Discussion
Conventional cytotoxic chemotherapy has played an important role in the
comprehensive treatment of cancer. However, it has limitations
associated with side effects and requires long break periods, generally
ranging from 2 to 3 weeks between treatment cycles, during which time
tumors sometimes grow.18 MC refers to the chronic
administration of chemotherapeutic agents at relatively low, minimally
toxic doses, without prolonged drug-free breaks.1
Here, we report the results of a single-center retrospective analysis of
children with relapsed or refractory solid tumors who received a
metronomic regimen based on low-dose continuous oral administration of
anticancer drugs. In line with most published studies on pediatric MC,
we have found benefits in terms of disease stabilization, defining
“responders” as tumors that presented CR, PR, and
SD.8,10–12,14 The overall response rate was 61%, and
11 patients were defined as responders. Even among the patients who
started MC in PD status, 45% presented with PR or SD.
Seven out of 11 responders turned to PD during MC, and 5 of them
switched back to conventional chemotherapy. Of 5 responders who were in
PD status at the start of MC, all died of the disease after tumor
re-progression. However, the responders had prolonged survival times and
maintained good QOL when compared to non-responders, with a median
duration of response of 8 months (range, 3.3–102.3 months).
To date, most previous clinical trials and retrospective analyses of
pediatric MC have focused on relapsed or refractory progressive
tumors.1,11 Although only a few cases achieved CR with
MC, most reports indicate that some clinical benefit, including PR or
SD, occurs in 25–67% of cases.
Robinson et al. performed a phase 2 trial on a metronomic 5-drug regimen
including celecoxib, thalidomide, fenofibrate, and alternating 21-day
cycles of etoposide and cyclophosphamide.10 Of the 96
patients who were evaluated for tumor response, 1 achieved CR, 12
achieved PR, 36 achieved SD, and 46 showed PD; the response rate was
51% according to the same definition as in our study.
Zepletalova et al. reported the results of a prospective study for the
COMBAT metronomic regimen that included low-dose daily temozolomide,
etoposide, celecoxib, vitamin D, fenofibrate, and retinoic
acid.8 Of 62 patients with measurable disease, 40%
improved and achieved remission or SD. The 2-year overall survival (OS)
in all patients was 43.1%, which is statistically prolonged compared to
historical controls (median OS was 15.4 months vs. 3.0 months). Our
study suggested that MC can contribute to tumor dormancy and prolonged
survival time, as expected from these previous larger-scale studies.
On the other hand, some clinical studies have reported discouraging
data. For example, Pramanik et al., who performed a randomized control
study (RCT) for altering oral etoposide and cyclophosphamide with
celecoxib and thalidomide, reported that 6-month PFS was not improved
when compared to placebo.12
However, subgroup analyses revealed some encouraging results; patients
who had received the drugs for at least 9 weeks without tumor
progression had prolonged PFS. In other words, the initial treatment
response after the start of MC is important for improving the prognosis.
This is consistent with our analysis indicating that most of the
responders showed radiographic response at the first imaging performed
1–3 months after the initiation of MC.
Because of the variety of patient backgrounds and previous treatments,
it is difficult to discuss the tolerance of MC. However, our report has
shown that MC is at least associated with fewer infectious episodes and
transfusion dependence. In previous metronomic
trials,4–10 dosage regulation was permitted to reduce
clinically significant toxicities or to avoid chemotherapy
discontinuation. Most of our patients also received adjustment of oral
dosage, and although hematological toxicity was almost inevitable, the
episodes of FN in individual patients were significantly fewer when
compared to conventional chemotherapy (Fig. 4: P <
0.01, paired t-test). This is considered an important advantage of MC
because FN usually requires intravenous antibiotic treatment and
hospitalization.
In Japan, cytotoxic chemotherapy is usually performed in the setting of
continuous hospitalization in case of infection or the need for a blood
transfusion. Consequently, pediatric patients spend less time with their
families and hence sometimes experience loneliness. Moreover, if they
are of school age, they have to give up their regular school
life.19,20 Treatment options on an outpatient basis
are important for patients with a poor long-term prognosis.
In our retrospective analysis, AEs directly related to QOL, such as
appetite for food, sense of fatigue, or performance status, were not
evaluated sufficiently. However, MC can induce tumor dormancy without
forcing hospitalization. Rather than simply seeking to prolong life, MC
has the potential to provide a continuous treatment environment for the
patient that prioritizes their life in the family and society.
Another expected role of MC is maintenance therapy.13In our study, two patients received MC in CR, and both patients
completed the therapy without relapse and maintained CR. It is not clear
whether the success of treatment in these two cases depended on MC. In
the past, studies of MC limited to solid tumors in remission were rare.
Senerchia et al. performed a controlled study on operated osteosarcomas
comparing a regimen of methotrexate, anthracycline, cisplatin (MAP
regimen), with MAP combined with MC, but no advantage was demonstrated
in the combination therapy.21 However, as mentioned
later, patients with osteosarcomas are not suitable for verifying the
advantage of MC.
Bisogno et al., in an RCT on children with RMS, reported that the
addition of metronomic maintenance therapy with daily oral
cyclophosphamide and weekly intravenous vinorelbine resulted in a
significant increase in overall and event-free
survival.17 Although this trial was targeted to
primary non-metastatic disease, efficacy in a palliative setting has
also been reported.22
Focusing on adult oncology, MC as a maintenance therapy has been tried
in various combinations, including for colorectal cancer, breast cancer,
and ovarian cancer.13 Although most of these studies
are small, single-arm observations, a good safety profile and promising
efficacy have been demonstrated. Of course, delayed complications (such
as secondary malignancies due to long-term maintenance use of
alkylators) should be considered,23 and the
appropriate treatment duration should also be discussed. Metronomic
maintenance therapy for pediatric tumors requires further studies and
accumulation of evidence, including treatment duration and delayed
complications.
Recently, many molecular-targeted drugs have been developed that are
becoming an important part of cancer treatment, either in combination
therapy with anticancer drugs or as maintenance therapy. However, the
identified actional mutations do not cover all cancers. Pediatric
tumors, in particular, are known to have fewer target gene mutations
than adult tumors.24 MC may be a useful option as
maintenance therapy for patients with cancers that are inappropriate for
targeted agents.
This study has some limitations, as it was a small-scale, single-center
retrospective analysis. The survival time after MC initiation was not
directly compared with that of conventional chemotherapy or no
treatment. Moreover, tumor pathogenesis, primary site, clinical course,
disease status before MC, combination therapy, and details of the
metronomic regimen were variable. Although univariate analysis could not
reveal significant confounding factors (expect for tumor response),
there may have been a bias in the disease groups of the patients.
Previous studies have indicated that low-grade glioma, NBL, and RMS are
likelier to respond to MC than high-grade glioma and
osteosarcoma,12,21,22,25 which could affect our
response rate. It may be difficult to eliminate all of these limitations
or to conduct comparative studies with a specific disease population,
considering the rarity of pediatric cancer.
The literature on pediatric MC mostly includes case reports,
retrospective analyses, and phase I and II clinical studies performed on
heterogeneous populations. Our study, although even smaller with a more
limited and variable patient population, demonstrated that MC can play
an active role in palliative and maintenance therapy for relapsed or
refractory pediatric solid tumors. These results are in line with the
results of previous reports, and it would be worthwhile to accumulate
experience and clinical data on MC for pediatric patients.