Integration of chemotherapy into the combined modality therapy of head and neck squamous cancer

Inr. J. Radiation Oncology Biol Phys Vol. Printed in the U.S.A. All rights resewed.

13. pp. 779-783 Copyright

0

0360-3016/87 1987 Pergamon

$3.00 + .OO Journals Ltd.

??Oncology Intelligence

INTEGRATION OF CHEMOTHERAPY INTO THE COMBINED MODALITY THERAPY OF HEAD AND NECK SQUAMOUS CANCER SAMUEL G. TAYLOR IV, M.D. Associate Professor, Department of Medicine, Rush-Presbyterian-St. Luke’s Medical Center, Suite 830, 1725 W. Harrison Street, Chicago, IL 606 12

INDUCTION CHEMOTHERAPY

effective regimen (response rate only 40%), responders

showed a significantly superior disease-free survival advantage over non-responders.34 However, when corrected for the site-stage prognostic groupings of these patients, using a Cox regression analysis, this benefit disap peared and, indeed, the chemotherapy group as a whole did no better than the control group in disease-free or survival status. Correcting for prognostic variables, using a Cox regression model, Price et al. have still found highly significant survival benefit for responders to their induction regimen. 26Nevertheless, a randomized study showed actually worse survival for patients treated with this regimen compared to the control group.” Ensley et al. have offered an explanation as to why induction chemotherapy responders do better than nonresponders.” They have identified patients who have had either a partial response or no response to chemotherapy and who then have proceeded directly to radiation therapy. Out of 42 partial responders and 18 nonresponders to chemotherapy, 4 1(98%) of the responders subsequently responded to radiation therapy compared to 1 of the 18 non-responders (p < .OOl).Chemotherapy response may thus predict for response to radiation therapy, while not necessarily contributing to a survival benefit. Other investigators have observed the same effect when noting that only radiation therapy may be required following good chemotherapy response (tumor < 3 cm.) whereas surgery appears to be a necessary addition if the tumor bulk remains larger than this following induction chemotherapy.” It is also well recognized that tumor response is dependent on tumor bulk.‘F9 Induction chemotherapy pilot studies have failed to alter the pattern of failure of head and neck cancer. The majority of patients who fail still fail in the first 2 years and still fail regionally. Even complete response to chemotherapy is not likely to sterilize a bulky tumor with greater than 1O*cells. No evidence exists indicating that a centripetal cell kill oc-

Administering chemotherapy prior to regional treatment (induction or neoadjuvant chemotherapy) has become a popular approach for incorporating chemotherapy into multimodality treatment programs for head and neck squamous cancer. Numerous studies support the general observation that response rates, and especially rates for complete response, are higher in patients who have not had prior regional treatment. These tumors often respond to the chemotherapy rapidly and dramatically, leading to a great sense of accomplishment by physicians and patients. The goal of this treatment has been to increase the effectiveness of local treatment (surgery and radiation therapy) by reducing tumor bulk, thereby improving the chances for cure. The cited success of this approach has been used as justification for its routine use in advanced head and neck cancer and as incentive for

exploring this approach in other cancers. Although the development of carefully designed clinical trials is welcome, the current wave of popularity for an induction chemotherapy approach warrants a critical appraisal of its benefits. The most frequently sited evidence for the effectiveness of induction chemotherapy programs in head and neck cancer (other than the high response rates) has been the observation that chemotherapy responders do better in follow-up than non-responders. This observation, however, should be interpreted with extreme caution. Many factors that also affect prognosis may influence response to chemotherapy in head and neck cancer, the most important one being tumor bulk (not always reflected well in the current staging classifications). Yet rarely has multiple regression analysis been performed to differentiate the roles of the sundry potential prognostic variables in analyzing the results of these studies. Our randomized trial of a methotrexate-leucovorin induction regimen found that, even with this relatively inAcknowledgement-The excellent technical assistance of Phyllis Velez is gratefully acknowledged.

Accepted for publication 8 December 1986. 779

780

I.J. Radiation Oncology 0 Biology 0 Physics

leaving viable cells only in the central portion of the tumor. We would not expect an inoperable patient to become operable with induction chemotherapy in view of these considerations. Also, the short duration of response, characteristic of chemotherapy responses in recurrent head and neck cancer, indicates that the killing of proliferating cells is limited in this disease and drug resistence develops rapidly. Given these considerations, chemotherapy would be expected to impact more on disease-free survival if used to destroy microscopic residual disease following definitive regional therapy. These observations may explain why, despite all the generated optimism from sundry pilot studies with induction chemotherapy, four randomized studies examining this approach and reported at the International Conference on Head and Neck Cancer in Baltimore, 1984, all failed to find any disease-free or survival benefit _with induction chemotherapy.20*2*“3~39 Most disappointing was the Southwest Oncology Group experience with an induction regimen that achieved a 35% complete response rate prior to any regional therapy.28 That analysis is early, however, so final interpretation should await more follow-up. Table 1 shows the results of several randomized trials with induction chemotherapy in the literature. Two trials were positive. One, with a 5-year follow-up, used intra-arterial methotrexate. The authors found that benefit from this therapy was restricted to Stage II disease and oral cavity cancers3 Stage III and IV disease (the stages included in all the other randomized series) derived no benefit. The other positive study tested a modification of the Price-Hill regimen along with split dose radiation. Although the median survival of the chemotherapy patients was double that of the control group, the split course radiation was so ineffective (only 2 complete responses in the 58 patients) that no conclusions about the curs

Table 1. Randomized Chemotherapy MTX low dose MTX-IA MTX low and high dose MTX/LCV MTX-IA DDP/BLM DDP/PU infusion X 3 cycles DDP/VCR/MTX/BLM CTX/MTX/l=U/BLM DDPfBLM/MTX/FU x 3 cycles VCR/MTX/BLM/PU/LCV/HDU/MP/CTX VCR/MTX/BLM/PU ADM/HDU/MP

May 1987, Volume 13, Number 5 efficacy of the chemotherapy can be drawn.4 Using more conventional and effective regional therapy Stell et al. found a similar induction regimen to actually worsen survivaL3’All the other randomized trials testing induction chemotherapy in head and neck cancer were negative, questioning the rationale for continued optimism for this scheduling of chemotherapy. The hope that more effective chemotherapy may change these results has not yet been realized. The combination of cisplatin and 5-FU infusion has produced the highest complete response rate of any induction chemotherapy program. 37A complete respo use rate of 42% in 203 patients has been observed over the past 5 years32 (Table 2). Yet a randomized trial testing induction cisplatin and 5-FU infusion given for 3 cycles prior to radiation and surgery has shown a significant survival advantage for the control group.14The negative effect on recurrence and survival was found despite a very high response rate with the drug combination consistent with experience seen in the literature. Indeed, the three induction chemotherapy regimens that have produced the widest divergence in disease-free survival of responders over non-responders in pilot studies (the Price-Hill regimen, PMB, and cisplatin/5-FU infusion) have resulted, in randomized trials, in 2 studies aborted early because of significantly worse survival in the chemotherapy group ‘4q3’and one trial with no difference.28These results argue against the sentiment that induction chemotherapy only requires more effective drug treatments to be successful.

ADJUVANT CHEMOTHERAPY If these drug combinations are so active in producing responses, but do not alter disease-free survival when used as induction chemotherapy, clearly other ap

trials with induction chemotherapy No. pts.

Result

Author

638 142 96 52 38 443 57 101 83 60 86 58

No difference 43% vs 25% at 5 yr* No difference No difference Only 1st yr. better No difference Chemotherapy worse No difference No difference No difference Chemotherapy worset Chemotherapy betters

Pazekas et al. ” Archangeli et al.3 Knowlton et al. ‘9 Taylor et al, 34 Richard et aL2’ Wolf et al.39 Haas et al. I4 Schuher et aL2’ Kun et a1.20 Martin et al.23 Stell et al.3’ Bezwoda et a1.4

* Significant difference favoring chemotherapy attributed primarily to patients with survival advantage with more advanced disease. t 30 month survival was 22% with chemotherapy induction vs. 55%. $ Median survival 18 weeks for control vs. 36 weeks with chemotherapy, using a split 2 complete responses in all 58 patients (one each group). MTX = Methotrexate, LCV = Leucovorin, MTX-IA = Intra-arterial Methotrexate, DDP = Cisdiaminedichloroplatinum, VCR = Vincristine, CTX = cyclophosphamide, ine.

Stage II disease and oral cavity lesions. No

course radiation therapy that produced only BLM = Bleomycin, HDU = Hydroxyurea, PU = 5-Pluorouracil, MP = 6-Mecaptopur-

Adjuvant chemotherapy in headand neck cancer 0 S. G. TAYLOR IV Table

1 2 3 4 5 6 7

reason.34,39Adjuvant chemotherapy requires testing without first giving induction chemotherapy before con-

2. Induction combination chemotherapy in head and neck cancer

Treatment DDP/FU x 3 DDP/PU x 2 DDP/BLM DDP/MTX DDP/VCR/BLM DDP/VCR/MTX DDP/MTX/BLM

No. pts.

%CR

203 56 580 82 195 190 238

42 18 8 4 22 14 12

781

%CR+PR 79 71 49 E 69 45

proaches are needed. One such approach is to administer

chemotherapy following regional treatment. A provocative study by Huang and associates’8 examined the use of adjuvant chemotherapy given after definitive local treatment. The chemotherapy was certainly suboptimal by today’s standards: Bleomycin and methotrexate given on days 1 and 4, every 6 weeks, along with vinblastine and CCNU (both considered relatively inactive in head and neck cancer). Nevertheless, with all patients followed for at least 14 months (median 3 1 months) only 5 have recurred out of 3 1 patients entered (8 Stage III, 12 Stage IV, and 11 recurrent cases). Ignoring the actual recurrence rate, which has always been difficult to interpret in pilot studies of head and neck cancer, what makes this report extraordinary is that no patient recurred within the first 18 months and, of the 5 recurrences, only 3 were regional whereas 2 were distant. In contrast, a concomitant group of 24 patients, who did not elect to participate in the study (not a randomized control group), had a 63% recurrence rate with the vast majority of recurrences being regional and occurring within this first 18 months, as would be expected with this disease. A randomized trial testing adjuvant consolidation chemotherapy with cisplatin, methotrexate, and bleomycin (with all patients getting induction chemotherapy) has reported significantly superior disease-free survival in the group receiving the consolidation treatment.38 In addition, a small randomized trial with oral cavity lesions compared post-operative chemotherapy to postoperative radiation therapy.5 The authors found a significantly superior relapse-free survival rate for the chemotherapy group, unfortunately stopping the trial with only 33 patients entered. Certainly these trials justify further phase III clinical research with post-operative adjuvant chemotherapy. The difficulties in giving adjuvant chemotherapy following regional treatment have been stressed by several authors. Most investigators agree difficulty with patient compliance is the most frequent reason for not administering chemotherapy as consolidation.39 Giving induction chemotherapy may especially result in patients refusing to undergo further chemotherapy later. Several studies, including our own, have experienced difficulty in administering adjuvant chemotherapy to patients who were initially exposed to induction therapy for just this

cluding it is impractical or ineffective. Patient compliance problems may be augmented by lack of physician acceptance. The RTOG is currently testing giving cisplatin and S-FU infusion following sur-

gery but before radiation therapy (now an intergroup study). Medical oncologists and surgeons have expressed concern over this scheduling because of their conviction that chemotherapy must precede surgery. The concern of Radiation Therapists is the delay in starting radiation until after chemotherapy, a concern based on results of retrospective analyses of patients not subjected to chemotherapy. (These radiation oncologists should be reminded that their colleagues are routinely following this treatment scheduling in regionally localized breast cancer.) The danger is that these physician concerns translate into poor patient compliance, making testing new scheduling of chemotherapy with surgery and radiation therapy difficult. CONCOMITANT

CHEMOTHERAPY

A further encouraging way of administering chemotherapy with regional therapy is simultaneous treatment with radiation, taking advantage of the potential radiation sensitizing properties of some antineoplastics. Increased normal tissue toxicity however, may result in no therapeutic gain from this approach. Such an absence of therapeutic gain because of enhanced normal tissue toxicity would be expected with methotrexate, bleomycin, and adriamycin. Bleomycin is the best studied of these three and has shown limited disease control and no survival benefit apart from the Indian experience.7v30*36 The differences observed by Shanta et al. may be due to the biologic characteristics of Indian oral cavity cancers, which are all well differentiated.30 Fu et al. have reported significant benefits from combining bleomycin with radiation therapy, but they also gave bleomycin and

Table 3. Head and neck cancer: Simultaneous radiation and cisplatin DoseCDDP

Stage No. pts. III/IV % CR

20 mg/M’/wk

35

6129

86

20 mg/M2 Dl-5,2932 100 mg/M2/3 wk 15 mg/M2 Dl-5,22-

32

all

66

D&BLM induction plus 20 mg/ M’/wk

Median survival

Ref. 15

69

51%NED@ 14 months Not stated

12154

83

72%@ 12mo.

2

33

O/33

61

13months

21

25

8117

57

19 months

8

17

782

I. J. Radiation Oncology 0 Biology ??Physics

methotrexate as adjuvant therapy for 16 weeks.13The relative importance of concomitant versus adjuvant therapy in that study is therefore unclear. In addition, the radiation sensitizer, misonidazole, which has no independent anti-neoplastic activity, has now undergone several randomized trials which have all been negative 16.25.29 5-FU and cisplatin both have evidence of an improved therapeutic ratio when combined with RT and have been used with greater success. Concomitant 5-m and radiation has produced one of the few positive randomized chemotherapy trials in head and neck cancer, despite bo1~s5-FU having a low response rate when used by itselE22 Byfield has pilotted 5-m infusion given concurrently with split course radiation in a small series of advanced head and neck cancers with results that warrant further exploration of this approach.6 Cisplatin has been used in a variety of schedules with concomitant radiation therapy (Table 3). The best studied series is that of the Radiation Therapy Oncology Group which has reported a higher regional control rate and survival results compared (retrospectively) to their large registration study.2 This approach is being tested in an ongoing randomized study using a once weekly schedule during radiation therapy. We have used a combination of cisplatin, 5-w infusion and radiation, using a split course schedule similar to that of Byfield ef ~1.~’In an updated analysis of 34

May 1987, Volume 13, Number 5

patients treated “curatively” (5 Stage III, 24 Stage IV, 6 recurrent) with a median follow-up of 36 months (range 24-58 months) all achieved initial disease control but 4 have subsequently failed locally and 7 distantly.24 Recurrences developed only in those patients who initially had N3 or T4 disease. None of the 9 patients with lesser disease have failed. Again, ignoring the actual recurrence rate, the pattern of recurrence appears a&cted by this approach. Regional failure has developed in only 12%of patients and comprised only 36% of the failures. Consequently, there may well be good reason for optimism that chemotherapy can impact on head and neck cancer. I do not share the negativism generated by results of recent induction chemotherapy trials. However, to achieve the goals of improved relapse&e status and survival, as well as to lead to more conservation surgery, we may need to rethink how best to integrate chemotherapy with other modalities of treatment. There are potential advantages to induction chemotherapy such as knowing the responsiveness of the cancer to chemotherapy that may predict for subsequent prognosis of the patient. Despite this information, induction chemotherapy has failed, in randomized trials, to improve disease-free survival. To alter recurrence patterns and survival results, surgical, radiation and medical oncologists should recognize the deficiencies of current treatment approaches and be willing to explore, in randomized studies, new ways to integrate our respective therapies.

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Adjuvant chemotherapy in head and neck cancer 0 S. G. TAYLOR

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