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Japanese Journal of Clinical Oncology Advance Access published online on February 1, 2008
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hym166
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© The Authors (2008). Published by Oxford University Press. All rights reserved

Pseudoprogression of Lung Cancer after Concomitant Chemoradiotherapy

Eiki Ichihara1, Katsuyuki Kiura1,, Nagio Takigawa1, Masako Omori2, Motoi Aoe3, Mitsune Tanimoto1 and Hiroshi Date3

1 Department of Hematology, Oncology and Respiratory Medicine
2 Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
3 Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan

For reprints and all correspondence: Katsuyuki Kiura, Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata, Okayama, Okayama 700-8558, Japan. E-mail: kkiura{at}md.okayama-u.ac.jp

Received July 17, 2007; accepted November 21, 2007


   Abstract
TOP
 Abstract
INTRODUCTION
 CASE REPORT
 DISCUSSION
 References
 
We observed re-enlargement of a squamous cell carcinoma without recurrence. The tumour regressed markedly after concomitant chemoradiotherapy, but within 1 month, we supposed that the tumour had enlarged again and resection was performed. The resected tissue showed evidence of haemorrhage and several lymphocytes and macrophages, but no malignant cells were detected. We herein report a rare case of lung cancer showing a pathological complete response despite re-enlargement of tumour lesion.

Key Words: lung cancer • pseudoprogression • complete response • haemorrhage • necrosis


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
CASE REPORT
 DISCUSSION
 References
 
Despite controversial treatments of surgery after concomitant chemoradiotherapy, we have reported promising results of surgery followed by cisplatin plus docetaxel with concurrent radiotherapy against locally advanced non-small cell lung cancer (1). In the treatment of cancer, tumour size is the primary indicator of the efficacy of chemotherapy. Tumour shrinkage is normally viewed to denote therapeutic effectiveness, while enlargement is regarded as a sign of tumour progression. Here we report a rare case involving a pathological complete response despite the regrowth of a lung tumour lesion after concomitant chemoradiotherapy.


   CASE REPORT
TOP
 Abstract
 INTRODUCTION
 CASE REPORT
DISCUSSION
 References
 
A 50-year-old male smoker presented with an abnormal shadow on a chest radiograph to our hospital in June 2005. The patient complained of a dry cough and weight loss, and his serum cytokeratin 19 fragment level was elevated to 3.9 ng/ml. A chest radiograph revealed an ill-defined opacity in the right upper lung field, and a computed tomography (CT) scan showed an emphysematous change with an enhanced ill-defined mass in the right lower lobe and stenosis of the right upper bronchus (Fig. 1a). A bronchial biopsy revealed stage IIIB (T4N2M0) squamous cell carcinoma, and the patient was treated with concomitant chemoradiotherapy for neo-adjuvant therapy (two cycles of 40 mg/m2 each cisplatin and docetaxel on days 1, 8, 22 and 29 concurrent with 2 Gy of thoracic radiation at 5 fr/week for a total of 45 Gy (1,2). The tumour regressed markedly following chemoradiotherapy (Fig. 1b) but the tumor lesion re-enlarged within 1 month following the last day of radiation (Fig. 1c). We reassessed the indications for surgery and a right upper sleeve lobectomy was judged to be technically feasible. The tumour was successfully removed in September 2005. The resected tissue showed evidence of haemorrhage, and several lymphocytes and macrophages were observed (Fig. 2). The chemoradiotherapy may have induced the haemorrhage, since iron staining revealed numerous haemosiderin-laden cells in the haemorrhagic focus. No malignant cells were detected. Twenty months after surgery, the patient was doing well without any evidence of disease.


Figure 1
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  		Figure 1. (a) A CT scan of the chest showing an enhanced ill-defined mass 48 mm in diameter in the right lower lobe and stenosis of the right upper bronchus. (b) The tumour regressed markedly after concomitant chemoradiotherapy. (c) The tumour was again enlarged 1 month after the last day of concomitant radiation therapy.

 

Figure 2
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  		Figure 2. Haematoxylin and eosin staining of the resected tissue shows evidence of haemorrhage with giant multinucleate cells and the presence of several lymphocytes and macrophages, but no malignant cells. Please note that a colour version of this figure is available as supplementary data at http://www.jjco.oxfordjournals.org

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 CASE REPORT
 DISCUSSION
References
 
According to the Response Evaluation Criteria in Solid Tumors (RECIST), the efficacy of treatment for solid tumours is usually determined by the tumour size. RECIST criteria are the golden standard to evaluate the tumour. We now all agree with the RECIST criteria and are supposed to follow them. As described, however, the tumour in this case regressed markedly after concomitant chemoradiotherapy but seemed to regrow within 1 month of treatment. A CT scan performed just before the operation showed re-enlargement of the tumour lesion. Subsequent surgery revealed that the re-enlargement lesion was not due to exacerbation of the cancer, but rather to haemorrhage and immune cell migration caused by the chemoradiotherapy.

To our knowledge, pseudoprogression of lung cancer has not been previously reported. For brain tumours, it appears that tumour re-enlargement without progression can result from radiation-induced necrosis (3). A similar phenomenon may occur in lung tumours following concomitant chemoradiotherapy (4), which may cause tumour necrosis in lung cancer and thereby mimic disease progression. It may be possible to distinguish brain tumour recurrence from radiation-induced necrosis using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) (5). Similarly, FDG-PET may also be useful in distinguishing lung tumour progression from post-radiation effects in this case, but the patient did not undergo FDG-PET. In addition, such lesions have been shown to be false-positive for FDG-PET after radiation therapy (6).

In contrast to the current case, patients rarely undergo surgery after chemoradiotherapy to treat enlarged tumour lesion. Instead, such patients usually receive chemotherapy and/or radiotherapy without pathological confirmation. Some cases of re-enlargement of the tumour lesion following chemoradiotherapy do not include disease progression. Indeed, we have seen few cases of a complete radiographic response after concomitant chemoradiotherapy, but approximately one-quarter of patients with locally advanced non-small lung cancer (NSCLC) show a pathological complete response after concomitant chemoradiotherapy (1). Some cases of locally advanced NSCLC achieve a pathological complete response after chemoradiotherapy despite a partial radiographic response, and the residual lesion seen on the CT scan is necrotic tissue instead of cancer. Thus, evaluating the condition of a tumour after concomitant chemoradiotherapy is very difficult.

Surgical resection after concomitant chemoradiotherapy still has no definite evidence to prolong overall survival in locally advanced non-small cell lung cancer (7). Phase II trial of neo-adjuvant concomitant chemoradiotherapy is ongoing in our group. If we could remove the tumours technically in our clinical trial, even when no radiological change or slight enlargement of tumour-like lesion occurred after concomitant chemoradiotherapy, we will try surgical resection whenever it is possible, because we had no accurate, non-invasive methods to detect viable tumour cells after concomitant chemoradiotherapy.

The causes of enlargement of tumour-like lesion are unclear. Haemorrhage and immune cells are detected pathologically. Directed effects of local haemorrhage and/or reactions of immune response to inflammation due to radiation are speculated for causes of enlargement of tumour-like lesion.

In conclusion, when a tumour exhibits rapid regrowth after concomitant chemoradiotherapy, one must consider surgical indications cautiously and carefully. A precise method for detecting tumour cells after intensive concomitant chemoradiotherapy is therefore needed to treat such patients.


   Acknowledgment
 
We thank Dr Brian Quinn of Kyushu University for the critical reading of our manuscript.

Conflict of interest statement

None declared.


   References
TOP
 Abstract
 INTRODUCTION
 CASE REPORT
 DISCUSSION
 References
 
1 Katayama H, Ueoka H, Kiura K, Tabata M, Kozuki T, Tanimoto M, et al. Preoperative concurrent chemoradiotherapy with cisplatin and docetaxel in patients with locally advanced non-small-cell lung cancer. Br J Cancer (2004) 90:979–84.[CrossRef][Web of Science][Medline]

2 Kiura K, Ueoka H, Segawa Y, Tabata M, Kamei H, Takigawa N, et al. Phase I/II study of docetaxel and cisplatin with concurrent thoracic radiation therapy for locally advanced non-small-cell lung cancer. Br J Cancer (2003) 89:795–802.[CrossRef][Web of Science][Medline]

3 Ohashi K, Kiura K, Takigawa N, Shigeki U, Kondo N, Tabata M, et al. Radiation necrosis mimicking progressive brain metastasis in a patient with non-small cell lung cancer. J Thorac Oncol (2007) 2(8):762–3.[Medline]

4 Mesurolle B, Qanadli SD, Merad M, Mignon F, Baldeyrou P, Tardivon A, et al. Unusual radiologic findings in the thorax after radiation therapy. Radiographics (2000) 20:67–81.[Abstract/Free Full Text]

5 Chao ST, Suh JH, Raja S, Lee SY, Barnett G. The sensitivity and specificity of FDG PET in distinguishing recurrent brain tumor from radionecrosis in patients treated with stereotactic radiosurgery. Int J Cancer (2001) 96:191–7.[CrossRef][Web of Science][Medline]

6 Ohtsuka T, Nomori H, Watanabe K, Naruke T, Orikasa H, Yamazaki K, et al. False-positive findings on [18F]FDG-PET caused by non-neoplastic cellular elements after neoadjuvant chemoradiotherapy for non-small cell lung cancer. Jpn J Clin Oncol (2006) 36:271–3.

7 Albain KS, Swann RS, Rusch VR, Turrisi AT, Shepherd FA, Smith CJ, et al. Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA(pN2) non-small cell lung cancer (NSCLC): Outcomes update of North American Intergroup 0139 (RTOG 9309). 2005. ASCO Ann Meeting Proc (2005) 23:7014. (abstract).


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This Article
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