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Sociodemographic, clinical profile, and treatment characteristics of oncology patients developing radiation recall phenomenon: Two tertiary care center's experience of an eternal unpredictable phenomenon of cancer treatment

ABSTRACT Objectives: To determine the socio-demographic and clinical profile of cancer patients developing radiation recall phenomenon or radiation recall dermatitis following chemotherapy administration, previously treated with external irradiation. We assessed its incidence, severity, frequency, differentiation from radio-sensitization and radiation-dermatitis, its correlation with radiation dose and chemotherapeutic agent, and various parameters affecting its occurrence. Materials and Methods: This observational prospective study was designed for 1092/2676 (50.2%) patients of histologically proven carcinoma breast, carcinoma lung, lymphomas, chest wall sarcomas, thymomas, thymic carcinomas, nasopharyngeal cancer, bladder carcinoma, rectal cancer, and metastatic cases who received radiation therapy followed by chemotherapy. Intake, treatment, observation, and follow-up were done from July 2014 to July 2021 for 7 years in two tertiary care cancer institutes of government setup. Results: In our study, majority of recall phenomena were reported in breast carcinoma 43/71 (60.5%) followed by carcinoma esophagus with 07/71 (9.8%) cases. Females developed 54.9% grade-I/II and 90% grade-III/IV recall cases compared to males with 45.1% and 10% cases, respectively (P = 0.005). Median radiation dose used was 45 Gy (dose range 8–70 Gy) (P = 0.656). Docetaxel resulted in 55% recall cases followed by paclitaxel with 12.7% of cases. Combination therapy reported 71.8% of cases compared to monotherapy with 28.2% of cases. Recall-cases recorded in the time period of 3–4 weeks between radiation and chemotherapy were 59/71 (83%) and those reported in >4 weeks were 12/71 (17%). Time-gap between 3 and 4 weeks reported 49% grade-I/II and 100% grade-III/IV recall-cases while time-gap >4 weeks resulted in 26% and 0% cases respectively (P = 0.000). Conclusion: In this study, taxanes and platinum-agents were the most common chemotherapeutic drugs involved in the occurrence of the recall phenomenon. Multi-drug regimens resulted in higher recall cases compared to monotherapy. Radiation dosage did not cause any significant impact. The risk and severity of recall reactions increased with female gender and shorter time-interval between radiation and systemic therapy, while early-onset recall cases displayed greater severity. This precedented but unpredictable phenomenon ceases to be a topic to be discarded in this modern era of highly conformal radiation therapy techniques and targeted cancer therapy.


Introduction
R adiation recall phenomenon (RRP) or radiation recall in 1959 by D'Angio [2] describing recall associated with actinomycin-D [2,3]. In this rather interesting phenomenon, the skin/mucosa recalls the earlier irradiation effect after chemotherapeutic, cytotoxic agents, or other drug classes are administered, in the form of inflammatory reactions ranging from mild to severe [4,5], resulting in significant morbidity and even mortality. Majority of published literature have described RRD as a synonym of RRP, others have reported reactions affecting the internal tissues [6] such as oral mucosa, lung parenchyma, gastrointestinal tract (GIT), especially esophagus, genitourinary tract [7,8], central nervous system [9], and even muscular layer [10], RRD has been mainly reported in breast carcinoma patients receiving thoracic irradiation, while its occurrence in malignancies such as melanoma [11], lung [7,8,12], oropharynx [13], nasopharynx [8], and non-Hodgkin lymphomas [8] have also been published.
RRP is generally diagnosed based on presenting history, symptoms, signs, and clinical examination without any substantial need of pathological [7,14,15] or radiological confirmation [15]. However, biopsy may be done in case of suspicion of skin infection or recurrence [15]. The severity of RRD ranges from mild to moderate to severe [12], graded as per various versions of the United States National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) published over the years. Radiation-dermatitis (RD) is the most common acute manifestation of radiation which may mimic RRD making it imperative to differentiate between RD and RRD. RD generally appears within the second week of the RT schedule and majority of patients who develop RRD have no RD during or at the conclusion of RT. RRD must occur after completion of RT and resolution of acute RD. Another clinical entity resembling RRD is radio-sensitization (RS) which is any physical, chemical, or pharmacological intervention that increases the lethal effects of radiation when administered in conjunction with it within a week [4]. A week less and a week more between RT and systemic therapy has been described as the discriminating point between RS and RRD respectively [4][5][6][7][8]. RRD being rarer than RS, have a time-frame of days to months to years for its initial occurrence [13][14][15]. Cellulitis, fungal infection, contact dermatitis, eczema, lichen planus, pemphigus, erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome are few dermatological pathologies which need to be ruled out.

Study design, sample size, inclusion, and exclusion criteria
A prospective observational study was designed to determine the clinical profile of cancer patients developing RRP/RRD undergoing treatment in the department of malignant disease treatment center of two tertiary care cancer institutes with academic and research potential of government setup. Cases who were actively undergoing RT and CMT were periodically observed and evaluated for the occurrence of RRP. All patients were treated as per standard of care and international guidelines. The only intervention done was to manage the recall reactions. The intake planned treatment, and follow-up were conducted from July 2014 to July 2021 over 7 years. The study population consisted of patients belonging to any gender, race, or ethnicity from both rural and urban backgrounds. Out of the total of 2676 cases registered during the study period, 1092 histologically confirmed locally advanced cases of carcinoma breast, lung, lymphomas, soft-tissue sarcoma (STS), thymomas, thymic carcinomas, nasopharyngeal cancers, bladder, and rectal cancer cases were enrolled. Metastatic cases were also included as per inclusion criteria: (1) age18-75 years, (2) cases receiving CMT after previous RT, (3) Karnofsky Performance Status (KPS) of ≥60%, (4) no allergic/anaphylaxis history, and (5) no active skin infection. Exclusion criteria: (1) cases receiving RT or CMT from other institutes, (2) patients who discontinued RT before completion, (3) time-interval between RT and CMT <07 days, (4) nonhealing RD, (5) RS, and (6) patients with KPS <60%. All procedures were in accordance with the institutional scientific advisory, ethical and regulatory committee, National research committee, and 1964 declaration of Helsinki. The IRB (Institutional review board) reference number of the manuscript is IRB/CHSC/64/2019. Consent of the patients and their relatives were taken.

Disease evaluation
To maintain the uniformity of study, severity grades of recall phenomenon were evaluated according to CTCAE versions 4.0: Grade-I: Combined area of ulcer <1 cm; nonblanchable erythema of intact skin with associated warmth or edema; Grade-II: Combined area of ulcer 1-2 cm, partial thickness skin loss involving skin or subcutaneous fat; Grade-III: Combined area of ulcer >2 cm, full-thickness skin loss involving damage to or necrosis of subcutaneous tissue that may extend down to fascia; Grade-IV: Any size ulcer with extensive destruction, tissue necrosis, or damage to muscle, bone or supporting structures with or without full-thickness skin loss; Grade-V: Death. When the patients presented with lesions characteristic of RRP/RRD, they were jointly and exhaustively evaluated by the principal workers of two institutes in concurrence with the medical oncologists in multi-disciplinary tumor boards and oncology clinics. Further, these patients were regularly monitored in the weekly radiation clinics to confirm the morphology of RRP/RRD.

Treatment and follow-up
As this study was undertaken in a government set-up, all patients were treated with the 2-dimensional-RT (2-DRT) technique in both institutes. RT doses were imparted according to the stage of malignancies, ranging from 8 Gy in metastatic cases to 70 Gy in primary cases. CMT regimen was chosen according to the neoplastic pathology and stage. Three monthly follow-ups included physical examination, laboratory analysis, chest radiography, and pan-endoscopy. Computed tomography, magnetic resonance imaging, and 18-fluoro-deoxy glucose whole-body positron-emission tomography scan were performed at 6 months and 12 months, thereafter on case-to-case basis. Telephonic follow-up was done for patients who were unable to come physically. Patients developing RRP/RRD were managed symptomatically and ongoing treatments were resumed after their resolution.

Statistical analysis
Data were entered from predesigned forms into an electronic spreadsheet (Microsoft-excel) and analyzed using Statistical Product and Service Solutions version-20 (SPSS-20, IBM, Armonk, NY, USA). Pearson Chi-square test for Fisher's Exact was used to compare proportions. Univariate analysis was used to assess the severity of RRP/RRD as per specific sociodemographic and clinical factors. Two-tailed P < 0.05 was taken as statistically significant. To assess the precision of the estimate 95% confidence intervals for all probabilities were calculated.

Results
Overall, 2676 cases of various malignancies were registered over 7 years duration and 1092/2676 (50.2%) cases of malignancies fulfilled the eligibility criteria. Patient characteristics and distribution of malignancies as per inclusion criteria registered from July 2014 to July 2021 are shown in Table 1 Table 2].
Statistical significance was seen only with gender and time-gap between RT and CMT. Females developed 54.9% grade-I/II and 90% grade-III/IV recall cases compared to males with 45.1% and 10% of cases, respectively (P = 0.005). Time-gap between 3 and 4 weeks reported 49% grade-I/II and 100% grade-III/IV recall cases, while time-gap >4 weeks resulted in 26% and 0% cases, respectively (P = 0.000) [ Table 4].

Discussion
In this prospective observational study, we investigated the clinical profile of cancer patients developing RRP/RRD covering all parameters that may affect its occurrence. This study recorded an overall incidence of 6.5% [ Table 1] compared to the reported incidence of 8.8% by Kodym et al. [28], 9.7% by Harsh et al. [29], and 1%-10% as per previous studies [1,2,7]. Maximum recall cases were of breast carcinoma, so the overall number of females was more compared to males (F:M = 46:25). Univariate analysis showed statistically significant higher severity grades in females compared to males (P = 0.005) [ Table 4]. However, no gender predilection has been reported by previous studies [5,7,[26][27][28][29]. The median age of males was 65 years (40-78) and of females was 61 years (45-71). No statistical correlation was found between occurrence and severity of RRP with the age of the patient (P = 0.173), maybe because of the heterogeneity of this phenomenon. Patients who had no RD initially developed grade-IV RRD later, as was seen in patients of carcinoma lung with brain metastasis [ Figure 4]. Those with grade-I RD developed grade-III RRD in breast cases, while those with initial grade-III proctitis developed grade-II recall-proctitis [ Figure 6]. The area of RRD was comparable to the earlier RD area, however, some spread or generalization was observed.
In our study, the median RT dose was 45 Gy (dose range 8-70 Gy), while Harsh et al. [29], used median RT dose of 36.4 Gy (30-50 Gy) in breast carcinoma cases. We observed that 30 Gy resulted in grade-IV, while 70 Gy caused grade-I recall reactions [ Table 3] consistent with previous studies [7,27,30]. This study could not attribute any threshold RT dose for the severity of RRP (P = 0.656) [ Table 4], similar to world literature [7,27,30]. However, few studies have postulated that photon energy ≤6 MV [7,30] and higher  Discontinuation of CMT + oral prednisone 60-100 mg/day for 2 weeks followed by a slow taper over 3-12 weeks + antitussive syrups + supplemental oxygen + oral antibiotic 12-14=1/1 (100) SSD: Silver sulfadiazine cream, APC: Argon plasma coagulation, PPI: Proton-pump inhibitor, NSAIDs: Nonsteroidal anti-inflammatory drugs, CMT: Chemotherapy, RRP: Radiation recall phenomenon, RRD: Radiation recall dermatitis RT dose may cause greater recall reactions [26]. Being a government set-up with no conformal RT techniques available, we used the 2-DRT technique to treat all patients. Since it was an observational study with no comparative-arm-like intensity-modulated RT (IMRT)/image-guided RT (IGRT)/volumetric-modulated arc therapy (VMAT), we were not able to correlate the occurrence of RRP with the RT technique. However, highly conformal RT techniques like IMRT, IGRT, VMAT, and precise target-dosimetry may reduce the incidence of RRP/RRD as it has benefitted in the reduction of RD [29][30][31]. No CMT was started within 7 days of completion of RT to differentiate with RS. For all malignancies included in this study, docetaxel was the most common drug involved and was taken as the prototype while determining its effect on the severity of RRP, however, no statistical significance was derived (P = 0.110) [ Table 4]. Herceptin, tamoxifen, pemetrexed, nivolumab, and pembrolizumab were also involved, apart from variety of cytotoxic drugs with diverse doses and diverse regimens, making it extremely difficult to pinpoint which drug reacted in which patient. Although most reports have described single drug involvement [4,7,29], our study observed combination therapy resulting in 71.8% recall-cases compared to monotherapy with 28.2% recall reactions, although no statistical significance was seen (P = 0.711) [ Table 4]. We also observed that capecitabine was associated with esophagitis and proctitis which may be attributed to enhanced mucosal involvement due to pro-drug activation [6,7,23].
This study highlighted the importance of time-gap between completion of RT and initiation of CMT. RRP/ RRD cases observed in 3-4 weeks period were 83% and those reported in >4 weeks were 17%. Earlier studies have reported recall incidence of 5.1% in >4 weeks [29], 19.4% in ≤4 weeks, 7.4% in >3 weeks, 18% cases in ≤3 weeks, and 28.6% in <1 week [32] [ Table 2]. Our study reaffirmed the postulated theory that the shorter the interval between RT and CMT, higher the risk of developing RRP/RRD [4,7,25,27]. The time gap also affected the grades of recall reactions. Time-gap between 3 and 4 weeks reported 49% grade-1 and 2 and 100% grade-3 and 4 recall-cases compared to time-gap >4 weeks which resulted in 26% and 0% cases, respectively (P = 0.000) [ Table 4]. The above result verified the observation that the severity of RRD tends to be greater when the time period between RT and CMT is shorter [28]. The number and severity of cases were more when the time of onset of RRP/RRD after CMT was shorter. Onset of symptoms in <1 week showed total 49.3% cases compared to onset >5 weeks with 1.9% recall-cases [ Table 3]. Management of RRP/RRD depends on its severity and the organ system involved [33]. Mild reactions resolved spontaneously or with symptomatic therapy but severe cases were managed with hospitalization, medical and surgical interventions [ Table 5].

Conclusion
RRP/RRD is a puzzling phenomenon which has kept researchers and clinicians at bay regarding its occurrence and pathophysiology for over more than 60 years. In our experience, it is impossible to predict which drug, either single or in combination will cause RRP in which patient and which patient will react to which drug. No CMT regimen or RT dosage can be designed to prevent RRP. Females may be at increased risk of developing severe RRP compared to males. Taxanes, platinum agents, pyrimidines, and anthracyclines were identified as the serial culprits in the study. The treating clinician/oncologist should have a high degree of suspicion to differentiate between RS, RD, and RRD and report such cases whenever possible. However, prolonging the intervening period between the termination of RT and the start of CMT can reduce both the incidence and severity of RRP. The treatment approach for RRP remains organ-specific symptomatic management, with steroids and analgesics forming the cornerstone of therapy. Presently there is a dearth of published data which elaborates the correlation of different RT techniques with the occurrence of RRP and therefore, we recommend that more such comparative studies be undertaken in near future.

Financial support and sponsorship
Nil.

Conflicts of interest
There are no conflicts of interest.