The integration of chemotherapy into a combined modality approach to cancer therapy

Cancer Treatment Reviews(I975) 2, 137-158

The integration o f chemotherapy into a c o m b i n e d modality approach to cancer therapy V. Squamous cell cancer of the head and neck Michael A. Goldsmith

Mt Sinai Hospital, New York, N.Y., U.S.A. and

Stephen K. Carter

Deputy Director, Division of Cancer Treatment, National Cancer Institute, Bethesda, Md 20014, U.S.A.

Introduction Cancer of the head and neck presents a continuing challenge in the use of combined modality therapy, requiring the expertise of surgeons, radiotherapists, medical oncologists, prosthodontists, plastic surgeons, and pathologists. Head and neck cancers account for a relatively small portion (5%) of malignancies in the United States but the pronounced cosmetic deformities and associated social stigma heighten their relative importance. These tumors are a heterogeneous group of lesions involving the upper digestive tract between the vermilion surfaces of the lips and the constrictor muscle at the entrance to the surgical esophagus. This mucosa-lined muscular tube contains two important structures, the tongue and larynx, on its ventral surface and has direct communication with the upper airway. T h e majority of lesions in this area are squamous cell carcinomas of the oral cavity, pharynx, larynx, and sinuses. A lesser fraction includes tumors of the salivary glands. In parts of the Orient and Africa, nasopharyngeal cancer, which is uncommon in western countries, is the prevalent lesion. The epidermoid lesions originating in the tongue, buccal mucosa, gingiva, and anterior pillar often are highly differentiated, while those of the floor of the mouth usually are less differentiated. The tumors in the head and neck area are characterized by local extension and invasion, with subsequent cervical lymph node metastases. Death, in most instances, results from local disease rather than distant metastasis. Because cancer of the head and neck is a conglomerate of neoplasms arising from different sites and, occasionally, different histological types, it is difficult to assess response ~"To whom reprint requests should be addressed. 137

138

M.A. GOLDSMITH AND S. K. CARTER

rates and survival for the group as a whole. Ideally, response data should be recorded by the specific site of tumor origin. For example, the 5-year survival in patients with squamous cell carcinoma of the lip is twice that for squamous cell carcinoma of the anterior two-thirds of the tongue. Table 1 gives the determinate 3- and 5-year survival data of M a c C o m b & Fletcher (52) according to the site of the primary lesion for all stages treated with surgery, radiation, or both. Clearly, an assessment of any data must carefully take into account the primary site and stage. The T N M classification (76) has been used extensively in this area and, naturally, larger tumors with node involvement do more poorly than small localized neoplasms without nodal metastases. Table 1. D e t e r m i n a t e s u r v i v a l in h e a d and n e c k cancer (52)

Survival rate Site

3-year

5-year

Lip Tongue Floor of mouth Buccal mucosa Lower gmn Upper gum and hard palate Nasopharynx Base of tongue ? Tonsillar fossa Pharyngeal walls ]" Retromolar trigone and anterior tonsillar pillar ~"Soft palate and uvula Pyriform sinus Larynx Glottis Supraglottis Paranasal sinus Anterior to Ohngren's line~ Posterior to Ohngren's line wParotid wSubmaxillary wMinor salivary glands

2891305 (95%) 68]129 (52%) 74/114 (65%) 57/80 (71%) 48/102 (47%) 23/42 (55%) 25/50 (50%) 53/124 (43%) 51/91 (56%) 63/140 (45%) 109/158 (69%) 39]55 (70%) 39/150 (26%)

230]243 (95%) 45]99 (45%) 46/74 (62%) 42/59 (70%) 37/80 (46%) 19/37 (51%) 14/36 (39%) 4.6/124 (37%) 45/91 (49%) 57/140 (41%) 87/158 (55%) 32/55 (59%) 23/117 (19%)

243/303 (80%) 791149 (53%)

160/208 (77%) 43]97 (43%)

17124 (71%) 11139 (28%) 58/I 11 (52%) 7]16 (44%) 33/87 (38%)

]" By life table analysis. ++Perpendicular line drawn through the maxillary sinus on the lateral projection of the skull X-ray. wAll cell types. Chemotherapy

The heterogeneity of head and neck tumors and the small n u m b e r of patients treated in studies with most antitumor drugs make a precise analysis of response rates for particular sites impossible. There are no data comparing specific primary site and response to a particular agent.

Single agents Methotrexate has been the most extensively studied drug in head and neck cancer. It has been administered either by continuous intra-arterial (IA) infusion, or by systemic routes

COMBINED MODALITY APPROACH T O CANCER THERAPY

139

( I V or P O ) w i t h o r w i t h o u t l e u c o v o r i n " r e s c u e " . A l l o f t h e s e a p p r o a c h e s h a v e s h o w n significant antitumor activity but unfortunately the available data do not permit a definitive choice of an optimum approach. A r e v i e w o f t h e l i t e r a t u r e shows a 5 3 % r e s p o n s e r a t e in 340 cases t r e a t e d b y I A m e t h o t r e x a t e ( T a b l e 2). T h i s c o m p a r e s to a n o v e r a l l 4 0 % r e s p o n s e r a t e for s y s t e m i c m e t h o t r e x a t e o n a v a r i e t y o f schedules. T h e r e s p o n s i v e n e s s to I A i n f u s i o n is n o t t h a t i m p r e s s i v e w h e n o n e c o n s i d e r s t h a t t h e p a t i e n t s s e l e c t e d for this m o d e o f t h e r a p y u n d o u b t e d l y c o n s t i t u t e d a g r o u p h a v i n g m o r e l o c a l i z e d disease. T a b l e 2. C o n t i n u o u s i n t r a - a r t e r l a l i n f u s i o n s o f m e t h o t r e x a t e cancer

Investigators Yollick & Corgill (81) Acquarelli et al. (1) Hayes et al. (33)

Jesse et al. (40)

Espiner & Westbury (21)

Watkins & Sullivan (80)

Behrs et aI. (6)

Baker & Gaertner (4)

Burnetal.

(10)

Gorgun & Watne (30)

Tindel (75)

Couture (16) Totals

Dose schedule 50 mg/d with intermittent, conconaitant leucovorin 50 mg/d with conconaitant leucovorin (5 rag q 4 h IM) 40-50 nag/d with concomitant leucovorin (0.085-0.125 mg/kg/d IM divided daily doses) ~ 50 mg/d with concomitant leucovorin (20 mg/d IM divided daily doses for 3 ~ mos) 50 mg/d until local or systemic limiting toxicity (usually 5-6 d). Leueovorin simultaneously (18 mg/d IM) 50 mg]d with leucovorin (6 mg q 6 h IM) for duration of infusion. Infusion continued until toxicity (7-30 d); repeated for up to 3 mos 340--610 mg total dose over 10-14 d with intermittent leucovorin 50 mg/d with concomitant leucovorin vs 5-FU (1 gin/d) by IA infusion for average duration of 6 d 50 nag/d with concomitant leucovorin (6 nag q 6 h IM) Varying daily doses up to 25 nag/d, with 3 mg leucovorin q 6 h 25-50 nag/d for varying intervals + leucovorin (9 nag rid, IM) 50 nag/d+ leucovorin given for 5 d to 3 wks

f o r t h e r a p y of h e a d a n d n e c k

No. Response evaluable patients No. % 13

3 --

30

8

13

7 --

16

5 --

27

Remarks "Moderate" or "definite" objective regression Only 1 response >3 naos duration

Responses classedas"good results"

74

56

76

11 CR, 1 lasting 14+ mos

68

42

62

15 CR and 27 PR; 6 CRs lasted >6 mos, 4 had "major" embolization related to treatment

7

0 --

21

7 33

45

25

56

11

7 --

14

4 --

28

17 61

340

181

53

5-FU gave responses in 2/18 patients

4 CR

All >_-50% regressions, Of 25 pts, 4 died as a result of treatment All had oral cancer; 1 CR

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M. A. GOLDSMITH AND S. K. CARTER

W h e n the toxicity o f I A infusion is e x a m i n e d , t h e justification for this a p p r o a c h becomes questionable. I n the series o f 68 patients c a t h e t e r i z e d b y W a t k i n s & Sullivan (80), eight d i e d o f h e m o r r h a g e a n d four h a d " m a j o r " e m b o l i z a t i o n r e l a t e d to the t r e a t m e n t . Nevertheless, this is a r e a s o n a b l y g o o d series from the p o i n t of view of toxicity. T i n d e l (75) has r e p o r t e d four d e a t h s a n d serious c o m p l i c a t i o n s in t e n others from a g r o u p o f 25 t r e a t e d patients. I n view o f t h e fact t h a t infusion has n o t given results superior to systemic use o f the d r u g , further s t u d y o f this a p p r o a c h does not a p p e a r indicated. Systemic m e t h o t r e x a t e has b e e n given p r e d o m i n a t e l y b y either a n i n t e r m i t t e n t w e e k l y or b i w e e k l y I V injection or as m o n t h l y courses o f a five-dose p r o g r a m o f oral or I V d r u g a d m i n i s t r a t i o n . T h e d a t a for t h e w e e k l y or b i w e e k l y a p p r o a c h show t h a t 50% of t h e p a t i e n t s achieve > 5 0 % r e d u c t i o n in t u m o r size as c o m p a r e d to 2 9 % of those on m o n t h l y courses ( T a b l e 3), T h i s a p p a r e n t l y indicates s u p e r i o r i t y for weekly or b i w e e k l y m e t h o t r e x a t e a d m i n i s t r a t i o n . O t h e r schedules t h a t have shown a c t i v i t y i n c l u d e I V injection e v e r y two weeks (14), a n d 1 to 3 m g / k g over 24 h o u r s b y c o n t i n u o u s infusion plus leucovorin in some cases (47). T a b l e 3. E/l'ect o f m e t h o t r e x a t e s c h e d u l e o n r e s p o n s e i n h e a d a n d n e c k c a n c e r

Investigator

Dose schedule

No. of Number of responses'~ evaluable , , ~ patients >50% CR All

Drug, related deaths

W E E K L Y OK B I W E E K L Y

(61) (45) Leone et al. (48) Papacetal. I~ane et al.

DePalo et al. (18)

0.8 mg/kg q 4 d IV to toxicity 25-50 mg q 4-7 d IV 60 mg/m2/wk IV or 40 mg/mz biwk 40 or 60 mg/m~/wk IV Totals

15 27 35 23 I00

8 14 20

-4 11

9 14 20

-1 3

8 50 (50%)

-15

15 58 (58%)

1

1

M O N T H L Y COURSES

Huseby & Downing (36) 25 mg total in 5 d PO Papac et al. (60) 25 rng/d x 5 IV 15-20 mg/d x 5 PO Hellman et al. (34) 0.2 mg/kg/d x 5 IV Vogler et al. (77) 1.25-5 mg qid or 5-20 mg/d • 5 Kligerman et al. (42) 0.2 mg/kg/d x 5 IV Andrews & Wilson (2) 1.25 mg qid PO = 5 mg/d x 5-10 or same dose as infusion Sullivan et al. (74) 0.2 mg[kg/d x 4; then, 0.1 mg/kg qid • 4 PO, repeat d42 Totals

8 23 23 10

3 4 4 4

-----

3 12 9 6

8

1

--

2

11 13

5 7

---

5 7

11

3

--

3

107

31 (29%)

--

3 w

--

47 (44%)

J" Percent (%) response rate given in parentheses. T h e e x p e r i m e n t a l basis of t h e m e t h o t r e x a t e - c a l c i u m l e u c o v o r i n a p p r o a c h derives from studies o f G o l d i n et al. (95, 26) showing t h a t leucovorin, given 12 to 24 hours after m e t h o t r e x a t e , i m p r o v e t h e t h e r a p e u t i c i n d e x o f t h e d r u g in mice b e a r i n g the L1210 l e u k e m i a . F o u r studies in h e a d a n d neck c a n c e r h a v e p r o d u c e d > 5 0 % r e d u c t i o n o f t u m o r size in 4 3 % (36/83) o f p a t i e n t s ( T a b l e 4), w h i c h a g a i n does n o t a p p e a r s u p e r i o r

COMBINED MODALITY APPROACH T O CANCER THERAPY

141

T a b l e 4. M e t h o t r e x a t e a n d l e n c o v o r i n t h e r a p y in h e a d a n d n e c k c a n c e r

Dose schedule ,^ r

Investigator Lefkowitz

et al. (47) MacComb & Fletcher (52) Capizzi

etal.(ll) Levitetal. (49)

Methotrexate

Leucovorin

No. of responses-~ DrugNo. of 9 ~ . related patients >75% >50% >25% deaths

24-h IV infusion, 1-3 mg/kg 24-h IV infusion q 5 d, 2 mg/kg

6mgIMql2h•

18

3

I

--

0

6mglMq6h•

19

3

3

3

1

24-h IV infusion q 4 d, 240mg/m 2

75 mg in 12-h IV infusion; then 12 mg IM q6hx4 40 mg/m 2 in 6-h IV infusion; then, 25 nag PO q6h•

21

7

6

--

1

25

--

13

--

1

83

36 (43%)

36-42-h IV infusion q 2 wk, 360-1080 mg[m z Totals

I" Per cent (%) response rate given in parentheses. to results a c h i e v e d w i t h s y s t e m i c m e t h o t r e x a t e a l o n e . I n a r e c e n t s t u d y , B e r t i n o et al. (8) r a n d o m i z e d p a t i e n t s to e i t h e r m e t h o t r e x a t e a l o n e (80 to 110 m g / m 2) as a 3 0 - h o u r i n f u s i o n o r o v e r 36 to 42 h o u r s (240 to 1080 m g / m z) w i t h l e u c o v o r i n rescue. I n b o t h cases t h e infusions w e r e a d m i n i s t e r e d e v e r y t w o weeks. T h e r e s p o n s e r a t e a m o n g p a t i e n t s r e c e i v i n g m e t h o t r e x a t e a l o n e was 4 4 % w h i l e it was 5 2 % in t h e c o m b i n e d g r o u p . H o w e v e r , t o x i c i t y was less in t h e c o m b i n e d g r o u p a n d B e r t i n o feels t h a t this is a safer, i f n o t m o r e efficacious, a p p r o a c h . The Eastern Cooperative Oncology Group recently initiated a comparative study of t h e r e s p o n s e r a t e a n d d u r a t i o n o f r e s p o n s e to m e t h o t r e x a t e a l o n e o n a n o p t i m a l s c h e d u l e v e r s u s h i g h - d o s e i n t e r m i t t e n t m e t h o t r e x a t e w i t h l e u c o v o r i n r e s c u e ( F i g u r e 1). I n addition, a third treatment arm of the study will determine whether the addition of c y e l o p h o s p h a m i d e a n d c y t o s i n e a r a b i n o s i d e w i l l i m p r o v e t h e efficacy o f t h e r e s c u e approach. B l e o m y c i n , t h e g e n e r i c n a m e for a g r o u p o f a n t i b i o t i c s i s o l a t e d in J a p a n f r o m Streptomyces verticillus, has s h o w n a c t i v i t y a g a i n s t s q u a m o u s cell c a r c i n o m a o f t h e h e a d A

M T X 40 mg/m z weekly IV (initial dose). M T X 240 mg/m 2 every 2 weeks (over 5 min IV push) (initial dose), then escalated + Leucovorin 25 mg orally 42 h after M T X and at every 6 h thereafter for a total of 8 doses.

M[

~'C

M T X 240 mg/m 2 every 2 weeks (over 5 min IV push) (initial dose) + Leucovorin 25 mg orally 42 h after M T X and at every 6 h thereafter for a total of 8 doses + Cyclophosphamide 0.5 g/m 2 IV just before M T X + Cytosine arabinoside 300 mg/m 2 IV 15 rain after MTX.

Figure 1. Eastern Cooperative Oncology Group Study for patients with epidermoid carcinoma of the head and neck.

142

M. A. GOLDSMITH AND S. K. CARTER

a n d neck (9). I n the U n i t e d States, d a t a on 158 e v a l u a b l e p a t i e n t s ( T a b l e 5) show a n overall response r a t e o f 31 ~/o. H o w e v e r , i f o n l y responses of > 5 0 % t u m o r shrinkage a r e a c c e p t e d this rate falls to o n l y 15% a n d t h e m e a n d u r a t i o n o f remission is quite short. Clearly, b l e o m y c i n is inferior to m e t h o t r e x a t e as a single a g e n t b u t its l a c k of bonem a r r o w toxicity m a k e s it a p r i m e c a n d i d a t e for c o m b i n a t i o n regimens. Table 5. Etficaey of bleomycin in squamous cell carcinoma (United States experience by anatomical site) (9)

Number of patients ~-rEntered Evaluable"

Site Mouth Tongue Nasopharynx Tonsil Sinuses Larynx Other sites Total

21 34 22 25 11 46 31 190

Number of responses i00%

>50%

3 0 2 0 0 0 0 5

5 1 2 3 2 4 2 19

18 26 19 20 10 37 28 158

Overall 25-50~; response rate 5 2 2 3 1 5 7 25

72% 12% 32% 30% 30% 24% 32% 31%

Mean duration of remission (mos) 1.6 2 4 2 2.7 1.8 -2

T h e activity of o t h e r single agents has b e e n considered r e c e n t l y b y Bertino et al. (8) using d a t a g a t h e r e d in a review b y L i v i n g s t o n & C a r t e r (51). These d a t a a r e o u t l i n e d in T a b l e 6. T h e r e are indications of a c t i v i t y b y c y c l o p h o s p h a m i d e , 5 - F U , a n d h y d r o x y u r e a b u t the d a t a a r e so l i m i t e d w h e n various t u m o r sites a r e considered t h a t no definitive s t a t e m e n t can be m a d e . Table 6. Activity of systemically administered single agents (excluding methotrexate and bleomycln) in head and neck cancer (51)

Response Drug 5-Fluorouracil 6-Mercaptopurine Hydroxyurea Mechlorethamine (HC1) Cyclophosphamide Chlorambucil Vinblastine Procarbazine

Number of evaluable patients

{No. >50% tumor regression

. Overall rate

Range of response rates in individual studies

118 45 18 66 77 34 35 31

18 6 7 5 28 5 I0 3

15% 12% 39 % 7.5% 36% 14.7% 29% 10%

0-33 % 0-15.6 % -0-12% 0-39% ---

Combination regimens C o m b i n a t i o n regimens h a v e only been i n v e s t i g a t e d to a l i m i t e d extent ( T a b l e 7) a n d u s u a l l y h a v e not been designed specifically for h e a d a n d neck cancer. T h e results with single agents do p r o v i d e a basis for c o m b i n a t i o n studies b y d e m o n s t r a t i n g t h a t h e a d a n d neck c a n c e r is responsive to drugs w i t h differing m e c h a n i s m s o f a c t i o n a n d w i t h o u t c o m p l e t e l y o v e r l a p p i n g toxicities.

COMBINED MODALITY APPROACH TO CANCER THERAPY

143

Table 7. Combination chemotherapy in bead and neck cancer

Investigator Mosher et al. ( 5 6 ) Nervi et al. ( 5 9 ) Clortes et al. ( 1 5 ) Hanham et al. ( 3 2 ) Jacquillat et al. (38)

Drug combination Bleomycin + methotrexate Methotrexate + vincristine Bleomycin + adriamycin Cyclophosphamide + methotrexate Vincristine + 5-fluorouracil Vinblastine, streptonigrin, thiophosphoramide, chlorambucil, 6-MP, methotrexate, and proearbazine

No. of evaluable patients 4 28 8 10 82

No. with >50% tumor regression 2 15 4 1 CR 7 PR'~ 45"~

I" Definition of response unclear. Radiotherapy and chemotherapy 5-Ffuorouracil

5-Fluorouracil, by I V or IA route, has been investigated as an adjuvant to radiotherapy in several studies (Table 8). When used as a single I V agent in advanced disease the drug has an overall response rate of 15% in a total of 11 studies, as indicated earlier (Table 6). Intra-arterial 5-FU reportedly produced a 75% response rate in a total of 28 patients treated (16, 41). Hall & Good (31) first reported the I V use of 5-FU in combination with radiotherapy. The ten objective responses were encouraging, especially in view of the suboptimal~ dose (2000 R) of radiotherapy. No data on survival, staging, or details on tumor site were given. In a definitive study, Gollin et at. (27) reported a randomized controlled trial of radiotherapy alone versus radiotherapy plus 5-FU (IV). The dose of radiotherapy was 6000 to 7000 R over six or seven weeks, with the patients treated before 1964 receiving the dose with orthovoltage equipment. 5-FU was given as an initial loading course with maintenance therapy throughout the duration of radiotherapy. The authors analyzed their cases by site of primary tumor and interestingly, but not surprisingly, found a differential effect between the two treatment groups on the basis of the primary site of disease. Patients with oral cavity (excluding the lip) and oropharyngeal lesions had a greater survival in the combined modality group compared to radiotherapy alone, while a small number of patients having laryngeal and nasopharyngeal lesions showed no significant differences between the two arms of therapy. The only true difference of statistical significance was in patients with oral cavity lesions, where the median survival was 13 months for radiotherapy alone and 25 months for the combined modalities; in the oropharynx, both groups had a 20-month median survival. One serious drawback in this study was the imperfect randomization in staging, so that bony involvement was present in 8 of the 16 patients with T4 lesions in the radiotherapy arm while none were included among nine T4 cases assigned to the combination treatment. The authors noted, however, that there was little difference between both treatment regimens for all T 4 lesions combined. Von Essen et al. (78, 79) studied epidermoid carcinoma of the buccal mucosa in India in relation to radiotherapy alone or radiotherapy combined with 5-FU or a number of other agents. No survival differences were found, although it should be noted that

144

M. A. GOLDSMITH AND S. K. CARTER

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COMBINED MODALITY APPROACH TO CANCER THERAPY

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patients with this cancer, which is especially prevalent in India, usually reach the physician at an extraordinarily late stage of the disease when a huge local tumor mass is present. There have been several other studies of 5-FU administered as a continuous IA infusion combined with radiotherapy in the treatment of head and neck cancer. Gollin & Johnson (28) performed a non-randomized study of 5-FU given for 3 to 27 days prior to radiotherapy, compared to radiotherapy alone. The radiation treatment was identical to that described earlier by the same investigators. Because of the previous study (27) indicating the effectiveness of 5-FU in oral and oropharyngeal lesions, patients with cancer of these sites received IV 5-FU in both treatment arms. In any event, for the group as a whole, including patients with primaries of the oral cavity, pharynx, hypopharynx, and nasopharynx, no difference in local disease control or survival could be demonstrated between radiotherapy alone and combined treatment. While this study was by no means controlled, there was a fairly equal distribution of cases by disease stage between the two arms. A number of studies using IA infusions have been addressed only to squamous cell carcinoma of the paranasal sinuses. Sato et al. (69) administered 21-day 5-FU infusions during a course of 7700 R over 44 days. Additionally, all patients had a maxillary antrotomy for removal of necrotic debris. In essence, this study used all three treatment modalities. Thirty-eight of 57 patients (67%) with T2 and T3 lesions had a complete remission at the end of therapy. Sixteen of the responders also underwent further surgery or X-ray because of the fear of residual tumor. T h e overall survival rate at two years was 60%. The authors compared these results to their previous experience with pre- or post-operative irradiation. The 1-year local recurrence rate was 43% (13/30) for preoperative X-ray, 45% (25/55) for post-operative X-ray, and 22% (12/54) for the combined therapy. Similarly, in another Japanese study, Shigematsu et al. (72) randomized patients to X-ray alone versus the combination and found an improved 1-year recurrence-free interval of 47% (8[17) for the combination versus 23% (7/30) for irradiation alone. Goepfert et al. (24) recently reported their experience with 24 T3 and T 4 carcinomas of the nasal cavity and paranasal sinuses treated with 5-FU (21 cases with a 10-day IA infusion) or methotrexate (5 cases with leucovorin alone or combined with 5-FU) and radiotherapy. Twenty-three of the 26 patients completed the therapy and 11 [23 (49%) were free of local recurrence for a median of 44 months. The 2-year determinate survival was 48% and the 5-year, 26%; again, as performed by Sato et al. (69), most patients had an intraoral drainage procedure. The significance of the survival data is that although it may not be better than that reported for combined surgery and radiotherapy, patients achieved equally good results without undergoing mutilating surgery. Only 3 of the 23 patients subsequently required maxillary resection. The toxic effects of combined therapy in these studies, above and beyond those usually accompanying radiotherapy alone, were essentially of two types. The first related to the drug, which usually increased the stomatitis, occasionally produced myelosuppression, and sometimes caused nausea and vomiting. T h e second type of toxicity was due to catheter complications in prolonged IA infusion. These included catheter displacement, bleeding, infection, and cerebrovascular accidents. The toxicities .and relative value of prolonged IA infusions have been extensively described (67). 5-FU has been fairly well evaluated as an adjuvant to radiotherapy in head and neck cancer. It appears to add something to survival when given IV to patients with oral tumors, but apparently does not significantly improve survival in patients with disease

146

M. A. GOLDSMITH AND S. K. CARTER

at other sites. The drug may be of value when administered IA as part of triple modality therapy (24, 69) for carcinoma of the paranasal sinuses. In these cases, its use would be in obviating the need for major surgery rather than increasing survival. Admittedly, the data are still scanty and the argument can be made that the drug has not been adequately evaluated in a controlled fashion when administered during the course of radiotherapy (Gollin's study (27) was a preirradiation infusion). Methotrexate

Despite the criticism that can be made of 5-FU in combination with X-ray, there are even fewer well-designed and controlled studies of methotrexate (MTX) and radiotherapy. This is quite surprising, since methotrexate has been the most extensively evaluated drug in head and neck cancer. Friedman & Daly (17, 22, 23) were among the first to employ M T X and radiotherapy simultaneously in the primary treatment of head and neck cancer (Table 9). Methotrexate was given daily for one or two weeks and, when effective, was continued further; radiotherapy started three to five days after beginning the M T X therapy. Pre-irradiation M T X produced >~50~ shrinkage of tumor size in 56 out of 168 cases. The 2-year survival was analyzed by disease stage in 104 cases at risk and was felt to be superior to historical controls. It was noted that many patients died of distant metastases after local control of disease was achieved. This initial uncontrolled study suggested an enhanced effect of combined therapy over historical controls and prompted numerous other investigations of M T X and radiotherapy. Condit (13) used M T X on an intermittent IV schedule plus a similarly intermittent schedule of radiotherapy. The combination was randomized against radiotherapy alone. No significant difference between therapies was noted, although the number of evaluable patients in each treatment arm was too small (10 in M T X + R T and 15 in R T alone) for a definitive conclusion. Perez-Tamayo et al. (62, 63) found that an IV schedule of M T X every three days given with irradiation was better tolerated than daily oral administration of M T X . Both regimens gave a 42 to 70% response rate, although no survival or detailed data by tumor type were reported. Mechl & Kadlecava (55) also reported good responses to either PO or I V M T X combined with irradiation but, significantly, there was no data on response duration or survival. Von Essen et al. (78, 79), in their buccal cancer study, compared M T X plus radiotherapy to irradiation alone. Although the combination produced an 82~/o response rate versus 53% for X-ray alone, there was no difference in the short-term tumor control achieved by the two therapies. Subsequent analysis of over 200 patients showed that short-term tumor control was similar in all four arms of the study (RT alone, I U d R + RT, M T X + RT, and 5-FU + RT) and there was no difference in 2-year survival. Most lesions recurred, and only 19% were salvaged and underwent subsequent surgery. However, excluding massive (T5) tumors, combined therapy did produce a difference in 2-year survival, with radiotherapy alone having 11~/o versus 260/o for combined radiotherapy and chemotherapy (no data available for the individual type of chemotherapy). Kligerman et al. (42) also have published a preliminary report of a controlled study of radiotherapy alone versus M T X followed by irradiation, but no major conclusions were made. K r a m e r (43) utilized a number of M T X schedules (continuous PO, intermittent PO and IV) followed by radiotherapy and reported results in T3 and T4 lesions. In an effort

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to firmly establish the role of systemic methotrexate plus radiotherapy in head and neck cancer, the Radiation Therapy Oncology Group (RTOG) is currently conducting a randomized controlled study of radiotherapy alone versus M T X (25 mg IV q 3 d • 5 doses) by Kramer's schedule followed by irradiation. The type of radiotherapy is controlled and appropriate consideration has been given to staging and site of origin of the primary tumor. Several hundred patients have been entered on the study and definitive results should be available in the near future. The toxic effects noted in the M T X studies varied with the intensity of drug use but generally the dose-limiting toxicities were the expected mucositis and myelosuppression. In Condit's study (13) 5 of the 90 patients did not complete therapy because of severe toxicity. While there have been many studies of systemic M T X plus irradiation, there is not yet a clear-cut demonstration (pending the R T O G study) that this therapy is better than X-irradiation alone. A nearly equivalent number of studies employing IA infusion of M T X plus radiotherapy also has given no definitive answer (Table 10). Helman et al. (35) and Sealy & Helman (70) used a multidrug IA infusion followed by orthovoltage radiotherapy. Nitrogen mustard was administered on day 1, based on the authors' experience that this rapidly relieved pain, M T X was infused for one or two weeks with leucovorin and thiotepa was administered the last two or three days of the infusion. This regimen was felt to have no value in patients who had received prior radiotherapy; there were partial responses in 16 of 36 such patients but 11 were dead in four months. Patients without prior therapy experienced a better overall response (21/43, 49%), including eight complete responses, with fewer complications and a longer duration of survival (3 to 36+ mos for responders versus an average of 8.1 mos for non-responders). The authors compared these results to those obtained with a vinblastine IA infusion followed by radiotherapy. Interestingly, they noted that more patients responded initially to M T X but vinblastine was superior from the standpoint of the greater percentage of patients free of disease at 6 and 12 months (P = 0.05). Jesse (39) compared M T X to 5-FU infusion in a non-randomized fashion, with both drugs used in combination with X-ray therapy. In 38 patients without prior therapy, local control of disease for >15 months was secured in 14.3% of those receiving M T X + R T and 45.8}/o of those on 5-FU + RT. Six remained alive at a mean follow-up of 42 months. Seven often previously treated patients were free of local cancer > 15 months (5 after M T X + R T and 2 after 5-FU + RT) ; four of them were alive at a mean follow-up of 48 months. The results in T3 and T4 lesions tend to show better responses to 5-FU although the patient numbers are too small, the radiotherapy was administered differently, and non-randomization of the study makes interpretation difficult. A large-scale uncontrolled study by Nervi et al. (58) employed M T X plus vinblastine followed by radiotherapy in 129 patients with various lesions of head and neck cancer. The results by site of disease and stage are given in Table 10. These investigators felt that the results in Stage II and III disease with the combination were equivalent to previously reported findings with radiation therapy alone. There has been one controlled study of infusion plus irradiation versus X-ray alone. Bagshaw & Doggett (3) achieved successful local therapy in 32% (7/22) of patients using M T X plus X-ray versus 38% (6/16) for radiotherapy alone. There appeared to be no difference between any of several chemotherapeutic agents ( M T X , 6-MP, or BUdR) used with radiotherapy and radiotherapy alone. The status of intra-arterial infusion of M T X plus X-ray will probably not be resolved

COMBINED MODALITY APPROACH TO CANCER THERAPY

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without a study similar to the type currently in progress for systemic M T X in the Radiation Therapy Ontology Group. However, since published results with M T X infusion do not seem to show any major superiority to data on systemic M T X , there would appear to be little reason to consider performing such a study. In addition, the well-established complications produced by IA catheterization would make such a study even less attractive. Hydroxyurea Hydroxyurea is the third most extensively evaluated agent that has been combined with radiotherapy and surgery in head and neck cancer (Table 11). A 39% (7/I8) response rate is reported with use of the drug as a single agent (51). Lipshutz & Lerner (50) recently reported a 6-year follow-up of 82 patients treated with hydroxyurea and radiotherapy. There was speedy regression of the primary tumor in all patients and maximum regression was evident 6 to 8 weeks after radiation therapy. O f the 82 patients, 65 had 100% regression of tumor, 9 had 80% regression, and 8 had t>50% regression. Fifty-three patients were disease-free for 3 to 72 months. Thirty-eight patients underwent subsequent surgery and ten were alive at six years. Twenty of the 44 patients who did not undergo surgery were still living, for an overall 6-year survival of 36%. There was no breakdown of the data by disease stage or site of primary tumor and this uncontrolled study is difficult to evaluate. A smaller series by Hussey & Samuels (37), which also lacks details on site and stage, reported 7 of 15 previously untreated patients with local control for 5 to 24 months. A similar percentage of previously treated patients achieved local control but, while six of the first group had no evidence of disease at 9 to 24 months, none of the latter group were disease-free. Rominger (68) has also reported better responses among previously untreated patients, with the impression that drug enhances the radiation effect. Stefani et al. (73) performed a double-blind controlled study of hydroxyurea plus radiotherapy versus placebo plus radiotherapy, largely in patients who were previously untreated. As shown in Table 11, there was no therapeutic difference between regimens except for increased gastrointestinal and bone-marrow toxicity in the group treated with hydroxyurea. Interestingly, a higher percentage of patients (22.8%) in the drug + R T arm developed distant metastases than in those treated with placebo (7.5%). The study was well balanced in terms of stage and site of primary disease, and a significant point is that only orthovoltage and interstitial irradiation were used. Richards & Chambers (65) initially reported a controlled double-blind study of hydroxyurea or placebo plus radiotherapy followed by surgery, where possible, using 20 patients comparable for site and stage in each of the treatment arms. Radiotherapy alone induced 1 CR among 15 patients, irradiation plus surgery 13/13, irradiation plus hydroxyurea 7/9, and radiotherapy plus hydroxyurea plus surgery 11/I1. T h e most significant difference between the two arms was that pathological examination of the resected lymph nodes showed 7 positive of 12 in the placebo group and none of 11 in the hydroxyurea group. Five-year survival was 1/7 (14%) for radiotherapy alone, 6/13 (46 %) for irradiation + surgery, 3/9 (33%) for irradiation + hydroxyurea, and 7/11 (64%) for the three modalities combined. Over the next several years (66), these authors made a non-randomized uncontrolled study of 610 additional patients with head and neck cancer of whom 423 received hydroxyurea, radiation therapy, and surgery in some cases (255). Table 11 gives the

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5-year survival for all stages by the site of primary and type of therapy employed. The authors felt that hydroxyurea combined with surgery and radiotherapy produced increased survival in this class of patients. The toxicity of the drug was tolerable and consisted mainly of gastrointestinal disturbances and myelosuppression that were not inordinately difficult to control. The study of Stefani et al. (73) is fairly convincing that hydroxyurea does not add anything positive to irradiation alone. The fact that it was done with orthovoltage irradiation really does not detract significantly from these conclusions. Whether the drug adds anything to radiotherapy plus surgery is still not definitively answered. The nonrandomized nature of the series of Richards & Chambers (66), together with the variability in mode of therapy employed and the selection factors in choosing the particular modality, make it impossible to draw satisfactory conclusions from the study. Miscellaneous agents

Bleomycin is one of the new agents being investigated in a combined modality approach. As a single agent it is reported to have a response rate of 31% in advanced disease (Table 5). Berdal et al. (7) have reported responses without survival or staging data for this agent combined with radiotherapy (Table 12). In a Japanese study, Matsumuri et al. (54) obtained a 2-year survival rate of 40% with this combination plus surgery in carcinoma of the paranasal sinuses. Toxicity apparently was mainly mucocutaneous and pulmonary (interstitial fibrosis). Aside from the study of vinblastine (Table 10) described by Scaly & Helman (70), Probert et al. (64) used IA infusion of this agent to obtain 5 of 11 patients free of local disease at 1-year but only three were tumor free after two years (Table 12).

Surgery and chemotherapy In contrast to the relatively large number of published studies on chemotherapy plus radiotherapy in head and neck cancer, there is very little data for surgery plus chemotherapy. Generally, these studies involve drug administered intra-arterially by either perfusion or prolonged infusion. Nahum & Rochlin (57) have cited a small number of epidermoid head and neck cancer patients who underwent surgery following continuous IA infusion of M T X with folinic acid rescue. While responses were seen after the infusion, no definitive conclusions could be reached concerning the effect of the combined therapy on survival or local control of the disease. Similarly, Balla et al. (5) reported on four patients treated inconclusively by this approach. Golomb & Wright (29) reported a series of ten cases of squamous cell head and neck cancer treated with simultaneous tumor resection, neck dissection, and IA perfusion with nitrogen mustard or Dihydro E73. This study demonstrated the feasibility of a simultaneous combined approach, with seven of ten patients free of disease 19 to 46 months after surgery The small number of patients from three different sites and the lack of controls make the study impossible to evaluate from the standpoint of therapeutic efficacy. Similarly, Clifford (12) reported limited experience with IA infusion and Surgery in a small number of patients. He used mainly M T X or F U D R as the IA agents and reported responses in the M T X treated group (4 patients with 4 different sites), but little response in the F U D R treated group (9 patients with 6 different sites).

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The most definitive study of chemotherapy and surgery in oral carcinoma was performed by Desprez et al. (20). M T X was given by the standard 10-day IA infusion technique with simultaneous leucovorin followed by surgery three to six weeks after the infusion. The patients fell into two categories. One group (28 patients) had complete response following the infusion, with no residual tumor present and uniformly good results postoperatively. The second group (75 patients) had residual tumor following infusion and results on long-term follow-up were probably not different from what has historically been accomplished by surgery alone. At the beginning of the study, the response group was, by and large, a more favorable one. O f the 28 patients, only 4 were N+; 19 had T1 and T2 lesions and 9 had T3 and T4 lesions. While these patients would undoubtedly have responded well to surgery alone, the authors felt they nevertheless exhibited improved survival. In addition, because they experienced complete resolution of tumor after the infusion, less radical surgery was performed than if they had originally undergone surgery without prior infusion. The group of 75 patients who had residual tumor after M T X infusion originally presented with more advanced disease; 41 had T1 and T2 lesions, while 34 were classified T3 and T4. Thirty-five of the patients showed positive node involvement. Despite residual tumor, the infusion did relieve pain, decrease local inflammation, decrease tumor size by 50 to 60%, and occasionally converted an inoperable to an operable lesion. The overall 3-year survival for the favorable and unfavorable groups combined was 60% compared to an expected 35 to 40%. Desprez et al. (19) analyzed the characteristics of the infusion responders and nonresponders. The responders were previously untreated and had small exophytic tumors which were limited to the lateral surface of the tongue, gingiva, buccal mucosa, and tonsil. The poor responders often had previous X-ray therapy and their tumors were large with ulcerations, widespread lesions of the floor of the mouth, tonsil-palate area, base of tongue, lateral pharynx, and metastatic cevical nodes. The common denominator for poor response was inadequacy of the blood supply as a vehicle for M T X distribution, with the sites of poor prognosis not receiving an effective drug concentration. Other studies of surgery plus chemotherapy have generally included radiotherapy, thus combining all three modalities. Most of these have been cited earlier in this paper, including the IA infusions of 5-FU for maxillary cancer by Sato et al. (69) and Goepfert et al. (24). In addition, Shaw (71) has reported on a triple modality approach to cancer of the nasal cavity and paranasal sinuses. Patients were given IA infusions of M T X and nitrogen mustard followed by irradiation and radical surgery. Among 39 squamous cell carcinomas, there were 8 PR and 7 CR for a total response rate of 37% prior to X-ray and surgery. O f the 45 patients treated, including all cell types, 22 were alive and free of disease for 3 to 48 months. It is interesting that the therapeutic failures died from distant metastases rather than regional recurrence. The studies of Lipshutz & Lerner (50) and Richards & Chamber (66) also used all three modalities with hydroxyurea as the chemotherapeutic agent. Conclusion It is quite apparent from this review that there has not yet been a clear delineation of the role of chemotherapy in combination with surgery and radiotherapy in the treatment of early head and neck cancer. There is evidence suggesting that therapeutic enhancement by chemotherapy can be obtained in tumors at specific sites, notably the oral cavity and

COMBINED MODALITY APPROACH TO CANCER THERAPY

157

m a x i l l a r y sinuses. H o w e v e r , t h e r e has b e e n no d e m o n s t r a t i o n t h a t I A perfusion affords b e t t e r results t h a n those o b t a i n e d b y systemic a d m i n i s t r a t i o n o f the s a m e drug. S i m i l a r l y , no j u d g m e n t s can be m a d e o f the relative efficacy o f one d r u g over a n o t h e r as a n a d j u v a n t to surgery a n d r a d i o t h e r a p y . O n e critical s t u d y still p e n d i n g is t h e R T O G e v a l u a t i o n o f i r r a d i a t i o n w i t h or w i t h o u t M T X in a w e l l - d e s i g n e d a n d c o n t r o l l e d c o m p a r i s o n . T h e highest priorities for f u t u r e trials m u s t be assigned to studies t h a t will d e t e r m i n e w h e t h e r or not d r u g plus i r r a d i a t i o n a n d / o r s u r g e r y is b e t t e r t h a n t h e local m o d a l i t i e s alone. I n a d d i t i o n , high p r i o r i t y m u s t be given to identify the p a r t i c u l a r significant variables (site o f p r i m a r y , stage, etc.) t h a t m a y define t h e p a t i e n t p o p u l a t i o n w h i c h w o u l d most benefit from c o m b i n e d t h e r a p y . S u b s e q u e n t studies c o u l d t h e n s y s t e m a t i c a l l y c o m p a r e o t h e r agents a g a i n s t a s t a n d a r d " c o n t r o l " r e g i m e n . U l t i m a t e l y , if several agents do i n d e e d a p p e a r to e n h a n c e t h e r a p e u t i c efficacy, c o n s i d e r a t i o n c a n be given to c o m b i n i n g t h e m in a n o p t i m u m fashion. T h e a u t h o r s gratefully a c k n o w l e d g e the editorial assistance o f M r W i l l i a m S o p e r a n d M r s Alice G o t t .

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