Chlebowski et al. (1979)

Chlebowski et al. (1979)
Design: Randomized controlled trial (therapy) evidence level: 1
Country: United States
Inclusion criteria:
Histologically confirmed MBC with measurable disease
No prior cytotoxic chemotherapy
No response to endocrine therapy
Rapidly progressing disease
Exclusion criteria:
Evidence of severe renal or liver impairment (parameters given)
Population:
Number of patients = 121
Interventions:
Combination arm - 2 week cycle (n = 61):
Cyclophosphamide at 2 mg per kg daily by mouth
5′-FU at 15 mg per kg on day 1 i.v.
Methotrexate at 30 mg per m2 on day 8 i.v.
Prednisone at 0.5 mg per kg daily by mouth
Triiodothyronine at 0.005 mg daily

Sequential arm (n = 60):
Drugs were given as single agents at the same dosages as above and treatment was switched on disease progression after initial response or after 4 weeks if no response occurred.

5′-FU was given for a minimum of 4 weeks followed by cyclophosphamide similarly for a minimum of 4 weeks, then triiodothyronine with prednisone for a minimum of 6 weeks and then methotrexate for a minimum of 4 weeks.
Outcomes:
Tumour response (ORR = CR + PR) compete response (CR) partial response (PR) overall survival (OS) response duration (RD) adverse events
Follow up:
Baseline assessments included physical examination, chest X-ray, bone X-ray, liver scans, bone marrow aspiration and/or biopsy, ECG, routine biochemical and haematological tests.

All patients were followed until death. 5 patients originally entered on the trial were ineligible because they had received endocrine therapy at the time of study entry.

5 patients in the sequential arm broke protocol by not receiving cyclophosphamide as their 2nd drug. These patients were censored in the survival analysis but included in the analyses for toxicity and response.
Results:
Median OS:
Combination arm = 14.8 months
Sequential arm = 11.4 months
Analysis of projected survival 12 months after entry of the last patient (and after the death of 51 patients) showed a significant difference between arms. However, life table analysis found NSD between the arms when real patient survival data were applied.

Median OS for patients with liver metastases:
Combination arm (n = 29) = 15.2 months (P < 0.04)
Sequential arm (n = 22) = 8 months
The majority of patients without liver metastases did not differ significantly from one another between arms for any time period.

ORR:
Combination arm (n = 61): CR (n = 9) + PR (n = 25) = 56%
Sequential arm (n = 60): CR (n = 2) + PR (n = 19) = 32%
Individual drugs on sequential arm:
5′-FU (n = 60): CR (n = 2) + PR (n = 12) = 23%
Cyclophosphamide (n = 46): PR (n = 5) = 9%
Triiodothyronine + prednisone (n = 34): PR (n = 1) = 3%
Methotrexate (n = 24): PR (n = 1) = 4%

Median RD:
Combination arm: 13.4 months
Sequential arm: 7.7 months (P < 0.01)

Median RD for patients achieving CR or PR:
Combination arm: 18 months
Sequential arm: 17.6 months (NSD)

Adverse events (all grades):
Combination arm: Leukopenia (n = 42) Thrombopenia (n = 12) Nausea and vomiting (n = 33) Stomatitis (n = 7)

Sequential arm: Leukopenia (n = 22) Thrombopenia (n = 7) Nausea and vomiting (n = 30) Stomatitis (n = 2).

There were 2 treatment related deaths, both of which occurred in the combination arm.
General comments:
This paper describes a study in which the aim was to see if a regimen of 5 drugs taken sequentially at the time of treatment failure would prolong the survival of patients with MBC when compared to the same 5 drugs given as a concurrent combination. Patients were recruited between February 1971 and November 1973.

Patients were randomly assigned to one of two arms by Statistical Analysis Centre - the methodology is not given.

Baseline demographics were similar between arms for the number of metastatic sites, disease- free interval and menopausal status (no statistics were shown). Subsequent post-study treatment was recorded and was found to be similar in both arms (details given).

The response frequency and duration was higher for patients taking the combination therapy. In terms of survival, the authors conclude that combination therapy was of more use to patients with life threatening disease in other areas of the body but that otherwise there was no significant difference between arms.

Survival analysis would tend to project a better outcome for patients on combination therapy because of the more immediate and superior tumour response but, as this study suggests, following all participants to the end of their lives, the survival advantages are not apparently greater over the longer term.

As a RCT the reporting of the findings is of only moderate quality but the study was probably thorough and well conducted.

From: Chapter 4, Systemic disease-modifying therapy

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