What is the optimal timing for implant placement in oral cancer patients? A scoping literature review

Abstract Background Oral cancer patients can benefit from dental implant placement. Traditionally, implants are placed after completing oncologic treatment (secondary implant placement). Implant placement during ablative surgery (primary placement) in oral cancer patients seems beneficial in terms of early start of oral rehabilitation and limiting additional surgical interventions. Guidelines on the ideal timing of implant placement in oral cancer patients are missing. Objective To perform a scoping literature review on studies examining the timing of dental implant placement in oral cancer patients and propose a clinical practice recommendations guideline. Methods A literature search for studies dealing with primary and/or secondary implant placement in MEDLINE was conducted (last search December 27, 2019). The primary outcome was 5‐year implant survival. Results Sixteen out of 808 studies were considered eligible. Both primary and secondary implant placement showed acceptable overall implant survival ratios with a higher pooled 5‐year implant survival rate for primary implant placement 92.8% (95% CI: 87.1%–98.5%) than secondary placed implants (86.4%, 95% CI: 77.0%–95.8%). Primary implant placement is accompanied by earlier prosthetic rehabilitation after tumor surgery. Conclusion Patients with oral cancer greatly benefit from, preferably primary placed, dental implants in their prosthetic rehabilitation. The combination of tumor surgery with implant placement in native mandibular bone should be provided as standard care.


| INTRODUC TI ON
The general treatment timeline for oral cancer patients consists of diagnostics, surgical treatment followed by postoperative (chemo) radiation therapy depending on the surgical margins and specific tumor properties, or solely (chemo)radiation therapy. Traditionally, oral rehabilitation comes last, that is, after the oncologic treatment when the oral mucosa is completely healed (Figure 1). Oral function after treatment for a malignancy in the oral cavity is often compromised due to changed anatomy after surgery and/or the oral sequelae of radiotherapy like xerostomia and trismus (de Groot et al., 2019;Kamstra et al., 2011). Sometimes, teeth need to be extracted during ablative surgery because of their location in proximity to the tumor or as part of a preradiation screening examination (Spijkervet, Schuurhuis, Stokman, Witjes, & Vissink, 2020). This compromised oral condition also leads to a decrease in oral function and possible a negative effect on nutritional status and quality of life . Fabrication of functional prostheses, frames, and conventional partial dentures is often difficult to achieve after oncologic treatment and in some cases even impossible (Curtis & Cantor, 1974;Petrovic, Rosen, Matros, Huryn, & Shah, 2018).
Dental implants have shown to be a great asset in oral cancer patients and provide good results (Said et al., 2017;Schoen et al., 2007). When dental rehabilitation based on implants first was introduced in oral cancer patients, they were often placed after oncologic treatment (secondary implant placement) (Kim & Ghali, 2011). This implies an additional surgery, for irradiated patients under antibiotic prophylaxis, and an additional treatment burden in older patients with often multiple comorbidities. When pretreatment hyperbaric oxygen treatment is advised, the treatment burden increases even more (Spijkervet, Brennan, Peterson, Witjes, & Vissink, 2019). When offering implant treatment in a secondary phase, patients are less likely to accept or undergo additional procedures, even when they could benefit from an implant-supported prosthesis (Flores-Ruiz et al., 2018;Schoen et al., 2007). Implants can also be placed during tumor surgery (primary implant placement) (Schoen, Reintsema, Raghoebar, Vissink, & Roodenburg, 2004). An advantage of this treatment sequence is that most of the osseointegration takes place during the recovery phase, saving the burden of additional surgery and a considerable amount of time. The patient can function with an implant-supported prosthesis much earlier after completion of oncologic treatment (Petrovic et al., 2018).
Disadvantages are possibly improper placement of implants due to the changed anatomy during surgery or the risk of implants not being used because of tumor recurrence or patients passing away before a prosthesis can be made (loss of resources). The effects of radiotherapy on the osseointegration process and implant survival rates are also subject of debate (Chrcanovic, Albrektsson, & Wennerberg, 2016), and primary implant placement is not always available in the hospital setting (Shugaa-Addin, Al-Shamiri, Al-Maweri, & Tarakji, 2016;Tanaka, Chan, Tindle, MacEachern, & Oh, 2013).
Guidelines when to ideally start oral rehabilitation with dental implants in oral cancer patients are lacking. Several systematic reviews have been published, mainly dealing with timing of secondary implant placement after radiotherapy (Claudy et al., 2013;Filho, Souza, & Santos, 2015;Granström, 2003;Nooh, 2013;Schiegnitz, Al-Nawas, Kämmerer, & Grötz, 2014). Claudy et al. (2013) reported that dental implant placement between 6 and 12 months after radiotherapy was associated with a 34% higher risk of failure and therefore suggest waiting periods over 1 year after radiotherapy. On the contrary, it has been suggested that implant placement just becomes more critical over time because of the ongoing progressive decrease in healing capacity of bone after radiotherapy (Granström, 2003;Granström, Bergström, Tjellström, & Brånemark, 1994 41 full-text arƟcles assessed for 26 arƟcles excluded due to: eligibility -reviews: n = 6 -no details on implant therapy: n = 1 -arƟcle on transmandibular implant: n = 1 -animal study: n = 1 -also included benign lesions: n = 8 -also included craniofacial implants: n = 2 -same populaƟon as another Included study: n = 3 -case reports/series: n = 4 AŌer updaƟng the search, 1 addiƟonal arƟcle idenƟfied 16 arƟcles included significant relationship between time interval and dental implant survival rates (Nooh, 2013;Filho et al., 2015). The implant survival rate in patients with a history of radiotherapy seems to be more associated with the location of the implants (more implant loss in the maxilla than in the mandible) than with the time after radiotherapy (Buddula et al., 2012). Far less studies on primary implant placement have been published. A systematic review by Barber, Butterworth, and Rogers (2011) on primary implant placement provides an extensive literature overview, but no clear conclusions or recommendations were made.
The latter systematic review also included case reports and studies on patients with benign lesions, which could have influenced the outcome. The authors of another systematic review highlighted the importance of timing of implant placement and concluded that they could not extract scientific evidence for the optimal timing of implant placement (Shugaa-Addin et al., 2016).
Before being able to propose guidelines for optimal timing of implant placement in head and neck cancer patients needing radiotherapy, the following questions have to be answered: (a) what is the optimal timing of dental implant placement in oral cancer patients with regard to implant survival and functional outcomes, and (b) can all oral cancer patients benefit from primary placement or is this method of treatment only suitable for specific patient groups. As implant treatment and techniques have evolved during the last decade, we comprehensively reviewed the literature on the timing of implant placement in oral cancer patients to compose recommendations for clinical practice with regard to optimal timing of implant placement in this category of patients.  (Table S1). The titles and abstracts from all the searches were reviewed.

| ME THODS
Inclusion criteria were studies published in English regarding primary or secondary implant placement in oral cancer patients, cohort studies, case-control studies, (randomized) controlled trials. Review articles, animal studies, case reports, case series with <10 patients, and studies regarding extra-oral craniofacial implants were excluded.
When it was not clear from the title and abstract if the paper dealt with implant placement in the upcoming irradiated (primary implant placement) or already irradiated (secondary implant placement) mandible or maxilla, the full text was reviewed and the article was included or excluded. Forty-one full-text articles were assessed followed by exclusion of 26 articles due to various reasons ( Figure 2). Furthermore, hand searches of the references of retrieved articles were carried out.
The search was updated on December 27, 2019, and one additional article was included. Eventually, 16 studies were included.

| Data extraction
The following data were collected from the studies: patient demographics (age, oncologic diagnosis, patients' dental status before treatment), type of oncological treatment, timing of endosseous or zygomatic implant placement (primary, secondary), implant system, site of implant placement, type of tissue implants were inserted into (native or augmented bone), time until loading, implant loss, implant survival ratios, complications, perioperative measurements, type of prosthesis, and follow-up period (Tables 1-3). When available, the time span between (implant) surgery and prosthesis placement, and the time between radiotherapy and secondary implant placement were recorded.

| Statistical analysis
Quantitative data-synthesis was performed for the studies reporting 5-year dental implant survival rates of primary placed implants and secondary placed implants. Studies which did not report on the 5-year implant survival rate were not included in the quantitative analysis. The pooled 5-year implant survival rates were analyzed using a random effects model. Analyses were performed with Comprehensive Meta-Analysis software, Version 3 (CMA; Biostat).

| Implant survival
The pooled 5-year survival rate for primary placed implants was 92.8% (95% CI: 87.1%-98.5%) (Figure 3), while the pooled implant survival rate for secondary placed implants was 86.4% (95% CI: 77.0%-95.8%) ( Figure 4). The 5-year implant survival rate of primary placed implants tended to be higher compared to secondary placed implants. Survival ratios for dental implants placed in vascularized bone grafts varied between 54% and 93.8% ( Table 2). The implants in vascularized bone grafts were placed in a secondary procedure. Implant survival ratios in native maxillary bone ranged between 57.1% and 95.3%. One study focused mainly on zygomatic implants (Butterworth, 2019) and reported a 5-year implant survival rate of 92%.

| Time between ablative surgery, implant placement, radiotherapy, and prosthesis placement
In two studies on primary implant placement, a healing period of 6 months after radiotherapy was applied before second-stage surgery (Korfage et al., 2014;Seikaly et al., 2019). In another study, a waiting period of 9 months was applied (Schepers et al., 2006). Time from tumor surgery and implant placement until prosthesis placement from three studies varied from 6.3 to 21.4 months (Korfage et al., 2014;Mizbah et al., 2013;Seikaly et al., 2019).
In the secondary setting, there was a preference for waiting at least six months after completing radiotherapy before starting implant treatment. Some studies even preferred to wait at least 1 year (Mizbah et al., 2013;Wetzels et al., 2016). Generally, patients had to wait more than 1 year after oncologic treatment before the oral For zygomatic implants, there was also a difference between primary and secondary placed implants (median time until loading 1.7 months vs. 9.3 months) (Butterworth, 2019). Korfage et al. (2014)

TA B L E 2 (Continued)
| without a prosthesis (Korfage et al., 2014). A more objective method for measuring oral function was applied in the study by Wetzels et al. (2016) by determining masticatory performance. The authors showed an increased masticatory performance in all patients with implantsupported prostheses, supporting the assumption that implants are beneficial for improved oral function in oral cancer patients.

| Complications
Intra   (Butterworth, 2019). An explanation for these favorable outcomes could be that zygomatic implants are inserted in highly cortical bone of the zygoma, leading to a high initial stability. Because of their length, these implants may also be situated outside of the radiated field, therefore avoiding toxic radiation dosages. At this moment, functional results for zygomatic implants seem good and complication rates low, but guidelines on the optimal workflow are not yet available (Hackett, El-Wazani, & Butterworth, 2020).

| D ISCUSS I ON
A great advantage of primary implant placement is the earlier prosthetic rehabilitation after tumor surgery. The latter is a great asset, also because it is not uncommon that head and neck cancer patients refuse the burden of undergoing the secondary implant placement, notwithstanding the great advantage they could experience from an implant-supported oral rehabilitation (Schoen et al., 2007).
The costs and potential "loss of resources" from implants not being used are an important issue in primary implant placement. The percentage of incorrect placed implants varied between the studies.
We believe that with the help of 3D technology, implant positioning (especially in difficult cases) can be further improved as has already been demonstrated in small groups for primary implant placement (Chuka et al., 2017). Placing implants during ablative surgery slightly lengthens the operating time, but the extra costs and burden to the patient of an additional secondary implant procedure under local anesthesia are prevented.
As stated earlier, precision of implant placement can be improved further with 3D technologies or surgical design and simulation (SDS). In both primary and secondary implant placement, 3D planning software can be used to assess the amount of available bone height and width for dental implants after resection and to assess the ideal location for the implants from a prosthetic point of view (Witjes, Schepers, & Kraeima, 2018). The use of SDS has resulted in a high percentage of implant utilization (96%) for mandibular defects constructed with fibula free flaps (Seikaly et al., 2019).
We therefore consider the availability of 3D planning techniques a necessity in the reconstruction of oral cancer patients with complex (continuity) defects.
Only one study on primary implant placement in osseous free flaps for larger defects was considered eligible for our review (Seikaly et al., 2019). In this prospectively conducted study, dental implants were placed in bone grafts (mainly fibula grafts) during the ablative procedure. This resulted in a significant reduction of time to  Dental implants are more successful in the mandible than in the maxilla. No difference in survival rates between patients who received HBO and who did not. The restoration of oral function in radiotherapy patients with tumor resection using implant-supported prostheses is a viable treatment option Not reported Implant therapy can be considered in irradiated patients when from an oncologic standpoint the tumor prognosis is benign and the risk of recurrence is poor. Higher implant success rates in the mandible and in irradiated implant sites with a dosage no more than 40−50 Gy Technical complications: Replacement of 11 bar-retained dentures. 2 patients with mucosa ulcers after loss of retention of the removable denture. 3 patients with dehiscence and disturbed wound healing The mean 10.3-year survival rate was low, and there was no statistically significant difference in implant survival between irradiated and non-irradiated patients. The increased failure rate was caused by the higher mortality rate of the patients; it was not the result of lack of osseointegration. There was no difference between implant survival in grafted and non-grafted patients There is a strong indication of superior bite force and masticatory performance after 5 years in primary group when compared to postponed placement. It seems that primary placement is superior to secondary placement (Continues) challenging as reviewed by Bodard, Salino, Bemer, Lucas, and Breton (2011). One way of partially reducing these challenges is through the use of occlusion-driven reconstructions aided by 3D planning, as is demonstrated in the article of Seikaly et al. (2019). However, the essential difference in tissues covering the grafted bone of the fibula and native mandibular bone remains.  (Chang et al., 1997;Patel et al., 2019).
In our clinic, we prefer to place dental implants as much as possible in the remaining native mandibular bone (during ablative surgery) in order not to jeopardize the vitality of the vascularized fibula flap.
As mechanical stability comes from the more anterior region of the mandible, this approach is successful in lateral and antero-lateral defects.
Limitations of this scoping review include, as stated earlier, the retrospective study designs, heterogeneous patient populations, exclusion of non-English papers, the use of one database, and the fact that screening by carried out by assessor. These factors could result in bias. Due to the unavailability of large prospective studies on the timing of implant placement in oral cancer patients, the treatment of choice will mainly depend on surgeon experience and preference.
However, based on the findings in the current study and our own experience in treating these patients, we composed treatment recommendations on the timing of implant placement in patients with malignant intraoral tumors ( Figure 5). We realize that these recommendations may not be applicable to all hospital settings as 3D planning software and the financial resources for primary implant placement may not be available in every center.

| CON CLUS ION
Based on the studies included in this review, as far as the timing of implant placement is regarded, we propose to routinely combine tumor surgery with implant placement in native mandibular bone as standard care (primary implant placement). The functional benefits of primary implant placement outweigh the risk of leaving (some) implants unused. For more complex reconstructive cases, a personalized treatment approach (aided by 3D technologies) is necessary and is more often in need of a secondary implant placement. It seems that primary placement of zygomatic implants is accompanied by a high implant survival and good oral rehabilitation although more research is needed on this particular topic.

CO N FLI C T O F I NTE R E S T
The authors have stated explicitly that there are no conflicts of interest in connection with this article. contributed to the analysis of the results. All authors discussed the results and contributed to the final manuscript at all stages.

Complications Overall conclusion
Not reported Using primary placement, more patients benefit and receive their overdentures at an earlier stages (20 months earlier) compared to secondary placement 5 patients with ORN in proximity to the implants. Pathological mandible fracture in 1 patient with a recurrent tumor and ORN More limitations in oral function and less satisfaction in irradiated patients. Better oral function with than without prosthesis. A large number of patients with oral cancer in whom implants are inserted during resection may benefit at an early stage from an overdenture and develop good function, satisfaction. Primary insertion should be routinely incorporated into surgical planning. More implant loss in irradiated patients -thinning of the overlying soŌ Ɵssues might be needed as a secondary treatment during second-stage surgery.
-apply 3D planning techniques when available for both primary and secondary implant placement.
-consider hyperbaric oxygen therapy in cases of treatment in irradiated Ɵssues.