Tongue Cancer Related to Lenalidomide Medication in Patient … · analogue, appears to be equally...

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Taiwan J Oral Maxillofac Surg 台灣口外誌

Introduction

Mu l t i p l e m y e l oma (MM ) , w h i c h i s

characterized by a malignant proliferation of

plasma cells, is a fatal disease with short life

expectancy1, 2. However, the introduction of new

agents has brought the hope to the patients.

Lenalidomide, an orally administered thalidomide

analogue, appears to be equally efficacious and

less toxic than thalidomide3. It has multiple

mechanisms of action, inclusive of direct anti-

tumor effect, inhibition of angiogenesis, and

Tongue Cancer Related to Lenalidomide Medication in Patient with Multiple Myeloma and

Medication-Related Osteonecrosis of Jaw— A Case Report and Literature Review

Yu-Hsin Tan, Jang-Jaer Lee

Department of Oral and Maxillofacial Surgery, National Taiwan University Hospital, Taiwan, R.O.C.

Graduated Institute of Clinical Dentistry, National Taiwan University Hospital, Taiwan, R.O.C.

Abstract

Clinical trial results indicate that lenalidomide, a thalidomide analogue, is a promising treatment in multiple myeloma. However, it has adverse effects. Although it was not well proved yet, the risk of causing second primary cancer related to lenalidomide medication has been reported before. We present the case of multiple myeloma in a 64-year-old Asian female who had been treated with thalidomide and melphalan for about ten years, while the same time she has also used zometa. Later she had joined a clinical trial using vorinostat and bortezomib. During this period she stopped the zometa and was diagnosed of Medication-Related Osteonecrosis of Jaw and several times of sequestrectomy was performed. After that she started another new clinical trial under lenalidomide. Ten months later after trial began, the tongue cancer was found and diagnosed. The tumor has grown so fast in such a short period of time. The neck dissection and wide excision of tumor was performed. However, patient expired due to multiple organ failure caused by cancer metastasis in the same year. This case report may shed light on the controversies about the risk of lenalidomide on inducing new cancer.

Key words: Lenalidomide, Multiple Myeloma, Second primary cancer, Tongue cancer.

Taiwan J Oral Maxillofac Surg29: 172-181, September 2018 台灣口外誌

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台灣口外誌 Tongue Cancer Related to Lenalidomide Medication in Patient with Multiple Myeloma and Medication-Related Osteonecrosis of Jaw

immunomodulatory reaction4. The lenalidomide-

based therapy has improved the outcome of

patients with relapsed/ refractory multiple

myeloma (RRMM) to a great extend5, and also

associated with significant progression-free

survival benefits in patients with newly diagnosed

multiple myeloma6, 7. However, an increased risk

of second primary malignancies (SPM), including

solid tumors and cancers of the blood and the

immune system has been described in patients

receiving lenalidomide8-11.

In this art icle, we present a case of

tongue cancer identified 120 months after the

diagnosis of multiple myeloma and 10 months

after lenalidomide treatment. It was considered

the second primary cancer induced by the

lenalidomide use, although the mechanism and

association remain unsure. To the best of our

knowledge, this is the first case report related to

the occurrence of oral cancer in a patient after

treatment by lenalidomide.

Case report

A 64-year-old female presented herself to

the department of oral and maxillofacial surgery,

National Taiwan University Hospital on May 20,

2010. Her chief complaint was pain over bilateral

maxilla for 10 months. Reviewing patient's past

medical history, she was diagnosed of multiple

myeloma in 2002, then referred to our hospital

for treatment. At first, she had been treated

by thalidomide, melphalan and zometa, then

she joined a clinical trial using vorinostat and

bortezomib in 2009. She stopped using zometa in

Jan 2010, which was few months before she came

to our clinic due to jaw pain. She denied any

tobacco, alcohol and betel nuts related history.

On physical examination, there were bone

exposure over molar area over bilateral maxilla,

bony destruction was observed on panoramic film

(Fig. 1, 2), the clinical diagnosis was medication-

related osteonecrosis of the jaw (MRONJ). During

Aug 2010 to Dec 2011, she received four times

of sequestrectomy under general anesthesia due

to MRONJ. Meanwhile, the patient joined the

new clinical trial in April 2011 and started using

lenalidimide plus dexamethasone.

During regular follow up on 1 Feb, 2012,

an exophytic tumor over her right side of

tongue was found, measuring 2.0 × 2.0 cm (Fig.

3), the incisional biopsy was performed and

histopathology was moderately-differentiated

squamous cell carcinoma. A head and neck

magnetic resonance imaging (MRI), abdominal

sonar as well as a whole body bone scan were

performed as per standard oncological staging.

MRI revealed an abnormal mass lesion at right

lateral tongue, 2.4 cm in size (Fig. 4). No

evidence of locoregional lymphatic spread or

distant metastasis could be found which led to a

cT2N0M0 staging. The treatment plan was tumor

wide excision and modified radical neck dissection

(mRND) of right side of neck. After discussion

with the patient, she refused the mRND and

preferred upper neck dissection instead. Thus

she was arranged for admission and surgical

intervention. The pre-op CBC-DC data listed

below. (Table 1).

The wide exc is ion o f tumor (part ia l

glossectomy) and right side supraomohyoid neck

dissection were conducted on 17 Feb, 2012 (Fig.

5). Pathological report revealed moderately-

differentiated squamous cell carcinoma over right

side of tongue and one lymph node metastasis

(1/8) which led to pT2N1M0 staging, no other

risk factors were found. We suggested patient

to receive the radical neck dissection, but she

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rejected.

After discharge, the patient kept regularly

followed up in our clinic. On the visit of three

months after surgery, the lymphadenopathy

(LAP) was detected on palpation. MRI revealed

abnormally enlarged cervical LAPs with evidence

of necrosis at left level I, right level II and level

III (Fig. 6). Then the right side radical neck

dissection and left supraomohyoid neck dissection

were conducted on June 1, 2012. Pathological

report showed there were four metastatic lymph

nodes at right side (4/34), one at left side (1/7),

the staging of lymph node was pN2c. One month

follow up after surgery, the skin metastasis over

left neck was found (Fig. 7), the last time she

visited our clinic was on July 4, 2012, then went

back to original hospital for supportive care. She

expired on the same year due to multiple organ

failure caused by cancer metastasis.

Discussion

The combination of lenal idomide and

dexamethasone (Len-dex) is a standard treatment

option for patients with multiple myeloma

receiving one or more prior therapy12. Two large

phase 3 trials showed that Len-dex significantly

improved overall response, complete response

rate, time to progression and duration of response

compared with placebo plus dexamethasone13, 14.

At a median follow-up of 48 months for surviving

patients, a significant benefit in overall survival

was observed15.

However, many clinical trials reported

there was an increased risk of developing second

primary cancer after the use of lenalidomide8-11.

In a retrospective pooled analysis of 11 clinical

Table 1. Pre-op CBC-DC data

WBC (K/μL) 5.0 Blast (%) 0.0

RBC (M/μL) 3.08 Promyl. (%) 0.0

HB (g/dL) 10.6 Myelo. (%) 0.0

HCT (%) 30.8 Meta (%) 0.0

MCV (fL) 100.0 Band (%) 0.0

MCH (pg) 34.4 Seg (%) 43.0

MCHC (g/dL) 34.4 Eos. (%) 0.8

PLT (K/μL) 135.0 Baso. (%) 0.2

RDW-CV (%) 17.7 Mono. (%) 7.6

PS 0.0 Lym. (%) 48.4

Fig. 1. Clinical photography at first appointment, the bone exposure over both right. (a) and left side (b)

of maxilla.

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Fig. 2. The panoramic film showed bony destruction over tooth 14, 15 area and upper left molar area.

Fig. 3. (a) Tongue tumor photoed on 1 Feb, 2012; (b) Tongue tumor photoed on 17 Feb, 2012 (operation

date). Compare these two photos, the tumor had grown larger during 17 days.

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Fig. 4. MRI image in coronal view. (a) T1. (b) T1FS. (c) T2. A heterogenous mass lesion at right lateral

tongue, 2.4 cm in size.

Fig. 5. (a) Wide excision of tumor (partial glossectomy). (b) Right SOHND. (c) Specimen of tumor. (d)

Specimen of lymph node.

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Fig. 6. (a) T2, axial view: an abnormally enlarged lymph node over right level II, with signal enhanced,

heterogeneous, ring-enhancement and central necrosis. (b) T2, axial view: LAPs over left level

I and right level II. (c) T1FS+C, coronal view: LAPs over right level II and level III. (d) T1FS+C,

coronal view: LAP over right level II.

Fig. 7. The skin metastasis over left neck.

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trials of lenalidomide-based therapy involving

3846 patients with relapsed/refractory multiple

myeloma, the overall incidence rate (IR, events

per 100 patient-years) of second primary

malignancies (SPMs) was 3.62, and IR of invasive

SPMs including hematologic and solid tumor

was 2.08. In a separate analysis of pooled data

from the pivotal phase 3 trials with 703 patients

reported that the IR of SPMs were 3.98 and 1.38

for patients in the Len-dex and the placebo/

dexamethasone groups, respectively. The higher

incidence of non-melanoma skin cancers with

Len-dex (2.40 vs 0.91) and invasive SPMs (1.71

vs 0.91) were also reported8.

Palumbo et al. conducted a meta-analysis

from 3254 patients with newly diagnosed multiple

myeloma showed that lenalidomide is associated

with an increased rate of haematological second

primary malignancies9.

The former reports and FDA pointed out

the second primary malignancies related to

lenalidomide are mostly confined to hematological

cancer such as acute myelogenous leukemia

(AML) and myelodysplastic syndromes (MDS)16,

17, however, there are more and more cases

reported by clinicians in different second primary

malignancies such as non-melanoma skin cancers9,

solid tumor in breast, colon, prostate and lung10.

Rouslan et al. did a retrospective review of

195 patients who received treatment with Len-

dex, there were 11 patients developed SPM, 6

patients (3.07%) developed AML/MDS, 5 patients

(2.56%) were diagnosed with a nonhematological

malignancy which included adenocarcinoma of

the rectum, cholangiocarcinoma, urethral cancer,

and two patients with squamous cell carcinoma

(one of the head and neck and the second of

the tonsil)11. Xu et al presented a rare case of

nasopharyngeal carcinoma considered to be as

a second primary cancer after 21 months after

lenalidomide treatment18.

The mechanism of lenalidomide causing

secondary malignancies has not been fully

understood, further studies are required to

evaluate whether lenalidomide can potentiate

the carcinogenic properties of certain agents

when used in sequence11. Rouslan et al observed

that the development of AML/MDS relatively

early after the initiation of Len-dex (median:

25 months) compared with median time from

multiple myeloma diagnosis to therapy-related

myeloid neoplasms (7 years)19, speculating that

development of SPM occurs relatively early

in the course of Len-dex therapy. As for the

observation on the patients who received long

term treatment of Len-dex, Rossi et al. showed

that there were no increased rate of SPMs after

6 years of follow-up20 while Meletios et al. found

that no increased risk of SPM in patients treated

with Len-dex achieving progression-free survival

more than or equal to 2 years after median

treatment duration of 46 months8. These results

indicate that long-term treatment with Len-dex

is not associated with an increased risk of SPMs,

and imply that the SPMs tend to develop in the

early phase of Len-dex treatment.

In our case, the tongue cancer developed

ten months after the begin of Len-dex treatment,

the tumor has grown fast in such a short

period of time, the invasive pattern of cancer

and subsequent metastasis led to multiple

organ failure and mortality. Considering of the

treatment course, we believe the tongue tumor

as a second primary malignancy associated with

lenalidomide, though the association of multiple

myeloma, lenalidomide and tongue cancer has

not previously reported. As an oral surgeon, we

should keep in mind that the development of a

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more aggressive oral neoplasm on the patient

with multiple myeloma, the risk of drug-related

second primary cancer has to be taken into

consideration.

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Received: July 23, 2018Accepted: September 03, 2018Reprint requests to: Dr. Jang-Jaer Lee, Department of Oral and Maxillofacial Surgery, National

Taiwan University Hospital, No.1, Changde St., Jhongjheng District, Taipei City 100, Taiwan, R.O.C.

使用Lenalidomide治療多發性骨髓瘤後引發

舌癌—病例報告及文獻回顧

譚玉欣　李正喆

台大醫院牙科部口腔顎面外科

台灣大學臨床牙醫學研究所

摘　　要

Lenalidimide (Revlimid

®；中文名：瑞復美)為一治療多發性骨髓瘤的

新藥，是thalidomide的類似物。近期研究顯示，使用Lenalidimide有比較高

的比例發生第二原發癌症，原因尚不清楚，仍需較多的臨床研究觀察才能下

結論。本病例報告一罹患多發性骨髓瘤的64歲女性，原先使用thalidomide及

melphalan治療，並有使用zometa，之後加入vorinostat/bortezomib的臨床

試驗。病患由於服用雙磷酸鹽藥物而引起的顎骨壞死於本院進行多次腐骨清

創的手術，在治療期間加入Lenalidomide的臨床試驗。於服藥開始後的十個

月回診，發現在舌部有一約兩公分大小的鱗狀細胞癌，之後進行腫瘤廣泛性

切除及舌骨上頸部淋巴廓清術。而腫瘤生長速度快且具侵略性，術後仍發生

雙側淋巴及皮膚轉移，之後因癌症轉移造成多重器官衰竭並於同年病逝。回

顧文獻，由lenalidomide引發的第二種原發癌症很少發生於頭頸部或口腔，

本篇論文發表的結果值得臨床醫師的注意。

關鍵詞： Lenalidomide，多發性骨髓瘤，第二種原發癌症，舌癌。

Tongue Cancer Related to Lenalidomide Medication in Patient … · analogue, appears to be equally...

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