REFEREED SCIENTIFIC ARTICLE

South African Dental Journal, 53, 469-471. 

A review of the Marx protocols: prevention and management of osteoradionecrosis by combining surgery and hyperbaric oxygen therapy

FJ Cronje, MBChB (Pretoria), BSc (Hons), AEROSP. Med, CHT

Institute for Aviation Medicine, Hyperbaric Oxygen Therapy Department, Pretoria

INTRODUCTION 

Advances in surgery and radiotherapy in head and neck malignancies have resulted in a significant improvement in the rate of survival. Unfortunately, this often leaves an aftermath of severe facial disfigurement and oral incontinence. Reconstructive efforts in an irradiated field are frequently complicated by wound dehiscence and infection so that ultimately, many patients become social outcasts. ln addition 5 to 10 percent of patients that have received high doses of therapeutic radiation develop osteoradionecrosis,s (ORN) over the ensuing years – either spontaneously or as a result of simple tooth extraction in the irradiated jaw. The cost of managing osteoradionecrosis is staggering in addition to often being unsuccessful. Many patients with ORN, due to ongoing suffering from intractable, inoperable pain and malnutrition, eventually also succumb to substance abuse and drug dependence. 

Various protocols have been suggested for the management of this notorious disorder and have met with variable and often inconsistent outcomes (Marx, 1983a). Dr. Robert Marx, a maxillofacial surgeon at Miami University has researched the field of radiation tissue damage and osteoradionecrosis extensively and has treated in excess of 400 patients with this disorder over the past 20 years. His protocols for combining hyperbaric oxygen therapy (HBO) and surgery in the prevention and management of osteoradionecrosis have become the standard of care (Marx, Johnson, and Kline, 1985). 

IRRADIATION TISSUE DAMAGE 

Since 1983 the pathophysiology of the irradiated wound has been better defined (Marx, 1983a). It is now understood to be a sequence of events the following radiation: a gradual and progressive obliterative endarteritis and cellular dysfunction lead o a hypoxic, hypovascular, and hypocellular (3-H) tissue (Marx, 1983a, 1983b, 1988, 1994). This issue is vulnerable and may eventually undergo spontaneous breakdown due to an imbalance between cell death and collagen lysis versus cell replacement and collagen formation. The end result is a non-healing wound in which the metabolic demands for healing and homeostasis exceed the oxygen and vascular supply (Marx, 1983a: Johnson. Marx and Buckley,1992). Hyperbaric oxygen therapy (HBO) has demonstrated a unique ability to reverse some of the cellular changes and restore micro-vascular density to within 75-85 percent of normal (Marx, 1990). This restores the tissue’s ability to heal and affords the clinician with surgical, dental, and reconstructive options that would otherwise be impossible or unpredictable (Johnson, Marx, and Buckley, 1992). Although the overall incidence of ORN is low, the risk multiplies whenever surgical wounding occurs within 21 days of commencing radiotherapy or after 4 months following radiotherapy. The threshold radiation dose above which the risk for ORN increases dramatically is 60 grays (Johnson Marx and Buckley, 1992). The gray (Gy) is the amount of absorbed radiation in any tissue and applies to all types of radiation. For practical purposes, 1000 rads (R) is equal to 10 gray.

PREVENTION OF OSTEORADIONECROSIS (20/1 0 PROTOCOL) 

All patients that have received > 60 Gy to the jaw are at risk of eventually developing ORN (Marx. 1983a, 1983b, 1988, 1990, 1994; Johnson et al 1992). Due to the unique nature of the radiated wound, it never heals or revascularizes normally and is at risk for spontaneous or trauma-induced breakdown (Marx, 1983b). Three types of osteoradionecrosis have been identified (Marx, 1983b, 1988; Marx et al, 1995): 

1. Type 1 ORN occurs when the time between a dental or an extirpative surgical procedure and radiotherapy is too short. Typically this involves radiotherapy within 21 days of tooth extraction or mandible lobotomy. The risk of developing ORN is very high if radiotherapy is commenced within 14 days of surgery. If at all possible mandibulotomies should also be planned outside the irradiated field. Tooth extraction during radiotherapy must be avoided at all costs. Within the first 4 months following radiotherapy – the so-called golden period, healing usually occurs normally. Dentectomies and other surgical procedures can usually be performed without complications and HBO is not required in the prevention of ORN within this period. HBO is not routinely indicated in the management of acute radionecrosis or radiation burns.
2. Type 2 ORN is trauma induced. It mainly occurs three to six years after radiotherapy typically following the extraction of a tooth. 
3. Type 3 ORN occurs spontaneously the following radiotherapy. It is associated with higher radiotherapy doses, neutron beam therapy, or brachytherapy and occurs six months to two years after radiotherapy.

The overall incidence of ORN in irradiated patients is low (5-10 percent). However, in patients who have received > 60 Gy and require surgery or tooth extractions, it is high; 89 percent of all trauma-induced ORN occurs secondary to tooth removal in the period 6 months to 3 years following radiotherapy. 

In a study by Marx et al (1990), 7 4 patients requiring discectomies with an average dose of 72 Gy were randomized in two groups: The first group received 20 HBO treatments before extraction and 10 HBO treatments thereafter. In this group, the incidence of ORN after six months was 5, 4 percent (n=2). In the nonHBO (penicillin) group the incidence was 29,9 percent (p=0,005). However, 8 of the 11 patients in the nonHBO group that developed ORN required jaw resections. Neither of the two HBO patients required resections, indicating that even where ORN did occur after HBO, it was less severe and could be treated by simpler and less expensive means than where HBO was not given. 

If more than 4 months have elapsed since the last course of radiotherapy, 20 daily HBO treatments should be given before performing any surgery in an irradiated field, including discectomies (Marx, 1983a, 1994; Johnson et al, 1992). Pre-surgical HBO treatment reverses the vascular changes of radiotherapy and restores vascular density to between 75-85 percent of normal after 18 to 23 treatments. After surgical wounding, an additional 10 treatments of HBO are recommended to ensure uncomplicated healing. This protocol has become the standard of care since 1985 in the US. Although this approach may seem expensive, the cost of managing ORN (once established) is infinitely greater and frequently unsuccessful. 

The prognosis of mandibular reconstruction in an irradiated field has improved from a 40-50 percent chance of success without HBO to a 90-93 percent chance with the 20/10 protocol (Marx, 1994). 

Free microvascular flaps that are brought into an irradiated field, although independent in their own blood supply, must still heal into the Irradiated tissue. Eventually, many flaps are lost when this does not occur. In a detailed randomized, prospective study by Marx – looking at wound dehiscence, infection, and delayed healing in 160 patients with soft tissue reconstruction using vascularised flaps in an irradiated field (>64 Gy), the following results were obtained (Marx, 1994 ): incidence of dehiscence 11 percent (HBO) versus 48 percent (Non-HBO) p= 0,001; infections: 6 percent versus 24 percent; delayed healing: 11 percent versus 55 percent. Delay in healing was measured as extended hospitalization required specifically by the non-healing irradiated wound. 

Osseointegrated implants present two problems when inserted in irradiated bone: failure to integrate and precipitation of ORN. By using the 20/10 protocol in conjunction with implant insertion, the success rate of integration has been 83-86 percent (compared to 94 percent in normal bone) with no precipitation of ORN (Marx, 1994). 

Summary

The 20/1 O protocol is of great benefit in the prevention of ORN or soft tissue necrosis to all patients undergoing surgical procedures in a > 60 Gy irradiated field after 4 to 6 months of completing the radiotherapy. If possible, surgical procedures to the mandible should also be avoided within 21 days of commencing radiotherapy. 

MANAGEMENT OF OSTEORADIONECROSIS (30/10 PROTOCOL) 

Once radiological osteolytic changes are visible or alveolar bone has remained exposed for more than 6 months in an irradiated field, the clinical diagnosis of osteoradionecrosis can be made (Marx, 1983a, 1994). ORN, is not osteomyelitis. In a study by Marx in 1983, comparing cultures from mandibular ORN and osteomyelitis patients, he clearly demonstrated that ORN was a radiation osteomyelitis as previously conceived (Marx. 1983b). 

The only cost-effective way to manage ORN is to eradicate the disease. This means that all necrotic bone has to be removed. As the trauma of debridement and sequestrectomy may lead to further propagation of the necrosis, pre-HBO surgery in an irradiated mandible 1s contra-indicated. All patients should receive 30 daily sessions of hyperbaric oxygen therapy (5 days a week) before any surgery is performed. This preserves and improves the vascularity of any viable bone adjacent to the ORN before debridement or resection. Early surgery before HBO reduces the chances of resolving the disease 1n a milder form (earlier stage) Pre-operative HBO will also better define the margin between necrotic and healthy bleeding (viable) bone intra-operatively (Marx. 1994; Johnson et al, 1992). The final 1 O HBO treatments ensures that the viable bone remains viable postoperatively and also support the primary closure of the gingiva after debridement or resection, thereby preventing complications of inf ect1on or dehiscence. 

As the clinical presentation of ORN may range from slight radiological osteolytic changes to a pathological fracture or percutaneous fistula, it is important to carefully plan the type of surgery that will be required in combination with HBO to provide the best, most cost-effective, and predictable results. To achieve his goal, Marx proposed a system of staging the disease to better define the surgical management of ORN.

Staging

The Staging is done to optimize the type of surgical intervention required, depending on the severity of the disease. Staging is dynamic (i.e. patients not responding to Stage 1 are advanced/reclassified to Stage 2 or Stage 3) and is based on the following selection criteria (Marx, 1988, 1994; Johnson et al, 1992): All patients are initially entered as Stage 1. Exceptions to this are patients with percutaneous fistulae, pathological fractures through the mandible, or those with resorption/osteolysis of the inferior border of the mandible who are managed as Stage 3, i.e. discontinuity resection of the mandible (see below). 

Stage 1

The Stage 1 ORN usually presents with mild or no osteolytic changes and exposed alveolar bone. Antibiotics are not usually required but may be administered when there is evidence of soft tissue infection. No surgery is performed other than irrigation and removal of bone fragments. After 30 treatments the tissue is reassessed. If the bone has softened and there are good signs of granulation tissue. the patient is classified as a Stage 1 responder. These patients require no or only minimal surgery after which they receive the final 10 HBO treatments. If the exposed bone does not respond, the patient is classified as a Stage 1 non-responder and advanced to Stage 2. Fifteen percent of patients with ORN resolve as Stage 1.

Stage 2

The Stage 2 ORN patients (or Stage 1 non-responders) will already have received the initial 30 HBO treatments. They differ from Stage 1 ORN in that the extent of the disease is greater and requires more aggressive transoral surgery, sequestrectomy, or partial resection of the mandible. Stage 2 treatment still maintains the continuity of the mandible. Fifteen percent of patients with ORN resolve as Stage 2 (Marx, 1994; Johnson et al, 1992).

Stage 3 

The Stage 3 ORN patients are those failing Stage 2 management or those admitted with percutaneous fistulae, pathological fractures, or evidence of resorption or osteolysis of the inferior border of the mandible. These patients require a discontinuity resection of the mandible back to bleeding bone and bleeding soft tissue {Johnson et al, 1992). After the resection, maxillo-mandibular relationships need to be maintained by one of two methods. Ideally, the Joe-Hall-Morris pin fixation should be used as suggested by Marx (1994) or maxillo-mandibular wiring may be used. Rigid internal fixation plates must not be used or be used very cautiously as exposure of the plates frequently occurs. Intra-operatively the soft tissue may be reconstructed (if resection has created a defect) by way of a free vascular transfer or my cutaneous flap if there is no overt infection (Marx, 1994). The pectoralis major cutaneous flap is the one that has provided consistently the best results in Marx’s experience (Marx, 1988, 1994; Johnson et al, 1992). Following resection and/or soft tissue reconstruction, the last 10 HBO treatments are given to complete the 30/10 protocol. Patients requiring bony reconstruction are usually grafted at three months post-resection (Marx, 1994; Johnson et al, 1992). Allogenous split rib or hollowed-out mandible, packed with densely packed autologous cancellous bone, has proven to be the most effective in Marx’s experience (Marx, 1983a; Marx and Kline, 1983; Johnson et al, 1992). Such graft procedures may be provided without further HBO as the angiogenesis and fibroplasia are long-lasting and need not be reinforced (Marx, 1990). If there are intra-operative complications or the quality of the recipient bed seems inadequate, a further 10 hyperbaric treatments may be given. Sixty-four percent of patients resolve as Stage 3.

Summary 

The 30/1 O protocol is employed in the treatment of established osteoradionecrosis. No surgery should be attempted before the first 30 HBO treatments have provided sufficient angiogenesis to support surgical wounding. After 30 treatments surgical management can be staged according to the extent of improvement achieved after HBO and the size of the sequestrum or area of osteolysis. If the ORN extends to the inferior border of the mandible or if it manifests as a percutaneous fistula or pathological fracture, discontinuity resection of the necrotic bone and soft tissue will be required to resolve the disease. Unless HBO and surgery are combined in the management of ORN, the results are not long-lasting or satisfactory. Even though the resection of stage three ORN seems unduly aggressive, it has stood the test of time. By using the Marx protocols in the treatment of ORN, more than 95 percent of patients can be successfully cured of their disease with predictable, functional, and aesthetically acceptable outcomes.

REFERENCES

• Johnson. RP, Marx. RE & Buckley SB (1992) Hyperbaric Oxygen in oral and Maxillofac Surgery In Controversies in Oral and Maxillofacial Surgery. Worthington P & Evans JR (Eds). London: WB Saunders Co. pp. 107-126
• Marx, RE, (1983a) A new concept in the treatment of osteoradionecrosis. Journal of Oral Maxillofacial Surgery. 41, 351-357
• Marx. RE. (1983b) Osteoradionecrosis: A new concept in, its pathophysiology, Journal of Oral Maxillofacial Surgery. 41, 283-288
• Marx. RE & Kine SN (1983) Principles and methods of osseous reconstruction. In International Advances m Surgical Oncology. AP Murphy (Ed). 167-228. New York: Alan R Liss Inc. 
• Marx. RE (1988) Problem wounds in oral and maxillofacial surgery. In: Problems Wounds The Role Of Oxygen. JC Davis & TK Hunt (Eds) The role of hyperbaric oxygen. New York: Elsevier Science Publication Co. 4, 65-123 
• Marx, RE. Ehler. WJ. Tayapongsak. PT. & Pierce. LW, (1990) Aelat10nsh1p of oxygen dose to angiogenesis Induction in the irradiated and tissue deficient patient. American Journal of Surgery, 160. 519-524
• Marx, RE. Johnson. AP. & Kine. SN (1985). Prevention of osteoradionecrosis: A randomized prospective clinical trial of hyperbaric oxygen versus penicillin. Journal of the American Dental Association, 111, 49-54
• Marx, RE (1994) Radiation injury to tissue. In: Hyperbaric Medicine Practice. EP K1ndWall (Ed.) Flagstaff. Best Publishing Co. pp.448-503.  

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