Radical Conformal Radiotherapy versus Two-Dimensional Radiotherapy in Oligometastatic Breast Cancer Patients: Response, Toxicity, and Survival

1.Introduction

Breast cancer frequency patterns in Egyptian females in lower, middle, and upper Egypt were 33.8 %, 26.8  %, 38.7 % respectively [1]. 25 – 40 % of breast cancer patients diagnosed initially by bone distant metastasis, 60 – 80 % of recurrent breast cancer patients developed skeletal metastasis [2].

Systemic therapy is the standard of care in metastatic breast cancer, many metastatic patients enrolled in breast cancer trials have a limited metastatic site [3-8].

The clinical scenario of oligometastases describes a limited metastatic site in the absence of full metastatic potentiality [9], hence the usefulness of local therapy purposes such as surgery, ablative radiotherapy in hope for better local control and overall favorable outcome achievement [10].

Despite that, the majority of breast cancer patients have proposed chemotherapy in positive hormonal receptor condition signifying the systemic therapy intensity hypothesis rather than radiotherapy strategy, oligometastatic breast cancer patients achieved better progression-free survival without significant toxicity, so this urge patients subgroups identification who might gain more benefit from aggressive local therapy [11]. 

        Conventional radiotherapy is important in primary symptomatic bony metastatic site treatment, high conformal irradiation strategies such as three-dimensional conformal radiotherapy, stereotactic body radiotherapy, and intensity-modulated radiotherapy were allowed for treatment delivery [12].

In comparison to antro posterior, post anterior, and direct post anterior techniques, 3-dimensional conformal irradiation delivered for treatment of lumbar vertebrae metastasis was much better in the decrease of bowel and spinal cord exposure. Application of treatment delivery by stereotactic body radiation as well as intensity-modulated radiation therapy is associated with resource expenditure and complexity of clinical evaluation [13].

        Improvement of isodose distribution and spare of organ at risk achievements are considered as an advantage of high conformal irradiation techniques, obtained for treatment planning and delivery in comparison to conventional irradiation because of inevitable reachable doses to organ at risk in the treatment portals unselectively, but in contrary high conformal treatment advances allow better conformality as well as dose escalation in the favor of tumor control and local pain improvement [14].  

Costly modern linear accelerators with image guidance, immobilization devices, competent expertise, quality assurance measures for treatment implementation are essential as high conformal radiotherapy requirements, some patients with severe pain can not tolerate the rigid immobilization devices   [14], treatment time is long, 45 minute or more so this is difficult in an emergency scenario as well as an organ at risk may suffer from the probability of dose complication uncertainties  [15,16].

Aim of the study was to evaluate the clinical outcome gains achieved by 3D radiotherapy versus 2D radiotherapy in certain breast cancer patients with  bony oligo metastasis

2.Patients and methods

    In a retrospective cohort study, 60  patients with oligometastatic bony lesion who conducted at Clinical Oncology Department, Zagazig University Hospitals from January 2016 to January 2020 to receive radiotherapy for bony oligometastatic lesions, The patient's data  were collected from the patient's records. Written informed consent was obtained from all participants. The study was done according to the Code of Ethics of the World Medical Association (Declaration of Helsinki) for studies involving humans. (Approval no: 6623-23-12-2020, Date: 23.12.2020) . Patients were enrolled in two groups of treatment:  Group 1; 30 patients who received two-dimensional radiotherapy group (2D), group 2; 30 patients who received three-dimensional conformal radiotherapy (3DCRT). Inclusion criteria:Histopathological confirmation of breast cancer, Eastern Cooperative Oncology Group (ECOG) score ≤ 2 ,confirmed oligometastatic lesions by positron emission tomography (PET CT) scan ± computed tomography with a bone window or magnetic resonance imaging  and treatment was delivered at a linear accelerator machine. Exclusion criteria:Presence of visceral metastasis, previously irradiated lesions  ,data shortage and suboptimal follow up.

In radiotherapy all patients were simulated, comfortably positioned, and fixed by a thermoplastic mask. For the 2D group, field arrangement obtained from simulation, one vertebral body above, and one below the lesion identified by PET CT. field coverage either by a direct field with lateral film to determine the depth for dose calculation or sometimes antro posterior and post anterior in lumbar vertebral lesions with the estimation of patient separation proposed in  30 Gy in 10 fractions while in long bone opposing antro posterior and post anterior with the estimation of patient separation. In the 3DCRT arm, the visible lesion on PET CT imaging was encompassed to create gross target volume, clinical target volume included the involved vertebral body as well those above and below immediately, planning target volume encompassed clinical target volume plus 1 cm margin, mostly arranged to be delivered with 3 or 4 anteroposterior/ posteroanterior beams (figure 1). Treatment of long bone lesion was covered by at least 2 cm margin proximal and distal to the evident lesions, mostly by opposed fields, encompassing of the target in irradiation portals with collimator angulations and multileaf collimator configurations minimize dose to the organ at risk such as spinal cord, esophagus, bowel, both lungs, kidneys ..etc which were delineated,  with treatment dose of 30 Gy in 10 fractions, verification of treatment delivery was done by digitally reconstructed radiographs. Anti-inflammatory, corticosteroids, and antiemetics were given to minimize symptoms.

Our patients underwent proper follow-up to assess response, toxicity, and survival outcome. evaluation of local control was through the performance of PET at 12 months post-radiotherapy. Local progression was defined as > 25% of measurable lesion size increase evaluated by the MDA response criteria [17]  with the use of Response Criteria in Solid Tumours (PERCIST 1.0)[18].Pain response evaluation was according to chow et al [19]: Complete ( no increase in analgesic intake such as tramadol or morphine, partial (reduction of 25% of analgesic dose from base line) , pain progression (increase of 25% of analgesic dose from base line), and intermediate (not fill full CR,PR and PP criteria). pain response  was assessed prior to radiotherapy  and 3 months later via horizontal visual analog scale. Toxicity assessment was scaled according to different grades  RTOG and EORTC [20],[21].

Statistical analysis:Continuous variables were expressed as the mean ± SD & median (range), and the categorical variables were expressed as a number (percentage). Percent of categorical variables were compared using Pearson's Chi-square test or Fisher's exact test when was appropriate. The trend of change in the distribution of relative frequencies between ordinal data was compared using the Chi-square test for trend.  Overall Survival (OS) was calculated as the time from diagnosis to death or the most recent follow-up contact (censored).Progression free survival (PFS) was calculated as the most recent follow-up contact that patient was known as progression free. All tests were two-sided. A p-value <0.05 was considered significant. All statistics were performed using SPSS 16.0 for windows (IBM Inc., Chicago, IL, USA).

3.Results

1-Patients characteristics

Fifty (83%)  of the studied patients were > 40 years old, 42 (70%) patients were scaled 2 ECOG, 38(70%) of patients shown grade III disease, 52 (86.7%) patients had IDC histopathology, 43 (71.7%) patients had positive ER and 44 (66.7%) patients had negative HER2, 43 (71.7%)  of patients shown ≥ 2 metastatic lesions demonstrated by PET study, during treatment we observed that 51(58%) of patients became metastatic and only 9 (15%) of patients presented by oligometastatic bony lesions at the initial diagnosis, 34 (56.7%) of patients were on hormonal therapy (Table 1). 

No statistical difference between both groups regards the patient's characteristics except for the treatment condition, there was highly statistical significance between 2D and 3D arm p=0.002**(Fisher test).  

2- Assessment of pain and PET CT response and toxicity.

Three diminesional radiotherapy results were highly significantly better than those of 2D radiotherapy in the term of better pain response in the form of complete pain response observed in 17 (56.7%) patients in the 3D arm and only 2 (6.7%) patients had a progressive pain response versus  4 (13.3%) patients had complete pain response, 10 (16.7%) patients had pain progression in the 2D arm, p-value =0.004. Complete PET  CT response is noticed in 18 (60%) patients and progression were notified in 3 (10%) patients were treated by 3D versus only 6 (20%) patients shown complete response and 13 (21.7%) had a progressive PET results in 2D technique, p-value =0.002. Regards toxicity, the 3D technique had shown better toxicity profiles significantly p-value = 0.004, only 3 (10%) patients had toxicity in the 3D arm versus 13 (43.3%) patients in the 2D arm. In 2D arm 10 (33.3%) patients  showed G2 radiodermatitis , 2 (6.6%) patients showed G1 radiodermatitis , 6 (20%) patients exhibited G1 fatigue, 5(16.6%) patients showed G2 emesis and 4(13.3%)  patients exhibited G2 dysphagia  versus 1(3.3%) patients exhibited  G2 radiodermatitis, 2 (6.6%) patients exhibited G2 emesis, 2 (6.6%) patients showed pain  in 3D arm (Table 2).

3- Assessment of survival

Patients were delivered 2D radiotherapy had shown a progressive disease than those treated by 3D radiotherapy with statistical significance p-value = 0.01. The 3D arm was better than the 2D arm in the term of better significant  PFS and non-significant OS but, p-value = 0.04, 0.14 respectively (Table 3, figure 2).

4.Discussion

          Sixty patients were conducted at the Clinical Oncology and Nuclear Medicine Department and Zagazig University Hospitals were enrolled in a retrospective study. In the current study, we reported that 3D radiotherapy results were highly significantly better than those of 2D radiotherapy in the term of better pain response in the form of complete pain response observed in 17 (56.7%) patients in the 3D arm and only 2 (6.7%) patients had a progressive pain response versus  4 (13.3%) patients had complete pain response, 10 (16.7%) patients had pain progression in the 2D arm. Complete PET CT response is noticed in 18 (60%) patients and progression were notified in 3 (10%) patients were treated by 3D versus only 6 (20%) patients shown complete response and 13 (21.7%) had a progressive PET  CT results in 2D technique. 

      Eighty percent of patients with bone metastasis, exhibited pain relief with up to one-third of reported complete response [22]. Sprave et al evaluated pain response using stereotactic radiotherapy versus 3D conformal radiotherapy, with the assessment of 3-month pain response and revealed that 10(43.5%) patients who had exhibited a complete pain response in stereotactic radiotherapy versus only 4 (7.4%) patients received 3D conformal radiotherapy with significance, this differs with our study due to different some patient characteristics and used technique [23].

      David et al studied 15 patients diagnosed with oligometastatic breast cancer treated with stereotactic body Radiotherapy and reported that PET CT overall response was observed in 7(46%) patients and only 2 (13%) patients who exhibited a progressive metabolic study and this nearly agree with our results, may due to small sample size and different used technique [24].

            Three dimensional technique had shown better significant  toxicity profiles only 3 (10%) patients had toxicity in 3D arm versus 13 (43.3%) patients in 2D arm . In 2D arm 10 (33.3%) patients  showed G2 radiodermatitis , 2 (6.6%) patients showed G1 radiodermatitis , 6 (20%) patients exhibited G1 fatigue, 5(16.6%) patients showed G2 emesis and 4(13.3%)  patients exhibited G2 dysphagia versus 1(3.3%) patients exhibited G2 radiodermatitis, 2 (6.6%) patients exhibited G2 emesis in 3D arm .

Treatment delivery by 3DCRT depends on CT simulation, hence enable visualization of the target and dose constrains properly with accurate calculation of dose volumes [25]. [ 26] stated that 3DCRT allows beam arrangement optimization and sparing of dose constains dosimetrically such as the heart, esophagus, and spinal cord in patients with dorsal spinal metastasis and this completely agree with our justification for better toxicity profile in the favor of 3D than in 2D treatment technique.

Soyfer et al[13] notified that treatment delivery by 3D in lumbar metastasis was of great value in decreasing spinal cord and bowel dose exposure versus the traditional single PA or parallel opposing AP/PA technique.

 Seven (47%) patients were presented by bony pain, 3(20%) patients were presented by hyperpigmentation,2(13%) patients were presented by emesis and another 2(13%) patients were presented by skin induration as toxicity profile analyzed by David et al during stereotactic ablative body treatment implementation to breast cancer patients with only bony oligometastatic lesions [24].

Sprave et al observed that 7 patients were presented by fatigue, 5 patients were G1 and 2 were G2, 5 patients were presented by G1 radiodermatitis and 3 patients were presented by dysphagia and one patient was presented by emesis in the studied 3DCRT arm and this nearly to our results, the minor difference may be due to different patient characteristics [23].  

 In our study, we observed that patients who were delivered 2D radiotherapy had shown a progressive disease than those treated by 3D radiotherapy of statistical significance, mean 3 years PFS  (months) was 22.5 ± 2 in the 2D arm versus 26.2 ±  2 in the 3D arm, 2 years PFS were 50% and 60% respectively.. The 3D arm was better than the 2D arm in the term of non-significant OS, , The mean 3 years OS was 27.2 ± 1.5 (months) in the 2D arm in comparison to 30.4 ± 1.3 (months) in the 3D arm, 2 years OS were 60% and 70% respectively.

Coleman et al stated that patients who were presented by only bony metastasis could exhibit a longer survival than those with visceral metastasis at 5 years OS up to 20 % with 3 years median survival in patients with favorable pathology [27 -29 ], so this justifies proper patients selection for survival improvement intention.

Marco Trovo et al. reported that long progression-free survival could be achieved in breast cancer patients with oligometastatic lesions by radical radiotherapy by individualized recommendations in a study included 44 patients underwent stereotactic radiotherapy and 10 patients underwent intensity-modulated radiotherapy, 2 years PFS and OS were 53% and 95% respectively[11]. This agrees with our objectives, although some differences due to the patient's characteristics and other vary comorbidities.

Our study limitations: Some patients were under systemic therapy such as hormonal, chemotherapy and target therapy which may interfere with our results and may be considered as a bias, urge and emphases the complementary role of such treatments abutting the role of local radiotherapy, the study was a retrospective cohort with small sample size, lack of resources such as stereotactic radiotherapy, although PET CT scan without available fusion advantage, it strength our study because of high sensitivity and specificity, its valuable role on initial patients enrollment and delineation guidance and local control assessment, hence we recommend more studies with more patients inclusion and future promising radiotherapy technological advances with proper patients individualization. 

Conclusion

Three dimensional  conformal radiotherapy is of great value in the improvement of local control, pain response, progression-free survival, and overall survival with tolerable toxicity profile in breast cancer patients diagnosed by bony oligo metastasis at low socioeconomic societies, where lack of more precise high conformal radiotherapy such as intensity-modulated radiotherapy and stereotactic body radiotherapy.      

Conflict of interest

None