Concomitant Chemo And Radiotherapy

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Is concomitant chemo- and radiotherapy better than radiation alone? Early concomitant trials employed single-agent chemotherapy with simultaneous radiotherapy. Agents included methotrexate, hydroxyurea, bleomycin, 5-FU, and cisplatin.48-50 Except for a few trials, one each with methotrexate, bleomycin, and 5-FU, all results showed no significant difference over radiation alone. Recent trials have more often used combination chemotherapy in conjunction with various delivery schedules of radiation.45' 51-56 The subjects are varied, but most trials concentrate on previously untreated patients with or without resectable disease. The locoregional control and survival statistics of the combined-modality arms of these trials are improved from their predecessors (Table 8-3).

TABLE 8-3

Randomized Concomitant Chemo- and Radiotherapy Trials+

TABLE 8-3

Randomized Concomitant Chemo- and Radiotherapy Trials+

First Author,

H&N

LRC#

Overall

Dz. Free

Year

N

Chemo1

Resectable

sites§

Survival

survival

Comments

Lo,50 1976

136

F

Y

OC OP HP L

<G.G5

<G.G5

NA

Shanta,57

157

B

Y

OC OP L

G.G5

<G.G5

< 0.05

Used IV, IM, and IA

1980

delivery of chemo

Stefani,58

15G

Hu

Y

OC OP

NS

NS

NA

Median survival better in

1980

HP L

control

Vermund,59

222

B

Y

OC NP S

NS

NS

NS

Trend for control to live

1985

OP HP L

longer

Gupta,60

313

M

Y

OC NP

G.G16

NS

NA

OP only has significant

1987

OP HP L

survival difference

Fu,49

96

B

N

OC NP

G.GG1

NS

0.043

Adjuvant chemo also

1987

OP HP L

Weissberg,61

117

Mito

Y

OC NP

<G.G2

NS

<0.07

1989

OP HP L

Sanchiz,62

577

F

Y

OC NP S

NA

<G.GG1

<0.001

3rd arm of hyperfraction

1990

OP HP L

XRT equal to comb tx

Weissler,51

58

P-F

Y

OC OP

NA

NS

NS

radiation

1992

N

HP L E

NA

G.G13

0.002

hyperfractionated

Salvajoli,45

6G

B-P

Y

OC OP

NS

NS

NA

3rd arm neoadjuvant also

1992

HP

NS

Merlano,52

157

P-F

N

OC NP

<G.G5

G.G1

0.008

Alternating schedule

1992

OP HP L

Herskovic,63

123

P-F

Y

E

G.G1

<G.GGG1

0.0003

Early closure of study,

1992

adjuvant P-F

Keane,55

212

F-Mito

Y

HP L

NS

NS

NS

Split course radiation

1992

Browman,64

175

F

Y

OC OP

NS

NS

NS

Trend for increased

1994

HP L

(0.06)

survival in combination

Smid,56

49

B-Mito

N

OC OP

<G.GG1

NA

0.001

Median follow-up 18

1994

HP

months

Bachaud,65

83

P

Y

OC OP

G.G8

<G.G1

<0.02

Treatment delivered

1996

HP L

postoperatively

Adelstein,53

1GG

P-F

Y

OC OP

G.G3

NS

0.03

Excluded T4 with bone

1997

HP L

involvement

Haffty,66

2G3

Mito

Y

OC NP S

G.GG2

NS

0.002

Disease-specific survival

1997

OP HP L

p0.005, post-op treatment

Jeremic,67

159

P

N

OC NP

G.G18*

G.G11

0.018

* local control only,

1997

CP

OP HP L

G.G4*

G.G19

0.040

regional control = NS

Al-Sarraf,68

147

P

Y

NP

<G.G1

G.GG5

<0.001

Early closure of study,

1998

adjuvant P-F

Brizel,69

116

P

Y

OC NP S

G.G1

G.G7

0.08

Radiation

1998

OP HP L

hyperfractionated

Wendt,54

27G

P-F-LV

N

OC OP

<G.GG4

G.GG3

NA

4-year survival 49% vs

1998

HP L

24%

t Results are p values comparing radiation alone to concomitant therapy (p<0.05 favors concomitant).

*B = bleomycin, F = fluorouracil, Hu = hydroxyurea, LV = leucovorin, M = methotrexate, Mito = mitomycin-C, P = cisplatin §E = esophagus, HP = hypopharynx, L = larynx, NP = nasopharynx, OC = oral cavity, OP = oropharynx, S = sinus #LRC = Loco-Regional Control

Of interest are five trials employing cisplatin and 5-FU with different radiation regimens. Using a hyperfractionation scheme with 150 centigray (cGy) twice a day (b.i.d.) with a 2-week scheduled break after the first 10 treatments, Weissler et al.51 found a significant difference in locoregional control and overall survival rate only in those patients who were deemed to be unresectable. Merlano et al.52 used alternating radiotherapy and chemotherapy in unresectable patients and also found a significant difference between the treatment and control arms in several areas, including progression-free survival (25% vs 7%, respectively). Adelstein's group53 used standard daily radiation with 4 days of chemotherapy initiated on days 1 and 28; non-responders underwent surgical salvage. Relapse-free survival was better in the treatment arm (67 to 52%). All these trials used cisplatin at a dose of 100 mg/m2. In 1998, Wendt et al.54 reported on a trial of unresectable patients using accelerated fractionated radiation (1.8 cGy b.i.d.). They used only 60 mg/m2 of cisplatin, but leucovorin was added to the combination. A 3-year overall survival rate difference of 48 to 24% was found in favor of the combined therapy. An important Intergroup trial focusing on esophageal cancer was first reported in 1992 and updated in 1997.63 70 This trial included both squamous cell carcinoma and adenocarcinoma of the esophagus. Patients were stratified on the basis of histopathologic status, tumor size, and weight loss. They were randomly divided between concomitant chemo- and radiotherapy with cisplatin (75 mg/m2) and 5-FU, also receiving two courses of adjuvant therapy with the same agents, and with radiotherapy alone. Surgical resection was reserved for those failing the primary therapy. The trial stopped accruing patients at the interim analysis, when investigators noted a 2-year survival difference of 38 to 10% (P < 0.0001) favoring the combined modality group. The follow-up report showed that none of the patients who received radiotherapy alone was alive at 3 years, whereas the 3- and 5-year survival rates for the combined group were 30% and 27%, respectively (P < 0.0001). A similar survival rate was found for other patients treated with this regimen since the conclusion of the trial. So, despite certain differences, all these trials of cisplatin-based concomitant chemo- and radiotherapy demonstrated improved survival, as compared with the control (radiotherapy-only) arm of each study.

A meta-analysis evaluated 25 prospective randomized studies. A control arm was included for definitive locoregional control, to which chemotherapy was added as a treatment arm.71 When all reports were summated, there was no difference in survival rates. However, when only those trials that used concomitant chemo- and radiotherapy were evaluated, a 0.78 reduction in mortality rate from the radiotherapy-only control group was observed.

While the great majority of trials show no difference between standard radiotherapy and concomitant chemo- and radiotherapy, the newer trials have often shown differences in survival.42, 45, 51-56 58-69 72-74 These longer survival rates come at the expense of increased short-term morbidity, mostly in the form of grade 3 and 4 mucositis. But there is evidence that chemotherapy is having an impact not only on tumor regression, but on both disease-free and, occasionally, overall survival, as well.

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