Abstract
Solitary plasmocytoma occurring in bone (solitary plasmocytoma of the bone, SBP) or in soft tissue (extramedullary plasmocytoma, EP) can be treated effectively and with little toxicity by local radiotherapy. Ten-year local control rates of up to 90% can be achieved. Patients with multiple myeloma often suffer from symptoms such as pain or neurological impairments that are amenable to palliative radiotherapy. In a palliative setting, short treatment schedules and lower radiation doses are used to reduce toxicity and duration of hospitalization. In future, low-dose total body irradiation (TBI) may play a role in a potentially curative regimen with nonmyeloablative conditioning followed by allogenic peripheral blood stem cell transplantation.
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1 Solitary Plasmocytoma
Solitary plasmocytoma are rare neoplasms originating from plasma cells in bone (solitary plasmocytoma of the bone, SBP) or in soft tissue (extramedullary plasmocytoma, EP). SBP comprise about 10% of plasma cell neoplasms and are mainly found in the axial skeleton (Holland et al. 1992), while EP are even more rare (about 3%) with most manifestations in the head-and-neck region (Bachar et al. 2008). Patients typically present with symptoms caused by local tumor mass: pain and neurological deficits in the case of SBP; dysphagia, breathing problems, and epistaxis in the case of EP. Both SBP and EP can be treated effectively and with little toxicity by local radiotherapy (Kumar 2008; Michalaki et al. 2003).
1.1 Diagnostic Workup
Before starting local treatment of solitary plasmocytoma, thorough diagnostic workup is essential to rule out occult multiple myeloma, as patients having already progressed to multiple myeloma may require systemic treatment. Most authors define solitary plasmocytoma as one single, histologically confirmed lesion with normal bone marrow biopsy (<10% plasma cells), negative skeletal survey on plain film, normal blood count, normal serum calcium, and normal renal function (Tsang et al. 2001). The addition of whole-body MRI scans to diagnostic schedules may increase the sensitivity to detect multiple myeloma in up to 25% of patients initially considered to have solitary plasmocytoma (Wilder et al. 2002). In addition, MRI is helpful for definition of treatment volumes by clear delineation of soft tissue masses.
1.2 Radiotherapy of SBP
Concerning the definition of clinical target volumes of SBP, there is still ongoing debate whether the whole bone marrow of affected bones should be included. In the case of vertebral bodies, most authors recommend the inclusion of the affected bone and the two neighboring vertebral bodies (Tsang et al. 2001). If long bones are affected, some groups define clinical target volumes as radiographically visible mass surrounded by a 2–5 cm margin (Jyothirmayi et al. 1997; Ozsahin et al. 2006; Wilder et al. 2002) and achieve excellent local control rates. However, in a small retrospective series, Mayr et al. (1990) reported local relapse in three out of five patients with only partial bone irradiation compared to 100% local control in 12 patients with treatment of the whole bone. Unaffected regional lymph nodes were not included in the target volume. As to radiation doses, most authors recommend application of 40–50 Gy in 1.8–2.0 Gy fractions (Bolek et al. 1996; Holland et al. 1992; Kumar 2008) based on observations of Mendenhall et al. (1980) that doses >40 Gy resulted in local control rates of 94% compared to 69% after <40 Gy.
All studies reported excellent local control of SBP with 10-year local control rates of up to 90% (Liebross et al. 1998; Wilder et al. 2002). Tumor remission after radiotherapy was achieved after 3–5 months (Jyothirmayi et al. 1997). Interestingly, persistence of tumor mass after therapy had no influence on survival rates (Bolek et al. 1996). Local failure inside or outside the radiation field rarely occurred, and very few patients developed solitary lesions in other locations (Frassica et al. 1989). However, overall survival was diminished severely by a high rate of progression to multiple myeloma: About half the patients developed multiple myeloma after 1–3 years (Bolek et al. 1996; Holland et al. 1992) resulting in 5-year overall survival ranging from 32% (Bolek et al. 1996) to 74% (Frassica et al. 1989). Most studies observed a 10-year disease-free survival of about 25% (Frassica et al. 1989; Ozsahin et al. 2006). Given the high probability of systemic disease development, a small prospective study by Aviles et al. (1996) achieved much lower progression rates of 12% in patients treated with radiotherapy followed by administration of low-dose prednisone/melphalan over 3 years compared to 54% progression to myeloma in patients treated with radiotherapy alone. However, the question of adjuvant chemotherapy remains to be addressed by larger prospective studies.
1.3 Radiotherapy of EP
For radiation therapy of EP, especially in the head-and-neck region, most authors followed guidelines for squamous cell carcinoma in that location for definition of target volumes and radiation doses. Most groups applied doses of 40–60 Gy in 1.8–2.0 Gy fractions (Creach et al. 2009; Michalaki et al. 2003). Tournier-Rangeard et al. (2006) found a much better local control with doses to the target volume >45 Gy than with <45 Gy (100% vs. 50% 5-year local control rate) and even recommended a 10 Gy boost in case of bulky disease if toxicity is tolerable. For EP of nasal cavity or paranasal sinuses, three portal fields were used (one anterior and two lateral wedged fields), EP of nasopharynx, oropharynx, or hypopharynx were usually treated with two laterally opposing fields (Chao et al. 2005; Liebross et al. 1999). In recent years, more complex techniques have evolved that provide a better protection of uninvolved tissues with a high susceptibility to radiation such as the parotid or submandibular gland: Intensity-modulated radiotherapy (IMRT) with up to nine or more photon beams allows the formation of individually shaped treatment volumes.
Concerning the question whether unaffected cervical lymph nodes should be treated (elective neck irradiation, ENI), discussion is still ongoing. Some authors observed recurrences in cervical nodes in up to 30% of patients with untreated cervical lymph nodes and thus recommended ENI, at least for high-risk locations such as oral cavity, naso- and oropharynx and larynx and for bulky tumors (Chao et al. 2005; Liebross et al. 1999; Mayr et al. 1990; Tournier-Rangeard et al. 2006). Others finding recurrence rates in local lymph nodes of <4% advised against the application of ENI in order to reduce long-term toxicity (Chao et al. 2005; Jyothirmayi et al. 1997; Susnerwala et al. 1997).
EP can be controlled locally by radiotherapy in a similarly effective fashion as SBP: 5-year local control rates 72–100% were reported for EP (Liebross et al. 1999; Tournier-Rangeard et al. 2006). However, most studies observed a better overall survival for EP patients of 76% after 5 years (Bachar et al. 2008; Ozsahin et al. 2006) and 54–72% after 10 years (Chao et al. 2005; Ozsahin et al. 2006). Ten-year disease-free survival rates ranged from 55% to 75% (Chao et al. 2005; Ozsahin et al. 2006; Tournier-Rangeard et al. 2006). Concerning progression to multiple myeloma, EP patients seemed to have lower conversion rates of 10–32% after 10 years compared to SBP patients (Bachar et al. 2008; Bolek et al. 1996; Kumar 2008; Liebross et al. 1999).
1.4 Treatment Toxicity
Very little data can be found in literature addressing treatment toxicity, probably because of small patient numbers and a variety of different locations. Creach et al. (2009) described toxicity in 18 patients treated for EP in the head-and-neck region (10 patients received an additional irradiation of cervical lymph nodes): 10 of 18 patients reported xerostomia, 5 complained of nose bleedings. Other side effects were nasal obstruction, larynx edema, dysfunction of the lacrimal canal, hypothyreosis, problems related to the paranasal sinuses and Lhermitte’s sign, each occuring in one patient. In this small group of patients, two developed a secondary malignoma: one patient suffered from a myxoid fibrous histiocytoma in the radiation field 6.5 years after radiotherapy, another developed a malignant brain tumor after 6.9 years. The reason for this unusually high rate of secondary malginoma remains unclear.
2 Palliative Treatment of Multiple Myeloma
In spite of considerable progress in the treatment of multiple myeloma, the disease still is not curable. Thus, effective palliation is an important issue in treatment concepts. Local radiotherapy is used in the palliative treatment of the most frequent symptoms of multiple myeloma: Reduction of pain due to osseous or soft tissue masses, prevention or additive treatment of bone fractures, and reduction of neurological symptoms due to spinal compression.
2.1 Pain Control
Local pain caused by irritation of spinal nerves or spinal cord is often the first and the most common symptom in patients with multiple myeloma, occurring in 55–90% of patients (Plasswilm and Belka 2004; Mose et al. 2000). Local radiotherapy has been an important part in the palliative treatment of painful spinal masses for a long time: A study published in 1975 (Mill 1975) reported the palliation of pain by local radiotherapy in 81% of 65 patients presenting with multiple myeloma. Over time, many groups achieved similar results (Rostom 1988; Yaneva et al. 2006). A complete elimination of pain could not be achieved in all patients, but most profited from radiotherapy by a reduction of their symptoms. Mose et al. (2000) reported complete elimination of pain in 34.4% of 71 treated volumes and partial analgesia in 50.7%.
The irradiated volume usually contained the whole affected bone, in the case of vertebral manifestations including the neighboring vertebral bodies, in order to prevent spreading via the dorsal venous vascular plexus connecting neighboring vertebral bodies (Wilkowski et al. 2002). However, Catell et al. (1998) have shown that in the case of long bones, effective pain reduction is possible by irradiation of only part of the respective bone. Planning should be based on CT scans for better evaluation of pasaosseous soft tissue masses (Wilkowski et al. 2002). Various techniques are applied for irradiation: In most cases, photon beams are used for treatment of bone lesions in a single-field or multi-field technique. Electron beams (with the maximum radiation dose occurring near the body surface) are used for treating superficial lesions (e.g., treatment of the rib cage or sternum).
Wilkowski et al. (2002) reported significant pain reduction by radiation doses as small as 10–15 Gy, but most groups applied higher doses of 25–30 Gy in 10–15 fractions (Bosch and Frias 1988; Leigh et al. 1993). However, hypofractionated irradiation (e.g., 1 × 8 Gy, 4 × 4 Gy, 4 × 5 Gy) was shown to relieve pain in a similarly effective manner (Falkmer et al. 2003).
Pain reduction was in some cases already perceived during radiation therapy but usually started 2–3 weeks after therapy (Plasswilm and Belka 2004). The analgetic effect was described as long-lasting, with relapse rates of 6% after a median of 16 months (Leigh et al. 1993).
A predictive factor for good clinical response was a high Karnofsky performance score of 80–90% (Mose et al. 2000). In addition, the simultaneous application of chemotherapy seemed to enhance the analgetic effect of radiotherapy. Mose et al. could induce pain reduction in 96.3% of patients receiving simultaneous chemotherapy and radiotherapy but only in 77.5% of patients treated with radiotherapy alone. Adamietz and Bottcher (1994) reported local response in 80% of patients under radiochemotherapy compared to 39.6% of patients under radiotherapy alone.
In summary, local radiotherapy has been shown to be an effective tool for pain control in multiple myeloma. However, it had no effect on survival rates (Mose et al. 2000; Yaneva et al. 2006).
2.2 Recalcification
Osseous instability, particularly of vertebral bodies, is another challenge in palliative treatment of multiple myeloma. The pathologically upregulated osteoclastic activity in multiple myeloma patients can be compensated for some time by increased osteoblast function, but in later disease stages, this compensation fails, and osteolytic lesions threaten spinal stability (Hjertner et al. 2006).
Local radiotherapy should be started as soon as possible after diagnosis of an unstable osteolytic lesion, as it has been shown that radiologically unstable lesions without actual fracturation of the bone responded much better to radiotherapy than already fractured bones (Liebross et al. 1998, 1999). Mose et al. could induce recalcification in 47.4% of irradiated bones. In a small series published by Lecouvet et al. (1997), fractures occurred in 5% of irradiated vertebrae compared to 20% of nonirradiated vertebrae. In addition, manifestation rates of new focal lesions could be reduced by spinal radiotherapy.
A comparatively small group of patients (about 10%) present with neurological impairments due to spinal compression. The most common causes for spinal compression are vertebral fractures, however, some patients suffer from weakness of limbs or inability to walk caused by extradural extension of plasmocytoma of an adjacent vertebra or extradural compression without bone disease. The therapeutic approach recommended by most authors is local radiotherapy, preferably after local decompression by laminectomy. Although life expectancy of patients with malignant spinal compression is limited and therefore short-course radiotherapeutic schedules (e.g., 1 × 8 Gy, 5 × 4 Gy) seem a sensible option, it has been shown that long-course schedules (e.g., 10 × 3 Gy) result in much better improvement of motor function. Rades et al. (2006) reported an improvement of motor function in 52% of patients with neurological impairments. Of 70 nonambulatory patients, 47% even regained the ability to walk.
3 Total Body Irradiation (TBI)
Autologous transplantation of peripheral blood stem cells after myeloablative conditioning has been shown to improve long-term survival but cannot achieve long-term cure. Until recently, the standard conditioning regimen comprised total body irradiation (TBI) with a radiation dose of 8 Gy followed by chemotherapy. This concept was changed by the publication of the Intergroupe Francophone du Myélome 9502 trial (Moreau et al. 2002): The authors observed equal event-free survival in patients conditioned with 8 Gy TBI plus melphalan 140 mg/m2 compared to patients treated with melphalan 200 mg/m2. However, toxicity was lower and 45-month survival slightly favorable in the latter group. Thus, TBI lost importance in a potentially curative setting.
In recent years, a new role for TBI in pretransplantation conditioning seems to emerge: Several studies described a potentially curative regimen with nonmyeloablative conditioning with 2 Gy TBI in one single fraction alone or combined with fludarabine followed by allogenic peripheral blood stem cell transplantation (PBST) and immunosuppressive treatment. In this concept, TBI causes a transient immunosuppression and helps to induce a graft-versus-myeloma effect with tolerable graft-versus-host disease (Gerull et al. 2005; Bruno et al. 2009; Georges et al. 2007).
The target volume for TBI are all tumor cells and all lymphatic tissues, so the whole body including the skin must be treated. This requires large radiation fields of up to 210 × 70 cm, compared to the radiation fields of 40 × 40 cm in 1 m distance from focus that conventional linear accelerators usually provide. Radiation Oncology departments developed different techniques for covering such large treatment volumes. One approach is to increase the distance between focus and patients by treating the patient sitting on a special chair and applying laterally opposing fields with a focus distance of 3.5 m.
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Krause, S., Debus, J., Neuhof, D. (2011). Radiotherapy. In: Moehler, T., Goldschmidt, H. (eds) Multiple Myeloma. Recent Results in Cancer Research, vol 183. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-85772-3_13
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