Table 4 Results of irradiation with systemic therapy

Felix Zwicker, 2011

R

10

Median time to previous irradiation: 52 mo;

Median dose of prior irradiation: 66 Gy (range, 30–71.4 Gy)

IMRT

Cetuximab

6.5 (0.5–16)

PTV: 182.5

(48–1320)

28 (22–36)

50.4 (39.6–64.8)

1-year LC: 61%;

1-year LRC: 44%;

1-year DMFS: 75%;

1-year OS: 40%;

Median OS: 7 mo

Severe acute toxicity:

Fatal infield arterial bleeding: 10%;

Flap necrosis: 10%;

Severe late toxicities:

Fibrosis of the temporomandibular joint: 10%;

Stenosis of the cervical esophagus: 10%

[45]

Jacques Tortochaux, 2011

Randomized phase III trial

30

Time to previous irradiation ≥ 6 mo;

Median dose of prior irradiation: 62.5 Gy

Conventional treatment planning system or 3D-CRT

Fluorouracil and hydroxyurea

NA (maximum: 60)

NA

30

60

6-month OS: 50%;

9-month OS: 30%;

1-year OS: 23%;

Median OS: 6 mo

Grade ≥ 3 acute toxicities:

Mucositis:6.7%;

Radio-dermatitis: 3.3%;

Thrombocytopenia: 6.7%;

Leukopenia: 10%;

Anemia: 3.3%;

Stomatitis and pulmonary adverse event: 10%;

Infectious shock: 3.3%

Grade ≥ 3 late toxicities: 36.7%

[42]

Dwight E Heron, 2011

Retrospective matched cohort study

35

Median time to previous irradiation: 18.4 mo (range, 8.3–311.5 mo);

Median dose of prior irradiation: 69.2 Gy (range, 36–129.5 Gy)

SBRT

Cetuximab

15.9 (3.1–36.5)

28.7 (5–91.7)

5

40 (20–44)

1-year LC: 78.6%;

2-year LC: 49.2%;

Median LC: 23.8 mo;

1-year OS: 66%;

2-year OS: 53.3%;

Median OS: 24.5 mo

Grade 3 acute toxicities:

Xerostomia: 2.9%;

Dysphagia: 2.9%;

Grade 3 late toxicities:

Xerostomia: 2.9%;

Dysphagia: 2.9%

[50]

35

Median time to previous irradiation: 19.2 mo (range, 4.4–269.7 mo);

Median dose of prior irradiation: 68 Gy (range, 32–140 Gy)

SBRT (matched)

None

14.6 (2.2–39)

29.0 (4.8–86.8)

5

40 (20–44)

1-year LC: 53.8%;

2-year LC: 33.6%;

Median LC: 13.2 mo;

1-year OS: 52.7%;

2-year OS: 21.1%;

Median OS: 14.8 mo

Grade 3 acute toxicities:

Xerostomia: 2.9%;

Grade 3 late toxicities:

Xerostomia: 2.9%

L Vormittag, 2012

Prospective phase II trial

31

Median interval to failure from prior irradiation: 15 mo;

Median dose of prior irradiation: 62 Gy (range, 45–80 Gy)

3D treatment planning radiotherapy

Capecitabine

NA

NA

25 (15–30)

50 (30–60)

CR: 19%;

PR: 48%;

1-year OS: 42%;

2-year OS: 10%;

Median OS: 8.4 mo

Grade 3 or 4 mucositis: 16.1%;

Grade 3 skin reactions: 6.5%;

Grade 3 anemia: 3.2%;

Grade 3 late toxicities:

Xerostomia: 7.7%;

Dysphagia: 23%;

Pain: 7.7%

[43]

Jordan Kharofa, 2012

R

38

Median time to previous irradiation: 28 mo (range, 3–228 mo);

Median dose of prior irradiation: 68 Gy (54–70 Gy)

IMRT: 76%;

3D-CRT: 24%

Carboplatin and paclitaxel

16

NA

30

60

1-year PFS: 44%;

2-year PFS: 34%;

5-year PFS: 29%;

Median TTP: 7 mo;

1-year OS: 54%;

3-year OS: 31%;

5-year OS: 20%;

Median OS: 16 mo

Acute toxicities:

Grade 2 neutropenia: 5%;

Grade 3 neutropenia: 15%;

Grade 1/2 thrombocytopenia: 8%;

Significant late toxicities: 16%

[44]

Eric F Lartigau, 2013

Prospective phase II trial

60

Mean time to previous irradiation: 38 mo;

Median dose of prior irradiation: NA

SBRT

Cetuximab

11.4

Median tumor size: 29 mm

6

36

Median PFS: 7.1 mo;

1-year OS: 47.5%;

Median OS: 11.8 mo

Toxic death from hemorrhage and denutrition: 1.8%;

Grade 3 toxicities: 32.1%

[51]

D Milanović, 2013

R

23

Median time to previous irradiation: 102.2 mo (range, 12–293 mo);

Median dose of prior irradiation: 64.3 Gy (range, 50–70 Gy)

Re-irradiation

Cetuximab

11.04 (1–37)

NA

NA (28–36)

NA (50.4–66)

1-year OS: 34.8%;

Median OS: 9 mo;

Median PFS: 4.3 mo

Grade 3 acute toxicities:

Dermatitis: 35%;

Dysphagia: 30%;

Acneiform rash: 30%;

Mucositis:15%;

Voice change: 15%;

Pain: 9.6%;

Grade 3 late toxicities:

Dysphagia: 17.6%;

Pain: 17.6%;

Fibrosis: 11.8%;

Voice changes: 5.9%;

Xerostomy: 5.9%;

Trismus: 5.9%

[46]

John A Vargo, 2015

Prospective phase II trial

48

Median time to previous irradiation: 18 mo (range, 3–423 mo);

Median dose of prior irradiation: 70 Gy (52.5–118.2 Gy)

SBRT

Cetuximab

18 (10–70)

GTV: 36.5 (3.6–209.2)

5

NA (40–44)

1-year LPFS: 60%;

1-year locoregional PFS: 37%;

1-year distant PFS: 71%;

1-year PFS: 33%;

1-year OS: 40%;

median OS: 10 mo

Acute grade 3 toxicities: 6%;

Late grade 3 toxicities: 6%

[52]

Nicolas Dornoff, 2015

Retrospective comparative study

33

Median time to previous irradiation: 24 mo (range, 5–281 mo);

Median dose of prior irradiation: 64 Gy

3D-CT-based conformal radiotherapy

Cetuximab

18.3

GTV: 35 (2.9–213);

PTV: 159.5 (22.8–1345)

28

50.4 (1.8–72)

1-year OS: 44.4%;

2-year OS: 11.9%;

1-year LC: 46.4%;

1-year FFM: 73.6%

Grade ≥ 3 acute toxicities: 57.6%;

Grade ≥ 3 late toxicities:

Dysphagia: 21.2%;

Trismus: 6.1%;

Xerostomia: 6.1%

[48]

33

3D-CT-based conformal radiotherapy

Cisplatin with/without 5-fluorouracil

1-year OS: 45.5%;

2-year OS: 30.3%;

1-year LC: 54.2%;

1-year FFM: 81%

Grade ≥ 3 acute toxicities: 51.5%;

Grade ≥ 3 late toxicities:

Lymphedema: 3.1%;

Dysphagia: 21.2%

M Ritter, 2016

R

18

Median interval to failure from prior irradiation: 2.3 mo (range, 2–8 mo);

Median dose of prior irradiation: 68.1 Gy (range, 50–105 Gy)

HDR-BRT

Cetuximab plus paclitaxel

13.4 (0.1–72.9)

CTV (V100): 61.9 (22.3–149.5)

10.6 (6–14)

27.0 (15–35)

1-year DFS: 32%;

2-year DFS: 24%;

1-year OS: 85%;

2-year OS: 65%

Grade 3 acute toxicities: 11.1%;

Grade 3 late toxicities: 5.6%

[53]

18

Median interval to failure from prior irradiation: 38.1 mo (range, 18–99 mo);

Median dose of prior irradiation: 66.2 Gy (range, 59–77 Gy)

HDR-BRT (matched)

None

CTV (V100): 46.4 (4.0–111.1)

10.8 (8–12)

27.1 (20–30)

1-year DFS: 17%;

2-year DFS: 17%;

1-year OS: 68%;

2-year OS: 58%

Grade 3 acute toxicities: 11.1%;

Grade 3 late toxicities: 5.6%

M J Awan, 2018

Prospective phase II trial

45

Median time to previous irradiation: 30 mo (range, 6–219.6 mo);

Median dose of prior irradiation: 70 Gy (range, 63–75.6 Gy)

IMRT

Cisplatin plus cetuximab

16.6

NA

30

60 (60- 70.29)

1-year RFS: 34.1%;

2-year RFS: 27.3%;

1-year OS: 60.4%;

2-year OS: 45.3%

Grade ≥ 3 acute toxicities:

Lymphopenia: 46%;

Pain: 22%;

Dysphagia: 13%;

Radiation dermatitis: 13%;

Mucositis: 11%;

Anorexia: 11%;

Grade 3 late toxicities: 17.4%

[47]

Yungan Tao, 2018

RCT

26

Median time to previous irradiation: NA;

Dose of prior irradiation ≥ 50 Gy

3D-CRT with or without intensity-modulation (60 Gy over 11 weeks radiation, six cycles with each cycle delivering 2 Gy/fraction, 5 days/week)

5FU and hydroxyurea

36

NA

30

60 (60–80)

Median DFS: 11.2 mo;

2-year OS: 45%;

Median OS: 21.9 mo

Grade 3 or 4 toxicities:

End of reirradiation: 42.3%;

6 months from randomization: 28.0%;

12 months from randomization: 17.6%;

24 months from randomization: 0%

[49]

27

3D-CRT with or without intensity-modulation (60 Gy over 5 weeks radiation, 1.2 Gy twice daily)

Cetuximab

36

NA

50 (bid)

60

Median DFS: 12.0 mo;

2-year OS: 67%;

Median OS: 37.4 mo

Grade 3 or 4 toxicities:

End of reirradiation: 37.0%;

6 months from randomization: 20.0%;

12 months from randomization: 27.8%;

24 months from randomization: 14.3%