Evaluation of Protracted
Cisplatinum Infusion in Advanced Anaplastic Thyroid Cancer
Ghosh G1,
Singh
OP2
1Dr. Gopa Ghosh, Consultant, Radiation & Clinical Oncology, L N
Medical College & Research Centre, Bhopal, India. 2Dr. O.P.
Singh, Professor, Radiation & Clinical Oncology, Gandhi Medical
College, Bhopal, India.
Address for
correspondence: Dr Gopa Ghosh, Email:
gopaghosh571@yahoo.in.
Abstract
Introduction:
Anaplastic thyroid cancer (ATC) constitutes 1-3% of all thyroid
malignancies. Most of the patients of anaplastic thyroid cancer
presents with advanced inoperable lesion associated with neck mass
dysphagia, and SVC syndrome. At this stage only treatment that can be
offered is chemotherapy, as this variety of thyroid cancer does not
generally concentrate iodine. Present study evaluates protracted (8 hr)
Cisplatinum (CDDP) infusion along with doxorubucin in comparison to
conventional (1hr) Cisplatinum + doxorubucin in advanced anaplastic
thyroid cancer in terms of tolerance, toxicities and response rates. Methods: 32
previously untreated cases of stage III/IV inoperable anaplastic
thyroid cancer were included in the present study. Patients
were divided into 2 arms of 16 patients each. Arm I (16 patients)
received 1 hr Cisplatin (CDDP) infusion 75mg/m2 + Doxorubicin 60mg/m2
infusion & Arm II (16 patients) received protracted 8
hrs CDDP infusion 75mg/m2+ Doxorubicin 60mg/m2 infusion. All patients
were evaluated for tolerance, toxicities and response rate. Results: Arm II
patients showed better locoregional response with CR 31.25%, PR 50%, SD
6.25%,PrD. 12.5% as compared to Arm I patients with CR 12.5%, PR
43.75%, SD 18.75%, Pr. D 25%, p= .02. Toxicities like mucositis, nausea
& vomiting, diarrhea, nephrotoxicity were also significantly
less in Arm II. After completion of 3-4cycles of Induction CT, all
patients were treated with External Radiotherapy of 60-66Gy, followed
with 2-3 cycles of adjuvant CT. Conclusion:
From the present study it can be concluded that protracted cisplatinum
infusion along with other chemotherapeutic drugs is an effective and
acceptable CT regimen in advanced inoperable thyroid cancer.
Key words:
Anaplastic thyroid cancer, chemotherapy, prolonged cisplatinum.
Manuscript received:
13th Aug 2013, Reviewed:
26th Aug 2013
Author Corrected:
29th Aug 2013, Accepted
for Publication: 20th Sep 2013
Introduction
Historically,
ATC was said to constitute 5-15% of all thyroid carcinomas in United
States [1] and 10-50% in Europe [2]. Current epidemiologic studies
indicate that this lethal form of thyroid cancer has decreased to
between 1-3% worldwide of the total number of cases [3]. The decrease
over time may be partially related to iodine prophylaxis and an overall
decrease in endemic iodine deficient goiter [3-6]. Anaplastic cancer
originates from follicular cells of thyroid. Tumor grows rapidly and
prognosis is grave. Local invasion of structures like trachea,
esophagus and superior mediastinum is followed by distant metastasis
& death [4-7]. Management of anaplastic thyroid cancer
advocates debulking by surgical resection, External radiotherapy (RT)
chemotherapy (CT) [7-10].
Most of the patients present with advanced non operable lesion
associated with neck mass, dysphagia, dysphonia and SVC syndrome [6,7].
In such cases the only form of treatment that can be offered is
chemotherapy. These cancers do not concentrate iodine [6]. The most
common chemotherapeutic drug used in such cases is Doxorubicin used
singly or in combination. Combination of Cisplatinum and Doxorubicin is
the most common combination that has been widely tried [7, 10-12].
Cisplatinum is usually administered as 1hr infusion but
nowadays-protracted infusion like 6 hrs or 24 hrs has been tried in
advanced head& neck cancer [11-13]. Other chemotherapeutic
regimens that have been tried are Adriamycin, Bleomycin, and Paclitaxe
[l7,14].
Combinations like CDDP +Doxorubicin +Etoposide+Peplomycin have been
investigated by some researchers like (Japanese society of thyroid
surgery) [15]. Voig et al [16] evaluated Gemcitabine +CDDP in
anaplastic thyroid cancer. Protracted cisplatinum infusion
has been explored in Paediatric tumours like neuroblastoma as well
[17]. In view of prolonged cisplatinum infusion being tried in Head
& Neck cancer previously as mentioned above, protracted 8 hrs
cisplatinum infusion in combination with Doxorubicin has been evaluated
in advanced anaplastic thyroid carcinoma in terms of response rate and
toxicity as compared to 1 hr infusion in this study
Material
and Methods
32
previously untreated histopathologically proved advanced thyroid
carcinoma patients who were reported in department of
Radiotherapy S.S. Medical College Rewa & Gandhi Medical College
Bhopal between Jan 2004 to Jan 2009 constitutes the study subject.
Inclusion criteria of
patients were:
1. Patients with T3/T4 tumours with/ without neck nodes, ECOG
performance status 1-2, Age between 45-60 yrs, Informed consent
2. Laboratory investigations criteria were: Hb > 10 gm %,
TLC>2500cells/cc, Platelets > 100000/cc, S. Creatinine
<1.5 mg/dl, S. Bilirubin<2mg/dl
31 patients were histopathologically proved anaplastic carcinoma one
patient was of medullary carcinoma thyroid.
Treatment Protocol:
The patients were divided in to 2 arms of 16 each
Arm I (16) patients received CDDP75 mg /m2 (1hr) infusion + doxorubicin
60 mg/m2 I.V.
Arm II (16) patients received CDDP 75/m2 (8 hrs infusion)+ doxorubicin
60mg/m2 I/V
Hydration with normal saline, mannitol and prophylactic premedication
with dexamethasone, diphenhydramine and ondensetron were administered
to all patients. LFT, KFT and haematological tests were done before
every cycle of chemotherapy. Patients were observed for toxicities of
chemotherapy like nausea and vomiting diarrhea, alopecia, stomatitis
ototoxicity, neurotoxicity, cardiotoxicity etc and response was
assessed after every cycle of CT. Response was assessed for primary
tumour, nodal disease and distant metastatic sites like lung, bone etc.
Response was assessed as: CR- Complete response, PR- Partial response,
SD- Stable disease, NR-No response, Pr. D- Progressive disease
Follow up:
First follow up was done after one week of first cycle of chemotherapy
to note skin and mucosal toxicities and hematological toxicities.
Subsequent follow up at 2 weekly intervals till 1year after completion
of treatment, (6 cycles of chemotherapy and radiotherapy 60 Gy)
Follow up consisted assessment of response, Toxicities like
haematological, gastrointestinal, nephrotoxicity, Residual and
progressive disease at primary or metastatic site
Results
Table 1: Response (Locoregional)
of Chemotherapy
|
Response
|
Arm I (1hr)
|
Arm
II (8hr)
|
|
CR
|
2(12.5%)
|
5(31.25%)
|
|
PR
|
7(43.75%)
|
8(50%)
|
|
SD
|
3(18.75%)
|
1(6.25%)
|
|
Pr. D
|
4 (25%)
|
2(12.5%)
|
Arm II (8hr) patients had better loco regional response than
Arm I (1hr) in terms of CR /DFS (Disease free survival), PR. p=0.02
Table 2: Response at
metastatic sites
|
|
No
|
CR
|
PR
|
Pr D
|
SD
|
|
No.
|
CR
|
PR
|
Pr.D
|
SD
|
|
Lung
|
4
|
0
|
2/4(50%)
|
2/4(50%)
|
-
|
Lung
|
6
|
2/6(33%)
|
4/6(67%)
|
Nil
|
-
|
|
Bone
|
4
|
0
|
2/4(50%)
|
2/4(50%)
|
|
Bone
|
4
|
0%
|
4/4(100%)
|
Nil
|
-
|
|
Brain
|
Nil
|
|
-
|
-
|
-
|
Brain
|
Nil
|
|
-
|
-
|
-
|
Arm II patients showed improved response at
metastatic sites like lung & bones as well, p=0.06
Table 3: Side Effect/
Toxicity: Acute Mucositis
|
|
Arm I
|
Arm II
|
|
Grade I
|
4 (25 %)
|
3 (18.75 %)
|
|
Grade II
|
7 (43.75 %)
|
4 (25 %)
|
|
Grade III
|
5 (31.25 %)
|
2 (12.5 %)
|
|
Grade IV
|
-
|
-
|
Mucositis Gr II/III was less in Arm II, p= 0.08
Table 4: Side
Effect/ Toxicity: Hematological toxicities
|
|
Arm I
|
Arm II
|
ARM I
|
ARM II
|
|
Gr I
|
6 (37.5%)
|
6 (37.5%)
|
|
2 (12.5%)
|
|
Gr II
|
6 (37.5%)
|
2
(12.5%)
|
5(37.5%)
|
6 (37.5%)
|
|
Gr III
|
4 (25%)
|
-
|
6 (37.5 %)
|
6 (37.5%)
|
|
Gr IV
|
-
|
-
|
5 (31.25%)
|
2 (12.5%)
|
Myelosuppresion in the form of Anemia and Neutropenia were more common
in Arm I, p=0.06
Table 5: Gastrointestinal
toxicities / nausea and vomiting:
|
|
Arm I
|
Arm II
|
|
ARM I
|
ARM II
|
|
Gr I
|
2 (12.5%)
|
2 (12.5%)
|
Gr I
|
6 (37.5%)
|
5(37.5%)
|
|
Gr II
|
8 (50%)
|
3 (18.75%)
|
Gr II
|
6 (37.5%)
|
2
(12.5%)
|
|
Gr III
|
6 (37.5%)
|
2 (12.5%)
|
Gr III
|
4 (25%)
|
1 (6.25%)
|
|
Gr IV
|
|
|
Gr IV
|
-
|
-
|
Gastrointestinal toxicities like nausea & vomiting
were significantly less in Arm II p=0.06 and diarrhea was also less
common in Arm II, p=0.09
Table 6: Side
Effect/ Toxicity: Nephrotoxicity
|
|
ARM I
|
ARM II
|
|
G I
|
4(25%)
|
1(6.25%)
|
|
G II
|
-
|
-
|
|
G III
|
-
|
-
|
|
G IV
|
-
|
-
|
Nephrotoxicity in the form of rise in Blood urea/ S.
creatinine was also more in Arm I than Arm II, which was managed easily
with hydration, injection Furesemide and oral Allopurinol. As sample size was small p values of</= 0.05 could
not be derived and p values response & toxicities were between
0.02-0.09, mean p=0.06 was calculated using chi square test
& graph pad software.
Discussion:
Anaplastic Thyroid Cancer is one of the most aggressive and difficult
human malignancies to treat and subsequently is one of the most lethal.
As opposed to the excellent long-term survival for well-differentiated
thyroid carcinoma, ATC in most series has a median survival of 4-5
months from the time of diagnosis with rare long-term survivors [1,3].
Aim of the present study is to evaluate response and toxicities of
protracted cisplatinum infusion (8hr) + doxorubicin in comparison to (1
hr) cisplatinum infusion + doxorubicin. Arm II (8 hr) infusion resulted
better locoregional response with CR 31.25 %, PR 50%, SD 6.25%, Pr.D
12.5% as compared to Arm 1with CR12.5%, PR43.75%, SD 18.75%, Pr.D25%.
Arm II showed improved response in metastatic sites like lung, bones
and brain as well with CR 33.3%, PR 50% in lung, PR 100% in bone
compared to CR 0%, PR 66.6% in lung and PR 50% in bone. Grade IV
myelosuppresion is proportionately less in Arm II, Gastrointestinal
toxicity which were dose limiting in Arm I were significantly less in
Arm II. On follow up in Arm II,5 patients had CR and survived DF 1 year
on completion of CT+RT, whereas there were 2 patients showing CR in Arm
I. Eight patients had partial remission lasting 3-4 months in Arm II
whereas only 7 patients showed PR lasting 2-3 months in Arm I. Three
patients in Arm I and one patient in Arm II had SD for 3-7 months
whereas 4 patients in Arm I died of progressive disease during follow
up period of 3-9 months after completion treatment compared to 2
patients who died of Pr.D in Arm II.
Presently very few literatures are available on use of protracted CDDP
infusion in anaplastic thyroid cancer. Japanese society of thyroid
surgery [15] evaluated efficacy of prolonged CDDP +doxorubicin +
etoposide+ Peplomycin, in 18 patients of Stage III/IV of anaplastic
thyroid cancer and 12 patients showed PR for 2-3 months. 3 patients had
progressive disease and died in 3-7 months, 3 had stable disease for
3-11 months. Results are comparable to present study. Myelosuppression
was the major toxicity observed by them. Tavecchio et al [19] studied
trial with prolonged cisplatin infusion through central venous catheter
in thoracic malignancies with superior vena cava obstruction. Jelic S
et al [12] investigated 6 hr cisplatin +5FU in 170
Head& Neck cancer patients with CR 11, SD 15,PR 54, Pr D 20
percentage respectively and overall response 65%, which is to some
extent similar to our study.
Arcangeli G et al [18] attempted accelerated hyper
fractionated RT with protracted concurrent CT with cisplatinum and
concluded that this regimen has potential of achieving significant
improvement as compared to standard concurrent chemotherapy schedule
while avoiding significant toxicities. Grade III or greater systemic
toxicity occurred in 9 of 65 (14%) patients and was never the cause of
drug dose reduction. CR was observed in 69% of the patients with gross
disease and DFS of 45% was observed in 43.5 months follow up. Response
and DFS observed in this study is much higher than our trial.
Hence it can be summarized from the present study which is in
accordance with trials of few other researchers that protracted
cisplatinum infusion offers better response rates at loco regional and
metastatic sites and is much better tolerated especially due to less
pronounced gastrointestinal side effects than usual short duration
cisplatinum infusion in anaplastic thyroid cancer
Conclusion
From the present study it can be concluded that protracted cisplatinum
(CDDP) infusion combined with other chemotherapeutic drugs like
doxorubicin is a well-tolerated regime with significantly less systemic
toxicity especially (GI toxicity) as compared to 1 hr infusion and can
be used effectively as chemotherapy regimen in advanced inoperable
anaplastic thyroid and head & neck cancer.
More studies on protracted cisplatinum in various combinations with
bigger sample size in order to reach to a more statistically
significant conclusion are required to further establish its efficacy
in this variety of cancer.
Funding: Nil, Conflict of interest:
Nil
Permission from IRB: Yes,
Acknowledgement:-We
acknowledge support of our departmental colleagues, staff nurses and
the patients who were subject of this study.
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How to cite this article?
Ghosh G, Singh OP. Evaluation of Protracted Cisplatinum Infusion in
Advanced Anaplastic Thyroid Cancer. Int J Med Res Rev 2013;1(4).
doi:10.17511/ijmrr.2013.i04.004.