Abstract
Objective.
Wee1 kinase is a crucial regulator of the G2/M check point which prevents entry of damaged DNA into mitosis. Adavosertib (AZD1775), a selective inhibitor of Wee1, induces G2 escape and increases cytotoxicity when combined with DNA damaging agents. We aim to evaluate the safety and efficacy of adavosertib in combination with definitive pelvic radiotherapy and concurrent cisplatin in patients with gynecological cancers.
Methods.
A multi-institutional, open-label phase I trial was designed to assess dose-escalation (3+3 design) of adavosertib in combination with standard chemoradiation. Eligible patients with locally advanced cervical, endometrial or vaginal tumors were treated with a 5-week course of pelvic external beam radiation 45–50 Gy in 1.8–2 Gy daily fractions plus concurrent weekly cisplatin 40 mg/m2 and adavosertib 100 mg/m2 days 1, 3 and 5 of each week during chemoradiation. Primary endpoint was to determine the recommended phase II dose of adavosertib. Secondary endpoints included toxicity profile and preliminary efficacy.
Results.
Ten patients were enrolled (9 locally advanced cervical and 1 endometrial cancer). Two patients experienced a dose-limiting toxicity at dose level 1 (adavosertib 100 mg po daily days 1, 3 and 5), including one patient with grade 4 thrombocytopenia, and one with treatment hold >1 week due to grade 1 creatinine elevation and grade 1 thrombocytopenia. At dose level −1 (adavosertib 100 mg po daily days 3 and 5), 1 out of 5 patients enrolled had a dose-limiting toxicity in the form of persistent grade 3 diarrhea. Overall response rate at 4 months was 71.4%, including 4 complete responses. At 2 years follow-up, 86% of patients were alive and progression-free.
Conclusion.
The recommended phase II dose could not be determined due to clinical toxicity and early trial closure. Preliminary efficacy appears promising; yet selecting the adequate dose/schedule in combination chemoradiation warrants further investigation to limit overlapping toxicities.
Keywords: Adavosertib, WEE1, chemotherapy, radiation, gynecologic cancer
INTRODUCTION
Locally advanced gynecologic cancers encompass heterogeneous groups of tumors that are at risk of both local and systemic recurrences. Multimodal approaches including surgery, chemotherapy and radiation are frequently used to improve outcomes in this complex population.
Cervical cancer ranks 4th both in incidence and mortality from cancer among women worldwide1. Patients with early-stage tumors have an excellent prognosis, but unfortunately most patients are diagnosed in more advanced Federation of Gynecology and Obstetrics (FIGO) stages, where 5-year overall survival is significantly lower, ranging from 76% in stage IB3 to 24% in stage IVA2.
In the locally advanced setting, phase III trials conducted in the late 1990ś demonstrated a survival benefit with concurrent chemoradiotherapy versus radiation alone3–7, establishing chemoradiation as standard of care. While this therapy is potentially curative, the recurrence rate remains high, between 28% to 64% for FIGO stages IIB-IVA8.
After chemoradiation, locoregional failure accounts for up to 27% of all recurrences9. Treatment of local recurrence is challenging as the minority of patients will be eligible for pelvic exenteration and chemotherapy is less successful in treating recurrences in previously irradiated areas. Patients with systemic recurrence have dismal prognosis, with a life expectancy of around 16–24 months10 Efforts have been made to increase cure rates, but unfortunately most have proven unsuccessful. Immune checkpoint inhibitors and targeted agents have shown promising in patients with metastatic disease, and currently four clinical trials are evaluating these agents in combination with chemoradiation in the locally advanced setting11–14. The phase III trial CALLA evaluating Durvalumab plus chemoradiotherapy failed to meet its primary endpoint of significantly improved progression-free survival (PFS) compared with chemoradiotherapy and placebo among patients with high-risk locally advanced cervical cancer15. New strategies are needed to improve curability in this population.
High-risk endometrial cancer is a heterogeneous subgroup at risk of local and systemic failure. Surgery plus adjuvant chemoradiation is the standard of care in this population, as it showed an overall survival benefit versus radiotherapy alone16. Despite this approach, distant failures occur in more than 20% of patients, highlighting the need to explore new approaches to improve outcomes.
DNA damage response comprises a network of molecules involved in cell cycle regulation and DNA repair17,18. Cell cycle genes guard cellular integrity by halting proliferation at various checkpoints (G1/S, G2/M), allowing repair of damaged DNA19.
The tumor suppressor protein p53 regulates the G1/S checkpoint and the majority of gynecological cancers harbor abnormalities in this pathway. Moreover, human Papillomavirus (HPV)-related cancers exhibit high levels of replication stress due to loss of RB1 and p53 control of G1/S checkpoint caused by HPV E6 and E7 proteins, as well as other mechanisms20.
Tumors harboring G1/S dysregulation become more dependent on G2/M phase checkpoints21; Wee1 is a tyrosine kinase involved in regulation of G2/M cell cycle checkpoint22. Inhibition of Wee-1 with adavosertib (AZD1775), combined with DNA-damaging agents, causes mitotic entry without completion of DNA repair and replication, leading to mitotic catastrophe and tumor cell death23. Adavosertib increases cytotoxicity when used in combination with DNA damaging agents in p53-deficient cell lines24. In xenograft models, adavosertib enhanced the anti- tumor effect of cisplatin, carboplatin, gemcitabine, 5-Fluoruracil, and radiotherapy25–27.
In the PN001 phase I trial evaluating adavosertib as single agent and in combination with chemotherapy, the maximum tolerated dose was determined to be 200mg in combination with Cisplatin every 21 days, and 225mg twice daily for 2.5 days during week 1 with Carboplatin every 21 days. The dose-limiting toxicities experienced were grade 3 diarrhea, fatigue, nausea and vomiting28.
We hypothesized that the combination of adavosertib with standard chemoradiation will increase DNA damage and lead to improved local control in high-risk population of gynecological cancer. As limited data are available for adavosertib in combination with chemoradiation, we conducted a phase I trial to assess safety and feasibility.
METHODS
Study design and participants
This was multi-institution, open-label, dose escalation phase I trial performed in 5 academic centers in the United States (four sites) and Canada (one site). The study was approved by the NCI Central Institutional Review Board (CIRB), study ID 10132, and by the Ontario Cancer Research Ethics Board (OCREB), reference ID 1064. All patients provided written informed consent.
Eligible patients were aged 18 years or older, with biopsy proven newly diagnosed carcinoma of the cervix (cT1B-3B, N0/1, M0/1), carcinoma of the upper 1/3 vagina (T1–3, N0/1, M0/1) or endometrioid adenocarcinoma of the uterus (cT1–3, N0/1, M0) unsuitable for primary surgery, and local recurrence of cervical/endometrial cancer after surgery without previous pelvic radiotherapy. All patients were amenable for treatment with radiotherapy and concurrent cisplatin chemotherapy. Additional criteria included Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, normal bone marrow (hemoglobin >9 g/dL, absolute neutrophil count >1,500/μL, platelets 100,000/μL), renal (creatinine clearance >60 mL/min) and liver function (total bilirubin <1.5x upper limit of normal, alanine aminotransferase and aspartate aminotransferase <1.5x upper limit of normal, or <3x upper limit of normal if liver metastases). Patients who have received any radiotherapy or chemotherapy for their current gynecological cancer were ineligible.
Treatment plan
A 3+3 design was performed to identify the recommended phase II dose. A cohort of 3 patients per dose level was planned. Starting dose level 1 was adavosertib 100 mg on Day 1, 3, and 5 weekly for five weeks during chemoradiotherapy.
If treatment was tolerable with no dose-limiting toxicities, three additional patients entered dose level 2. If the first two patients enrolled in the starting dose level 1 experienced a dose-limiting toxicity, further enrollment in that dose level stopped and a lower dose level was explored. If one dose-limiting toxicity occurred, the level was expanded to six patients. If two of six patients experienced dose-limiting toxicity at dose level 1, a de-escalation level was tested (adavosertib 100 mg on Day 3 and 5 during the 5 weeks of chemoradiation). The recommended phase II dose was defined as the dose level in which 1 or less of 6 patients experienced a dose-limiting toxicity.
All patients received external beam pelvic radiotherapy (45–50 Gy in 25 daily fractions of 1.8–2 Gy) with concurrent weekly cisplatin (40 mg/m2) chemotherapy and adavosertib for 5 weeks. Patient management after the initial five weeks of radiotherapy/cisplatin/adavosertib varied depending on the patient cohort (cervix, upper vagina, uterus, recurrent disease) and treatment response. Surgery, brachytherapy, further external beam radiotherapy for residual pelvic disease or no further treatment were allowed. A detailed description of radiotherapy is included in the supplementary material (S1 and S2).
Treatment with adavosertib continued to completion of chemoradiation, or until disease progression, unacceptable adverse events, dose-limiting toxicity or patient withdrawal. It was not continued beyond five weeks during brachytherapy or additional external beam radiotherapy. Patients were followed to evaluate toxicity or disease relapse every 4 months for 2 years. Response Rate was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Duration of response was assessed in patients with measurable disease and progression free survival was defined as the duration of time from start of treatment to time of progression or death, whichever occurred first. Patients without an event were censored at the end of 2-year follow-up period.
Definition of Dose-limiting toxicity.
Hematologic Dose-limiting toxicities were considered: grade 4 thrombocytopenia, grade 3 thrombocytopenia with bleeding and grade 3 febrile neutropenia. Non-hematologic Dose-limiting toxicities were grade 3 persistent or grade 4 vomiting or diarrhea, grade 3 or 4 rash, grade 3 or 4 radiotherapy associated acute toxicity, interruption of radiotherapy for more than 3 days due to toxicity, inability to receive at least 3 of the 5 planned doses of cisplatin and omission longer than one week in the administration of adavosertib and/or Cisplatin. The Dose-limiting toxicity period was the 5 weeks of chemoradiation.
Endpoints
Primary endpoint was to determine the recommended phase II dose and safety profile of adavosertib in combination with radiotherapy and concurrent cisplatin in women with locally advanced gynecological cancer.
Secondary endpoints were to evaluate the acute and late toxicity, and assess preliminary information about response rate and progression–free survival.
Statistical analysis
A standard 3 + 3 dose escalation scheme was used and 5 dose levels were planned (Dose level −1 to 4). A minimum of 9 patients and a maximum of 33 patients were required for this study.
Summary statistics were used to describe patients’ clinical and demographic characteristics. Frequency and severity of adverse events were tabulated using counts and proportions.
RESULTS
From May 2018 to July 2020, a total of 10 patients were included. Median age was 50 years. Nine patients had cervical cancer (90%) and one had endometrial cancer (10%). 8 out of 9 patients with cervical cancer had squamous-cell carcinoma, and the patient with endometrial cancer had a grade 1 endometrioid adenocarcinoma. Five patients had an ECOG performance status (PS) of 0 and five patients had a PS of 1. One patient had documented right hydronephrosis at screening, which was resolved via ureteric stent before the start of treatment. Baseline characteristics are summarized in Table 1, including FIGO stage. Magnetic Resonance Imaging was used as primary imaging modality in three patients, Computed Tomography (CT) scan in six patients and CT/Positron Emission Tomography in one patient.
Table 1.
Demographic characteristics.
| Characteristic | Number of patients (N=10) |
|---|---|
| Median age (range), years | 50 (35–78) |
|
| |
| Sex | |
| Women | 10 |
|
| |
| ECOG performance status | |
| 0 | 5 |
| 1 | 5 |
|
| |
| Primary site | |
| Cervical | 9 |
| Uterine | 1 |
|
| |
| Histology | |
| Cervical squamous-cell carcinoma | 8 |
| Cervical adenocarcinoma | 1 |
| Uterine endometrioid adenocarcinoma | 1 |
|
| |
| FIGO Stage Cervical (2009) | |
| IB | 2 |
| IIA | 2 |
| IIB | 2 |
| IIIB | 3 |
| FIGO stage Uterine | |
| IA | 1 |
|
| |
| Grade | |
| 1 | 2 |
| 2 | 4 |
| 3 | 3 |
| Unknown | 1 |
|
| |
| Prior treatment | |
| None | 9 |
| Surgery | 1 |
ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation of Gynecology and Obstetrics.
Dose level 1.
Five patients were enrolled at dose level 1. One patient was unevaluable for dose-limiting toxicity due to consent withdrawal before starting treatment; one patient reported grade 2 fatigue and grade 1 nausea, and decided to withdraw consent after 2 doses of adavosertib (200 mg total). Median number of Cisplatin cycles at this dose level was 3.5 (range 2–5). From the three evaluable patients, two experienced dose-limiting toxicities: One patient had grade 4 thrombocytopenia (<25,000/μL), and one patient had treatment hold for more than one week due to grade 1 thrombocytopenia and grade 1 creatinine increase not attributable to new hydronephrosis or other causes. Dose level 1 was considered excessively toxic and this cohort was closed.
Dose level −1
A dose level −1 was explored, corresponding to adavosertib 100 mg on Day 3 and 5 of each week; the standard of care Cisplatin and Radiation dosing/schedule was not modified. Median number of Cisplatin cycles was 5 (range 2–5). The first three patients enrolled at this level did not experience a dose-limiting toxicity and the cohort was expanded to two additional patients; one of which had a dose-limiting toxicity with persistent grade 3 diarrhea despite optimal treatment.
The study was closed after enrollment of the fifth patient in dose level −1 due to clinically significant toxicity, slow accrual and significant adverse events also reported with the combination of adavosertib and chemoradiation in other studies.
Radiotherapy dosimetric parameters.
Radiotherapy dosimetric parameters were available for eight patients. All of them were treated with whole-pelvis external beam radiotherapy (EBRT) to a total dose of 45 Gy in 22–25 daily fractions. Three patients received further external beam pelvic radiotherapy to enlarge pelvic lymph nodes or residual tumor (18, 5.4 and 9 Gy) after the initial phase of treatment and completion of adavosertib and Cisplatin. Brachytherapy to the primary tumor was delivered post chemoradiation to seven patients at a dose ranging from 24–30 Gy in 3–5 fractions, except for one patient who received 16.5 Gy (Figure 1).
Figure 1.
Study overview.
Efficacy.
Seven patients were evaluable for objective response. At the end of treatment, there were 2 complete responses, 2 partial responses and 3 patients with stable disease. At 4 months after completion of treatment, overall response rate was 71.4%, with 4 complete responses (Table 2). At 2-year follow-up, 6 out of 7 patients (86%) were alive and free of disease.
Table 2.
Best tumor response at 4 months.
| N= 7 (%) | |
|---|---|
| Complete response | 4 (57.1) |
| Partial Response | 1 (14.3) |
| Stable disease | 1 (14.3) |
| Progression of disease | 1 (14.3) |
Toxicity.
A total of eight events of grade 3–4 toxicity were reported in dose level 1 and three events in dose level −1. Most common hematologic toxicities were anemia and thrombocytopenia. Most common non-hematologic toxicities were nausea, vomiting, diarrhea, fatigue, anorexia and dermatitis (Table 3). A complete list of adverse events is available in the supplementary material (S3).
Table 3.
Summary of adverse events.
| Dose Level 1 (n=4) | Dose Level −1 (n=5) | |||
|---|---|---|---|---|
| AE | All grades | Grade 3–4 | All grades | Grade 3–4 |
| Nausea | 4 | 0 | 4 | 0 |
| Diarrhea | 3 | 2 | 4 | 1 |
| Fatigue | 3 | 0 | 3 | 0 |
| Hypomagnesemia | 3 | 0 | 0 | 0 |
| Thrombocytopenia | 3 | 1 | 0 | 0 |
| Anemia | 3 | 0 | 0 | 0 |
| Anorexia | 3 | 0 | 0 | 0 |
| Abdominal pain | 2 | 0 | 1 | 0 |
| Creatinine increased | 2 | 0 | 1 | 0 |
| Hyponatremia | 2 | 1 | 0 | 0 |
| Neutropenia | 1 | 1 | 1 | 1 |
| Lymphopenia | 1 | 1 | 1 | 1 |
| Hypoalbuminemia | 1 | 1 | 0 | 0 |
| Vomiting | 1 | 0 | 4 | 0 |
| Dermatitis | 0 | 0 | 3 | 0 |
| Alanine aminotransferase | 0 | 0 | 1 | 0 |
DISCUSSION
Summary of main results.
To our knowledge, this is the first trial evaluating the combination of WEE-1 inhibitor adavosertib in combination with definitive chemoradiation in locally advanced gynecologic tumors. Despite potential biological synergy on synthetic lethality, the overlapping toxicities are limiting this current strategy in clinical setting. The recommended phase II dose could not be determined in the present study with the pre-defined dose levels of adavosertib in combination with standard definitive chemoradiation.
Results in the context of published literature.
In a phase I trial of locally advanced head and neck cancer, patients were initially treated with chemoradiation consisting of weekly cisplatin at 40 mg/m2 plus Intensity-modulated radiation therapy at the dose of 70 Gy and adavosertib 50 mg twice daily three times per week for 7 weeks29. After the first three patients developed dose-limiting toxicity, cisplatin dose was reduced to 30 mg/m2 and adavosertib adjusted to 50 mg twice daily three times per week, in a 2 weeks on/1 week off fashion29. Another phase I trial in advanced pancreatic cancer used adavosertib at dose of 150 mg daily on days 1, 2, 8 and 9 every 3 weeks, concurrent with gemcitabine and 52.5 Gy of radiotherapy; treatment was well tolerated, with 2 dose-limiting toxicities reported among 9 pts enrolled at this dose level30. In our study, adverse events were more frequent even at lower doses of adavosertib probably relating to additive or synergistic interactions between radiotherapy, cisplatin and adavosertib. At the time the study was designed, conformal, field-based pelvic radiotherapy with concurrent weekly cisplatin was still in widespread use for patients with cervical cancer and was generally well tolerated. More conformal intensity modulated radiation treatment (IMRT) or volumetric modulated arc therapy (VMAT) techniques had not yet been broadly adopted because of concerns about inter- and intra-fractional target motion during treatment increasing the risk of cancer recurrence. It is possible that the use of IMRT or VMAT may have resulted in a more tolerable toxicity profile, as these techniques have been associated with reductions in hematologic (neutropenia, thrombocytopenia) and gastrointestinal (diarrhea) side effects and improved quality of life31,32.
Previous data from head and neck cancer suggests that a cumulative dose of cisplatin 200 mg/m2 is recommended to maintain efficacy33, thus the authors were able to reduce cisplatin dose without compromising efficacy. In gynecologic cancers, cisplatin dose of 40 mg/m2 weekly is considered standard of care, and doses below this have not demonstrated comparable efficacy. Since chemoradiotherapy in this context is considered potentially curative, the decision was not to reduce standard cisplatin dose; yet overlapping toxicities with adavosertib were challenging. Based on preclinical and early clinical data demonstrating a synergistic effect between WEE-1 inhibitors with radiotherapy and different types of chemotherapy, decreasing the standard dose of chemotherapy may reduce toxicity without compromising efficacy, but this requires investigation in further clinical trials.
In terms of efficacy, expected 2-year progression-free survival in locally advanced cervical cancer is expected to be around 70–80%4,34. In the present study, six out of seven patients (86%) were alive and progression-free at 2-year follow-up; complete responses were seen in 4/7 patients at 4 months. These results are encouraging, but due to the small number of treated patients need to be confirmed in larger studies with modified dose/schedule for safety with new targeted pelvic radiotherapy techniques.
Strengths and weaknesses.
The present study provides the first clinical data on safety, toxicity and preliminary efficacy of Wee1 inhibitor adavosertib in combination with radiotherapy and concurrent cisplatin in locally advanced gynecologic tumors.
The main limitation of our study is the small number of patients enrolled due to premature closure; yet the study showed the limiting toxicities of this triplet combination. This trial highlights the need to decrease overlapping toxicity during chemo-radiation while targeting treatment synergy.
Implications for practice and future research.
Preliminary efficacy of adavosertib in combination with chemoradiation is encouraging, but overlap toxicity is challenging. As synergy with Wee1 inhibitor is expected, dose adjustment of standard cisplatin may be required and more precise guided radiation delivery needed for precision therapy.
CONCLUSION
Recommended phase II dose could not be determined due to clinical toxicity and early trial closure. Targeting DNA repair is an interesting strategy in the first line treatment setting and require further investigation to select the adequate drug/dose/schedule in combination with chemotherapy and radiation.
Supplementary Material
S1. Radiotherapy overview.
S1.1 External beam whole pelvis radiotherapy planning and delivery.
S1.2 Brachytherapy.
S1.3 External beam pelvic boost radiotherapy for residual disease.
S2. Individual dosimetry parameters.
S3. All grade related adverse events (all patients).
What is already known on this topic.
Wee-1 inhibitors have shown synergistic antitumor activity in combination with DNA-damaging agents in preclinical models and early clinical setting.
What this study adds.
This is the first study evaluating safety and preliminary efficacy of the combination of WEE-1 inhibitor adavosertib in combination with radiotherapy and concurrent Cisplatin in locally advanced gynecologic tumors.
How this study may affect research, practice or policy.
This study provides new clinical information on adavosertib to further investigate the adequate dose and schedule in combination with chemoradiation.
FUNDING
This study was supported by the NCI Cancer Therapy Evaluation Program (contract N01-CM-2011-0032) and NCI UM1 Grant CA186644.
BRC is on advisory Board for GSK, Merck, Immunogen, Imvax, AstraZeneca and Gilead; research funding from Clovis and Immunogen. JLA reports research support from Pfizer and Amgen. HM has been part of advisory boards for Merck, Essai and GSK. YCL in on advisory board for GSK. VB has been on advisory boards for GSK and AstraZeneca. AMO is PI and on steering committees with AstraZeneca, GSK and Clovis; advisory boards for AstraZeneca and Morphosys; CEO in Ozmosis Research (uncompensated). SL reports support for grants or contracts to their institution from Merck, AstraZeneca, Regeneron, Roche, Repare, GSK, and Seagen; consulting fees from Novocure, Merck, AstraZeneca, GSK, Eisai, and Shattuck Labs; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, GSK, and Eisai; and participation on a data safety monitoring board or advisory board for AstraZeneca.
Footnotes
CONTRIBUTORSHIP
All authors of this manuscript have directly participated in conceptualization, drafting, and revisions for important intellectual content. All authors have read and approved the final submitted version.
COMPETING INTERESTS
Rest of authors declare no potential conflicts of interest.
REFERENCES
- 1.Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians. 2021;71(3):209–249. doi: 10.3322/caac.21660 [DOI] [PubMed] [Google Scholar]
- 2.Wright JD, Matsuo K, Huang Y, et al. Prognostic Performance of the 2018 International Federation of Gynecology and Obstetrics Cervical Cancer Staging Guidelines. Obstet Gynecol. 2019;134(1):49–57. doi: 10.1097/AOG.0000000000003311 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Keys HM, Bundy BN, Stehman FB, et al. Cisplatin, Radiation, and Adjuvant Hysterectomy Compared with Radiation and Adjuvant Hysterectomy for Bulky Stage IB Cervical Carcinoma. New England Journal of Medicine. 1999;340(15):1154–1161. doi: 10.1056/NEJM199904153401503 [DOI] [PubMed] [Google Scholar]
- 4.Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med. 1999;340(15):1144–1153. doi: 10.1056/NEJM199904153401502 [DOI] [PubMed] [Google Scholar]
- 5.Peters WA, Liu PY, Barrett RJ, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol. 2000;18(8):1606–1613. doi: 10.1200/JCO.2000.18.8.1606 [DOI] [PubMed] [Google Scholar]
- 6.Whitney CW, Sause W, Bundy BN, et al. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol. 1999;17(5):1339–1348. doi: 10.1200/JCO.1999.17.5.1339 [DOI] [PubMed] [Google Scholar]
- 7.Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med. 1999;340(15):1137–1143. doi: 10.1056/NEJM199904153401501 [DOI] [PubMed] [Google Scholar]
- 8.Quinn MA, Benedet JL, Odicino F, et al. Carcinoma of the cervix uteri. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet. 2006;95 Suppl 1:S43–103. doi: 10.1016/S0020-7292(06)60030-1 [DOI] [PubMed] [Google Scholar]
- 9.Lin AJ, Dehdashti F, Massad LS, et al. Long-term Outcomes of Cervical Cancer Patients Treated with Definitive Chemoradiation following a Complete Metabolic Response. Clin Oncol (R Coll Radiol). 2021;33(5):300–306. doi: 10.1016/j.clon.2021.01.010 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Colombo N, Dubot C, Lorusso D, et al. Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. New England Journal of Medicine. 2021;385(20):1856–1867. doi: 10.1056/NEJMoa2112435 [DOI] [PubMed] [Google Scholar]
- 11.Lorusso D, Colombo N, Coleman RL, et al. ENGOT-cx11/KEYNOTE-A18: A phase III, randomized, double-blind study of pembrolizumab with chemoradiotherapy in patients with high- risk locally advanced cervical cancer. JCO. 2020;38(15_suppl):TPS6096-TPS6096. doi: 10.1200/JCO.2020.38.15_suppl.TPS6096 [DOI] [Google Scholar]
- 12.Mayadev J, Nunes AT, Li M, Marcovitz M, Lanasa MC, Monk BJ. CALLA: Efficacy and safety of concurrent and adjuvant durvalumab with chemoradiotherapy versus chemoradiotherapy alone in women with locally advanced cervical cancer: a phase III, randomized, double-blind, multicenter study. Int J Gynecol Cancer. 2020;30(7):1065–1070. doi: 10.1136/ijgc-2019-001135 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Roussy Gustave, Campus Cancer, Paris Grand. Randomized Phase II Trial Assessing the Inhibitor of Programmed Cell Death Ligand 1 (PD-L1) Immune Checkpoint Atezolizumab in Locally Advanced Cervical Cancer. clinicaltrials.gov; 2021. Accessed February 20, 2022. https://clinicaltrials.gov/ct2/show/NCT03612791 [Google Scholar]
- 14.Oaknin A, Iglesias M, Alarcon JD, et al. 880TiP Randomized, open-label, phase II trial of dostarlimab (TSR-042), as maintenance therapy for patients with high-risk locally advanced cervical cancer after chemo-radiation: ATOMICC study. Annals of Oncology. 2020;31:S645. doi: 10.1016/j.annonc.2020.08.1019 [DOI] [Google Scholar]
- 15.Monk B, Toita T, Wu X, et al. Durvalumab, in combination with and following chemotherapy, in locally advanced cervical cancer: results from the phase 3 international, randomized, double-blind, placebo-controlled CALLA trial. Presented at: 2022 International Gynecologic Cancer Society Annual Meeting; September 29-October 1, 2022; New York, NY. Abstract O001. [Google Scholar]
- 16.de Boer SM, Powell ME, Mileshkin L, et al. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. The Lancet Oncology. 2019;20(9):1273–1285. doi: 10.1016/S1470-2045(19)30395-X [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Hustedt N, Durocher D. The control of DNA repair by the cell cycle. Nat Cell Biol. 2016;19(1):1–9. doi: 10.1038/ncb3452 [DOI] [PubMed] [Google Scholar]
- 18.Branzei D, Foiani M. Regulation of DNA repair throughout the cell cycle. Nat Rev Mol Cell Biol. 2008;9(4):297–308. doi: 10.1038/nrm2351 [DOI] [PubMed] [Google Scholar]
- 19.Funk JO. Cell Cycle Checkpoint Genes and Cancer. In: ELS. John Wiley & Sons, Ltd; 2006. doi: 10.1038/npg.els.0006046 [DOI] [Google Scholar]
- 20.da Costa AABA, Chowdhury D, Shapiro GI, D’Andrea AD, Konstantinopoulos PA. Targeting replication stress in cancer therapy. Nat Rev Drug Discov. Published online October 6, 2022. doi: 10.1038/s41573-022-00558-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Sherr CJ. Cancer cell cycles. Science. 1996;274(5293):1672–1677. doi: 10.1126/science.274.5293.1672 [DOI] [PubMed] [Google Scholar]
- 22.Sørensen CS, Syljuåsen RG. Safeguarding genome integrity: the checkpoint kinases ATR, CHK1 and WEE1 restrain CDK activity during normal DNA replication. Nucleic Acids Res. 2012;40(2):477–486. doi: 10.1093/nar/gkr697 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Aarts M, Sharpe R, Garcia-Murillas I, et al. Forced mitotic entry of S-phase cells as a therapeutic strategy induced by inhibition of WEE1. Cancer Discov. 2012;2(6):524–539. doi: 10.1158/2159-8290.CD-11-0320 [DOI] [PubMed] [Google Scholar]
- 24.Hirai H, Iwasawa Y, Okada M, et al. Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents. Mol Cancer Ther. 2009;8(11):2992–3000. doi: 10.1158/1535-7163.MCT-09-0463 [DOI] [PubMed] [Google Scholar]
- 25.Hirai H, Arai T, Okada M, et al. MK-1775, a small molecule Wee1 inhibitor, enhances anti-tumor efficacy of various DNA-damaging agents, including 5-fluorouracil. Cancer Biol Ther. 2010;9(7):514–522. doi: 10.4161/cbt.9.7.11115 [DOI] [PubMed] [Google Scholar]
- 26.Rajeshkumar NV, De Oliveira E, Ottenhof N, et al. MK-1775, a potent Wee1 inhibitor, synergizes with gemcitabine to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts. Clin Cancer Res. 2011;17(9):2799–2806. doi: 10.1158/1078-0432.CCR-10-2580 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Lee YY, Cho YJ, Shin S won, et al. Anti-Tumor Effects of Wee1 Kinase Inhibitor with Radiotherapy in Human Cervical Cancer. Sci Rep. 2019;9(1):15394. doi: 10.1038/s41598-019-51959-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Leijen S, van Geel RMJM, Pavlick AC, et al. Phase I Study Evaluating WEE1 Inhibitor AZD1775 As Monotherapy and in Combination With Gemcitabine, Cisplatin, or Carboplatin in Patients With Advanced Solid Tumors. J Clin Oncol. 2016;34(36):4371–4380. doi: 10.1200/JCO.2016.67.5991 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Chera BS, Sheth SH, Patel SA, et al. Phase 1 trial of adavosertib (AZD1775) in combination with concurrent radiation and cisplatin for intermediate-risk and high-risk head and neck squamous cell carcinoma. Cancer. 2021;127(23):4447–4454. doi: 10.1002/cncr.33789 [DOI] [PubMed] [Google Scholar]
- 30.Cuneo KC, Morgan MA, Sahai V, et al. Dose Escalation Trial of the Wee1 Inhibitor Adavosertib (AZD1775) in Combination With Gemcitabine and Radiation for Patients With Locally Advanced Pancreatic Cancer. J Clin Oncol. 2019;37(29):2643–2650. doi: 10.1200/JCO.19.00730 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Roeske JC, Lujan A, Rotmensch J, Waggoner SE, Yamada D, Mundt AJ. Intensity-modulated whole pelvic radiation therapy in patients with gynecologic malignancies. Int J Radiat Oncol Biol Phys. 2000;48(5):1613–1621. doi: 10.1016/s0360-3016(00)00771-9 [DOI] [PubMed] [Google Scholar]
- 32.Klopp AH, Yeung AR, Deshmukh S, et al. Patient-Reported Toxicity During Pelvic Intensity-Modulated Radiation Therapy: NRG Oncology-RTOG 1203. J Clin Oncol. 2018;36(24):2538–2544. doi: 10.1200/JCO.2017.77.4273 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Strojan P, Vermorken JB, Beitler JJ, et al. Cumulative cisplatin dose in concurrent chemoradiotherapy for head and neck cancer: A systematic review. Head Neck. 2016;38 Suppl 1:E2151–2158. doi: 10.1002/hed.24026 [DOI] [PubMed] [Google Scholar]
- 34.Mileshkin LR, Moore KN, Barnes E, et al. Adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone: The randomized phase III OUTBACK Trial (ANZGOG 0902, RTOG 1174, NRG 0274). JCO. 2021;39(18_suppl):LBA3–LBA3. doi: 10.1200/JCO.2021.39.15_suppl.LBA3 [DOI] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
S1. Radiotherapy overview.
S1.1 External beam whole pelvis radiotherapy planning and delivery.
S1.2 Brachytherapy.
S1.3 External beam pelvic boost radiotherapy for residual disease.
S2. Individual dosimetry parameters.
S3. All grade related adverse events (all patients).