The value of gallium imaging after therapy for Hodgkin's disease

Article (PDF Available)inCancer 82(4):754-9 · February 1998with22 Reads
DOI: 10.1002/(SICI)1097-0142(19980215)82:4<754::AID-CNCR19>3.0.CO;2-X · Source: PubMed
Abstract
Although it is used widely, the value of gallium imaging in managing Hodgkin's disease remains unclear. A retrospective review of gallium imaging and treatment outcome in 60 patients with Hodgkin's disease treated between January 1990 and July 1995 was conducted. The minimum follow-up was 1 year. Based on gallium imaging, 46 patients were in complete remission (CR) after initial treatment, 10 were in partial remission (PR), and 4 had persistent or progressive disease (NR). Ten of 29 patients (34%) with gallium CR after chemotherapy subsequently recurred, compared with no recurrences in 17 patients receiving initial radiotherapy or combined chemoradiation. Eight of ten patients received further therapy after gallium PR, and nine patients remained disease free at last follow-up. Survival did not differ in patients achieving a gallium CR or PR. Gallium-67 imaging may help confirm the presence of active Hodgkin's disease, but was unreliable in defining disease remission after chemotherapy in this study population. Patients with a gallium PR may still have a good prognosis after additional therapy.
754
The Value of Gallium Imaging after Therapy for
Hodgkin’s Disease
BACKGROUND.
Although it is used widely, the value of gallium imaging in managing
Jeffrey A. Bogart,
M.D.
1
Hodgkin’s disease remains unclear.
Chung T. Chung,
M.D.
1
METHODS.
A retrospective review of gallium imaging and treatment outcome in 60
Neil F. Mariados,
M.D.
1
patients with Hodgkin’s disease treated between January 1990 and July 1995 was
Andrei I. Vermont,
M.D.
2
conducted. The minimum follow-up was 1 year.
Sheila M. Lemke,
M.D.
3
RESULTS.
Based on gallium imaging, 46 patients were in complete remission (CR)
Sara Grethlein,
M.D.
3
after initial treatment, 10 were in partial remission (PR), and 4 had persistent or
Stephen L. Graziano,
M.D.
3
progressive disease (NR). Ten of 29 patients (34%) with gallium CR after chemother-
apy subsequently recurred, compared with no recurrences in 17 patients receiving
1
Department of Radiation Oncology, State Uni-
initial radiotherapy or combined chemoradiation. Eight of ten patients received
versity of New York Health Science Center, Syr-
further therapy after gallium PR, and nine patients remained disease free at last
acuse, New York.
follow-up. Survival did not differ in patients achieving a gallium CR or PR.
2
Department of Radiology, State University of
CONCLUSIONS.
Gallium-67 imaging may help confirm the presence of active Hodg-
New York Health Science Center, Syracuse, New
kin’s disease, but was unreliable in defining disease remission after chemotherapy
York.
in this study population. Patients with a gallium PR may still have a good prognosis
3
Department of Medicine, State University of
after additional therapy. Cancer 1998;82:7549.
New York Health Science Center, Syracuse, New
q 1998 American Cancer Society.
York.
KEYWORDS: gallium imaging, Hodgkin’s disease, recurrence, chemotherapy, radio-
therapy.
A
dvances in treatment over the past several decades have lead to
marked improvement in the survival of patients with Hodgkin’s
disease. However, as patients are cured of Hodgkin’s disease and live
longer, the serious late side effects of treatment with chemotherapy
and irradiation are increasingly recognized.
1,2
Recent efforts have fo-
cused on delivering less toxic treatment without compromising cure
rates. One tool that may be helpful in tailoring therapy is tumor
imaging with gallium (Ga)-67 citrate. Gallium theoretically takes up
in active tumor, but not in fibrosis, and may assess physiologic re-
Presented in part at the 32nd Annual Meeting
sponse to therapy.
3
However, reports of the utility of gallium imaging
of the American Society of Clinical Oncology,
have been mixed, perhaps due to factors including insufficient gallium
Philadelphia, Pennsylvania, May 1821, 1997;
and the 1996 Annual Meeting of the American
dose, older scanning techniques, and limited patient follow-up.
4–6
Society for Therapeutic Radiology and Oncol-
The goal of the current study was to evaluate the predictive value of
ogy, Los Angeles, California, October 27 30,
posttherapy gallium imaging in recently treated patients with ade-
1996.
quate follow-up.
Address for reprints: Jeffrey A. Bogart, M.D.,
MATERIALS AND METHODS
Department of Radiation Oncology, SUNY
Between January 1990 and July 1995, 101 patients were seen with the
Health Science Center, 750 E. Adams Street,
diagnosis of Hodgkin’s disease. Gallium imaging was performed at
Syracuse, NY 13210.
some time on 86 patients. Sixty patients had response to initial ther-
apy assessed with gallium and served as the basis for this retrospective
Received March 19, 1997; revision received July
16, 1997; accepted August 15, 1997.
review. Of these patients, 53 had positive gallium scans prior to the
q 1998 American Cancer Society
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Gallium Imaging for Hodgkin’s Disease/Bogart et al. 755
TABLE 1
initiation of therapy whereas 7 patients did not have
Prognostic Factors for Gallium-67 Remission
a pretreatment study. Patients were followed for a
minimum of 1 year, with a median follow-up of 37
Factor CR PR NR Chi-square P value
months (range, 1374 months). Patient age ranged
from 3 66 years, with a median of 24 years. Twenty-
Gender
Male 25 6 2 0.149 0.9281
seven patients were female and 33 were male. Forty-
Female 21 4 2
four cases were nodular sclerosing, 10 were mixed cel-
Symptoms
lularity, and 3 each were lymphocyte predominant and
A 28 6 0 5.607 0.06
lymphocyte depleted.
B1844
Staging workup included a history and physical
Stage
III 32 7 3 0.052 0.975
examination, complete blood count, electrolytes, and
III–IV 14 3 1
liver function tests. Imaging studies included poster-
Histology
oanterior (PA) and lateral chest X-rays and computed
NS 33 8 3 0.293 0.864
tomography (CT) scans of the chest, abdomen, and
Other 13 2 1
pelvis. Lymphangiography was performed in only
Age (yrs)
°25 19 6 3 2.536 0.281
eight patients. Staging laparotomy and splenectomy
ú25 27 4 1
were performed in ten patients, all of whom were
Mediastinal mass
treated with subtotal lymph node irradiation. Bone
Bulky 25 6 2 0.149 0.9281
marrow was evaluated in all patients. Large mediasti-
Not bulky 21 4 2
nal mass was defined as ú 33% of the transthoracic
Imaging
technique
dimension at the T5-T6 level on PA chest X-ray. Stag-
SPECT 30 7 1 2.793 0.2475
ing was as follows: IA, 5 patients; IIA, 19 patients; IIB,
Planar 16 3 3
17 patients; IIIA, 8 patients; IIIB, 3 patients; IVA, 2
patients; and IVB, 6 patients (Ann Arbor staging sys-
CR: complete remission; PR: partial remission; NR: no response; NS: nodular sclerosing; SPECT: single
tem).
photon emission computed tomography.
Treatment prior to restaging gallium scan was ra-
diotherapy alone in 11 patients, 26 cycles of combi-
nation chemotherapy in 41 patients, and chemother-
apy combined with radiation in 8 patients. Most pa- factors with gallium remission. The Kaplan-Meier esti-
mate was used to calculate survival and survival com-tients were treated with doxorubicin, bleomycin,
vinblastine, and dacarbazine (ABVD) or alternating parisons were performed using log rank comparison.
7,8
Prognostic significance for individual covariates andmechlorethamine, vincristine, procarbazine, and
prednisone (MOPP) and ABVD chemotherapy. Radia- potential covariate interactions were evaluated by use
of the Cox proportional hazards model.
9
tion doses ranged from 35 44 Gray (Gy) in patients
receiving primary irradiation, and from 1547 Gy
when given in conjunction with chemotherapy. Gal-
RESULTS
Response to Therapy
lium imaging generally was performed 38 weeks after
chemotherapy or irradiation. Single photon emission Forty-six patients were in gallium CR after treatment,
10 in PR, and 4 were NR. Eleven patients receivedcomputed tomography (SPECT) images were obtained
in 38 of 60 restaging gallium scans. A median dose of subtotal lymph node or mantle field radiotherapy prior
to restaging gallium imaging, with 9 CRs and 2 PRs.9.2 millicuries (mCi) Ga-67 citrate (range, 3.3 10.4
mCi) was used for imaging at restaging, and ú 6 mCi Both PR patients had persistent gallium uptake in the
mediastinum. All eight patients receiving combinedwas used in 90% of cases. Images generally were ob-
tained 48 72 hours after Ga-67 injection. chemotherapy and irradiation prior to restaging had
gallium CR. Of 41 patients treated with chemotherapyComplete remission (CR) was defined as the ab-
sence of abnormal uptake on posttherapy Ga-67 scin- prior to restaging, 29 had CR, 8 PR, and 4 NR, with
disease progression also noted clinically as well as bytigraphy, partial remission (PR) as ú 33% reduction in
the area of gallium uptake compared with pretreat- CT scan. Only three patients in CR after therapy did
not have a pretreatment gallium scan, and all had ament gallium or CT scan, and no response (NR) as
persistent or progressive disease on gallium scan. All large mediastinal mass at presentation.
Chi-square analysis (Table 1) was performed com-patients with clinical recurrence after CR had biopsy
proven disease. Survival was calculated from date of paring gallium remission (CR, PR, and NR) with gen-
der, age, stage, size of mediastinal mass, systemicdiagnosis of Hodgkin’s disease. Chi-square contin-
gency tables were used to test correlation of prognostic symptoms, and histologic subtype. Patients with B
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756 CANCER February 15, 1998 / Volume 82 / Number 4
TABLE 2
Prognostic Factors for Recurrence after Chemotherapy-Induced Gallium-67 Complete Remission
Log rank P Proportional hazards
Factor No. of patients 3-yr RFS value P value
Mediastinal mass
Bulky 12 66% 0.95 0.59
Not bulky 17 75%
Imaging technique
SPECT 17 62 0.88 0.81
Planar 12 75
Chemotherapy prior to gallium CR
56 cycles 14 68 0.95 0.76
°4 cycles 15 71
Gender
Male 18 61 0.74 0.75
Female 11 81
Symptoms
A 16 65 0.82 0.39
B1374
Stage
I–II 17 73
IIIIV 12 63 0.68 0.62
Histology
Other 9 89 0.19 0.14
NS 20 60
Age (yrs)
°25 14 68 0.95 0.30
õ25 15 68
Adjuvant RT
Yes 19 76 0.07 0.05
No 10 51
CR: complete remission; RFS: recurrence free survival; SPECT: single photon emission computed tomography; NS: nodular sclerosing; RT: radiotherapy.
symptoms more often had progressive disease, but ogy (P Å 0.08), although recurrence free survival was
not significantly decreased. Patients with early galliumthere were no other significant findings.
CR (four or more cycles of chemotherapy) showed a
rate of recurrence similar to those patients who were
Disease Recurrence and Survival
Of 46 patients with a CR, Hodgkin’s disease subse- gallium negative after five or more cycles.
Ten patients were in PR after initial therapy, in-quently recurred in 10 patients. No patient with a CR
after radiotherapy or combined chemoradiotherapy cluding four patients who did not undergo gallium
scans prior to the initiation of chemotherapy. Two pa-recurred, compared with 10 of 29 patients with a CR
after chemotherapy. Tumor recurred in or adjacent to tients had decreased but persistent gallium uptake on
imaging studies after completing subtotal lymph nodean area of initial disease involvement in nine of ten
patients (Table 2). All recurrences were gallium avid. irradiation. Both remained recurrence free without
further treatment with a follow-up of ú 4 years, andSalvage therapy included high dose chemotherapy
with autologous bone marrow or peripheral stem cell a subsequent gallium scan obtained 6 months later in
one of these patients was clear. Gallium PR was ob-support in nine patients and total lymph node irradia-
tion in one patient. At last follow-up, six of these pa- served after chemotherapy in eight patients, correlat-
ing to a residual mass on CT scan in seven. All under-tients were free of disease, two were alive with disease,
and two had died. Five of 19 patients receiving consol- went further therapy; four received mantle or subtotal
lymph node radiotherapy, 3 underwent autologousidative irradiation after a gallium CR to chemotherapy
recurred, compared with 5 recurrences in 10 patients bone marrow transplant (with posttransplant radio-
therapy in two patients), and one underwent two fur-treated with chemotherapy alone (P Å 0.07) (Table 3).
There was a trend toward an increased number of ther cycles of chemotherapy followed by mantle irradi-
ation. At last follow-up, 1 patient had died from a com-recurrences for disease with nodular sclerosing histol-
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Gallium Imaging for Hodgkin’s Disease/Bogart et al. 757
TABLE 3
Recurrence after Chemotherapy-Induced Gallium-67 Complete Remission
Chemotherapy
(cycles prior
Age to Ga CR/ Imaging Radiation Recurrence
(yrs) Gender Stage Histology total) technique consolidation location & time
26 Male IVA NS ABVD (6/6) SPECT 36 Gy Med Mediastinum (17 mos)
19 Female IIA NS EVA (3/6) SPECT 35 Gy Med Chest wall (14 mos)
43 Female IIA NS ABVD (6/6) Planar 47 Gy Med Med/lung (36 mos)
43 Female IIA NS M/A (6/6) Planar 35 Gy PAN Med/lung (11 mos)
22 Male IVB NS ABVD (4/6) SPECT None Mediastinum (22 mos)
42 Male IIB LD CHOPE (5/5) Planar None Axilla (2 mos)
16 Female IIB NS M/A (3/6) SPECT None Neck (49 mos)
12 Male IIIA NS M/A (4/8) SPECT None Mediastinum (4 mos)
28 Male IVB NS ABVD (3/8) SPECT None Neck (11 mos)
15 Male IIIB NS M/A (6/8) SPECT 21 Gy STN1 Mediastinum (2 mos)
NS: nodular sclerosing; LD: lymphocyte depletion; ABVD: doxorubicin, bleomycin, vinblastine, and dacarbazine; MOPP: mechlorethamine, vincristine, procarbazine, and prednisone; M/A: MOPP & ABVD; EVA:
etoposide, vincristine, and doxorubicin; CHOPE: cyclophosphamide, doxorubicin, adriamycin, vincristine, prednisone, and etoposide; SPECT: single photon emission computed tomography; Gy: gray; Med:
mediastinum; STNI: subtotal lymph node irradiation; Ga CR: complete remission on Gallium-67 imaging; PAN: paraaortic lymph nodes.
plication related to bone marrow transplant and the tablished, because most patients with PR went on to
further therapy.other seven patients remained free of disease.
Three of 4 patients with progressive disease (NR) A high negative predictive value for gallium im-
aging has been reported by Hagemeister et al,
15
withafter chemotherapy died 734 months after diagnosis,
and 1 patient was salvaged with autologous bone mar- only 1 recurrence of 33 patients with a negative SPECT
gallium scan after 3 cycles of mitoxantrone, vincris-row transplant followed by involved field irradiation.
Five-year Kaplan-Meier overall survival was 85%, tine, vinblastine, and prednisone (NOVP) chemother-
apy for Stage I-III Hodgkin’s disease. Similarly, Gaspar-with a 5-year clinical recurrence free survival of 66%.
There was no difference between 5-year clinical dis- ini et al
16
evaluated 16 patients at restaging and 18 with
suspected recurrence using planar imaging in mostease free (59% vs. 90%) or overall (88.5 vs. 90%) survival
for patients with a gallium CR or PR, respectively. Log instances, with a 93.9% negative predictive value.
However, most reports suggest a higher rate of recur-rank analysis did not demonstrate a significant associ-
ation between disease free or overall survival and gen- rence, especially for patients with advanced disease.
16
In a prospective Pediatric Oncology Group Study, re-der, B symptoms, stage, mediastinal mass size, histol-
ogy, or age. currence was observed in 3 of 18 gallium negative pa-
tients with mediastinal Hodgkin’s disease.
17
Cooper et
al
18
reported 12 recurrences (9 supradiaphragmatic) in
DISCUSSION
Since the discovery of Ga-67 responsiveness in 44 patients in gallium CR with mediastinal Hodgkin’s
disease. In addition, 4 of 19 patients in gallium CRlymphomas, several roles have been proposed for gal-
lium scintigraphy in the evaluation and management after 2 cycles of chemotherapy in the series by Ekert et
al recurred at sites of prior disease after 2 4 additionalof Hodgkin’s disease: identification of tumor-bearing
areas not detected on anatomic imaging, refinement cycles of chemotherapy.
19
Our results also demon-
strate that patients with negative gallium scans afterof tumor volumes for radiotherapy portals, and assess-
ment of early tumor recurrence.
10–12
The focus of the therapy remain at risk for recurrence at initial sites of
disease. Nine of ten recurrences were in or adjacentcurrent review was to evaluate the role of gallium in
predicting disease outcome, and hence the ability of to areas of initial disease, reflecting the inability of
gallium scintigraphy to detect small volume residualgallium response to treatment to guide further ther-
apy. disease.
Subset analysis did not reveal specific characteris-Predictive values of posttherapy gallium scanning
vary widely.
13,14
Considering the entire study popula- tics of patients who recurred after gallium CR. There
was a trend toward an increased absolute number oftion, the negative predictive value is 78%, but only 66%
for patients with normal gallium examinations after recurrences in patients with nodular sclerosis histol-
ogy, but recurrence free survival did not vary signifi-chemotherapy. A positive predictive value was not es-
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758 CANCER February 15, 1998 / Volume 82 / Number 4
cantly with histology in univariate or proportional haz- years after chemoradiotherapy. We do not believe the
inclusion of these patients biased our review, becauseard analysis. Adjuvant consolidative irradiation was
associated with a trend toward improved recurrence bulky mediastinal tumors have a very high rate of gal-
lium responsiveness (Cooper et al noted 100% galliumfree survival (P Å 0.05), but due to salvage therapy, no
variable correlated with overall survival. Furthermore, responsiveness in 45 patients with mediastinal Hodg-
kin’s disease).
18
In addition, excluding these patientsno conclusions can be drawn regarding treatment ef-
fects, given the retrospective nature of this study and from the study would not alter the ndings significantly.
We believe the value of gallium imaging has yet tothe potential for patient selection. An early gallium CR
(i.e., after four or fewer cycles of chemotherapy) did be clearly determined. Our current strategy is to deliver
treatment based on initial prognostic factors, and notnot provide assurance of a durable remission and re-
currences were comparable to patients with late CRs decrease therapy based on gallium resolution. However,
evaluation for further treatment may be warranted for(five to six cycles of chemotherapy), which corrobo-
rates the data from the study of Ekert et al showing that patients with persistent gallium uptake after chemother-
apy. The optimal extent of additional therapy is unclear.patients with early CR remain at risk of recurrence.
19
In addition, although SPECT is purported to be more Prospective trials are needed to further define the value
of Ga-67 imaging.sensitive than planar imaging, recurrence rates were
similar for both imaging techniques.
12
Overall, gallium
imaging was unable to detect patient subgroups that
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    • "Recurrence occurred in 34% of HD patients with a negative GS after treatment, mostly in or adjacent to the original sites of disease, indicating the failure of GS to detect small-volume residual disease [113]. Although SPET has improved lesion resolution, it is still limited, and small viable disease clusters may be overlooked, particularly if they are surrounded by a large amount of necrotic and fibrotic tissue [112, 114]. "
    [Show abstract] [Hide abstract] ABSTRACT: Until recently, gallium-67 scintigraphy (GS) has been the best available functional imaging modality for evaluating patients with non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD). The diagnostic accuracy of GS in detecting lymphoma is based on optimisation of the imaging protocol, knowledge of potential physiological and benign sites of (67)Ga uptake, and the Ga avidity characteristics of the individual lymphoma. As (67)Ga is a tumour viability agent, the role of GS is primarily at follow-up. A residual mass persisting on CT after treatment poses a common clinical dilemma: it may indicate the presence of viable lymphoma, which requires further treatment, or it can be benign, consisting of only fibrotic and necrotic tissues. GS can successfully differentiate between these conditions. Routine follow-up with GS may allow early diagnosis of recurrence and early institution of treatment. Reversion of a positive GS to a negative test, and the rapidity with which this occurs has a high predictive value for the outcome of the individual patient. Lymphoma showing a normal GS early during treatment has a better prognosis than lymphoma with persistence of pathological findings. Other tumour-seeking single-photon emitting agents, such as thallium-201, technetium-99m methoxyisobutylisonitrile and indium-111 octreotide, have been investigated in lymphoma, primarily as an alternative to GS in specific clinical settings, but are of limited value. The role of radioimmunoscintigraphy is gaining importance in conjunction with radioimmunotherapy. Fluorine-18 fluorodeoxyglucose (FDG) imaging of lymphoma using either dedicated or camera-based PET systems is gradually replacing GS for assessment of lymphoma. FDG overcomes some of the limitations of GS while sharing its tumour viability characteristics. The extensive clinical knowledge and experience accumulated over three decades with GS in lymphoma provides a solid background as well as a model for the assessment of new functional imaging techniques.
    Full-text · Article · Jul 2003
  • [Show abstract] [Hide abstract] ABSTRACT: We analysed the data of 56 patients retrospectively who got the diagnose of Morbus Hodgkin during the period of March 1985 to February 1994 at the Klinikum Rechts der Isar. The following entry criterias were set: A Gallium scan before treatment had to be positive. As for the patients characteristics we had a sexual division of 42% female and 58% male at an median age of 39. More than half of the patients were 21 to 42 years old. The nodular sclerosis and the mixed cellularity were the major histologic subtypswith an occurance of 70% and 22%. The clinical stages showed the following division: stage I 14%, stage II 38%, stage III 28% and stage IV 20%. Like Johnston 1977 we found a sensitivity of Gallium scans for each lymph node area which had to be considerated for the judgement of the scintigraphic pictures. The summed up sensitivities were about 65 % supradiaphragmal and 3 % infradiaphragmal. Until today the role of the Gallium scintigraphy for the primary diagnose is far behind all other procedures. The CT shows much better results in sensitivity as well as in specify. Generally our results are in good correlation to other publications that were made under the same conditions. The Gallium scans show a complete remission in 27 of 32 cases at the staging after therapy. All cases were judged as a complete clinical remission although partly in disagreement with the CT results. Two relapses occurred in this group during an average observing period of 53 months. There for the probability of a disease free survival with a negative Gallium scan is 93%. Gallium enrichments, that showed still active Hodgkin tissue, were found in five cases. Foue patients of those suffered a relapse which leads to a positive predictive result of 80%. The CT confirms a complete remission in 18 cases after therapy. One of those patients got a relapse. This results in a negative predictive rate of 95%. The CT of 14 patients after therapy still showed tissue in the meaning of a partial remission or a progression. Five of those suffered a relapse. This leads to a postive predictive value of 36%.
    Article · · European journal of nuclear medicine and molecular imaging
  • Article · · European journal of nuclear medicine and molecular imaging
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