1

Chemotherapy Definitions and Policies for Thymic Malignancies

Nicolas Girard; Rohit Lal; Heather Wakelee; Gregory J Riely; Patrick J Loehrer.

Address correspondence to Nicolas Girard: nicolas.girard@chu-lyon.fr

KEY-WORDS

Thymoma, Thymic carcinoma, Chemotherapy, Radiotherapy, Thymic hyperplasia, Corticosteroids,

Octreotide

Introduction

Thymic malignancies are rare epithelial tumors that may be aggressive and difficult to treat [1].

Thymomas are usually localized to the anterior mediastinum, and are frequently eligible for upfront

curative-intent surgical resection [1]. However, nearly 30% of patients present with an advanced tumor at

time of diagnosis, with invasion of neighboring organs, dissemination to the pleura, the pericardium, or

less frequently extra-thoracic organs. In such cases, chemotherapy has been used both to reduce the tumor

burden - possibly allowing subsequent surgery and/or radiotherapy- and to achieve prolonged disease

control. Recurrence after resection may be similarly treated with chemotherapy. Thymic carcinomas,

while rare, are usually already advanced at the time of presentation and systemic therapy is important for

almost all of these patients.

Knowledge regarding chemotherapy for thymic tumors has mainly been based on retrospective

series [2-9], although several prospective trials have also been conducted [10-21]. These studies have

clearly demonstrated the chemosensitivity of thymoma, and to a lesser extent thymic carcinoma, to

various cytotoxic agents and combinations. However, details of patient selection are often lacking (either

disease extent or general condition), and the intent and the treatment sequence are often vague.

Adoption of a common language and definition of terms is crucial for the International Thymic

Malignancies Interest Group (ITMIG) effort to develop a international prospective database of thymic

tumors. The paper “Standard Outcome Measures for Thymic Malignancies” provides definitions for

survival endpoints and for recurrences assessment, and discusses how to measure response to treatment

[22]. Here we discuss additional points with regard to chemotherapy, including treatment sequence,

general modalities, and impact of corticosteroids.

Methods

This paper represents a broad consensus within the ITMIG community, based upon available

underlying evidence. A core workgroup assembled data for discussion based on a literature review and

formulated proposed definitions for data elements (N. Girard, G. Riely, P. Loehrer, R. Lal, H. Wakelee).

These proposals were discussed at the ITMIG Definitions and Terminology workshop on November 16,

2010. Subsequent review with an extended workgroup including radiation oncologists led to refinement of

these definitions. The manuscript was distributed to all ITMIG members for further comment, and

ultimately the refined paper was approved and adopted by ITMIG members.

Chemotherapy in Thymic Malignancies

Intent of Treatment

Chemotherapy is used in various clinical scenarios for thymic malignancies (Table 1). First,

chemotherapy may constitute part of curative-intent treatment for locally-advanced tumors. The objective

of the treatment strategy is to achieve long-term survival with no evidence of recurrence. In this setting,

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chemotherapy is combined with local treatment (e.g. pre-operative and/or post-operative chemotherapy

and surgery or chemo-radiotherapy).

Chemotherapy may also be delivered as palliative-intent treatment in advanced or metastatic

thymic tumors in order to improve tumor-related symptoms. Despite a reasonable hope for prolonged

disease control, eradication of the tumor is not expected. Chemotherapy is then typically delivered as the

sole treatment modality.

The response and survival rates may significantly differ depending on the clinical context for

which chemotherapy is delivered. Our first recommendation is that before beginning chemotherapy the

intent of treatment is clearly stated (Table 1, Figure 1): (1) Is chemotherapy delivered as curative or

palliative-intent treatment?; (2) For curative-intent primary chemotherapy, is subsequent surgery or

radiotherapy or both planned?. Obviously the final treatment strategy may change depending on tumor

response and other criteria. Investigators should indicate which treatments the patient ultimately received.

A prospective database with such information will allow meaningful integration of reports from different

institutions.

The wide variation in the number of patients treated with surgery or radiotherapy after primary

chemotherapy suggests significant heterogeneity in the inclusion criteria among studies (Table 2). This

highlights the need to clearly state the inclusion criteria, the treatment intent and plan, as well as the

treatment that was eventually actually delivered.

General Reporting Guidelines for Chemotherapy

When reporting on primary, post-operative, and palliative chemotherapy, investigators should

clearly indicate (1) the cytotoxic agents used, (2) the number of cycles, and (3) whether more than 70% of

the planned dose-intensity was eventually delivered [23]. This threshold is usually chosen in

chemotherapy phase II trials to define the feasibility of a proposed treatment.

Acute and late toxicity of chemotherapy should be carefully and systematically evaluated

according to the CTC-CAE v4 system [24]. Grade 3-5 and dose-limiting toxicities should be documented.

Investigators should pay special attention to the accurate assessment of late and chronic toxicities, as

patients with thymoma live longer than patients with other types of cancers. In particular there may be an

underestimated increased risk of cardiac toxicity, due to repeated use of anthracyclins, often combined

with radiotherapy and surgery, and possibly the development of paraneoplastic myocarditis [25].

Response assessment recommendations for thymic malignancies are described in a previous

ITMIG paper [22]. Results for thymoma and thymic carcinoma should be reported separately. The main

imaging study used for tumor response assessment is computed tomography scan. Magnetic resonance

imaging may also be of interest. In patients receiving octreotide, octreoscan results should be documented

[26]. We also recommend systematic documentation of the effect of antitumor treatment on associated

parathymic syndromes (if present) [27], which should include documentation of any concurrent specific

therapies (e.g. symptom-palliation or immunosuppressive drugs).

Curative-Intent Chemotherapy Curative-intent chemotherapy may be delivered either before surgery or radiotherapy (primary

chemotherapy), concurrent with radiotherapy, or after surgery (post-operative chemotherapy) (Table 1,

Figure 1).

Primary Chemotherapy

Primary chemotherapy is chemotherapy delivered as first treatment in case of locally-advanced

non-metastatic thymic tumor (Masaoka-Koga stage III or IVA [28]). The chemosensitivity of thymoma

provides a strong rationale to use chemotherapy in this setting. The main objective of primary

chemotherapy is to make feasible subsequent R0 resection, which is the most significant prognostic factor

on survival in thymic malignancies [29].

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Several chemotherapy regimens have been used in this setting (Table 2). Usually 2-4 cycles of

primary chemotherapy are administered. Imaging reassessment with contrast-enhanced computed

tomography scan and sometimes magnetic resonance imaging is usually performed 3-4 weeks after the

last chemotherapy injection.

If surgical resection is the objective of the therapeutic strategy for locally-advanced thymic

tumors, the final treatment plan may change depending on tumor response to primary chemotherapy

(Figure 1). A response is observed in about 70-80% of cases in the largest studies (Table 2). Patients for

whom R0 resection is thought to be feasible undergo surgery. A time interval longer than 8 weeks

between the last cycle of chemotherapy and surgery is not considered appropriate. In the largest reported

series, surgery was performed in the majority of patients and complete resection was achieved in about

50% of cases. For those cases, the final treatment strategy is “primary pre-operative chemotherapy

followed by surgery”.

When the patient is not deemed to be a surgical candidate - either because R0 resection is not

thought to be achievable or because of poor performance status of the patient or co-existent medical

condition (“medically inoperable” patient), curative-intent, definitive radiotherapy may be delivered

(Figure 1) [30]. In the literature, radiotherapy is ultimately delivered in 0-50% of patients receiving

primary chemotherapy (Table 2). The final treatment strategy is “definitive chemo-radiotherapy”. A time

interval longer than 6 weeks between the last chemotherapy cycle and the delivery of the first radiation

fraction is not considered appropriate. Chemotherapy may be given concurrently with the radiation

therapy.

If curative-intent radiotherapy is not feasible, either because of a large tumor burden that

precludes safe delivery of appropriate doses or because of co-morbidities increasing the risks of radiation-

induced toxicity, treatment consists of chemotherapy alone. Treatment with chemotherapy alone is a

strategy that is ultimately palliative (Figure 1, see below). In the reported literature, 0-21% of patients

with locally-advanced thymic tumors receiving primary chemotherapy cannot receive either surgery or

radiation therapy or other local treatment (Table 2). The final treatment strategy is “palliative

chemotherapy” (see below).

Our recommendations for reporting on curative-intent chemotherapy for locally-advanced thymic

tumors are the following (Table 1): (1) the terms “induction chemotherapy” and “neoadjuvant

chemotherapy” should be replaced by the term “primary chemotherapy”; (2) the terms “marginally-

resectable”, “potentially resectable”, and “unresectable” tumors should be avoided; instead, investigators

should indicate tumor stage [28] and (3) intent of primary chemotherapy, i.e. prior to surgery or prior to

radiotherapy. (4) Final treatment strategy has to be detailed for all patients: preoperative chemotherapy

followed by surgery, definitive chemoradiotherapy, or palliative chemotherapy. (5) Thymomas and thymic

carcinomas should be analyzed separately.

Of note, some series including patients with locally-advanced thymic tumors reported on the use

of primary chemotherapy associated with sequential or concurrent radiotherapy in a preoperative intent

(Table 2). Such strategy should be referred to as “preoperative chemo-radiotherapy”.

Post-Operative Chemotherapy Post-operative chemotherapy is defined as chemotherapy delivered following surgery (Table 1).

The objectives of post-operative chemotherapy are to treat possible or known microscopic residual disease

and potential tumor cell seeding after surgery.

Only sparse evidence exists in the literature regarding post-operative chemotherapy in thymic

malignancies. The rationale is limited in thymomas given the low incidence of systemic recurrences after

surgery [29]. Adjuvant chemotherapy regimens are similar to those of primary chemotherapy. Post-

operative chemotherapy consisted of cyclophosphamide, doxorubicin, cisplatin (CAP) in a French series

of 21 stage III-IVA thymoma patients[31], and CAP plus prednisone was used in two prospective MD

Anderson Cancer Center trials of post-operative radiotherapy followed by chemotherapy[15, 32].

However, thymic carcinomas often exhibit frequent and early locoregional and systemic

recurrences after surgery [33]. In a large series that included 92 thymic carcinomas, five-year survival was

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82% with post-operative chemotherapy (n=12), 47% with post-operative chemoradiation (n=24), 74%

with post-operative radiotherapy (n=33), and 72% with no post-operative treatment (n=16) [29].

However, the number of patients is small and they were selected for a particular treatment approach,

highlighting the need for collaborative, well defined research.

Our recommendations for reporting on post-operative chemotherapy for thymic malignancies are:

(1) use the term “post-operative chemotherapy” instead of “adjuvant chemotherapy” or “consolidation

chemotherapy”; it is self-explanatory and is consistent with reporting guidelines for radiotherapy [30], (2)

Thymomas and thymic carcinomas should be analyzed separately, and (3) the completeness of the

resection should be indicated [i.e. complete resection (R0), microscopic residual disease (R1) or gross

residual disease (R2)].

Chemotherapy after R2 resection is considered as “post-operative” chemotherapy, provided

surgery is done with curative intent (not simply for diagnosis) – this definition maintains consistency with

that recommended for post-operative radiotherapy [30]. After an R2 resection, post-operative radiotherapy

may be combined sequentially or concurrently with chemotherapy (this latter instance is referred to as

“post-operative chemo-radiotherapy”).

Post-operative chemotherapy should be initiated within 12 weeks following surgery. The term

post-operative chemotherapy is still appropriate after more than 12 weeks when both chemotherapy and

radiotherapy are planned and the radiotherapy was initiated within 12-weeks, provided no tumor

recurrence is observed. Chemotherapy that is initiated post-operatively because imaging reveals

recurrence or progression of disease should be labeled as “chemotherapy for recurrent disease”, not “post-

operative chemotherapy”.

Palliative-Intent Chemotherapy

Palliative Chemotherapy Palliative chemotherapy is given as the sole treatment modality, with no plan for surgery or

radiotherapy, e.g. in patients with metastatic disease (Table 1). Palliative chemotherapy may also

ultimately be the treatment given in patients with locally-advanced tumors that do not respond sufficiently

to be eligible for subsequent surgery or radiotherapy (Figure 1). The objectives of palliative-intent

chemotherapy are to improve tumor-related symptoms, and -if possible- to achieve tumor response.

Prolonged disease control is possible, but tumor eradication is not expected.

Several prospective and retrospective studies have reported on palliative chemotherapy regimens

(Table 3), but because there are no randomized studies, it is unclear which regimen is best. In general a

combination regimen is recommended, for at least 3 and no more than 6 cycles.

In the palliative-intent setting, several consecutive lines of chemotherapy may be administered

when the patient presents with tumor progression. We recommend the use of the standard terms “first-

line”, “second-line”, “third-line” chemotherapy.

Chemotherapy for Recurrence

Chemotherapy for recurrence refers to chemotherapy delivered for tumor recurrence appearing

after previous curative-intent treatment leading to complete disappearance of tumor. This term should not

be used for tumor progression after palliative-intent chemotherapy without a complete response. In this

scenario, chemotherapy is referred as “second-line” or “third-line” chemotherapy.

Similar to what is done for initial management, the treatment of thymic tumor recurrences may be

palliative-intent or curative-intent, and in this latter situation may include chemotherapy, surgery, and/or

radiotherapy. As for radiotherapy, our recommendation is to use the same terms and policies as for initial

treatment, but stating that this is for recurrence.

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Corticosteroids in Thymic Malignancies

Impact on Response Assessment Corticosteroids have been known for a long time to have a “thymolytic” effect [34, 35]. The

thymuses of patients receiving corticosteroids have significantly increased fat and connective tissue,

decreased germinal centers, and poorer cortico-medullary differentiation than those of untreated patients

not receiving steroids. The changes following corticosteroid treatment mimic those following aging or

acute stress, with retention of the myoepithelial stroma but depletion of thymic lymphoid elements. In

lymphocytic thymomas (type AB, B1, and B2), corticoids may then produce a significant reduction of

lesion size at imaging studies through lymphocytic depletion, with no anti-tumor effect.

Only limited data is available regarding the significance of this phenomenon in a clinical setting.

In the ECOG phase II trial evaluating the combination of octreotide and corticosteroids (prednisone at a

dose of 0.6mg/kg/day) vs. octreotide alone, higher response rates were observed in patients receiving

corticosteroids (38% vs. 11% in patients treated with octreotide alone) [26].

Given the possible impact of corticosteroids on response assessment, our recommendation is to

document whether the patient has received corticosteroids at a dose higher than 0.5mg/kg/day of

prednisone (or a correspondingly equivalent dose of another steroid) as well as the duration of

corticosteroids treatment. The 0.5mg/kg/day cut-off is chosen based upon the dose delivered in the ECOG

trial and to avoid complex reporting of temporary administration of corticosteroids at low-doses to control

chemotherapy side-effects. We recommend that response rates be reported and analyzed separately for

patients receiving or not receiving steroids at this dose or higher. Ultimately, whether response criteria

should be modified for lymphocytic thymomas vs. other thymic malignancies when corticosteroids are

given is currently unknown and calls for prospective studies.

Impact on Definition of Recurrence/Progression

The thymus may enlarge in various circumstances, including infections, burns, and corticoid or

chemotherapy cessation (especially after an intensive regimen given to infants and young adults), [36-38].

This phenomenon is referred as “rebound thymic hyperplasia”. Rebound hyperplasia has been reported to

occur 2-14 months after cessation of corticosteroids, and may persist for 2-45 months. Histologically, it

corresponds to a true thymic hyperplasia, with enlargement of the thymus, and no increase in the number

of lymphoid follicles [39].

Rebound hyperplasia has not been reported to occur in patients with thymic tumors, but needs to

be discussed given the potential implication on outcome assessment. Given the reported timeframe of this

phenomenon, our recommendation is to consider rebound hyperplasia as in patients presenting with a

potential local recurrence who stopped chemotherapy or corticosteroids within 15 months of re-growth of

the thymic lesion.

Certain imaging characteristics may help distinguish thymic hyperplasia and tumor recurrence.

Typically thymic hyperplasia results in a symmetric, non-focal enlargement of the thymus on a CT scan.

Both thymic hyperplasia and thymoma may be intimately related to the vessels (without invasion) [39].

Fluorodeoxyglucose (FDG) positron emission tomography is not useful in this setting, as both entities

exhibit similar degrees of increased FDG uptake [40]. Chemical shift magnetic resonance imaging has

also been evaluated to distinguish thymoma and thymic hyperplasia [41]. If the nature of thymic

enlargement occurring within 15 month of treatment cessation is unclear based on imaging tissue biopsy is

recommended.

Discussion

Chemotherapy is a major treatment modality for thymoma and thymic carcinoma. This paper

defines terms and policies so that outcomes after chemotherapy can be reported in a consistent manner.

These measures represent a consensus of the ITMIG community and will be used in ITMIG collaborative

projects. Adopting these definitions will allow ITMIG members and others interested in the field to

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compare results and conduct collaborative investigations. The definitions may be updated in the future as

new information comes to light.

A major impediment to progress is the limited number of patients in studies to date (Tables 1, 2).

The ITMIG prospective international database together with consistently defined terms will allow analysis

of much larger patient cohorts over shorter period of time. Many questions regarding chemotherapy for

thymic malignancies remain unanswered; however the consistency afforded by the consensus definitions

in this paper and the collaborative spirit of ITMIG provides a framework so they can be addressed.

Acknowledgements

We thank Andrea Bezjak, Conrad Falkson, and Daniel Gomez for their contributions to

development of the definitions and policies in this paper.

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Table 1. Summary of Reporting Guidelines and Data Fields for Thymic Malignancies Treated with Chemotherapy

CHEMOTHERAPY STRATEGIES

Initial treatment

- Curative-intent Primary chemotherapy - Chemotherapy delivered prior to another focal

treatment – surgery or radiotherapy.

- Intent of the treatment has to be documented, i.e.

primary chemotherapy prior to surgery or primary

chemotherapy prior to radiotherapy.

- Final strategy has to be indicated for all patients:

primary preoperative chemotherapy or primary

chemo-radiotherapy.

Post-operative chemotherapy - Chemotherapy delivered following surgery.

- Completeness of the resection (R0, R1 or R2) should

be indicated.

- Palliative-intent Palliative chemotherapy - Chemotherapy delivered alone in cases for which there

is no plan for surgery or radiotherapy.

Chemotherapy for recurrence - Chemotherapy delivered for tumor recurrence

appearing after previous curative-intent treatment.

- Chemotherapy for recurrence may be curative-intent

(primary preoperative/chemoradiation, post-

operative) or palliative-intent (chemotherapy alone).

- Intent of the treatment and final strategy have to be

documented as for initial treatment.

CHEMOTHERAPY GENERAL REPORTING GUIDELINES

Modalities - Chemotherapy regimen

- Number of cycles administered

- Dose intensity: > or < 70% of the planned dose-intensity

Analysis - Treatment outcome has to be evaluated separately for thymoma and thymic carcinoma.

Toxicities - Grade 3-5 and dose limiting toxicities (acute and late) of the treatment may be reported

using the NCI-Common Toxicity Criteria Adverse Event (CTCAE) v4.

- Acute and late toxicities have to be reported. Special attention has to be paid to late and

chronic toxicities of the treatment, especially cardiac toxicities.

Response - Assessment of tumor response has been described in a previous paper.

- Octreoscan results should be reported for patients treated with octreotide.

- Effect of antitumor treatment on associated paraneoplastic manifestations has to be

documented.

- Corticosteroid treatment doses (equivalent prednisone doses above 0.5mg/kg/day) and

durations should be reported.

Recurrence - Rebound hyperplasia has to be considered as a differential diagnosis for local

recurrence when tumor re-growth occurs within the 15 months following treatment

cessation.

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Table 2: Primary chemotherapy or chemoradiation for locally-advanced thymic malignancies. Legend: T: Thymoma; TC: Thymic carcinoma; Retrosp: Retrospective. The CAP, ADOC, PE regimen are described in Table 1. The CODE

regimen consists of cisplatin (25mg/m2/week), vincristin (1mg/m

2/week), adriamycin (40mg/m

2/week), etoposide (80mg/m

2x3days/week), the CEE

regimen of cisplatin (75mg/m2/3 weeks), epirubicin (100mg/m

2/3 weeks), etoposide (120mg/m

2x3days/ 3weeks), and the CAMP regimen of CAP

with prednisolone (1000mg/m2x4days, 500mg/m

2x2d/3 weeks).

Author Primary chemotherapy regimen

n Period of accrual

Tumor Study Response rate (%)

Subsequent treatment (%)

(Years) Type Stage Surgery Complete resection

Radiotherapy (Definitive

Chemoradiation)

Palliative chemotherapy

Chemotherapy

Macchiarini et al. 1991 [14] CEE 7 2 T/TC III Phase II 100 100 57 0 0

Berruti et al. 1993 [16] ADOC 6 2 T III-IVA Phase II 83 ? 17 ? ?

Rea et al. 1993 [6] ADOC 16 6 T III-IVA Retrosp 100 100 69 0 0

Venuta et al. 2003 [3] CEE 15 14 T/TC III Retrosp 66 100 ? ? ?

Bretti et al. 2004 [7] ADOC / PE 25 11 T/TC III-IVA Retrosp 72 68 44 ? ?

Kim et al. 2004 [15] CAPP 22 10 T Phase II 77 100 72 0 0

Lucchi et al. 2005 [4] CEE 36 27 T/TC III-IVA Retrosp 67 69 78 19 3

Jacot et al. 2005 [5] CAP 5 6 T/TC III-IVA Retrosp 75 38 25 50 12

Yokoi et al. 2007 [8] CAMP 14 15 T/TC III, IVA-B Retrosp 93 64 14 14 21

Kunitoh et al. 2009 [17] CODE 21 8 T III Phase II 62 62 43 24 14

Chemoradiation

Loehrer et al. 1997 [18] CAP 23 12 T/TC III-IVA phase II 70 15 0 70 15

Berruti et al.1999 [19] ADOC 16 7 T III-IVA phase II 81 56 56 31 13

Wright et al.2008 [9] PE, ADOC, CAP, CEE

10 9 T/TC III-IVA Retrosp 40 100 80 0 0

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Table 3: Palliative chemotherapy regimens in advanced thymic malignancies Legend: T: Thymoma; TC: Thymic carcinoma; R: Retrospective

Author n Period of accrual (years)

Tumor type

Study Regimen Agents Doses Response rate (%)

Single-agent chemotherapy

Bonomi et al. 1993 [20] 21 4 T/TC Phase II Cisplatin 50mg/m² / 3 w 10-62

Highley et al. 1999 [21] 15 12 T/TC Retrosp Ifosfamide 1.5g/m² x 5 d / 3 w 46-54

Loehrer et al. 2006 [42] 27 1 T/TC Phase II Pemetrexed 500mg/m2/3 w 17

Combination chemotherapy

Fornasiero et al. 1990 [2] 32 11 T Retrosp ADOC Adriamycin 40 mg/m² / 3 w 85-92

Cisplatin 50 mg/m² / 3 w

Vincristin 0.6 mg/m² / 3 w

Cyclophosphamide 700 mg/m² / 3 w

Loehrer et al. 1994 [10] 30 9 T/TC Phase II CAP Cisplatin 50 mg/m² / 3 w 51

Adriamycin 50 mg/m² / 3 w

Cyclophosphamide 500 mg/m² / 3 w

Giaccone et al. 1996 [11] 16 6 T Phase II PE Cisplatin 60 mg/m² / 3 w 56-60

Etoposide 120 mg/m² x 3 / 3 w

Loehrer et al. 2001 [12] 34 2 T/TC Phase II VIP Etoposide 75 mg/m² x 4d / 3 w 32

Ifosfamide 1.2 g/m² x 4 d / 3 w

Cisplatin 20mg/m2x4d/3w

Lemma et al. 2008 [13] 46 7 T/TC Phase II Carbo-Px Carboplatin AUC 5 / 3 w 33

Paclitaxel 225 mg/m² / 3 w

12

Figure 1: Summary and Definitions of Treatment Strategies Involving Chemotherapy in Thymic Malignancies