INTRODUCTION:

For people with a life-threatening disease, palliative treatment is a tool that increases the quality of life. It helps to avoid and minimize suffering from other physical, social conditions through early recognition and treatment of pain. It is argued that death is a natural occurrence that does not have to be delayed or hastened. Palliative care includes a method of assistance to help people survive as actively as possible before death.^1,2

Metastatic bone disease is a common source of discomfort that is damaging to the quality of life. The frequency of bone metastasis relies on the primary location, with up to 70% of people with metastasis reporting breast and prostate cancer.³

Slow gradual, insidious pain is the most frequent sign of bone metastasis, and is reasonably localized. At night, this pain could be worse. Weight carrying or ambulation can exacerbate femoral pain. Pain will radiate to other areas⁴.

Pain may be classified according to source⁵. Cancer related pain is almost nociceptive which means tissue irritation due to tumor⁶. Nociceptive pain could be described as somatic or visceral pain. Somatic pain is sharp while visceral pain is generalized, throbbing, and aching⁷. Nociceptive pain is typically aching pain that is easily localized. Neuropathic pain is due to injury to the primary or peripheral nerves. Peripheral cancer pain is related to tumor-based nerve compression. Neuropathic pain criteria include burning or tingling feelings in the affected area.^1,7

Inadequate pain treatment raises stress, theoretically reduces immunity, aggravates pneumonia and thrombo-embolism tendencies¹. The term "palliate" originates in Greek and means "to cloak," meaning that we plan to "cloak" or avoid the patient from experiencing discomfort or other stressful effects while caring for a dying human¹.

Despite increasing understanding about the effective treatment of pain, patients with pain from bone metastases frequently have inadequate pain management. Barriers to pain treatment include physician underestimation of the patient’s pain and reluctance by the patient to report pain⁸. Brief Pain Inventory, offers an incentive for the patient to explain the intensity and interference of pain with function in a way that both the patient and the doctor comprehend⁹.

The first large randomized study evaluating different dose and fractionation schemes was the Radiation Therapy Oncology Group (RTOG) 74-02 trial¹⁰. The randomization of patients with solitary bone metastases was 40.5 Gy in 15 fractions vs 20 Gy in 5 fractions. Each of four treatment schedules was given to patients who had numerous excruciating metastases: 30 Gy in 10 fractions, 15 Gy in 5 fractions, 20 Gy in 5 fractions, or 25 Gy in 5 fractions. There was no statistically meaningful variation in reaction rates of any of the treatment arms in the original study by Tong et al.69 in 1982, with complete responses in 49-61 percent of patients¹¹. These results were questioned by Blitzer,¹² who reanalyzed the data using different criteria for complete response, which excluded patients who received repeat treatment, and defined complete response as no pain and no analgesic usage. With this adjustment in response definition, there was

There is a major disparity in favour of longer treatment: 40.5 Gy in 15 fractions for solitary metastases and 30 Gy in 10 fractions for multiple metastases. This was offered as evidence that higher doses were necessary for optimal palliation.

There have been multiple randomized, prospective trials in the last 30 years comparing shorter-course, lower-total-dose treatment to the more “standard” longer-course, higher-dose treatment. Several conclusions are clear from these studies:

1. The single 8 Gy dosage offers equivalent pain relief to longer regimens of treatment (30Gy in 10 fractions or 20 to 24 Gy in five to eight treatments).

2. Retreatment rates are higher by a factor of two or three after short-course rehabilitation.

3. When scored by the patient instead of by the prescribing specialist, reaction rates are lower.

4. Response rates are better when the initial pain scores are lower, that is, when the patients are treated for moderate pain rather than severe pain.

5. For palliation of bone metastases, there is no clear dose response relationship.

Many patients receive pain relief with minimal objectives (<3 months), and palliative radiotherapy can also be considered for those patients (10, 13). A longer course of intervention (30 Gy in 10 fractions) could be best suited to reduce the likelihood of retreat in patients with longer life expectancy, bone-only metastases, and good performance status. For selected patients with a solitary bone metastasis (oligometastatic), an even higher dose of treatment may be indicated.

AIMS OF THE STUDY:

1. To describe the efficacy of palliative radiotherapy in control of pain in metastatic cancerous patients.

2. To evaluation of radiotherapy doses in pain management.

3. To calculation of survival rates of patients with metastatic cancers treated by palliative radiotherapy.

Patients and methods:

Study design and Setting:

This is a prospective observational study carried out at the Baghdad Radiotherapy and Nuclear Medicine Center, at Baghdad Medical City Complex, Baghdad, Iraq, from the 1^st of December 2018 to the 30^th of May 2019. All patients recruitment and exposed to radiotherapy as palliative issues for pain control. Follow-up throughout period of radiotherapy and after finishing therapy done.

Data collection:

All information about variables collected from patient as age, tumor types, site of pain, words describe pain, characteristics of pain, timing of pain, any medication used to relief pain, conditions interfering with pain as general activity, mood, work, sleep, enjoyment, concentration, and relationship with others.

Participants:

88 Patients, who were referred for palliative radiotherapy for pain control, enrolled into the study after informed consent from all patients. We catch eligibility criteria, which include good performance status. The exclusion criteria include: end stage cases, patient with glioblastoma multiform and patient with melanoma. Selection of participants by using the questionnaires sheet.

Techniques:

All patients treated with three-dimensional conformal radiation therapy (3DCRT) according to their stage and followed the NCCN guideline for each of the specific tumor types which are known cases of metastatic carcinoma. They were treated with short course of at least 2000 GY for 5 fractionations. decision made by clinical oncologist at the time of referral according to hospital standards. Also, all of them received External beam radiotherapy (EBRT) range from 8-30 Gy as palliative course.

Follow-up:

Patients were assessed before received of radiotherapy, after 1st fraction, and at the day of last fraction. Then we assessed the quality of radiotherapy on pain control after finish fractions. A numerical scale was used for evaluation of pain relief. Two types of scores taken to assess the pain It scores the pain from 0 to 10. At eight weeks after and before radiotherapy, scoring was performed.

During this period, patients were followed by phone for assessment of pain status. Without the need for analgesics, total relief was described as a complete pain absence. Partial pain relief is the reduction in pain by a reduction by more than 2 in the pain score. While the progression in pain is the growth in pain score or increased use of drugs. From the day of care, the time of pain relief was reported. The pain relief period was determined as the interval from pain relief to pain development or an improvement in analgesic medicine.

Statistical methods:

All variables were collected in Excel sheet then analyzed by (SPSS software version 24). Frequencies and relative frequencies tabulation. Mean, and standard deviation describe normal distribution. Kaplan Meier survival curve used. A Chi secure two-sided P value of 0.05 or less and 95% confidence interval were considered statistically significant.

RESULTS:

Our findings regarding gender , there were 51(58%) male and 37(42%) female of patients studied, [Table 1], The mean ± SD of age was 55.44±11.1 years, and the most frequent age group was 41-50years as 37(42.1%), followed by 61-70 years of 24(27.2%), 51-61 years of 15(17.1%), and 6 (6.9%) of patients for 30-40 years and more than 70 years, [Table 1].

Table 1: gender and age frequencies of the study.

Variables		N	%
Gender	Male	51	58
	Female	37	42
	Total	88
Age (years)	30-40	6	6.8
	41-50	37	42.1
	51-60	15	17.1
	61-70	24	27.2
	>70	6	6.8
	Total	88

Among cancers types, the breast cancer came in 1^st rank cases studied in our research as 35(39.8%), followed by prostate carcinoma as 21(23.9%). Multiple myeloma presented in 10(11.4%) of patients. Six cases for bladder cancers, five cases for gastrointestinal, and carcinoma of unknown primary. Four cases of lung cancer, and only two cases of head and neck cancers, [Table 2].

Table 2: Cancer variables frequencies of the study.

Variables		N	%
Tumor types	Multiple myeloma	10	11.4
	Lung	4	4.5
	Breast	35	39.8
	Gastrointestinal	5	5.7
	Prostate	21	23.9
	Bladder	6	6.8
	Carcinoma of unknown primary	5	5.7
	Head and neck	2	2.3
	Total	88

The palliative 3DCRT performed for all patients studied. 42(47.7%) of patients received radio-therapy (RT) on metastatic spine vertebral lesions. 32(36.4%) cases received RT for pelvic bones secondaries. Whole-brain radiotherapy (WBRT) given for eight patients. Regarding RT doses used, the 2000 cGy was common dose recommended for 80(90.9%) of patients, followed by 800 cGy, and 1200 cGy as 6(6.8%), 2(2.3%), respectively, [Table 3].

Table 3: Radiotherapy criteria of this study.

Variables		N	%
RT sites	Spine [bone]	42	47.7
	Pelvic [bone]	32	36.4
	Bone lower limb	2	2.3
	Brain	8	9.1
	Other	4	4.5
	Total	88
RT dose (cGy)	800	6	6.8
	1200	2	2.3
	2000	80	90.9
	Total	88

Table 4: Pain characteristics of this study.

Variables		N	%
Pain descriptions	Aching	13	14.8
	Sharp	32	36.4
	Penetrating	6	6.8
	Burning	6	6.8
	Stabbing	11	12.5
	Exhausting	9	10.2
	Unbearable	11	12.5
	Total	88
Pain occurrence	Constant	31	35.2
	Frequent	57	64.8
	Total	88
Timing	Nighttime	79	89.8
	Daytime	6	6.8
	All time	3	3.4
	Total	88
Reliving factors	Sleeping	5	5.7
	Resting	16	18.2
	Drug	60	68.2
	No	7	8.0
	Total	88
Aggravating factors	No	9	10.2
	Movement	72	81.8
	Other thing	7	8.0
	Total	88

Pain characteristics of this study, illustrated in Table 4. Sharp pain was common describe by 32(36.4%) patients, followed by aching description in 13(14.8%). Frequent pain was more prevalent as 57(64.8%) of patients, whereas constant pain presented in 31(35.2%) of cases. Night was commonest timing of feeling pain in large number of cases as 79(89.8%). Pain mostly relief by take medication in 60(68.2%) and aggravated by movement in 72(81.8%) of patients.

Table 5: Pain scoring.

Pain score	Patients N(%) before RT	Patients N(%) after RT	P-value*
1	0	5 (5.7)	0.025
2	0	5 (5.7)	0.025
3	0	8 (9)	0.004
4	2 (2.3)	5 (5.7)	0.256
5	3 (3.4)	12 (13.6)	0.02
6	4 (4.5)	18 (20.4)	0.002
7	24 (27.3)	21 (23.8)	0.65
8	33 (37.5)	4 (4.5)	<0.000
9	14 (15.9)	5 (5.7)	0.038
10	8 (9.1)	4 (4.5)	0.248
*Chi-square for t test

Pain scoring in ascending manner from 1-10 estimated before palliative RT and after, which give us clue about efficacy of patients conditions. Before treatment, the most common scoring was (8) in 33(37.5%) patients, followed by score (7) as 24(27.3%) patients, score (9) in 14(15.9%) patients, score (10) in eight cases, and score (6) in four cases. Three cases for score (5) and two cases for score (4). After palliative RT the scoring shift downward. The scores (1), (2), (4), and (9) presented in five cases only for each. Both scores (8) and (10) present in four cases. Score (3) found in eight patients. Twelve cases recorded for score (5). Score six recorded in 18(20.4%) of patients. Finally, score (7) prevalent in 21(23.8%) of patients.

The follow-up and outcome of treated patients after 2-4 weeks beyond palliative RT estimated as stable conditions in 40(45.5%) patients, and no change in their conditions in 17(19.3%) of patients. Patients feel well and pain disappeared in 18(20.5%). However, the conditions became worse in 13(14.8%) patients, as showed in Table 5.

Table 5: Follow-up conditions of patients beyond palliative RT.

Conditions	N	%
Stable	40	45.5
No pain	18	20.5
No change	17	19.3
Worse	13	14.8
Total	88

RT dose of 1200 cGy improved overall survival of patients in this study to 21.5 weeks (95%CI= 20.2-22.8), whereas RT dose of 800 cGy give survival for 10.2 weeks (95%CI= 9.5-10.8). Furthermore, the 1200 cGy have OS 8 weeks. All those statistically significant by Log Rank test and Breslow Chi-square (P=0.012).

DISCUSSION:

Our findings regarding gender, were 51(58%) male and 37(42%) female of patients studied with the mean ± SD of age was 55.44±11.1 years, and the most frequent age group was 41-50 years as 37(42.1%), followed by 61-70 years of 24(27.2%). Among cancers types, the breast cancer come in 1^st rank cases treated in our research by palliative RT as 35(39.8%), followed by prostate carcinoma as 21(23.9%). The bone demonstrated most common site of pain cause, so most of patients received palliative RT for bone secondaries. The palliative 3DCRT performed for all patients studied. 42(47.7%) of patients received RT on metastatic spine vertebral lesions. 32(36.4%) cases received RT for pelvic bones secondaries. WBRT given for eight patients. Regarding RT doses used, the 2000 cGy was common dose recommended for 80(90.9%) of patients, followed by 800 cGy as single fraction, and 1200 cGy as two fractions as 6(6.8%), 2(2.3%), respectively. An successful intervention for the palliation of symptomatic bone metastases has been proven to be radiotherapy.

Either single 8 Gy or multiple fraction systems, e.g. 20 Gy in five fractions or 30 Gy in 10 fractions, are the most common doses for treating bone metastases^1,4,14. Latest meta-analyses have found that the multiple intervention regimens have similar success¹⁵.

Many cancers are also complicated by bone metastases, particularly prostate, lung and breast cancers. This can lead to skeletal events, including hypercalcemia, pathological fractures, compression of the spinal cord, where either orthopedic surgery or radiotherapy may be required. Palliative radiotherapy has been found to be an effective and main treatment tool for both pain management and bone metastasis symptom control¹⁵. In two thirds of patients, it is effective in managing pain, with only one-quarter of patients receiving full relief^1,16.

For instance, in 1998 Ratabatharathorn et al.¹⁷ In their meta-analysis, they stated that the effects of multiple fraction therapy regimens are greater than lower dose single fraction regimes, although McQuay et al.¹⁴ no substantial variation was found between the effectiveness of single and multiple fractional treatment regimens. Chow et al. in 2007¹ In 16 randomized experiments testing single and multiple fraction regimens, this meta-analysis compared reaction rates, determining that both single and multiple fraction treatment regimens were similarly successful. The single fraction versus multiple fraction randomized study by Sande et al.¹⁸ published in 2009 reaffirmed the same conclusion.

Given the resource benefits, patient comfort and cost-effectiveness of single fractions, multi-fractionated treatment regimens are still the most common among radiation oncologists^7,19.

Sharp pain was common describe by 32(36.4%) patients, followed by aching description in 13(14.8%). Frequent pain was more prevalent as 57(64.8%) of patients, whereas constant pain presented in 31(35.2%) of cases. Night was commonest timing of feeling pain in large number of cases as 79(89.8%). Pain mostly relief by take medication in 60(68.2%) and aggravated by movement in 72(81.8%) of patients. Patients should be asked to describe their pain, its quality, severity, location, temporal pattern, and relieving and aggravating factors when determining pain.²⁰ Treatment of cancer suffering should be carried out in a structured way, based on those concepts. First it is important to examine each pain independently and to ensure that it is linked to cancer²⁰.

All pain scoring change after RT at period of follow-up. Before treatment, the most common scoring was (8) in 33(37.5%) patients, followed by score (7) as 24(27.3%) patients, score (9) in 14(15.9%) patients, score (10) in eight cases, and score (6) in four cases. Three cases for score (5) and two cases for score (4). After palliative RT the scoring shift downward. The scores (1), (2), (4), and (9) presented in five cases only for each. Both scores (8) and (10) present in four cases. Score (3) found in eight patients. Twelve cases recorded for score (5). Score six recorded in 18(20.4%) of patients. Finally, score (7) prevalent in 21(23.8%) of patients. The follow-up and outcome of treated patients after 2-4 weeks beyond palliative RT estimated as stable conditions in 40(45.5%) patients, and no change in their conditions in 17(19.3%) of patients. Patients feel well and pain disappeared in 18(20.5%). However, the conditions became worse in 13(14.8%) patients.

In 1986 (revised in 1996), the WHO established recommendations for the management of cancer pain to minimize the incidence of insufficient analgesia, which is the most significant explanation for the use of such pain relief options in cancer patients²¹.

The Dutch trial found the median survival after treatment was 30 weeks, with no difference between the two treatment groups. There was no difference in overall or complete response rates between the single-dose versus longer-course treatment arms. Overall, 71% of patients achieved a response to therapy during follow-up, with 35% achieving a complete response²⁰.

The RTOG study 9714, demonstrated the median survival was 9.3 months. Overall toxicity rates were poor, with fewer patients in the 8-Gy treatment community suffering acute toxicity¹⁰.

CONCLUSIONS:

1. This study conducting in Iraq describing improvement of pain in patients undergo palliative radiation.

2. Breast cancer come in 1^st rank cases studies manage by palliative RT.

3. After receiving palliative RT the pain scoring shift downward and move from left to right.

4. RT dose of 2000cGY improved overall survival of patients in this study to 21.5 week.

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Received on 03.12.2020 Modified on 07.01.2021

Research J. Pharm. and Tech 2021; 14(11):5733-5738.

DOI: 10.52711/0974-360X.2021.00997