen in both lung fields [Figure 1]a. There was a large lytic lesion in the left scapula. The abdomen was normal.
|Figure 1a: CECT chest revealing an irregular spiculated mass, 3×2 cm in size, in right upper lobe. Diffuse areas of inter and intralobular septal thickening with extensive alveolar and interstitial ground glass opacities seen involving bilateral lung fields along with an expansile lytic lesion in the left scapula|
b: CECT chest done 10 months later revealing a 2×1.5 cm spiculated lesion in the right upper lobe. The left scapular lesion has healed. PET scan showing increased uptake in the mass and the pretracheal node
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MRI of the shoulder revealed an irregular expansile area of bone destruction and marrow replacement by soft tissue displaying variegated low signal intensities on T1 and hyperintensities on T2 weighted images affecting the glenoid, the coracoid process and medial aspect of the spine of the scapula.
Biopsy of the scapular lesion revealed a poorly differentiated adenocarcinoma. The lesion was immunohistochemically positive for cytokeratin and epithelial membranous antigen. A diagnosis of Stage IV adenocarcinoma of the lung was made. The patient was started on oral gefitinib 250 mg daily.
In two weeks, there was a marked reduction in his breathlessness and he was able to perform activities of daily living. The scapular swelling also decreased in size and became less painful. One month later, he developed a red rash over the face which persisted for four months but then resolved slowly. He became totally asymptomatic in eight weeks.
CECT chest done 10 months later revealed a 2×1.5 cm spiculated lesion in the right upper lobe. The left scapular lesion had healed. The positron emission tomography (PET) scan revealed a soft tissue mass in right upper lobe and the pretracheal node showing increased uptake; rest of the scan was normal [Figure 1]b. The patient stopped gefitinib on his own volition.
He presented with progressive, metastatic disease and severe dyspnea two months later and died within three days.
A 80-year-old female and a non smoker presented with a three month history of progressive anorexia, malaise, weakness, 12 kg weight loss and progressive breathlessness. She had mild pallor. Respiratory examination was suggestive of right sided pleural effusion.
CECT of the chest revealed a moderately enhancing, irregular 4 cm soft tissue mass in the right lower lobe abutting the right lower lobe bronchus with moderate right sided pleural effusion and metastatic pleural nodules. There were multiple nodules of variable size in the right lung fields, apical and posterior segments of the left upper lobe and apical segment of the left lower lobe. The abdomen was normal. The mammogram was normal.
Pleural fluid cytology revealed cells and fragments of an adenocarcinoma.
Her PS was 4. She was admitted to our palliative care ward. She was started on oral gefitinib 250 mg daily. Within two weeks, she reported major symptomatic improvement and her PS improved to 2 in four week's time.
At six months, CECT chest done revealed heterogeneously enhancing mass 2.5×2.5 cm in apical segment of right lower lobe. Small satellite lesions were seen adjacent to the mass.
As compared to the initial CT, the number of lung nodules had reduced by 70% and the mass by 30%. The pleural effusion had decreased and the pleural nodules had resolved. At one year, the patient continued to be asymptomatic and in good health.
| > Discussion|| |
Gefitinib is a small-molecule reversible competitive tyrosine kinase inhibitor (TKI) of ATP-binding at the active site of the epidermal growth factor receptor (EGFR) kinase. Sensitivity to gefitinib correlates strongly with activating mutations in the EGFR kinase domain which show a good correlation with favorable clinical parameters including non smoker status, female sex, East Asian ethnic background, adenocarcinoma and bronchioloalveolar histology. ,
Both our patients were non-smokers. Despite poor performance status, gefitinib was very well tolerated. Rash occurred in Case 1 only.
More than 70% of the NSCLC with EGFR mutations respond to EGFR TKI's compared with 10% tumors without EGFR mutations. ,
Patients with poor performance status (PS of 2 or more) and brain or liver metastases fare badly and are often excluded from chemotherapy clinical trials. 
Dramatic complete and partial remissions (Lazarus responses) have been documented in patients with lung adenocarinoma having multiple brain, lung and bone metastases on gefitinib including one such report in an 84-year-old female. , Interestingly Case 2 was also an octogenerarian.
60%-90% response rates (RR) have been described in chemotherapy-resistant NSCLC patients with PS - 2 and liver, bone and brain metastases harboring EGFR mutations, with time to progression (TTP) of 12 to 21 months. This is significantly beyond the 10% RR and three-month TTP observed in the general population of NSCLC patients with second- or third-line gefitinib or erlotinib. ,,,
This is the first report of 'Lazarus type' dramatic responses to gefitinib from India when used as first line therapy.
So far, only one retrospective analysis has found median survival of six months and response rates of 14% to gefitinib in refractory, advanced NSCLC in India. 
IPASS (IRESSA Pan-Asia Study) was a phase 3, open-label study in which treatment naïve, non smokers/light smokers with advanced pulmonary adenocarcinoma were randomized to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival (PFS). The 12-month rates of PFS were 24.9% with gefitinib and 6.7% with carboplatin-paclitaxel. The study showed the superiority of gefitinib with respect to PFS. In the subgroup of 261 patients who were positive for the EGFR mutation, PFS was significantly longer among those who received gefitinib than among those who received carboplatin-paclitaxel (P<0.001), whereas in the subgroup of 176 patients who were negative for the mutation PFS was significantly longer among those who received chemotherapy (P<0.001).
Thus, the presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib and such patients are candidates for upfront therapy with gefitinib. 
Two major trials, Intact Trial 1 and Intact Trial 2, were conducted to determine if addition of gefitinib to first line therapy in advanced NSCLC resulted in no improved survival.
Addition of gefitinib (in dosages of 250mg or 500 mg) to gemcitabine/cisplatin (in Intact 1 involving 1093 patients)  or to paclitaxel / carboplatin (in Intact 2)  was not associated with any survival benefit and hence a combination of gefitinib with chemotherapy as upfront treatment is not recommended.
These encouraging responses seen in our cases call for further evaluation of this drug in Indian patients, given the efficacy of this drug in East Asian populations.
| > References|| |
|1.||Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J. Geftinib plus best supportive care in previously treated patients with refractory advanced non small cell lung cancer: Results from a randomized, placebo controlled, multicenter study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005;366:1527-37. |
|2.||Ho C, Murray N, Laskin J, Melosky B, Anderson H, Bebb G. Asian ethnicity and adenocarcinoma histology continues to predict response to geftinib in patients treated for advanced non-small lung cancer of the lung in North America. Lung Cancer 2005;49:225-31. |
|3.||Rosell R, Cuello M, Cecere F, Santarpia M, Reguart N, Felip E, et al. Treatment of non-small-cell lung cancer and pharmacogenomics: Where we are and where we are going. Curr Opin Oncol 2006;18:135-43. |
|4.||Rosell R, Cecere F, Santarpia M, Reguart N, Taron M. Predicting the outcome of chemotherapy for lung cancer. Curr Opin Pharmacol 2006;6:323-31. |
|5.||Hoang T, Xu R, Schiller JH, Bonomi P, Johnson DH. Clinical model to predict survival in chemonaive patients with advanced non-small-cell lung cancer treated with third-generation chemotherapy regimens based on Eastern Cooperative Oncology Group data. J Clin Oncol 2005;23:175-83. |
|6.||Taron M, Ichinose Y, Rosell R, Mok T, Massuti B, Zamora L, et al. Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor are associated with improved survival in gefitinib-treated chemorefractory lung adenocarcinomas. Clin Cancer Res 2005;11:5878-85. |
|7.||Cortes-Funes H, Gomez C, Rosell R, Valero P, Garcia-Giron C, Velasco A, et al. Epidermal growth factor receptor activating mutations in Spanish gefitinib-treated non-small-cell lung cancer patients. Ann Oncol 2005;16:1081-6. |
|8.||Parikh P, Chang AY, Nag S, Digumarti R, Bhattacharyya GS, Doval DC, et al. Clinical experience with gefitinib in Indian patients. J Thorac Oncol 2008;3:380-5. |
|9.||Mok T, Wu YL, Thongprasert S, Yang CH, Chu D, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-57. |
|10.||Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: A phase III trial-INTACT 1. J Clin Oncol 2004;22:777-84. |
|11.||Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: A phase III trial-INTACT 2. J Clin Oncol 2004;22:785-94. |