One unifying concept of chemotherapy, as it applies to cervical and vaginal cancer management, is how administered chemotherapy damages DNA or slows its repair. One of the first anticancer strategies for cervical cancer targeted the RNR tyrosyl radical with HU by the Gynecologic Oncology Group (GOG-004).7
In its one-electron reductive state,46
oral HU irretrievably disrupts the M2/M2b diferric tyrosyl radical (•Y122), rendering the electron and proton tunnel to the M1 active site inactive. As it happens, women were assigned by random assortment to either HU (80 mg/kg, oral twice weekly) or placebo during pelvic radiation. Three-year endpoints of pelvic disease control and of progression-free survival (i.e., cancer relapse or death) were better after radiation–HU than radiation–placebo (see , p<0.05). As one of the first randomized clinical trials of its kind in gynecologic cancer, HU-mediated block of RNR during radiation became the measure of other radiochemotherapeutic agents in cervical and vaginal cancers. Capitalizing on this experience, GOG investigators tested whether a radiation–cisplatin–5FU combination stood up against a radiation–HU strategy (GOG-085).8
Here, it was thought that 5FU impeded thymidylate synthase, eventually dismantling the dNTP feedback ladder that determined the selectivity site of RNR. Also in this trial, a new chemical agent was introduced for study in cervical and vaginal cancers. In contrast to the almost instaneous damage induced by ionizing radiation, cisplatin renders cytotoxic DNA damage protracted over a 6–24 hour course to keep cells actively engaged in DNA-adduct repair for constant dNTP payouts from RNR.47
Thus, in this randomized clinical trial, women took radiation and HU (80 mg/kg, oral twice weekly) or had radiation, bolus infusion of cisplatin (50 mg/m2
four hours before radiation, days one and 29), and protracted infusion of 5FU (1,000 mg/m2
/day, days 2–5 and 30–33). Up to that time, the more common and consequential component of treatment failure was ineffective sterilization by radiation alone. Adding more DNA damage in the form of cisplatin adducts and impairing RNR ability to respond to the demands for dNTPs through 5FU’s skewing of the dNTP feedback ladder, the radiation–cisplatin–5FU treatment resulted in improved disease control (see ) and progression-free survival (p=0.033). In a similar way, investigators from the Radiation Therapy Oncology Group (RTOG-9001) found similar results.9,10
In this trial, conducted contemporaneously with GOG-085, women were allocated randomly either to a treatment arm of extended-field radiation alone or to four-field pelvic radiation, bolus cisplatin (75 mg/m2
within 16 hours of radiation, days one, 22, and 42), and 5FU (1,000 mg/m2
/day, days 2–5, 23–26, and 43–46). Compelling data for pelvic disease control, extrapelvic disease control (see ), and three-year progression-free survival (p=0.0003) were documented for the radiation–cisplatin–5FU regimen versus radiation alone regimen.
Clinical Trials Targeting DNA Damage and Deoxynucleotide Supply Inhibition
Soon afterward, investigators were motivated to explore coordinating optimal DNA damage wrought by radiation and by cisplatin with peak pharmacologic RNR blockade. First, the GOG conducted a randomized trial (GOG-0043) of three cisplatin dose schedules in 496 women for persistent pelvic or extrapelvic cervical cancer disease response. The majority (93 %) of women had received pelvic irradiation at a time prior to receiving cisplatin infusions. Regimen 1 was cisplatin 50 mg/m2 every 21 days, regimen 2 was cisplatin 100 mg/m2 every 21 days, and regimen 3 was cisplatin 20 mg/m2 daily for five consecutive days. Regimens were repeated for a total ceiling dose of 400 mg/m2 providing there was no evidence of tumor progression. In the 444 evaluable patients for responses attributable to cisplatin’s DNA-damaging effect, the sums of complete and partial response rates were 21 % for regimen 1, 31 % for regimen 2, and 25 % for regimen 3 (p=0.015). With a greater appreciation that cisplatin was cytotoxic on its own, had an ability to synchronize cells in radiosensitive phases of the cell cycle, and contributed damage that would tax dNTP supply, investigators sought out clinical trials of single-drug and multiple-drug combinations with radiation for the treatment of cervical cancer.
One clinical trial (GOG-120) in women with cervical cancer allotted, by random selection, one of three cisplatin-based radiochemotherapy treatments.11
Regimen 1 was daily pelvic radiation plus weekly cisplatin (40 mg/m2
) followed by brachytherapy. Regimen 2 was day one and day 29 bolus cisplatin (50 mg/m2
) plus 96 hour infusion of 5FU (4,000 mg maximum) plus oral HU (twice weekly, 2,000 mg/m2
) during radiation and followed by brachytherapy. Regimen 3 was twice-weekly oral HU (3,000 mg/m2
) during radiation and followed by brachytherapy. Three-year pelvic disease control and extrapelvic disease control was found to be superior with regimens 1 and 2 (see ). Mixing two RNR inhibitors, HU and 5FU, contributed no added clinical benefit over the weekly cisplatin regimen (see ). Long-term follow-up confirmed a progression-free survival advantage for regimen 1 (p<0.01) and regimen 2 (p<0.01), as compared to regimen 3.12
For ease of clinical administration, the weekly cisplatin regimen was adapted quickly to radiochemotherapy practice.48
To confirm the results in an independent trial, investigators then randomized women with cervical cancer to weekly single-agent cisplatin (40 mg/m2
) versus single-agent 5FU (protracted venous infusion 225 mg/m2
/day, days 1–5 of a five weekly cycles).15
The superiority of cisplatin was verified (see ).
The ability of radiochemotherapy to effect sterilization of primary cervical cancer has been interrogated in actual surgical specimens.14
It was hypothesized that through an analysis of extrafascial hysterectomy histopathologic samples from two randomized clinical trials (GOG-071, GOG-123) would provide in vivo
proof-of-principle evidence of a radiation and a radiochemotherapy effect.13,49
Among 464 hysterectomy samples, a significantly higher proportion of a good response (80 %, greater than 90 % sterilization) was observed after radiochemotherapy as compared to radiation alone (71 %, p<0.037). Efforts to improve primary disease have re-investigated the role of pharmacologic inhibitors of RNR.
To be pharmacologically useful, nucleoside analogs, such as cytarabine, fludarabine, and gemcitabine, require activation by deoxycytidine kinase in the salvage pathway of deoxynucleosides.50
Of these, gemcitabine annihilates the M1 catalytic site of RNR by a covalent bond when it appears as a cytidine diphosphate analog, thereby destroying both M1 subunits of a RNR α2
dimer.51 Phase 2 data of radiation, cisplatin (40 mg/m2
), and gemcitabine (125 mg/m2
) provided a 78 % complete response rate.52
In a phase 3 cervical cancer patient trial, regimen 1 consisted of once weekly cisplatin (40 mg/m2
) plus gemcitabine (125 mg/m2
) during pelvic radiation followed by two adjuvant 21-day cycles of cisplatin (50 mg/m2
, day one) plus gemcitabine (1,000 mg/m2
on days one and eight). Regimen 2 involved once weekly cisplatin (40 mg/m2
) and the same radiation.16
The hazard for relapse or death was reduced by 32 % when gemcitabine was included in the treatment (see , p=0.023). However, conflicting interpretations of this data emerged53
Gemcitabine radiochemotherapy may have been successful because it cured more women upfront from its radiosensitizing effect. Or else, gemcitabine radiochemotherapy may have been successful because it delayed scoring of disease relapses from an adjuvant lead-time bias effect. Either interpretation stands from the data reported. Also, in a GOG effort (GOG-9912), this regimen was deemed too toxic.54
Further study is warranted.
Attacking RNR at its M2/M2b diferric tyrosyl radical (•Y122) with the more potent RNR inhibitor 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) has also been investigated. The putative mechanism here is a molecular interaction of an Fe2+–3-AP chelate and of oxygen generating local reactive oxygen species capable of annihilating the nearby tyrosyl free radical.55
As such, timed after DNA damage (e.g., damage promulgated by ionizing radiation), 3-AP’s cell death-provoking effect may be due to its inability to supply on-the-spot dNTPs needed for DNA damage repair.39,40
A phase 1 clinical trial has been conducted in 10 women with cervical cancer involved intravenous 3-AP (25 mg/m2
, three times weekly) plus once-weekly cisplatin (40 mg/m2
) during daily radiation.17
Median survivor follow-up is now 38 months and progression-free survival is 88 % at three years (see ). A phase 2 study of 3-AP-cisplatin radiochemotherapy in 25 additional women with cervical and vaginal cancers has completed enrollment, with premature response data indicating comparable clinical advantage.