Radiotherapy

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					Radiotherapy
DEBORAH A. FRASSICA AND MARIA C. JACOBS


INTRODUCTION_____________________________________________

Radiotherapy has been utilized in the management of patients with plasma cell
malignancies for much of the twentieth century and continues today. It has been
estimated that radiotherapy will be required for up to 70% of patients with multiple
myeloma at some point in the course of their disease,¹ and it is the primary treatment
modality for patients with solitary extramedullary or bone plasmacytomas. The
radiosensitivity of myeloma has been well established through clinical experience and in
laboratory studies. Using a mouse plasma cell tumor model, Bergsagel estimated the Do
(dose required to produce one natural log of cell kill) to be 1.1 Gray (Gy).² This chapter
will review the current roles of radiotherapy in the palliative management of multiple
myeloma and as part of the conditioning regimens for bone marrow transplant for
multiple myeloma. In addition, the role of radioimmunotherapy will be discussed.


LOCAL RADIOTHERAPY_____________________________________

The primary indications for the use of radiotherapy in multiple myeloma are palliation of
pain, prevention of bone destruction leading to pathologic fracture, prevention or
treatment of neurologic complications of disease, such as nerve-root or spinal cord
compression, and relief of symptoms caused by soft-tissue involvement. External beam
treatment has been the mainstay of radiotherapeutic management. Both wide-field (total
body or hemi-body) and localized field treatment have been utilized. Localized fields are
most commonly used today owing to the low risk acute and late side effects, reduced
effect on bone marrow activity, and ease of administration compared with wide-field
therapy.

        The total dose and fractionation (size and number of daily treatments) utilized for
patients with multiple myeloma will vary based on the intent of treatment and the
patient’s prognosis and performance status. Patients with limited life expectancies and
who require treatment for pain relief may achieve the therapeutic goal with a shorter
course of therapy and a lower total dose. If the goal of treatment is long-term control of a
localized area of myelomatous involvement, more aggressive therapy should be used,
with doses similar to those for patients with solitary plasmacytomas (40-50Gy). The
potential side effects of radiotherapy are related to the total dose, fraction size, volume of
treatment, and the area of the body treated. Organ tolerances are based on the use of
‘standard fractionation’, 1.8-2.0 Gy per fraction administered once daily, five times per
week. When altered fractionation schemes are utilized, the total dose must be adjusted in
order to avoid a higher risk of complications. Generally accepted normal tissue


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tolerances, measured as the total dose in standard fractionation that is associated with a
5% risk of a given complication at 5 years, are shown in Table 15.1.



Palliative treatment for pain relief________________________________

Relatively low doses of radiation have been associated with effective symptom control in
patients with multiple myeloma, but controversy exists as to the optimal dose for
palliative treatment. Numerous groups have reported on their dose-response experiences
and rates of pain relief. Investigators at the Mallinckrodt Institute of Radiology³ recorded
the dose at which subjective pain relief was first reported by patients receiving localized
radiotherapy. The median dose range was between 10 and 15 Gy, with 29 of 34 patients

Table 15.1 Commonly accepted normal tissue tolerances using fractionated ionizing
irradiation (1.8-2.0 Gy/day)

Organ (volume)                        Complication                   Dose (Gy)

Spinal cord                           Myelopathy                     45-50
Brain (partial volume)                Necrosis                       60
Small bowel (large volume)            Chronic enteritis;
                                      Small bowel                    45
Small bowel (limited volume)          obstruction                    54
Kidney (whole organ)                  Renal failure                  20-25
Liver (whole organ)                   Hepatic failure                35
Esophagus                             Stricture, ulcer               60-65
Lung                                  Fibrosis                       20
Bone                                  Necrosis                       60
Bone marrow (partial)                 Fibrosis                       20


reporting pain relief with a dose of 20 Gy. In the same report, complete relief of pain by
completion of therapy was obtained in 21% and partial relief in 70% of 116 patients. The
authors commented that many of the patients with partial relief at completion of therapy
subsequently went on to achieve complete pain relief within the next few weeks. The
total dose most frequently prescribed was between 14 and 20 Gy. Six percent of the
fields treated required retreatment for recurrence of pain. Leigh et al. reviewed the
experience at the University of Arizona. Ninety-seven percent of patients achieved pain
relief with a median dose of 25 Gy. Complete relief was observed in 26% and partial
relief in 71%. No differences in pain relief outcome were noted with doses less than or
greater than 10 Gy (range 3-60 Gy), concurrent use of chemotherapy, or site of treatment.
As in Mill’s report,³ 6% of patients had a local relapse after initial treatment.
Retreatment of areas treated with lower doses of radiotherapy is generally considered
feasible with respect to normal tissue toxicity. The effectiveness of retreatment has,
however, been questioned by Adamietz and co-workers.⁵ They found that the rate of


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complete pain relief decreased with subsequent courses of treatment, with no responses
by the third course.

          In distinction to the lack of benefit with concurrent chemotherapy noted by Leigh
et al. , the Hanover group found an 80% local response rate in patients treated with
melphalan, prednisone, and radiotherapy compared with a 40% response rate in patients
managed with irradiation alone for local symptoms. The duration of response was also
greater in the combined therapy group. Rates of prior use of chemotherapy differed in
these studies, with nearly half of the Hanover patients being chemotherapy-naive and
nearly all of the Arizona patients being heavily pre-treated. One might expect a better
response to initial therapy in chemotherapy-naive compared with treatment of patients
whose disease has become chemoresistant.

       The issue of appropriate field size for localized treatment to long bones was
addressed in a study by Catell et al.⁶ They reviewed the experience at the New York
University Medical Center using fields encompassing the symptomatic lesion plus a 1-2
cm margin. No attempts were made to cover the entire bone, as has been occasionally
advocated. The average dose was 27.8 Gy. Even though the whole bone was not
targeted, the length of the field relative to the bone length was 42% for the femurs treated
and 68% for the humeri. Evidence of symptomatic progressive disease within the same
bone was found in four of 41 long bones treated. In three of the four cases, the
progressive disease was both adjacent to and within the previously irradiated volume.
Symptomatic disease developed exclusively outside the original treatment volume in only
one patient. This suggests that treatment to the symptomatic sites with an appropriate
margin is not associated with a high rate of in-bone failure. Limiting the field sizes may
help to limit marrow toxicity and other side effects of treatment.


Radiotherapeutic management of spinal cord compression___________

Neurologic compromise, such as nerve-root or cord compression, is an important
problem that may occur in patients with myeloma. Six to twenty-four percent of patients
with myeloma have been reported to require treatment for spinal cord compression.³٫⁷⁻¹⁰
Two of the more recent studies⁷٫⁸ have shown a risk of 10-15%. Treatment options
include non-operative therapy with radiation, surgical treatment, and combined modality
therapy. Patients with spinal instability or bone fragments from a compression fracture
causing cord compression are generally offered surgery followed by radiotherapy.
Wallington et al.⁷ reviewed a series of 48 cases of spinal cord compression from
myeloma (24 patients) and lymphoma (24 patients) treated with radiotherapy. Eleven of
the 24 patients with myeloma had surgical decompression prior to initiation of
radiotherapy. They evaluated factors leading to the endpoint of local control, defined as
maintenance of or improvement to a grade 1 neurologic deficit or better without
deterioration for 3 months from the start of radiotherapy. Sixty-three percent of the
patients with myeloma achieved local control. Characteristics associated with a
significantly improved chance of achieving local control on chi-squared analysis included


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age 65 or less, grade 1 or 2 neurologic deficit at presentation (ambulatory with or without
assistance), and biologically equivalent radiation dose of 40 Gy or more.
Benson et al’s 1979 report⁹ also showed an advantage to doses of 40 Gy compared with
lower doses for myeloma patients with cord compression. Surgical decompression prior
to radiotherapy was not associated with improvement in local control. Multivariate
analysis showed grade 3 neurological deficit to be independently significant for duration
of local control. Other studies¹¹⁻¹³ of treatment for spinal cord compression from all
primary tumor types confirm that ambulatory status at presentation is predictive of
outcome. Pain control can be achieved in patients with cord compression regardless of
grade of neurologic deficit at presentation.¹¹

       The long-term effectiveness of spinal radiotherapy for patients presenting with
neurologic symptoms (cord or nerve-root compression) was evaluated in an interesting
report from Belgium.¹⁴ Twelve patients were assessed with serial magnetic resonance
imaging (MRI) scans prior to and following radiotherapy. Fifty-seven vertebral segments
were included in the radiotherapy portals and were compared with 147 vertebrae outside
the fields. All patients received between 30 and 40 Gy in standard fractionation
(2 Gy/day) for neurological symptoms and pain. All of the patients also received
chemotherapy for systemic management. With a mean follow-up of 35 months, new
compression fractures were documented by MRI in 5% of irradiated and 20% of
untreated vertebrae. New focal lesions were found in 4% of irradiated and 27% of
untreated vertebrae. Management of vertebral disease with surgery or cement
vertebroplasty alone may, therefore, be associated with a greater risk of subsequent
disease, requiring additional procedures or radiotherapy. Whether this type of beneficial
long-term effect would be achieved with lower doses of radiation is unknown but worthy
of study. Treating a greater number of vertebral segments at the time of radiotherapy for
symptomatic disease in order to reduce subsequent disease must be balanced with the
effect of treating larger amounts of bone marrow, which could exacerbate hematologic
toxicity.

        Myelomatous involvement of the spine, ribs, or base of skull may cause
neurological dysfunction owing to irritation or compression of nerves or nerve roots.
Patients are more likely to have compressive symptoms when there is a soft-tissue
component of disease. In some situations, progressive bone disease may be treated prior
to development of significant symptoms, if the lesion is in a critical location, such as base
of skull, clivus, or orbit. In order to provide the greatest chance of long-term local
control, doses in the range of 40-45 Gy would be recommended.


Local radiotherapy for bone lesions_______________________________

Most patients with multiple myeloma and who are referred for radiotherapy have pain
secondary to bone involvement. Alleviation of pain is a major endpoint of therapy but
prevention of further destruction of bone and restitution of bone are also important goals,
especially if the patient is expected to live more than 3-6 months. When life expectancy


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is very limited, the short-term control of pain, avoidance of treatment-related side effects,
and ease of administration of therapy for the patient are the utmost concerns. However,
when it is anticipated that survival may be more extended, long-term local control or
eradication of local tumor is of importance. Patients should be assessed for the risk of
impending fracture when weight-bearing bones are involved. If the risk is felt to be high,
patients will be offered surgical intervention prior to radiotherapy. If surgical intervention
were not required, radiotherapy to the area of involvement would proceed. Fields
encompassing the radiographic abnormality plus a margin of 3-5 cm are generally used.
MRI may be helpful in delineating the extent of marrow involvement adjacent to the
lesion visualized on standard films. When long-term local control is desired, the total
dose should be higher (approximately 40-45 Gy or its equivalent) than if pain control is
the only concern. If it is anticipated that a large amount of normal tissue will lie within
the treatment fields, computed tomography (CT) planning could be utilized in order to
devise a plan that would limit normal tissue exposure and reduce the potential for side
effects. Radiographic evidence of healing may take many months following
radiotherapy. Patients should be warned that the bone strength will not be improved in
the short term after radiotherapy and care should be taken to avoid high stresses in the
treated site. Higher doses of radiation may be associated with a greater late risk of
fracture as noted in the study of fractionation patterns used for patients with metastatic
bone disease by the Radiation Therapy Oncology Group (RTOG).¹ The rate of fracture
was 17.5% in patients treated with 40.5 Gy in 15 fractions compared with 4% in patients
receiving 20 Gy in five fractions (P = 0.02).


Post-operative radiotherapy_____________________________________

Radiotherapy following surgical fixation for pathologic fractures, impending fractures, or
spinal instability is commonly recommended. In most situations, surgery for metastatic
bone disease or myeloma is not designed to provide complete oncologic resection of
disease. Post-operative radiotherapy has been associated with a decrease in the incidence
of reoperation for tumor progression or failure of fixation.¹⁶
In addition, the probability of achieving normal use of the extremity in one study was
found to be 53% with post-operative radiotherapy versus 11.5% with surgery alone.¹⁶ In
patients with newly diagnosed myeloma, chemotherapy may be able to provide control of
disease at surgical sites, eliminating the need for radiotherapy. Chen has indicated that
chemotherapy has been used in lieu of radiotherapy in this situation at the Mayo Clinic¹⁷
in recent years. Patients with chemorefractory disease or in whom chemotherapy will not
be utilized should receive radiotherapy post-operatively. Doses similar to those used for
primary palliative treatment are utilized for patients with widespread chemorefractory
disease, but higher doses may be indicated for patients with more favorable prognoses.
The field size is generally designed to encompass the entire prosthesis. Care should be
taken to ensure adequate coverage of soft-tissue extension of disease. Review of all
available pre-operative cross-sectional imaging may be helpful in defining the extent of
soft tissue involvement. MRI and CT scans generally have limited usefulness as well,
owing to the significant artifact produced by the rods or plates. In our experience, most


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patients will show evidence of radiographic healing; however, evidence of complete
union of a fracture is not necessary to achieve the goals of stability, pain relief, and
maintenance of fixation.


Osteosclerotic myeloma_________________________________________
An uncommon form of myeloma is the osteosclerotic variant. Lesions are often solitary
or few in number. Approximately 50% of these cases are associated with peripheral
neuropathy with or without the full POEMS syndrome (polyneuropathy, organomegaly,
endocrinopathy, M-protein, and skin changes).¹⁸⁻²⁰ Treatment of the bone lesion in
solitary cases has been associated with improvement in the neuropathy,²⁰٫²¹but reports of
significant improvement when multiple bone lesions are present have been uncommon.
Rotta and Bradley²² reported on a patient with three sclerotic bone lesions, features of
POEMS syndrome, and a negative bone marrow and who had a marked improvement in
the polyneuropathy that had left him non-ambulatory, with combined modality therapy,
including excision of the largest bone lesion (for diagnosis), radiotherapy to the other
skeletal lesions, plasmapheresis, and chemotherapy. This suggests that even patients with
greater skeletal involvement and severe neuropathies may benefit from aggressive
therapy.


Palliative wide-field radiotherapy_________________________________

Wide-field (total body or hemi-body) irradiation has a long history of use in multiple
myeloma. Total body irradiation (TBI) was utilized as initial management in the pre-
chemotherapy era.²³٫²⁴ With the advent of chemotherapy, wide-field therapy was
generally reserved for patients with refractory or recurrent myeloma, or for pain relief.
Holder²⁴ as early as 1965 found that significant pain relief could be achieved with TBI.
Hemi-body irradiation (HBI), which could be performed sequentially to the upper and
lower hemi-body regions, largely replaced total body irradiation due to better tolerance.
Numerous groups²⁵⁻³⁴ have reported their results using single fraction HBI or sequential
(double) HBI for palliation of pain and for treatment of refractory disease. Table 15.2
reviews the pain control results and hematologic toxicity from a number of studies.




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Table 15.2 Results of palliative single or double hemi-body irradiation for chemotherapy refractory myeloma

Study              Hemi-body radiation Hematologic toxicity                         Pain relief (%)

Bosch²⁷            Single                      Minimal                              94
McSweeney³¹ Double                             60% recovered sufficiently           95
                                               to receive α-interferon
Thomas³²           Double                      Severe; 1/7 fatal                    All patients
                                                                                    improved
Piesnicar³³        Double                      Full recovery by 6 weeks             83
Rostom³⁴          12 double, 7 single          50% recovered fully after            89.5
                                               DHBI; 89.5% recovered
                                               after single HBI

DHBI, double hemi-body irradiation; HBI, hemi-body irradiation.

         Palliative hemi-body therapy is generally administered in a single fraction. Doses
have ranged from 3 Gy³² to 10 Gy.²⁶ Generally, the upper hemi-body dose is limited to
6-7.5 Gy²⁷٫³¹٫³²٫³⁴ in order to reduce the risk of pneumonitis. Treating hemi-body
regions sequentially with a rest between each portion allows for improved marrow
tolerance compared with total body irradiation. The unirradiated marrow serves as a
reserve for hematologic function and may allow reseeding of the irradiated marrow.¹⁷٫³⁵
Hemi-body or sequential hemi-body therapy will lead to the need for red blood cell
transfusion in half to two-thirds of patients and approximately one-quarter will require
platelet support.²⁹٫³¹

         In chemorefractory patients, approximately 25-40% of patients will have a 50% or
greater reduction in M-protein levels.²⁵٫²⁸٫³¹ However, in a study from the Southwest
Oncology Group,³⁶ only 5% of chemotherapy non-responders were converted to
remission status. Plesnicar and colleagues treated six patients whose responses to
chemotherapy had plateaued with sequential HBI but saw only one objective response.³³
HBI has also been shown to be inferior to chemotherapy when administered for remission
consolidation following induction chemotherapy.³⁶ Therefore, the use of HBI for
chemotherapy responders or non-responders is not generally recommended except for
palliation of pain.³³٫³⁶٫³⁷




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TOTAL BODY IRRADIATION IN MULTIPLE MYELOMA________

Over the past decade, bone marrow transplantation (BMT) has become an effective
treatment for patients with various hematologic malignancies, particularly leukemias and
lymphomas. More recently, autologous and allogeneic BMT has been introduced in the
systemic treatment of multiple myeloma (see Chapters 16 and 17. Total body irradiation
has played a significant role in the development of BMT clinical trials because it
provided an effective cytoreductive conditioning regimen prior to high-dose
chemotherapy and BMT. The use of autologous BMT is now accepted as primary
treatment for younger patients with myeloma, but conditioning regimens, including
melphalan-TBI, have been found to be inferior to melphalan alone.³⁸ Allogeneic
transplant remains controversial because of the high mortality rate secondary to
treatment-related complications, but TBI continues to be part of the standard conditioning
regimens because it produces immunosuppression to allow engraftment of the donor
marrow.³⁹⁻⁴¹ Recently, non-myeloablative doses of TBI (200 cGy) have been used with
or without fludarabine, in an attempt to reduce the toxicities associated with allogeneic
transplants, with promising results.⁴²


Technical aspects of TBI________________________________________

Radiation delivery in TBI should be as accurate as possible, keeping in mind that the
dosimetry of this technique is most challenging, requiring the participation of the clinical
physicist, dosimetrist, and the radiation therapist. In view of the irregular contour of the
human body, to assure homogeneity in dose distribution most centers in the USA use
linear accelerators with photon beam energies of 6-10 MeV. Patient position and
immobilization must be considered during treatment planning to assure reproducibility.
Shank⁴³ has described a variety of positions, but today the most common positions are
either standing up with anterior and posterior fields, or lying supine and/or prone with
anterior and posterior fields, lateral fields, or a combination of both. Many centers have
developed some form of TBI technique, attempting to provide patient comfort, since each
treatment is significantly longer than the time required for delivery of standard-dose,
localized treatments. For instance, at Memorial Sloan Kettering Cancer Center
(MSKCCC), a stand was developed to provide support and immobilization, which
utilized a bicycle seat and handgrips for security.⁴⁴ At the University of Maryland
Medical Center, a team of physicists and radiation oncologists developed a ‘translational’
couch, which facilitates reproducibility.⁴⁵ Beam spoilers are recommended to ensure
adequate surface dose. At some institutions, compensators have been used at the neck,
feet, and other thinner areas to increase homogeneity.⁴³ It is also important to consider
the dose per fraction as well as the dose rate at which the treatment is delivered, since
these factors relate to normal tissue toxicity, particularly interstitial pneumonitis (IP).
Generally, treatment is administered with a dose rate of between 0.05 and 0.15Gy/minute,
significantly lower than the dose rates used for localized therapy of 2.0-3.0 Gy/minute.



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       The optimal schedule of TBI remains controversial. Most schedules have been
based on either empiric or radiobiologic calculations. Vriesendorp⁴⁶٫⁴⁷ concluded that
highly fractionated TBI with twice or three times daily regimen and total doses of 15 Gy
produced effective immunosuppression and impressive sparing of the normal tissues,
such as lung. Clinically, a variety of TBI regimens have been used, varying from single-
dose treatment, to a regimen with a few fractions and higher doses per fraction, to highly
fractionated daily regimens with multiple lower dose fractions per day. Ideally, when
using twice-daily treatments, a 6-hour interval should be allowed between the fractions.
This interval should be sufficient to allow maximal repair of sublethal damage of normal
tissues prior to the next fraction. Fractionation has been shown to play a prominent role
in the prevention of delayed toxicity of BMT. One of the major complications has been
interstitial pneumonitis. Most recent studies support the use of hyperfractionated TBI to
prevent this lethal complication. A randomized series from Seattle compared daily
fractionation of 2 Gy for six fractions for a total dose of 12 Gy with a single dose of 10
Gy. In that study, IP was reported 15% of the fractionated group compared with 26% of
the single-dose group.⁴⁸ In a non-randomized comparative study, Cosset et al.⁴⁹
demonstrated a reduction in IP from 45% to 13% with single-dose TBI (10 Gy) versus
fractionated TBI (13.2 Gy in 11 fractions over 4 days). A single dose of 10 Gy (lungs
limited to 8 Gy) was compared with 14.85 Gy delivered in 11 fractions over 5 days in a
prospective, randomized trial.⁵⁰ Cause-specific survival of patients receiving an
allogeneic transplant was not significantly different based on the treatment schema. The
incidence of veno-occlusive disease of the liver was significantly greater in the single
dose group (14%) compared with the fractionated group (4%), but no differences were
seen in the risk of IP. At the Mount Sinai Medical Center, a regimen consisting of a total
dose of 15 Gy in ten fractions (1.5 Gy per fraction) over 5 days appeared as effective in
achieving immunosuppression as 15 Gy in 12 fractions (1.25 Gy per fraction given three
times daily) over 4 days used extensively at MSKCC.⁴⁴ While a variety of treatment
schema have been used, the optimal fractionated regimen (total dose, number, and size of
daily fractions) has not been established (see Table 15.3)




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Table 15.3 Examples of total body irradiation techniques used for hematologic
malignancies

Study               Total           Number         Instantane        Toxicity(%)
                    dose            of             ous
                    (Gy)            Fraction       Dose rate         IP                        VOD        Comments
                                    s              (IDR)             Cataracts
                                                   (Gy/minut
                                                   e)
Cosset⁴⁹            10              1              0.125             45            -           13         Survival
                    13.2            11             -                 13                        0          similar

Girinsky⁵⁰          10              1              0.125             19            -           14         Survival
                    14.85           11             0.25              14                        4          Similar

Gopal⁵¹             10.2            6              -                 Same          -           -          OS 66%; FFP
                    12              4                                                                     31%
                                                                                                          OS 67%;
                                                                                                          FFP: 82%

Della               10              3              0.55              9             -           -          Lethal IP
Volpe⁵²                                                                                                   14.3% vs.
                                                                                                          3.8% for
                                                                                                          median lung
                                                                                                          dose > or ≤9.4
                                                                                                          Gy

Benyunes⁵³          10              1              -                 -             85 (11      -          Cataract risk
                    12-15.75        6-7                                            years)                 in patients
                                                                                   >12                    not receiving
                                                                                   Gy;50                  TBI – 19%
                                                                                   12
                                                                                   Gy:34

Belkacemi⁵⁴         10              1              0.03-0.15         -             11.3        -          High IDR and
                    12              6              0.03-0.089                      (5                     lack of
                                                                                   years)                 heparin for
                                                                                   4.4 (5                 VOD
                                                                                   years)                 independently
                                                                                                          associated
                                                                                                          with
                                                                                                          increased
                                                                                                          frequency of
                                                                                                          cataracts

Feinstein⁴²         2               1              -                 -             -           -          Non-relapse
                                                                                                          mortality –
                                                                                                          0%

FFP, freedom from progression; OS, overall; TBI total body irradiation; VOD, veno-occlusive disease of the liver




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Toxicity of TBI________________________________________________

Common acute side effects of TBI are nausea and vomiting, usually occurring a few
hours after the first fraction and improving over the course of hyperfractionated
radiotherapy. Acute parotiditis with transient xerostomia⁴⁴ and oral mucositis are also
common events in patients undergoing TBI. Fatigue, skin erythema, and
hyperpigmentation are almost the rule. Late toxicities include graft versus host disease,
interstitial pneumonitis, cataracts, liver and kidney dysfunction, hypothyroidism, and
decreased gonadal function. The incidence of alterations of cognitive function and
secondary malignancy is not well defined in the multiple myeloma population.

       One of the most challenging problems associated with TBI is the potential
development of interstitial pneumonitis, which has been reported to be fatal in the large
majority of patients who develop this complication.⁴⁴ Radiobiology studies in animals
have shown that increasing the number of fractions greatly decreases the incidence of
IP.⁴⁴ Two TBI fractionation regimen were compared by Gopal et al.⁵¹ to evaluate the
incidence of acute and late pulmonary toxicity. Regimen A consisted of twice-daily
fractions of 1.7 Gy over 3 days for a total dose of 10.2 Gy with no lung shielding.
Regimen B consisted of 3.0 Gy daily over 4 days for a total dose of 12 Gy with lung
shielding during the third dose. Patients were evaluated with pulmonary function tests
(PFTs) and, after a median follow-up of 48 months, there was no significant difference in
the PFTs or in late toxicity in either group, Della Volpe et al.⁵² analyzed the effect of
median lung dose on development of lethal pulmonary complications in patients treated
with TBI in the conditioning regimen for BMT for hematologic malignancies. A regimen
of fractionated TBI (10 Gy total dose in three fractions, one fraction/day, 0.055
Gy/minute) was utilized and individual lung doses were measured via in vivo dosimetry.
They found that the risk of lethal pulmonary complications was 14.3% in patients with a
median lung dose of greater than 9.4 Gy compared with 3.8% in patients with a lung dose
of 9.4 Gy or less.

       The lens is one of the most sensitive organs to ionizing radiation. Cataract
formation has been considered nearly inevitable following TBI for BMT. Benyunes
et al.⁵³ found that fractionated TBI regimens were associated with a reduction in cataract
formation. Eighty-five percent of patients treated with a single 10 Gy dose exhibited
cataract formation by 11 years compared with 34% of patients receiving 12 Gy
fractionated TBI. Belkacemi et al.⁵⁴ evaluated treatment factors associated with cataract
formation in patients treated with single-dose (10 Gy) or fractionated (12 Gy – 3 fractions
– 3 days) TBI for allogeneic or autologous transplant for a variety of hematologic
malignancies. For all patients, the estimated 5-year incidence of cataract formation was
23%. The risk was lower in patients receiving fractionated TBI than single-dose TBI
(11% vs. 34%). Dose rate was also analyzed and was found to influence the risk of
cataract formation. The 5-year risk was estimated to be 54%, 30%, and 3.5% for patients
in the high-dose-rate group (≥0.09 Gy/minute), the medium group (≥0.048 Gy/minute but
<0.09 Gy/minute), and low-dose rate group (<0.048 Gy/minute), respectively. In


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addition to the radiation-related factors, Belkacemi et al.⁵⁴ also found that the use of
heparin for prophylaxis against veno-occlusive liver disease was associated with a
reduction in cataract formation (16% with heparin vs. 28% without). In multivariate
analysis, only dose rate and heparin use were independently associated with the risk of
cataract formation. These complications of TBI, as well as thyroid and gonadal
dysfunction and decrease in cognitive abilities, are not life-threatening; however, they
must be closely evaluated when assessing quality of life issues after high-dose
chemotherapy and stem-cell rescue with TBI as part of the conditioning regimen. Many
of these problems will be significantly reduced if the non-myeloablative TBI techniques
become standard.


RADIOIMMUNOTHERAPY____________________________________

Radioimmunotherapy (RIT) has been shown to be a useful technique for tumors such as
the non-Hodgkin’s lymphomas. Its use in multiple myeloma would potentially allow
delivery of radiation to tumor cells while minimizing dose to normal tissue. A multitude
of factors must be considered in the design of RIT techniques, including target-cell
radiosensitivity, proliferation rate, ability to repair sublethal damage, tumor size, affinity
and avidity of the antibody, target-non-target distribution ratios, etc.⁵٫⁵⁶As with external
beam irradiation, currently available evidence does suggest a direct relationship between
the administered dose of radiolabeled antibody and efficacy, as well as toxicity. The
dosimetry of RIT, however, is less well defined and continues to be studied.⁵⁷

        In the myeloma model, where large, solid tumor masses are often not present, the
choice of an -emitting radioisotope with a very short range of action may be appropriate
in order to maximize the target-non-target dose ratio. Another choice would be
iodine-131 (¹³¹I), a β-emitter with a relatively short range of action.⁵⁸٫⁵⁹ The efficacy of
an -emitter to produce cell mortality was demonstrated for myeloma cells with
bismuth-213 (²¹³Bi) in an ex vivo model by Couturier et al.⁵⁹ Superiority of the
-emitter was validated in an in vitro study comparing ²¹³Bi and ¹³¹I recently published
by Supiot et al.⁵⁸

       The choice of an appropriate monoclonal antibody (MAb) is critical to RIT (see
Chapter 20). Antibody distribution depends on multiple factors such as specificity,
valency, and tumor-related conditions such as hypoxia.⁵⁵ Antibodies to epithelial mucin-
1 glycoprotein (MUC-1), such as the MA5 anti-MUC1 monoclonal antibody, were found
to be strongly reactive with human myeloma cell lines.⁶⁰ Supiot et al.⁵⁸ evaluated MA5
anti MUC1 and B-B4, a monoclonal antibody that recognizes syndecan-1 (CD138).
Treatment of myeloma cell lines with [²¹³Bi]B-B4 induced myeloma cell mortality and
caused cell arrest in G2/M. The concentration required to create the same effect was
fivefold higher with [²¹³Bi]MA5 than the B-B4 MAb. They also tested both MAbs


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with ¹³¹I. Following treatment with [¹³¹I] B-B4 MAb the percentage of cells arrested
in the G2/M phase was nil and the effect on cell mortality was very limited.
These results suggested that B-B4 was the more effective MAb and that use of an
-emitter was better than the use of ¹³¹I. Targeting of normal tissues was seen with both
MAbs. MA5 stained renal and pulmonary, tissues whereas B-B4 stained hepatic,
pulmonary and duodenal tissue. Another approach that is being studied is the use of
radioimmunoconjugates in the conditioning regimen for stem-cell transplantation. The
use of a radiolabeled monoclonal antibody to an antigen, such as CD45 (common
leukocyte antigen), may allow more specific targeting of the marrow and delivery of
additional dose without unacceptable normal tissue exposure.⁶¹ Clinical trials will be
necessary to further test the effectiveness of various types of RIT for patients with
multiple myeloma and assess for potential toxicities, but this type of targeted therapy
holds promise for the future.


KEY POINTS_________________________________________________

      Palliative external beam irradiation with doses in the range of 20-25 Gy is capable
       of providing the majority of patients with excellent pain control.
      Spinal cord compression and other symptoms of local disease can be treated
       effectively with radiotherapy. Slightly higher doses (30-40 Gy) may improve the
       likelihood of improving neurologic function and maintaining long-term local
       control.
      For long-term control of localized bone and soft-tissue lesions, doses of 40-45 Gy
       are generally recommended.
      Post-operative radiotherapy following fixation of pathologic or impending
       pathologic fractures is generally recommended to decrease the risk of further bone
       destruction and the need for additional surgery.
      Total body irradiation (TBI) is commonly used in the preparative regimen for
       allogeneic bone marrow transplantation. The use of fractionated TBI has
       significantly decreased the risk of interstitial pneumonitis. Low-dose, non-
       myeloablative TBI is being studied and appears to be associated with reduced
       toxicity.
      Radioimmunotherapy is currently being investigated and may become an
       important part of the armamentarium for the treatment of patients with multiple
       myeloma.




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