Radiotherapy alone or surgery in spinal cord compression? The choice depends on accurate patient selection

To the Editor: We read with great interest the editorial by Kwok, Regine, and Patchell,1 in which they suggest caution in implementing the results in clinical practice of our phase III randomized clinical trial on hypofractionated radiotherapy in metastatic spinal-cord compression (MSCC).2 We feel obliged to reply by answering point by point to the major reported criticisms. As stated in the paper, only MSCC patients with a short life expectancy entered onto the trial. The majority of patients (229; 83%) had low Karnofsky performance status (KPS) and the remaining 47 (17%) enrolled with a good KPS, and had poor life expectancy and bad prognosis for the presence of unfavorable histologies. Although 30 Gy in 3-Gy daily fractions represents the most common fractionation schedule used in patients with MSCC in the United States, the optimal radiotherapy (RT) regimen for treating MSCC is still unknown and many schedules are reported in the literature.3 In some published trials, 4 to 5 Gy daily for 3 days followed by 4 days of rest, and then five to 16 daily doses of 2 to 3 Gy have been administered with both good results and tolerance.4-8 Studies concerning RT for patients with painful bone metastases have shown that low fraction regimens and high single doses have a clinical outcome similar to more protracted regimens, also in patients with vertebral metastases.9 Considering that higher RT doses per fraction is one of the possible factors that may be associated with radiation-induced late spinal cord morbidity, in our previous trials we adopted different hypofractionation regimens on the basis of the patient's life expectancy.3,8 A safer fractionation of 3 to 30 Gy in 10 fractions over 2 weeks was administered to patients with a long life expectancy (approximately 15% of observed cases). Split-course RT of three fractions of 5 Gy each, 4 days of rest, and then five fractions of 3 Gy each, to a total dose of 30 Gy in 2 weeks, was adopted for patients with short life expectancy.8 In recent phase II trial, we have proved the feasibility and effectiveness of a short-course RT (two fractions 8 Gy) in the patients with less than 6 months of life.3 With this background, this prospective randomized phase III trial was performed to compare the aforementioned split-course regimen with the short-course RT in patients with MSCC and short life expectancy. Other MSCC patients who did not enter onto the study, underwent to 3 to 30 Gy regimen. We agree with Kwok, Regine, and Patchell in being worried about radiation-induced myelopathy (RIM) that may result in heavy neurologic deficits. Of 465 MSCC patients submitted to RT at our center between 1988 and 1997, 13 living patients treated with the aforementioned split- or short-course regimens survived for 2 years or more were reviewed to evaluate RIM. This trial, the only one published on RIM in long-term–surviving MSCC patients, showed an excellent spinal cord tolerance to the hypofractionated RT schedules adopted, with only one case of suspected RIM.10 Furthermore, three randomized Medical Research Council trials on non–small-cell lung cancer have shown the effectiveness of two fractions 8.5 Gy RT in the palliation of symptoms caused by thoracic disease. This regimen has given the same outcome and toxicity as three other regimens used for comparison. Only one of 550 patients submitted to this hypofractionation schedule presented a suspected RIM.11-13 Recently Macbeth14 encourage a wider use of 8 Gy × 2 fractionation in palliative RT. Another important support on the feasibility of the hypofractionated RT can be derived by the radiobiology. The effect of an RT schedule on tumor control and on late toxicity depends on both the total dose and the dose per fraction. Each schedule adopted can be compared with the equivalent dose in 2-Gy fraction (EQD2), which is calculated using the equation Undefined control sequence $$ derived from the linear-quadratic model.15 The tolerance dose (5% late toxicity within 5 years) for RIM is 50 Gy for conventional fractionation (a dose per fraction of 2 Gy).16 For the end point myelopathy, the EQD2 must be calculated with an α/β ratio of 2 Gy, resulting in an EQD2 of 45 Gy and 40 Gy for the split-course (5 Gy × 3; 3 Gy × 5) and short-course (8 Gy × 2) schedules, respectively. Thus, whatever of these two RT regimens are adopted, relevant late toxicity appears to be extremely unlikely. As reported in our article,2 responders were considered either those patients who retained or regained the ability to walk. This definition of response, shared by the majority of authors, can be acceptable because untreated MSCC patients generally deteriorate and develop neurologic dysfunction.3-7 Also the authors of the editorial have adopted these criteria in defining response in their recent trial.17 So, we do not understand the reason for which they argume against our results and want to limit the percentage of response to only patients who have improved after RT. The good response rate found in our trial is probably due to the early diagnosis and prompt treatment (in 67% of cases, MSCC was diagnosed and treated when patients were ambulant, and 90% of patients maintained this function).2 Considering that the pretreatment ambulatory function is the main determinant for post-treatment gait function, an important message we would like reinforce is the importance of the early diagnosis that can be obtained prescribing MRI or CT for all cancer patients with back pain, osteolysis and/or positive bone scan, even in the absence of clinical neurologic signs of MSCC.2,18 The best or most effective treatment for MSCC patients is still not defined, and the choice between surgery plus RT or RT alone is debatable. In fact, the two published randomized studies comparing surgery plus RT versus RT alone do not conclusively clarify what is the treatment of choice.5,17 Young's trial5 has shown no difference between laminectomy plus RT and RT alone; however, too few patients were enrolled and simple laminectomy is generally considered an inappropriate surgical approach. The other trial was closed at an interim analysis that showed a significant better response rate in the surgical group.17 In our opinion, these data give not a sufficient evidence in favor of surgery plus RT for two important reasons. First, this last randomized study cannot be considered good evidence to recommend surgery plus RT in all MSCC patients because it was available only as an abstract and was closed before reaching the established sample size. Second, in the clinical practice, only a minority of MSCC patients are eligible for surgery: Low KPS, old age, systemic progressive disease, and so on are characteristics that can prevent a surgical approach. Also, the authors of this editorial reported in their abstract that only patients with a single site of cord compression and an expected survival of at least 3 months were enrolled in their phase III trial.17 In conclusion, early diagnosis and a prompt treatment are very important for patients with MSCC. In the clinical practice, the best therapeutic approach might be discussed for each patient between surgeon and radiation oncologist. There are situations in which surgery is surely indicated before RT, but there is not convincing evidence that surgery must be performed for all MSCC patients

Prevention and Treatment of Bone Metastases in Breast Cancer

In breast cancer patients, bone is the most common site of metastases. Medical therapies are the basic therapy to prevent distant metastases and recurrence and to cure them. Radiotherapy has a primary role in pain relief, recalcification and stabilization of the bone, as well as the reduction of the risk of complications (e.g., bone fractures, spinal cord compression). Bisphosphonates, as potent inhibitors of osteoclastic-mediated bone resorption are a well-established, standard-of-care treatment option to reduce the frequency, severity and time of onset of the skeletal related events in breast cancer patients with bone metastases. Moreover bisphosphonates prevent cancer treatment-induced bone loss. Recent data shows the anti-tumor activity of bisphosphonates, in particular, in postmenopausal women and in older premenopausal women with hormone-sensitive disease treated with ovarian suppression. Pain is the most frequent symptom reported in patients with bone metastases, and its prevention and treatment must be considered at any stage of the disease. The prevention and treatment of bone metastases in breast cancer must consider an integrated multidisciplinary approach

Prevention and Treatment of Bone Metastases in Breast Cancer

In breast cancer patients, bone is the most common site of metastases. Medical therapies are the basic therapy to prevent distant metastases and recurrence and to cure them. Radiotherapy has a primary role in pain relief, recalcification and stabilization of the bone, as well as the reduction of the risk of complications (e.g., bone fractures, spinal cord compression). Bisphosphonates, as potent inhibitors of osteoclastic-mediated bone resorption are a well-established, standard-of-care treatment option to reduce the frequency, severity and time of onset of the skeletal related events in breast cancer patients with bone metastases. Moreover bisphosphonates prevent cancer treatment-induced bone loss. Recent data shows the anti-tumor activity of bisphosphonates, in particular, in postmenopausal women and in older premenopausal women with hormone-sensitive disease treated with ovarian suppression. Pain is the most frequent symptom reported in patients with bone metastases, and its prevention and treatment must be considered at any stage of the disease. The prevention and treatment of bone metastases in breast cancer must consider an integrated multidisciplinary approach

Correction: Ripamonti, C.; Trippa, F.; Barone, G.; Maranzano, E. Prevention and Treatment of Bone Metastases in Breast Cancer. J. Clin. Med. 2013, 2, 151–175

The authors wish to make the following corrections to this paper [1]: The authors’ names: [...

2016 updated MASCC/ESMO consensus recommendations:prevention of radiotherapy-induced nausea and vomiting

School of Nursin

Re-irradiation of brain metastases and metastatic spinal cord compression: clinical practice suggestions

The recent improvements of therapeutic approaches in oncology have allowed a certain number of patients with advanced disease to survive much longer than in the past. So, the number of cases with brain metastases and metastatic spinal cord compression has increased, as has the possibility of developing a recurrence in areas of the central nervous system already treated with radiotherapy.Clinicians are reluctant to perform re-irradiation of the brain, because of the risk of severe side effects. The tolerance dose for the brain to a single course of radiotherapy is 50-60 Gy in 2 Gy daily fractions. New metastases appear in 22-73% of the cases after whole brain radiotherapy, but the percentage of re-irradiated patients is 3-10%. An accurate selection must be made before giving an indication to re-irradiation. Patients with Karnofsky performance status >70, age <65 years, controlled primary and no extracranial metastases are those with the best prognosis. The absence of extracranial disease was the most significant factor in conditioning survival, and maximum tumor diameter was the only variable associated with an increased risk of unacceptable acute and/or chronic neurotoxicity. Re-treatment of brain metastases can be done with whole brain radiotherapy, stereotactic radiosurgery or fractionated stereotactic radiotherapy. Most patients had no relevant radiation-induced toxicity after a second course of whole brain radiotherapy or stereotactic radiosurgery. There are few data on fractionated stereotactic radiotherapy in the re-irradiation of brain metastases.In general, the incidence of an "in-field" recurrence of spinal metastasis varies from 2.5-11% of cases and can occur 2-40 months after the first radiotherapy cycle. Radiation-induced myelopathy can occur months or years (6 months-7 years) after radiotherapy, and the pathogenesis remains obscure. Higher radiotherapy doses, larger doses per fraction, and previous exposure to radiation could be associated with a higher probability of developing radiation-induced myelopathy. Experimental data indicate that also the total dose of the first and second radiotherapy, interval to re-treatment length of the irradiated spinal cord, and age of the treated animals influence the risk of radiation-induced myelopathy. An alpha/beta ratio of 1.9-3 Gy could be generally the reference value for fractionated radiotherapy. However, when fraction sizes are up to 5 Gy, the linear-quadratic equation become a less valid model. The early diagnosis of relapse is crucial in conditioning response to re-treatment