18-FDG-PET for the assessment of residual masses on CT following treatment of lymphomas

Annals of Oncology 11 (Suppl. I): S147-S150. 2000. © 2000 Kluwer Academic Publishers. Printed in the Netherlands.

Symposium article 18-FDG-PET for the assessment of residual masses on CT following treatment of lymphomas N. G. Mikhaeel, A. R. Timothy, S. F. Hain & M. J. O'Doherty Department of Clinical Oncology & Clinical PET Centre, St. Thomas' Hospital, London, UK

Summary

Introduction Between 20% and 40% of patients with lymphomas will have a residual mass on CT following completion of treatment [1, 2]. These masses may contain residual lymphoma, which needs further treatment or may represent fibrosis or necrotic tissue, which will remain stable or continue to regress on further imaging without the need for more treatment [3-5]. Studies have shown that only a small proportion of residual masses will progress or relapse, however, it is currently difficult to select out those masses which contain residual lymphoma. The management of these masses represents a continuing dilemma for the clinician. There are several possible approaches for dealing with post-treatment residual masses [6]. Many clinicians advise observation only, with repeated CT scanning [7, 8], however this carries the risk of delaying treatment for residual disease. Further biopsy for histological examination can sometimes confirm residual disease, however false negative results can occur due to sampling error [9]. Surgical resection may give a more definitive answer, however it may not be practical given the site of these masses in the thorax or abdomen. Further treatment may be given if the clinical suspicion of active disease is high, but this is associated with the risk of additional

Key words: lymphoma, PET, remission assessment, residual masses

morbidity. Improvements in imaging techniques, which allow differentiation of viable from ablated disease, would help to overcome the problem of post-treatment residual masses on CT. The newer functional imaging techniques reflect the metabolic activity of the tissues as compared to the purely anatomical information obtained from CT [1014]. In this report we present our initial experience on the use of 18-Fluoro-deoxy-glucose positron emission tomography (FDG-PET) in the evaluation of post-treatment residual masses.

Patients and methods Patients This study represents a retrospective analysis of 32 patients who achieved partial radiological response and had residual masses on CT ( ^ 2 cm in size) after the completion of all planned treatment. All patients had histologically proven lymphoma and were treated in The Department of Clinical Oncology at St. Thomas' Hospital, London, between January 1993 and December 1997. The study group included 15 patients with Hodgkin's disease and 17 patients with aggressive histology non-Hodgkin's lymphoma (diffuse mixed, diffuse large-cell and large-cell immunoblastic lymphoma). All patients underwent a whole-body 18-FDG-PET scan within one month of a post-

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Background: The problem of residual masses on post-treatment CT scans is a continuing dilemma for the oncologist treating malignant lymphomas. These masses may contain active disease or represent only necrotic tumour which continues to shrink without further treatment or post-treatment fibrosis which remains stable on continued follow-up. 18-FDG-PET offers a novel metabolic imaging modality, which can differentiate malignant from benign tissue on the basis of increased glycolytic activity. Patients and methods: Thirty-two patients (15 with Hodgkin's disease (HD) and 17 with aggressive histology non-Hodgkin's lymphoma (NHL)) who had residual masses on their posttreatment CT scans underwent 18-FDG-PET. The post-treatment CT and PET scans were compared and the accuracy of the 18-FDG-PET in assessing residual masses was evaluated using clinical and pathological follow-up data.

Results: Nine patients had positive post-treatment 18-FDGPET, eight (89%) of whom have relapsed. Twenty-three patients had negative post-treatment PET with only two relapses in this group. The 2 patients who relapsed had aggressive NHL while none of the 11 HD patients with negative PET relapsed. The median follow-up of patients in continued complete remission is 38 months. Conclusions: 18-FDG-PET can differentiate between residual masses containing viable lymphoma where further treatment will be required to achieve cure and those representing ablated disease, where unnecessary treatment and additional morbidity may be avoided.

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149 treatment CT showing residual abnormality. Patient characteristics are shown in Table 1.

Treatment Patients were treated according to departmental protocols. Radiotherapy was given with megavoltage energy using doses of 30-40 Gy in 1.7-2 0 Gy fractions. The ABVD regime (Adriamycin K . bleomycin. vinblastine and dacarbazine) in standard doses was used for HD [14], and CHOP regime (cyclophosphamide, Adriamycin", vincnstine and prednisolone) was used for aggressive histology NHL [15].

FDG-PET scans

Number of patients Age < 50 years > 50 years Sex Male Female Stage I—II III—IV Site of disease Nodal only Extranodal ± nodal Treatment Radiotherapy only Chemotherapy only Chemotherapy + radiotherapy

HD

NHL

15

17

14 1

8 9

10 5

12 5

8 7

5 12

14 1

10 7

0 6 9

1 9 7

Table 2. Correlation between PET result and disease outcome. PET

Number of patients

Lymphoma type

Number of patients

Residual/ relapse (%)

Continued remission (%)

Positive

9(28)

Negative

23(72)

HD NHL Total HD NHL Total

4 5 9 11 12 23

3 5 8(89) 0 2 2(9)

1 0 1(11) 11 10 21(91)

CT scans CT examinations were undertaken using a third generation whole body scanner (Siemens Somatron, DRH) in 10 mm contiguous axial slices. Scans were obtained from thoracic inlet to the pubic symphysis encompassing the chest, abdomen and pelvis. Oral contrast was administered prior to imaging with intravenous contrast administered whilst scanning (150 ml Niopam).

Assessment of residual masses and follow-up Patients were reviewed at regular but increasing time intervals without further treatment until relapse. The median follow-up of patients in continued CR is now 38 months (range 18-68 months). All relapses were confirmed histologically and correlated with the result of posttreatment PET.

Results Nine of thirty-two patients with residual masses on posttreatment CTscan (28%) had positive FDG-PET showing residual tracer uptake (Table 2). There was no signifi-

cant difference in the rate of positive FDG-PET between HD or aggressive NHL patients. With median follow-up of 38 months for the whole group, 10 patients (3 HD and 7 NHL) relapsed and all were proven histologically. Out of the nine patients with positive PET, eight relapsed (89%). This compares favourably to only 2 relapses in the 23 patients with negative PET (9%). The difference in relapse rates is statistically significant (x 2 = 15.8, P < 0.01). In the HD group, none of the 11 patients with negative PET have relapsed with median follow-up of 43 months. Of the 4 with positive PET, 1 had persistent disease following treatment, 2 relapsed at 2 and 10 months following the PET scan and the fourth patient

Figure I. A 26-year-old female with high-grade large B-cell NHL. stage Ha (right lower cervical nodes and bulky mediastinal mass): (a) Pre-treatment scans: left: PET scan showing increased uptake in the mediastinum and lower right neck (note the physiologic uptake in the myocardium below the mediastinal mass): Right: CTscan through the mediastinal mass. (b) Post-treatment scans, after completion of six courses of CHOP chemotherapy and modified mantle radiotherapy to the neck and mediastinum: left: PET scan showing residual uptake in the neck (impalpable disease clinically) and mediastinum (arrow); right: CTscan showing residual mediastinal mass. CT-guided needle biopsy was negative. (c) Follow-up scans three months later: left: PET scan showing more uptake in the neck and mediastinum; right: CT scan showing unchanged residual mediastinal mass. Mediastinoscopic biopsy was negative. (d) Follow-up scans eight months post-treatment showing radiologic progression: left: PET scan showing more mediastinal uptake (neck uptake is not shown on this coronal projection); right: CTscan showing increase in size of mediastinal mass. A third biopsy through an open thoracotomy confirmed the presence of lymphoma. The patient received high-dose chemotherapy and stem cell rescue and the post-transplant PET scan was negative. She remains in remission 24 months after her salvage treatment.

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2-[18F]-fluoro-2-deoxy-D-glucose (FDG) was produced from an onsite cyclotron and chemistry facility. Patients were fasted for at least four hours. Thirty minutes after the intravenous administration of 350 MBq of 18-FDG, a series of 10 minute, 10.6 cm scans were obtained to image from the vertex of the head to mid-thigh using an ECAT 951R PET scanner (Siemens, Knoxville, TN). Images were displayed for interpretation as whole body projections and transaxial, coronal and sagittal tomographic sections. When indicated higher resolution localised images were obtained with attenuation correction. The spatial resolution was approximately 12 mm and 8 mm for whole body and locally reconstructed images respectively. All scans were independently reported by two Nuclear Medicine Physicians

Table I. Patient characteristics.

150 continues without pathological confirmation of relapse (due to his psychiatric condition) at 2.5 years. In the NHL group, there were 2 relapses in the 12 patients with negative PET, at 7 and 12 months. The median follow-up of the 10 patients in continued remission is 31 months. None of the five patients with positive PET remains in remission. Two had persistent disease, and three relapsed at four, eight and twenty-four months after the PET. Discussion

References 1. Orlandi E, Lazzarino M. Brusamolino E et al. Residual mediastinal widenning following therapy in Hodgkin's disease. Hematol Oncol 1990; 8: 125-31. 2. Surbone A, Longo DL, De Vita VT Jr et al. Residual abdominal masses in aggressive non-Hodgkin's lymphoma after combination chemotherapy: Significance and management. J Clin Oncol 1988; 6- 1832-7. 3. Canellos GP. Residual mass in lymphoma may not be residual disease. J Clin Oncol 1988; 6: 931-3. 4. North LB, Fuller LM, Sullivan-Halley JA et al. Regression of mediastinal Hodgkin disease after therapy: Evaluation of time interval. Radiology 1987; 164: 599-602. 5. Lewis E, Bernardino ME, Salvador PG et al. Post-therapy CTdetected mass in lymphoma patients: Is it viable tissue9 J Comp Ass Tom 1982; 6: 792-5. 6. Djulbegovic B, Hendler FJ, Hamm J et al. Residual mediastinal mass after treatment of Hodgkin's disease: A decision analysis. Med Hypoth 1992; 38: 166-75 7. Bnsse H. Pacquement H, Burdairon E et al. Outcome of residual mediastinal masses of thoracic lymphomas in children: Impact on management and radiological follow-up strategy. Pediatr Radiol 1998; 28: 444-50. 8. Glenn LD, ICumar PP. The residual mediastinal mass following radiation therapy for Hodgkin's disease. Am J Clin Oncol 1991. 14: 16-24. 9. Wittich GR, Nowels KW, Korn RL et al. Coaxial transthoracic fine-needle biopsy in patients with a history of malignant lymphoma. Radiology 1992; 183. 175-8 10. Front D. Israel O. The role of Ga-67 scintigraphy in evaluating the results of therapy of lymphoma patients. Semin Nucl Med 1995; 25: 60-71. 11. Setoain FJ, Pons F, Herranz R et al. 67-Ga scintigraphy for the evaluation of recurrences and residual masses in patients with lymphomas. Nucl Med Commun 1997, 18: 405-11. 12. Mikhaeel NG, Ahern V, Barrington S et al. Post-treatment remission assessment in lymphoma using FDG-PET scanning. Br J Cancer 1997; 76 (Suppll): 32. 13. Cremerius U. Fabry U, Neuerurg J et al. Positron emission tomography with 18F-FDG to detect residual disease after therapy for malignant lymphoma. Nucl Med Commun 1998; 19: 1055-63. 14. Bonadonna G, Zucali R, Monfardini S et al. Combination chemotherapy for advanced Hodgkin's disease with Adriamycin, bleomycin, vinblastine. and imidazole carboxamide vs. MOPP. Cancer 1975; 36: 252-9. 15. McKelvey EM, Gottlieb JA. Wilson HE. Hydroxydaunomycin (Adriamycin) combination chemotherapy in malignant lymphoma. Cancer 1976: 38: 1484-93. 16. Lister TA, Crowther D. Sutcliffe SB et al. Report of a committee convened to discuss the evaluation of patients with Hodgkin's disease. Cotswolds meeting. J Clin Oncol 1989; 7: 1630-6. 17. International Commission on Radiological Protection (ICRP). Pergamon Press: Annals of the ICRP 53. 1987: 18: 1-4. 18. Shrimpton PC, Jones DG. Hillier MC et al. Survey of CT Practice in the UK. Part 2: Dosimetric Aspects. London: HSMO 1991; NRBP-R249. Correspondence to: A. R.Timothy. MD Department of Clinical Oncology St. Thomas' Hospital Lambeth Palace Road London SE1 7EH UK

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Assessment of response to treatment in lymphomas has relied mainly on the reduction in size of the enlarged lymph nodes or masses both clinically and radiologically. However, it has long been recognised that persistent radiologic abnormalities may not necessarily indicate residual lymphoma [5, 24-26]. The Cotswolds meeting report acknowledged 'the considerable uncertainty about the significance of persistent abnormalities after treatment' and introduced the category 'CRu' (complete remission unconfirmed/uncertain) [16]. The ability to establish the true nature of these residual masses is important. It will prevent delay of further treatment for those with persistent lymphoma, while avoiding the risk of additional morbidity for those in remission. Determining the exact nature at an early stage may also avoid the need for frequent CT scans during follow-up with the consequent implications for radiation exposure and resources. While CT scanning relies mainly on morphological changes, functional imaging reflects the metabolic activity of sites of disease by the preferential accumulation of radionuclide labelled tracers. In this study, metabolic imaging with FDG-PET appears capable of distinguishing, with a high degree of accuracy, residual masses containing active lymphoma from those containing ablated disease. With median follow-up of 38 months, patients with PET positive residual mass had a relapse rate of 89%, while those with PET negative residual mass had a relapse rate of only 9%. Although similar results have been obtained with Ga-67 scanning [10, 11], there are advantages for FDGPET. It offers higher resolution images with three-dimensional data and better ability to quantify radioactivity in small lesions, better visualisation of intra-abdominal disease, and more patient convenience with the whole examination completed in two hours at a single visit. Estimated average radiation exposure doses with FDGPET are significantly lower than either Ga-67 or wholebody CT scanning (9, 18, 27 mSv, respectively) [17, 18]. In conclusion, this study suggests that FDG-PET can differentiate between residual masses containing viable tumour, where further treatment will be required to achieve cure and those representing ablated disease, where unnecessary treatment and additional morbidity may be avoided. The increased availability of PET tech-

nology will hopefully enable large collaborative studies to confirm these findings.