Palliative Chemotherapy

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CHEMOTHERAPY TRIALS: SINGLE AGENTS AND COMBINATION THERAPY

Chemotherapy as the sole modality of treatment for head and neck cancer has been limited to almost exclusively recurrent or persistent disease after failure of primary locoregional therapy. In this setting, the goal of treatment is limited to palliation, as no improvement has been demonstrated for either disease-specific or overall survival.1,4-10 Treating recurrent or metastatic head and neck cancer is much different than treating a naive tumor. Previous therapy usually diminishes the effectiveness of chemotherapy by 30 to 50%.11 Theories to explain this include more hypoxic cells, decreased blood flow to the tumor, and chemical resistance.1,5,11,12 The difference in effectiveness can easily be seen when comparing the complete and partial responses achieved with induction (neoadjuvant) chemotherapy (30 to 92%)12-17 to the response rate of palliative treatment for recurrences (10 to 40%).4-10,13 This section discusses chemotherapy only as it applies to recurrent or metastatic head and neck cancer.

Deciding on which therapeutic endpoint to use in clinical trials becomes important, as the "gold standard" of increased survival is no longer applicable. The most easily and objectively measured

TABLE 8-1

Efficacy of Single Agent Chemotherapy

Drug Average Response (range)

TABLE 8-1

Efficacy of Single Agent Chemotherapy

Methotrexate

30% (16 to 58%)

Cisplatin

30% (8 to 46%)

Carboplatin

21% (14 to 27%)

Fluorouracil

15% (0 to 33%)

Bleomycin

20% (6 to 46%)

Vinblastine

29%

Hydroxyurea

25%

Paclitaxel

22% (20 to 45%)

Modified from Catimel,1 Stupp,2 and Schrivers.3

Modified from Catimel,1 Stupp,2 and Schrivers.3

outcome is tumor response (Table 8-1). Most trials measuring the benefit from chemotherapy use this as their main index of effectiveness, making the assumption that a decrease in tumor size will directly benefit the patient. For painful or obstructing lesions, as is often the case, this argument probably holds merit. However, a major concern relates to the toxicity of the treatment itself, as this group of patients receive no survival benefit. If the side effect profile of the treatment causes considerable discomfort, a few months of reduced tumor burden will not be worthwhile.

A counterargument is that an increase in side effects is acceptable if the probability of a complete response (CR) is increased, as a longer survival time has been associated with CR.18-20 However, as Adelstein11 and Fu12 point out, this association may simply reflect selection of those patients who have a better prognosis to begin with. Response to chemotherapy and improved survival are linked, both occurring in those patients with a better performance status, less prior treatment, and certain head and neck subsites (larynx, mobile tongue). This same selection bias has been used as the basis for the organ preservation strategy (as explained later). Other measurements of therapeutic improvement include an increase in quality-of-life scores and time to progression and, for those achieving a CR, time until recurrence.

that chemotherapy can have an impact on survival. Most trials, however, show that there is no survival advantage to chemotherapy over historical controls.1,4-10

Methotrexate (M) has been the standard therapy for palliation of advanced tumors for three decades. The dose is 40 to 60 mg/m2/week given intravenously (IV). The average response rate is 30% with a range of 8 to 57% (CR range from 6 to 26%).22,23 Toxicities are tolerable, with mild to moderate leukopenia, anemia, mucositis, and diarrhea the most commonly cited.5 The duration ofthe response is approximately 4 months.

Cisplatin has been used extensively with response rates of8 to 41%, also averaging around 30% (0 to 8% CR).21,24,25 Additional side effects of nephrotoxicity, neuropathy, and ototoxicity must be accounted for when choosing this drug over methotrexate. Carboplatin has fewer side effects than cisplatin, but the response rate is also decreased to around 21% (14 to 26%).

Three randomized studies have conducted direct comparison of cisplatin with methotrexate. In the first two studies, consisting of 144 patients, no difference was seen in response rate, response duration, or survival.24,26 The larger of these studies showed a low response rate to cisplatin (8%) and methotrexate (16%), with an overall survival of only 4.5 to 5 months. A third trial from the group in Liverpool showed a significantly higher response rate of the tumors to cisplatin (26% vs 12%) and, again, no improvement in survival.27

Bleomycin also produces a 21% response rate (6 to 45%) in refractory tumors, with the effects lasting 1 to 3 months.5 The standard dose is 15 U IV on a weekly schedule. Pulmonary toxicity is the main drawback, especially once a total dose of 200 to 400 U is reached.

5-FU is not often used alone to treat head and neck cancer, but response rates average 15% (0 to 33%).28 The optimal administration is a 5-day continuous infusion, rather than bolus treatment.20,29 Side effects include bone marrow suppression, cardiac toxicity, and mucositis.

The taxoids are generating some interest, with one phase II report showing a 40% response rate and another a 32% response.30,31 Hematologic toxicity was severe, however, even with the use of granulocyte-colony-stimulating factor (G-CSF).

Other less frequently used agents are hydroxyurea (25%); alkylating agents, including cyclophosphamide and ifosfamide (36%); vinblastine (29%); gemcitabine (13%); and the anthra-cyclines (5 to 8%)1 (Table 8-1).

SINGLE AGENTS

Does chemotherapy add any benefit beyond providing pain control? In one of the few randomized studies with a "no-treatment" control arm, Morton et al.21 compared the use of cisplatin, bleomycin, and the combination of cisplatin plus bleomycin. They found a statistically significant increased survival in the platinum arms (4.0 to 4.2 months) as compared with the control arm (2.1 months). The population in this study was relatively small, with about 24 patients in each treatment arm, and survival was relatively short, but this does provide some evidence

SINGLE AGENTS VERSUS COMBINATIONS

Combination chemotherapy takes advantage of two characteristics of chemotherapeutic drugs. The first is their mechanism of action. The rationale is that the addition of drugs that target different areas of the cell might overcome the selection pressure causing resistance to the agents. Also, separate subpopulations might be better targeted (mitomycin C and hypoxic cells). The second purpose of combining drugs is to take advantage of the different toxicity profiles and to reduce the severity of side effects experienced by the patient.

Do combination regimens improve tumor responsiveness as compared with single agents? In two studies comparing singleagent methotrexate with cisplatin plus 5-FU in recurrent or metastatic head and neck cancer, one showed a significantly higher response rate in the combination therapy arm, and the other showed a trend toward significance in the combination therapy arm.27'32 Two other studies compared the single-agent approach of cisplatin and 5-FU with the combination and again found a significantly improved response rate to the combination but no change in survival rate.33'34

A meta-analysis was undertaken by Browman and Cronin7 in 1994 to evaluate single-agent versus combination chemotherapy. These investigators analyzed 15 trials that included 1916 patients and 17 different treatment regimens. Single-agent methotrexate was less effective at reducing tumor size than was found in the pooled combination studies. The odds ratio (OR) was used to define statistical significance, with an OR of > 1 favoring comparison treatment); the OR was 1.71 with a 95% confidence interval (CI) of 1.28-2.31. Pooled combination treatments were also statistically better at achieving tumor regression than were the pooled single agents (M, P, B, 5-FU), with OR-1.59 and 95% CI-1.28-2.01. The combination of cisplatin and 5-FU was found to be the most efficacious. The side effects of the different regimens were also evaluated showing that the combinations have a greatly increased risk of nausea and vomiting. It appears that combination chemotherapy should be used for those patients with end-stage metastatic or recurrent squamous cell cancer if they have a life expectancy of more than 4 to 5 months and a good performance score and can tolerate the treatment.

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