Intensity modulated radiotherapy in locally advanced thyroid cancer: Outcomes of a sequential phase I dose-escalation study.

BACKGROUND AND PURPOSE: To determine the safety and tolerability of dose-escalation using modestly accelerated IMRT in high-risk locally advanced thyroid cancer requiring post-operative radiotherapy, and to report preliminary data on efficacy. MATERIALS AND METHODS: A sequential Phase I dose-escalation design was used. Dose level one (DL1) received 58.8 Gy/28F to the post-operative bed and 50 Gy/28F to elective nodes. DL2 received 66.6 Gy/30F to the thyroid bed, 60 Gy/30F to post-operative nodal levels and 54 Gy/30F to elective nodal levels. Acute (NCICTCv.2.0) and late toxicities (RTOG and modified LENTSOM) were recorded. The primary endpoint was the number of patients with ≥Grade 3 (G3) toxicity at 12 months post-treatment. RESULTS: Fifteen patients were recruited to DL1 and twenty-nine to DL2. At 12 months ≥G3 toxicities were 8.3% in both DL1 and DL2. At 60 months, ≥G3 toxicity was reported in 3 (33%) patients in DL1 and 1 (7%) in DL2. One patient in DL2 died at 24 months from radiation-induced toxicity. Time to relapse and overall survival rates were higher in DL2, but this was not statistically significant. Dose-escalation using this accelerated regimen can be safely performed with a toxicity profile similar to reported series using conventional doses.

Normal Tissue Complication Probability (NTCP) Modelling of Severe Acute Mucositis using a Novel Oral Mucosal Surface Organ at Risk.

AIMS: A normal tissue complication probability (NTCP) model of severe acute mucositis would be highly useful to guide clinical decision making and inform radiotherapy planning. We aimed to improve upon our previous model by using a novel oral mucosal surface organ at risk (OAR) in place of an oral cavity OAR. MATERIALS AND METHODS: Predictive models of severe acute mucositis were generated using radiotherapy dose to the oral cavity OAR or mucosal surface OAR and clinical data. Penalised logistic regression and random forest classification (RFC) models were generated for both OARs and compared. Internal validation was carried out with 100-iteration stratified shuffle split cross-validation, using multiple metrics to assess different aspects of model performance. Associations between treatment covariates and severe mucositis were explored using RFC feature importance. RESULTS: Penalised logistic regression and RFC models using the oral cavity OAR performed at least as well as the models using mucosal surface OAR. Associations between dose metrics and severe mucositis were similar between the mucosal surface and oral cavity models. The volumes of oral cavity or mucosal surface receiving intermediate and high doses were most strongly associated with severe mucositis. CONCLUSIONS: The simpler oral cavity OAR should be preferred over the mucosal surface OAR for NTCP modelling of severe mucositis. We recommend minimising the volume of mucosa receiving intermediate and high doses, where possible.

Delayed DNA double-strand break repair following platin-based chemotherapy predicts treatment response in head and neck squamous cell carcinoma.

INTRODUCTION: The aim of this study was to investigate if defective repair of DNA double-strand break (DSB) in head and neck squamous cell carcinoma (HNSCC) could be used as an early predictor of treatment response. METHODS: Tumour biopsy 24-36 h following induction chemotherapy (IC) and pre-treatment biopsies were stained for RAD51 and geminin (S-phase marker) for immunofluorescence in patients with HNSCC. The difference between RAD51 score (percentage of geminin-positive cells that were also positive for RAD51) was calculated for the two specimens. Tumours with a percentage difference of⩽10% were deemed to have repaired IC-induced DSBs, and were classified as 'RAD51 negative'. Response at 3 months post treatment and human papilloma virus (HPV) status were assessed. RESULTS: Thirteen pairs of samples were available for analyses. Three samples were classified as RAD51 negative and 10 as RAD51 positive at 24 h post IC. All of the three patients with tumours classified as RAD51 negative had partial response or progressive disease and the 10 patients with tumours deemed RAD51 positive had a complete response. 100% of the HPV-positive tumours were RAD51 positive and had a complete response. CONCLUSIONS: We have demonstrated that impaired DSB DNA repair may underlie enhanced treatment sensitivity of HPV-positive HNSCC and repair capacity following platinum-induced DNA damage predicts response in HNSCC. This has potential as a biomarker for patient selection in trials of DNA damage response pathway modulation.

Evaluation of radiotherapy techniques for radical treatment of lateralised oropharyngeal cancers : Dosimetry and NTCP.

AIM: The aim of this study was to investigate potential advantages and disadvantages of three-dimensional conformal radiotherapy (3DCRT), multiple fixed-field intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) in terms of dose to the planning target volume (PTV), organs at risk (OARs) and normal tissue complication probability (NTCP) for delivering ipsilateral radiotherapy. MATERIALS AND METHODS: 3DCRT, IMRT and VMAT were compared in patients with well-lateralised primary tonsillar cancers who underwent primary radical ipsilateral radiotherapy. The following parameters were compared: conformity index (CI); homogeneity index (HI); dose-volume histograms (DVHs) of PTVs and OARs; NTCP, risk of radiation-induced cancer and dose accumulation during treatment. RESULTS: IMRT and VMAT were superior to 3DCRT in terms of CI, HI and dose to the target volumes, as well as mandible and dose accumulation robustness. The techniques were equivalent in terms of dose and NTCP for the contralateral oral cavity, contralateral submandibular gland and mandible, when specific dose constraint objectives were used on the oral cavity volume. Although the volume of normal tissue exposed to low-dose radiation was significantly higher with IMRT and VMAT, the risk of radiation-induced secondary malignancy was dependant on the mathematical model used. CONCLUSION: This study demonstrates the superiority of IMRT/VMAT techniques over 3DCRT in terms of dose homogeneity, conformity and consistent dose delivery to the PTV throughout the course of treatment in patients with lateralised oropharyngeal cancers. Dosimetry and NTCP calculations show that these techniques are equivalent to 3DCRT with regard to the risk of acute mucositis when specific dose constraint objectives were used on the contralateral oral cavity OAR.

Total Mucosal Irradiation with Intensity-modulated Radiotherapy in Patients with Head and Neck Carcinoma of Unknown Primary: A Pooled Analysis of Two Prospective Studies.

AIMS: To determine the clinical outcomes of an intensity-modulated radiotherapy technique for total mucosal irradiation (TM-IMRT) in patients with head and neck carcinoma of unknown primary (HNCUP). MATERIALS AND METHODS: A single-centre prospective phase II trial design was used in two sequential studies to evaluate TM-IMRT for HNCUP. Patients were investigated for primary tumour site using examination under anaesthetic and biopsies, computed tomography ± magnetic resonance imaging (MRI) or 18-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT). Patients received IMRT to the potential primary tumour sites and elective cervical nodes. Concomitant chemotherapy was used in patients who received primary radiotherapy or those with nodal extracapsular extension. RESULTS: Thirty-six patients with HNCUP were recruited; 72% male. Twenty-five patients (69.4%) had p16-positive disease. Two year mucosal and local nodal control rates were 97.1% (95% confidence interval 91.4-100) and 89.8% (78.4-100), respectively. One mucosal primary was detected 7.3 months after TM-IMRT and three patients died from recurrent/metastatic squamous cell carcinoma of the head and neck. Twelve patients (33%) developed grade 3 (Late Effects in Normal Tissue-Subjective, Objective, Management and Analytical; LENT-SOMA) dysphagia with a 1 year enteric tube feeding rate of 2.7%. The high-grade subjective xerostomia rate (LENT-SOMA) at 24 months after IMRT was 15%. CONCLUSIONS: At a median follow-up of 36.1 months, the use of TM-IMRT was associated with good local control. Toxicity was comparable with previously reported TM-IMRT regimens encompassing similar mucosal volumes.

Recovery of Salivary Function: Contralateral Parotid-sparing Intensity-modulated Radiotherapy versus Bilateral Superficial Lobe Parotid-sparing Intensity-modulated Radiotherapy.

AIMS: To establish whether there is a difference in recovery of salivary function with bilateral superficial lobe parotid-sparing intensity-modulated radiotherapy (BSLPS-IMRT) versus contralateral parotid-sparing IMRT (CLPS-IMRT) in patients with locally advanced head and neck squamous cell cancers. MATERIALS AND METHODS: A dosimetric analysis was carried out on data from two studies in which patients received BSLPS-IMRT (PARSPORT II) or CLPS-IMRT (PARSPORT). Acute (National Cancer Institute, Common Terminology Criteria for adverse events - NCI CTCAEv3.0) and late (Late Effects of Normal Tissue- subjective, objective, management analytical - LENTSOMA and Radiation Therapy Oncology Group) xerostomia scores were dichotomised: recovery (grade 0-1) versus no recovery (≥grade 2). Incidence of recovery of salivary function was compared between the two techniques and dose-response relationships were determined by fitting dose-response curves to the data using non-linear logistic regression analysis. RESULTS: Seventy-one patients received BSLPS-IMRT and 35 received CLPS-IMRT. Patients received 65 Gy in 30 fractions to the primary site and involved nodal levels and 54 Gy in 30 fractions to elective nodal levels. There were significant differences in mean doses to contralateral parotid gland (29.4 Gy versus 24.9 Gy, P < 0.005) and superficial lobes (26.8 Gy versus 30.5 Gy, P = 0.02) for BSLPS and CLPS-IMRT, respectively. Lower risk of long-term ≥grade 2 subjective xerostomia (LENTSOMA) was reported with BSLPS-IMRT (odds ratio 0.50; 95% confidence interval 0.29-0.86; P = 0.012). The percentage of patients who reported recovery of parotid saliva flow at 1 year was higher with BSLPS-IMRT compared with CLPS-IMRT techniques (67.1% versus 52.8%), but the difference was not statistically significant (P = 0.12). For the whole parotid gland, the tolerance doses, D50, were 25.6 Gy (95% confidence interval 20.6-30.5), k = 2.7 (0.9-4.5) (CLPS-IMRT) and 28.9 Gy (26.1-31.9), k = 2.4 (1.4-3.4) (BSLPS-IMRT). For the superficial lobe, D50 were similar: BSLPS-IMRT 23.5 Gy (19.3-27.6), k = 1.9 (0.5-3.8); CLPS-IMRT 24.0 Gy (17.7-30.1), k = 2.1 (0.1-4.1). CONCLUSION: BSLPS-IMRT reduces the risk of developing high-grade subjective xerostomia compared with CLPS-IMRT. The D50 of the superficial lobe may be a more reliable predictor of recovery of parotid function than the whole gland mean dose.

Induction Chemotherapy Followed by Chemo-intensity-modulated Radiotherapy for Locally Advanced Nasopharyngeal Cancer.

AIMS: To determine the toxicity and tumour control rates after chemo-intensity-modulated radiotherapy (chemo-IMRT) for locally advanced nasopharyngeal cancers (LA-NPC). MATERIALS AND METHODS: Patients with LA-NPC were enrolled in a trial to receive induction chemotherapy followed by parotid-sparing chemo-IMRT. The primary site and involved nodal levels received 65 Gy in 30 fractions and at risk nodal levels received 54 Gy in 30 fractions. Incidence of ≥grade 2 subjective xerostomia was the primary end point. Secondary end points included incidences of acute and late toxicities and survival outcomes. RESULTS: Forty-two patients with American Joint Committee on Cancer stages II (12%), III (26%) and IV (62%) (World Health Organization subtype: I [5%]; II [40%]; III [55%]) completed treatment between January 2006 and April 2010 with a median follow-up of 32 months. Incidences of ≥grade 2 acute toxicities were: dysphagia 83%; xerostomia 76%; mucositis 97%; pain 76%; fatigue 99% and ototoxicity 12%. At 12 months, ≥grade 2 subjective xerostomia was observed in 31%, ototoxicitiy in 13% and dysphagia in 4%. Two year locoregional control was 86.2% (95% confidence interval: 70.0-94.0) with 2 year progression-free survival at 78.4% (61.4-88.6) and 2 year overall survival at 85.9% (69.3-93.9). CONCLUSIONS: Chemo-IMRT for LA-NPC is feasible with good survival outcomes. At 1 year, 31% experience ≥grade 2 subjective xerostomia.

A phase II trial of induction chemotherapy and chemo-IMRT for head and neck squamous cell cancers at risk of bilateral nodal spread: the application of a bilateral superficial lobe parotid-sparing IMRT technique and treatment outcomes.

PURPOSE: To determine the feasibility of induction chemotherapy and chemo-IMRT in head and neck squamous cell cancers at risk of bilateral nodal spread (midline tumours) and to evaluate whether bilateral superficial lobe parotid-sparing IMRT can reduce the incidence of ⩾G2 subjective xerostomia. METHODS: Patients with midline tumours were enrolled to a phase II trial to receive induction platinum/5-fluorouracil and concomitant platinum with combined superficial lobe parotid-sparing IMRT. The primary site and involved nodal levels received 65 Gy in 30 fractions (f) and at risk nodal levels, 54 Gy/30f. Incidence of ⩾G2 subjective xerostomia was defined as the primary endpoint. Secondary endpoints included incidences of acute and late toxicities and survival outcomes dependent on human papilloma virus (HPV) status. RESULTS: One hundred and twenty patients with midline cancers completed treatment between December 2005 and May 2010 with median follow-up of 50 months. Incidences of ⩾G2 acute toxicities were: dysphagia 75%; xerostomia 65%; mucositis 86%; pain 83%; and fatigue 64%. At 12 months, ⩾G2 subjective xerostomia was observed in 21% (17% in HPV +ve). Two-year loco-regional progression-free survival (PFS) was 90.7% (95% CI: 85.2-96.2). According to HPV status, there was a significant difference for 2-year loco-regional PFS, 76.8% (HPV-negative) vs 98.6% (HPV-positive), P=0.001. 2-year overall survival was 93% for HPV-positive compared with 52% for HPV-negative cases, P<0.001. CONCLUSIONS: Sequential chemotherapy/chemo-IMRT for midline tumours is feasible, with excellent survival outcomes. At 1 year, 21% experience ⩾G2 subjective xerostomia. Two-year survival outcomes differ significantly between HPV-positive and HPV-negative disease, suggesting development of different treatment schedules for the different disease entities.

Neurocognitive function after (chemo)-radiotherapy for head and neck cancer.

Radical radiotherapy has a pivotal role in the treatment of head and neck cancer (HNC) and cures a significant proportion of patients while simultaneously sparing critical normal organs. Some patients treated with radical radiotherapy for HNC receive significant radiation doses to large volumes of brain tissue. In fact, intensity-modulated radiotherapy techniques for HNC have been associated with a net increase in irradiated brain volumes. The increasing use of chemoradiotherapy for HNC has additionally exposed this patient population to potential neurotoxicity due to cytotoxic drugs. Patients with HNC may be particularly at risk for adverse late brain effects after (chemo)-radiotherapy, such as impaired neurocognitive function (NCF), as risk factors for the development of HNC, such as smoking, excess alcohol consumption and poor diet, are also associated with impaired NCF. The relatively good survival rates with modern treatment for HNC, and exposure to multiple potentially neurotoxic factors, means that it is important to understand the impact of (chemo)-radiotherapy for HNC on NCF, and to consider what measures can be taken to minimise treatment-related neurotoxicity. Here, we review evidence relating to the late neurotoxicity of radical (chemo)-radiotherapy for HNC, with a focus on studies of NCF in this patient population.

Current attitudes of head and neck oncologists in the United Kingdom to induction chemotherapy for locally advanced head and neck cancer: a survey of centres participating in a national randomised controlled trial.

OBJECTIVES: Induction chemotherapy (IC) followed by chemoradiation (CRT) for locally advanced squamous cell head and neck cancer (SCCHN) remains controversial in the absence of clear evidence to define its role. As part of a prospective, randomised, multicentre study of CRT for stage III/IV laryngeal/hypopharyngeal cancers (ART DECO, CRUK/10/018), we have examined the attitudes of oncologists in the United Kingdom (UK) to IC. MATERIALS AND METHODS: Head and neck oncologists across the UK who expressed an interest in participating in the ART DECO trial were asked to complete a short written questionnaire designed to identify current UK practice of IC for stage III-IVb SCCHN. Completed questionnaires were returned to the clinical trials office prior to patient recruitment. RESULTS: Clinicians from twenty-five/48 centres (52.1%) responded. Twenty centres (80%) elected to use IC in the trial. For stage III disease, 80% of centres did not prescribe IC for T1N1 disease and 60% did not offer IC for T3N0 disease. Patients with bulky primary tumours or extensive nodal disease were more likely to receive IC. Thirteen prescribing centres (65%) use 3 drugs (docetaxel, cisplatin, and 5-fluorouracil) compared to 7 (35%) using 2 drugs (cisplatin and 5-fluorouracil). Fifteen centres (75%) prescribed 2 cycles of IC, and 5 (25%) prescribed 3 cycles. There was variation in the dosage for both the 2- and 3-drug regimens. CONCLUSION: Results suggest that clinical practice in the UK is currently divided between a 2- versus 3-drug regimen for IC for specific subgroups of patients. A consensus regarding the optimal combinations and dosages is required before further optimization of systemic therapy with other cytotoxics and biological agents is attempted.

Equivalence of cisplatin and carboplatin-based chemoradiation for locally advanced squamous cell carcinoma of the head and neck: a matched-pair analysis.

BACKGROUND: Carboplatin can be substituted for cisplatin in concomitant chemoradiation (CRT) for locally advanced squamous cell carcinoma of the head and neck (LASCCHN) when the latter is contraindicated. This matched-pair study aimed to compare the efficacy and acute toxicity of carboplatin and cisplatin. METHODS: Patients treated with 2 cycles of concomitant carboplatin-based CRT were matched to patients treated with 2 cycles of cisplatin. Matching criteria included age, tumour site, stage, smoking status and use of induction chemotherapy. Radiation was delivered using conformal techniques. Data on weekly acute toxicity throughout CRT was compared using the chi-squared test for proportions. Kaplan Meier statistics described time to local relapse, distant relapse and overall survival, the log-rank test was used to compare 3-year survival outcomes. RESULTS: Sixty-five patients who received carboplatin were matched to 65 who received cisplatin. Significant differences in toxicity included increased emesis with cisplatin and more anaemia and thrombocytopenia with carboplatin. There was no significant difference in 3-year locoregional control (87% vs. 79%, p=0.54), freedom from distant metastases (88% vs. 85%, p=0.79) and overall survival (59% vs. 68%, p=0.24) between the carboplatin and cisplatin cohorts, respectively. CONCLUSIONS: When cisplatin is contraindicated, carboplatin-based CRT yields equivalent treatment outcomes in patients with LASCCHN.

Clinical evaluation of intensity-modulated radiotherapy for head and neck cancers.

Radiotherapy and surgery are the principal curative modalities in treatment of head and neck cancer. Conventional two-dimensional and three-dimensional conformal radiotherapy result in significant side effects and altered quality of life. Intensity-modulated radiotherapy (IMRT) can spare the normal tissues, while delivering a curative dose to the tumour-bearing tissues. This article reviews the current role of IMRT in head and neck cancer from the point of view of normal tissue sparing, and also reviews the current published literature by individual head and neck cancer subsites. In addition, we briefly discuss the role of image guidance in head and neck IMRT, and future directions in this area.

The role of intensity modulated radiotherapy in advanced oral cavity carcinoma.

It is increasingly being recognized that oral cavity cancer incidences are rising globally. Furthermore, these tumors represent a high risk group of tumors comparative to other head and neck tumor sub-sites and have a high preponderance of occult nodal metastases. Surgery alone leads to excellent outcomes in early stage disease. Advanced tumors require adjuvant radiotherapy with or without concomitant chemotherapy. Irradiation using 3D conformal radiotherapy results in high incidence of late radiation side-effects. Xersostomia and mandibular osteoradionecrosis result in most significant effects on patients' quality of life. Intensity modulated radiotherapy (IMRT) is an advanced approach to 3-D treatment planning and conformal therapy (3D-CRT). It optimizes the delivery of irradiation to irregularly-shaped volumes and has the ability to produce concavities in radiation treatment volumes and hence enables sparing of normal tissue while delivering adequate doses to the tumor volumes. In this manuscript, we discuss the advantages of IMRT based on review of published peer reviewed literature.

The role of intensity-modulated radiotherapy in head and neck cancer.

Intensity-modulated radiotherapy (IMRT) has been a significant technological advance in the field of radiotherapy in recent years. IMRT allows sparing of normal tissue while delivering radical radiation doses to the target volumes. The role of IMRT for parotid salivary gland sparing in head and neck cancer is well established. The utility of IMRT for pharyngeal constrictor muscle and cochlear sparing requires investigation in clinical trials. The current evidence supporting the use of IMRT in various head and neck subsites has been summarized. Sparing of organs at risk allows for dose-escalation to the target volumes, taking advantage of the steep dose-response relationship for squamous cell carcinomas to improve treatment outcomes in advanced head and neck cancers. However, dose-escalation could result in increased radiation toxicity (acute and late), which has to be studied in detail. The future of IMRT in head and neck cancers lies in exploring the use of biological imaging for dose-escalation using targeted dose painting.

Novel therapeutic approaches to squamous cell carcinoma of the head and neck using biologically targeted agents.

Despite significant improvements in the treatment and outcomes of patients with squamous cell carcinoma of the head and neck (SCCHN) that have resulted from technological advances in radiation delivery and the use of cytotoxic chemotherapy, there is still a pressing need for novel therapies. In the last two decades, our understanding of the molecular biological basis of cancer has provided us with a new framework for developing specific targeted therapies. It is likely that the next wave of developments will include active small molecule inhibitors of epidermal growth factor receptor (EGFR) (and other members of the c-erbB family of receptors), antiangiogenic agents, and drugs that can increase proapoptotic signaling in cancer cells. As with cetuximab, it is most likely that these new agents will first find a niche in the context of combination regimens with standard anticancer therapeutics.

Recent advances in radiotherapy.

Radiation therapy has come a long way from treatment planning based on orthogonal radiographs with large margins around tumours. Advances in imaging and radiation planning software have led to three-dimensional conformal radiotherapy and, further, to intensity modulated radiotherapy (IMRT). IMRT permits sparing of normal tissues and hence dose-escalation to tumours. IMRT is the current standard in treatment of head and prostate cancer and is being investigated in other tumour sites. Exquisitely sculpted dose distributions (increased geographical miss) with IMRT, plus tumour motion and anatomical changes during radiotherapy make image guided radiotherapy an essential part of modern radiation delivery. Various hardware and software tools are under investigation for optimal IGRT.

External beam radiotherapy for differentiated thyroid cancer.

The management of differentiated thyroid cancer involves a combination of surgery, thyroid stimulating hormone suppression and radioactive iodine for most patients. In a small subset of patients, external beam radiotherapy is also used. However, its role remains controversial and there are no randomised controlled trials to guide practice. In this overview we review the evidence from the published literature for the use of external beam radiotherapy in the management of differentiated thyroid cancer and discuss the indications for which it is most commonly used. The technique of external beam radiotherapy, including the emerging role for intensity-modulated radiotherapy, will also be discussed.

Advances in chemotherapy for head and neck cancer.

Systemic chemotherapy is increasingly being used with radiotherapy for the radical treatment of advanced head and neck cancers. Chemotherapy offers modest benefits in the metastatic setting. Platinum containing agents are the most active drugs and form the mainstay of most chemotherapy schedules. In recent years taxanes have been shown activity in head and neck cancers and are being incorporated into neo-adjuvant and concomitant chemotherapy regimens. Targeted agents EGFR inhibitors like cetuximab, in particular have shown benefit in the metastatic and the concomitant setting. EGFR inhibitors and other targeted agents form the thrust of pre-clinical and clinical research into systemic treatment of head and neck cancer.

Pre-clinical and clinical evaluation of PARP inhibitors as tumour-specific radiosensitisers.

Approximately two million fractions of radiotherapy are administered in the UK every year, as part of adjuvant, radical or palliative cancer treatment. For many tumour types, radiotherapy is routinely combined with concomitant chemotherapy as part of adjuvant or radical treatment. In addition, new agents have been developed in recent years and tested in phase 1, 2 and 3 trials concomitantly with radiotherapy or chemoradiotherapy. One such class of drugs, the poly(ADP-ribose) polymerase (PARP) inhibitors, has shown activity in conjunction with radiotherapy in several cancer cell lines. Pre-clinical data suggest that PARP inhibitors may potentiate the effects of radiotherapy in several tumour types, namely lung, colorectal, head and neck, glioma, cervix and prostate cancers. In vitro, PARP inhibitors are radiosensitisers in various cell lines with enhancement ratios of up to 1.7. In vivo, non-toxic doses of PARP inhibitors have been shown to increase radiation-induced growth delay of xenograft tumours in mice. Clinical trials to assess the toxicity and potential benefit of combining radiotherapy with PARP inhibition are now needed.