Follow-up of oral cancer patients: three uneventful years may be enough

Accepted Manuscript Follow-up of oral cancer patients; three uneventful years may be enough Sharon.J. Taslim, C.René Leemans, Isaäc van der Waal, K.H. Karagozoglu PII:

S2212-4403(16)30086-4

DOI:

10.1016/j.oooo.2016.05.009

Reference:

OOOO 1501

To appear in:

Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology

Received Date: 19 January 2016 Revised Date:

29 April 2016

Accepted Date: 15 May 2016

Please cite this article as: Taslim SJ, Leemans CR, van der Waal I, Karagozoglu KH, Follow-up of oral cancer patients; three uneventful years may be enough, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology (2016), doi: 10.1016/j.oooo.2016.05.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT 2nd Revision 29th April 2016

Follow-up of oral cancer patients; three uneventful years may be enough

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Sharon.J. Taslima, C.René Leemansb, Isaäc van der Waala*, K.H. Karagozoglua, a

Department of Oral and Maxillofacial Surgery/ Oral Pathology, VU University

Netherlands b

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Medical Center, Academic Centre for Dentistry (ACTA), Amsterdam, the

Department of Otolaryngology/Head-Neck Surgery, VU University Medical

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Center, Amsterdam, the Netherlands

*Corresponding author at: VU University Medical Center, Dept. of Oral and Maxillofacial Surgery/Oral Pathology, P.O. Box 7057,1007 MB, Amsterdam, the Netherlands.

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E-mail address: [email protected]/ [email protected]

ACCEPTED MANUSCRIPT Conflict of interest statement

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None declared.

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Abstract

Objectives: To explore the possibility of shortening the length of follow-up from five to three years in patients who have undergone curative treatment of an oral squamous cell carcinoma.

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Methods: The medical records of 225 patients who had undergone initial curative treatment at the VU University Medical Center in Amsterdam, the

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Netherlands, between 2004 and 2009 were analyzed. Results: In 96 patients (42.7%) a secondary event occurred. Eighty-six percent of the secondary events were detected within three years. In the fourth and fifth year 14% of the secondary events were found, consisting mainly of second primary tumors. Conclusions: Most secondary events occurred within the first three years of follow-up. Therefore, the case can be made for an altered regimen of followup beyond three years based on certain risk factors unique to the patient as well as the patient's ability to adequately report symptoms that may be associated with recurrent disease.

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ACCEPTED MANUSCRIPT Keywords: oral cancer; oral squamous cell carcinoma; follow-up Introduction The main goal of follow-up after treatment for oral cancer is early detection of recurrences, second primary tumors and cervical lymph node

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metastases. Timely detection of secondary events will more often allow treatment with curative intent. In some studies it is suggested that

asymptomatic recurrences or second primary tumors can be treated more

successfully than symptomatic ones, resulting in improved survival rates and

less morbidity.1-3 However, other studies showed no difference in survival and

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tumor mortality rates for patients with and without symptoms.4-7 Other purposes of follow-up programs are the guidance of the rehabilitation process

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and the provision of psychological support, if needed.1, 2, 4-16

A variety of follow-up guidelines for patients with head and neck cancer have been published.16-25 There is no international consensus on the optimum intervals and duration of follow-up visits after curative treatment of oral cancer. Some of the reported follow-up strategies were site-specific, e.g. laryngeal cancer, or applicable to head and neck cancers in general and

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having a duration of at least five years.26 The various follow-up schedules for oral cavity and head and neck cancer are listed in Table 1.1, 2, 7, 8, 12-14, 16-35 The majority of secondary events (69% - 100%) of head and neck

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cancer, including oral cavity, is detected within the first three years after treatment. The reported detection rates are listed in Table 2.1-8, 12, 13, 15, 25-28, Frequent follow-up, e.g. every two months, during the first three

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32-34, 36, 37

years after treatment may, therefore, be of great value for the detection of secondary events.1, 8, 9, 14, 15, 24, 33 After three years, the visit interval in most published studies is tapered down to six months in the fourth and fifth year. The aim of this retrospective study was to.explore the possibility of

shortening the length of follow-up from five to three years in patients who have undergone curative treatment of an oral squamous cell carcinoma.

Materials and methods

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ACCEPTED MANUSCRIPT The medical records of 270 patients who had undergone treatment for a histopathologically confirmed oral cavity squamous cell carcinoma from January 1st 2004 until December 31st 2009 in the VU University Medical Center Amsterdam, the Netherlands, were analyzed in this retrospective study.

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Tumor characteristics such as primary tumor location and stage, treatment modality, date of detection of a secondary event and date of death were registered . A secondary event was defined as the occurrence and

detection of a local recurrence (within five years post-treatment at the same

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location), a second primary tumor, and regional or distant metastases during the five-year follow-up program. Tumors were staged according to the TNMclassification of the Union for International Cancer Control (UICC).38

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Treatment modalities included surgery, radiotherapy, chemoradiotherapy, or a combination of surgery and radiotherapy with or without additional chemotherapy. All patients participated in the routine followup program according to the guidelines of the Dutch Cooperative Head and Neck Oncology for oral cavity and oropharyngeal cancer.16 After three

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uneventful years follow-up intervals of six months have been instituted until completion of the fifth year. At the follow-up visits during the fourth and fifth year additional tests, e.g. imaging, have been guided by signs or symptoms only.The design of this study adheres to the code for proper secondary

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use of human tissue of the Dutch Federation of Biomedical Scientific

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Societies (http://www.federa.org).

Results

In 13 patients the primary treatment has been of palliative intent, while

32 patients had a previous history of malignancy in the head and neck region. These 45 patients have been excluded from further analysis. The primary tumor distribution by stage, location and treatment modality of the remaining 225 patients are shown in Table 3. Sixteen (7.1%) of the 225 patients died within five years without a secondary event. Ten patients (4.4%) did not want to participate in the follow4

ACCEPTED MANUSCRIPT up program. Furthermore, in 10 patients (4.4%) the follow-up was ended by the physician before the fifth year. Their follow-up ranged from 1.80 to 4.28 years, with a mean interval of 3.26 years and a median of 3.40 years. Seven of these 10 patients were treated for lower lip carcinoma stage I. In 96 patients (42.7%) a secondary event occurred: 37 patients

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(38.5%) had a local recurrence, 24 patients (25.0%) regional metastases, 5 patients (5.2%) loco-regional recurrence, 23 patients (24.0%) second primary tumor and 7 patients (7.3%) had distant metastases. Sixty-nine percent of the secondary events consisted of local recurrences and regional metastases

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(Table 4). Of these 96 patients, 54 (56%) were male and 42 (44%) female,

with a mean age of 64 years (range 33-95 years) at the time of the primary treatment. The mean interval between the initial treatment and the secondary

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event was 19 months (range 1 to 59 months), and the median interval was 13 months.

In 83 patients (86%) secondary events were detected within three years after the treatment. Ninety-six percent of all local recurrences, regional and distant metastases were detected in this three-year follow-up period.

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In the fourth and fifth year after the initial treatment, 14% of the secondary events occurred, consisting of 10 second primary tumors and three local recurrences. The location of the primary tumor in these secondary events was generally the floor of the mouth (53.8%). The second primary

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tumors were located in the esophagus, the lung, hypopharynx, oropharynx or elsewhere in the oral cavity. The three local recurrences occurred in patients

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who only had radiotherapy with or without chemotherapy. None of the patients with primary tumor stage I had a secondary event in year 4 and 5. Curative treatment was possible in 59 patients (71.1%) with secondary

events detected within 3 years of the follow-up and in 7 patients (53.8%) with secondary events detected in the fourth and fifth year.

Discussion In this retrospective study, 86% of the secondary events were detected within three years after the curative treatment. In these three years 96% of local recurrences, regional and distant metastases were detected, being 5

ACCEPTED MANUSCRIPT somewhat similar as the results in other studies related mainly to head and neck cancer, laryngeal cancer and rarely to oral cancer only, as listed in Table 2, with percentages varying between 69% and 100%.1-8, 12, 13, 15, 25-28, 32-34, 36, 37 Since most of the secondary events in the present study were detected within three years, the existing five-year follow-up program may be reduced to three

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years. By doing so, the workload might be reduced without altering the standard of care.

Fourteen percent of the secondary events were detected in the fourth and fifth year of the follow-up. These secondary events were predominantly

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second primary tumors located in the esophagus, the lung, hypopharynx,

oropharynx or elsewhere in the oral cavity. The primary tumors of 7 (53.8%) in these patients were located in the floor of the mouth. The mean interval

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between initial treatment and detection of a second primary tumor was 3.74 years and the median interval was 3.85 years. This implies that follow-up visits after the third disease-free year mainly disclose the occurrence of second primary tumors, which is in accordance with the findings of Boysen et al.8, 28, Snow9 and Sasaki et al.33

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Treatment was of curative intent in 71.1% of the secondary events detected within the first three years of follow-up versus 53.8% in the fourth and fifth years. In the fourth and fifth year, 7 patients (54%) were treated with curative treatment. Unfortunately, three of these patients died within one year

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after treatment of the secondary event. Since the population of patients with secondary events in the fourth and fifth year of follow-up is relatively small, no

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conclusions can be drawn from this subset of patients. Curative treatment was offered in 64.9% of patients with local

recurrences, in 87.5% of patients with regional metastasis and in 78.3% of patients with second primary tumors. None of the patients with distant metastasis were offered with curative treatment. Nevertheless, all distant metastases in this study were detected within 3 years. Smoking and alcohol use were reported in several studies to be highrisk factors for developing a second event.6, 9 Whether or not patients continued their smoking and alcohol habits after the initial curative treatment was not reliably registered in the present study. Several authors recommend that this subgroup should be followed lifelong.5, 6, 39 6

ACCEPTED MANUSCRIPT To evaluate the efficacy of follow-up after a disease-free period of three years in patients with oral cancer, a prospective, randomized study with two groups of patients should be performed after the third year of the follow-up. In the fourth and the fifth year, one group would continue to participate in the follow-up program, e.g. twice a year, while patients in the other group would

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not, being instructed to contact the physician in case of symptoms. Interestingly, in some studies it has been suggested that patients with

asymptomatic recurrences or second primary tumors can be treated more

successfully than symptomatic ones, resulting in improved survival rates and

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less morbidity.1-3 However, several other studies did not show a significant

difference in survival and tumor mortality rates for patients with and without symptoms.4-7 Additionally, Boysen et al.8 reported that the majority of

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recurrences (61%) were diagnosed during the regular follow-up program through self-referral for specific symptoms.

The length of the follow-up after the third year can be individualized in high-risk patients (heavy smokers and drinkers) and in patients who need psychological support or guidance of their rehabilitation process. These kinds

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of consultations do not need to be held on a routine basis.5, 7, 8, 30, 37 Other possible risk factors such as resection margin status, the presence of lymph node metastases, histologic differentiation grade and the stage of the primary tumor 6, 34, 35 should also be taken in consideration when establishing an

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individualized follow-up program.

Conclusion

In this study, 86% of secondary events occurred within three years

postoperatively. In these three years 96% of local recurrences, regional and distant metastases were detected. In the fourth and fifth year of the follow-up 14% of the secondary events were detected. Most secondary events occurred within the first three years of follow-up. Therefore, the case can be made for an altered regimen of follow-up beyond three years based on certain risk factors unique to the patient as well as the patient's ability to adequately report symptoms that may be associated with recurrent disease. Ideally, a prospective randomized study with two groups 7

ACCEPTED MANUSCRIPT should be performed to evaluate more precisely the efficacy of regular followup in the fourth and fifth year after a disease-free period of three years in patients with oral cancer. However, such study does not seem feasible. Instead, the questionable value of regular follow-up after three years should

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be discussed with the patient.

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ACCEPTED MANUSCRIPT Table 1. Follow-up schedules for oral cavity and head and neck cancers1, 2, 7, 8, 12-14, 16-35 Follow-up schedule Author, year (country)

Type of study, if applicable

Year 2

Year 3

Year 4

Year 5

≥ Year 6

Guidelines

2-3 months

3 months

4-6 months

6 months

6 months

12 months

National Comprehensive Cancer [18] Network , 2014 (US)

Guidelines

1-3 months

2-6 months

4-8 months

National Guideline [22] Clearinghouse , 2009 (US)

Guidelines

3 months

4 months

6 months

1-3 months

2-4 months

3-6 months

American Society of Head and Neck [20] Surgery , 1996 (US)

4-8 months

4-8 months

12 months

-

-

-

4-6 months

4-6 months

12 months

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Dutch Cooperative Head and Neck [16] Oncology , 2004 (NL)

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Year 1

British Association of Head and Neck [19] Oncologists , 2011 (GB)

Guidelines

4-6 weeks

4-6 weeks

3 months

6 months

6 months

12 months

British Association of [19, 21] Otolaryngologists , 2011 (GB)

Guidelines

1-2 months

1-2 months

3- 6 months

3- 6 months

3- 6 months

12 months

British Association of OtorhinolaryngologyHead and Neck [23] Surgery , 2002 (GB)

Guidelines

German- Australian[24] Swiss DÖSAK , 2002

Guidelines

[17]

French ORL Society 2005 (FR)

,

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(for high-risk patients or rehabilitation)

1-3 months

2-4 months

6 months

6 months

6 months

-

1 month

2 months

3 months

6 months

12 months

12 months (discharged if healthy)

Guidelines

3 months

4 months

6 months

6 months

6 months

12 months

Guidelines

2 months

3 months

4 months

6 months

6 months

-

Cohort study

2 months

3 months

4 months

6 months

6 months

discontinued if >10 years no second events

Cohort study

2 months

3 months

4 months

6 months

6 months

12 months

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Danish Head and Neck Cancer Group [25] (DAHANCA) , 2003 (DK)

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Society of Head and [20] Neck Surgery , 1996 (US)

Guidelines

12 months, De Visscher 1994 (NL)

Merkx

[7]

[2]

,

, 2006 (NL)

(max. to 10 years)

ACCEPTED MANUSCRIPT Follow-up schedule

[28]

Boysen

[8]

Boysen

[27]

Haas

, 1992 (NL)

[13]

Rivelli

, 1985 (NL)

, 1994 (NL)

, 2001 (DE)

[29]

, 2011 (CH)

Lester and Wight 2009 (GB)

[30]

,

Year 2

Year 3

Year 4

Year 5

≥ Year 6

Retrospective study

2 months

3 months

4 months

6 months

6 months

Without symptoms discontinued

Retrospective study

2-3 months

2-3 months

2-3 months

6 months

6 months

Without symptoms discontinued

Prospective study

2-3 months

2-3 months

3-4 months

Prospective study

2-3 months

2-3 months

3-4 months

Retrospective study

1 months

2 months

3 months

Retrospective study

1 month

2 months

3 months

Prospective study

1 month

2 months

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Boysen

, 2011 (NL)

Year 1

3-4 months

3-4 months

-

3-4 months

3-4 months

6 months

6 months

6 months

-

6 months

6 months

12 months

3 months

4 months

6 months

12 months

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[12]

Wensing

Type of study, if applicable

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Author, year (country)

Manikantan 2009 (GB)

[14]

,

Review

2 months

3 months

3 months

4 months

-

-

Manikantan 2011 (GB)

[31]

,

Review

2 months

3 months

3 months

3 months

-

-

2-3 months

4-6 months

4-6 months

4-6 months

2 months

3 months

6-12 months

6-12 months

6-12 months

st

rd

Sasaki

Koo

Li

[34]

[35]

, 1999 (AU)

[32]

, 1982 (JP)

Retrospective study

Retrospective study

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Ohkubo

[1]

EP

Cooney

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1 –3 m month: 1 month

[33]

, 2011 (JP)

, 2006 (KR)

, 2011 (CN)

th

th

st

th

4 - 12 month: 2-3 months

1 –6 month : 2 weeks th

th

-

6 -12 month: 1 month

Retrospective study

1 month

2 months

2 months

2 months

2 months

2 months

Retrospective study

1 month

2 months

3 months

6 months

6 months

12 months

Retrospective study

1 month

2 months

4 months

4 months

6 months

6 months

ACCEPTED MANUSCRIPT Table 2. Reported detection rates of the secondary events in year 1, 2, 3, and >3 of follow-up1-8, 12, 13, 15, 25-28, 32-34, 36, 37

76% 87% 61% 85% 76% 47% 68% 47,3% 68,8% 50% 70% 90% 80% 90%

94% 87% 85% 76,1% 89% 78% -

100% 100% -

-

-

-

-

(mean interval 15 months)

Kissun

[15]

, 2006

90,7%

Koo

[34]

, 2006

78%

92%

(Mean interval 11.9 months)

Ritoe

[6]

, 2007

90%

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(median 8 months)

-

(mean interval 19 months, median 12 months) [12]

86.3% 56% 33%

83% 70% 55%

90% 100% 85% 69%

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Wensing , 2011 [33] Sasaki , 2011 [37] Kothari , 2011 [3] Pagh , 2013

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[32]

Ohkubo , 1982 [28] Boysen , 1985 [8] Boysen , 1992 [27] Boysen , 1994 [2] De Visscher ,1994 [1] Cooney , 1999 [13] Haas , 2001 [36] Schwartz , 2003 [25] Overgaard , 1986 [5] Ritoe , 2004 [7] Merkx , 2006

Secondary events (cumulative %) Year 1 Year 2 Year 3 > 3 years

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Author, year

83%

ACCEPTED MANUSCRIPT

Table 3. Primary tumor distribution by stage, location and treatment modality of 225 patients TNM stage stage I

stage II

stage III

n=59

n=54

n=44

n=64

n=4

n=225

(26.2%)

(24.0%)

(19.6%)

(28.4%)

(1.8%)

(100.0%)

21

22

21

12

-

76 (33.8%)

14

19

14

28

-

75 (33.3%)

Alveolar process

2

4

4

14

1

25 (11.1%)

Trigonum retromolar

5

4

3

6

2

20 (8.9%)

Lip

15

2

1

-

-

18 (8.0%)

Buccal mucosa

2

2

-

3

-

7 (3.1%)

-

1

1

1

1

4 (1.8%)

56

21

9

10

-

96 (42.7%)

25

17

35

1

81 (36.0%)

7

8

3

1

19 (8.4%)

-

5

12

1

18 (8.0%)

1

5

4

1

11 (4.9%)

Surgery +

3

radiotherapy Radiotherapy

-

Chemoradiotherapy

-

Surgery +

-

AC C

EP

TE D

chemoradiotherapy

Total

RI PT

SC

Hard palate Treatment Surgery modality

M AN U

Tumor Tongue Location Floor of the mouth

stage IVA stage IVB

ACCEPTED MANUSCRIPT Table 4. Characteristics of the secondary events FOLLOW-UP

Location of the primary tumor

Local recurrence

34

3

37 (38.5%)

Regional metastases

24

-

24 (25.0%)

Second primary tumor

13

10

Distant metastases

7

-

Loco-regional recurrence

5

-

stage I

29

-

stage II

17

4

stage III

13

4

stage IVA

23

stage IVB

1

Tongue

29

Floor of the mouth Alveolar process Trigonum retromolar Lip Buccal mucosa Hard palate

23 (24.0%) 7 (7.3%) 5 (5.2%)

29 (30.2%) 21 (21.9%) 17 (17.7%)

3

26 (27.1%)

2

3 (3.1%)

1

30 (31.2%)

25

7

8

1

9 (9.4%)

8

2

10 (10.4%)

6

-

6 (6.3%)

4

1

5 (5.2%)

3

1

4 (4.2%)

39

1

40 (41.7%)

24

6

30 (31.2%)

TE D

Surgery + radiotherapy

32 (33.3%)

Radiotherapy

12

3

15 (15.6%)

Chemoradiotherapy

6

3

9 ( 9.4%)

Surgery + chemoradiotherapy

2

-

2 (2.1%)

Curative

59

7

66 (68.8%)

24

6

30 (31.3%)

Palliative/ No treatment

AC C

Therapy intention of the secondary event

Surgery

EP

Treatment modality of the primary tumor

RI PT

Total n=96 (100.0%)

SC

TNM stage primary tumor

Year 4-5 n=13 (13.5%)

M AN U

Secondary event

Year 1- 3 n=83 (86.5%)

ACCEPTED MANUSCRIPT Clinical relevance Today, the follow-up period of patients treated for oral cancer is in most head and neck centers reduced to five years. In the present study it has been shown that a 3

AC C

EP

TE D

M AN U

SC

RI PT

year follow-up period may be sufficient.