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Support Care Cancer DOI 10.1007/s00520-013-1954-9 ORIGINAL ARTICLE Detecting lung cancer relapse using self-evaluation forms weekly filled at home: the sentinel follow-up Fabrice Denis & Louise Viger & Alexandre Charron & Eric Voog & Christophe Letellier Received: 6 May 2013 / Accepted: 21 August 2013 # Springer-Verlag Berlin Heidelberg 2013 Abstract Purpose We aimed to assess if patients' ratings of symptoms can be used to provide an early indication of disease recurrence or progression in lung cancer. We proposed a simple self-evaluation form made of six clinical parameters weekly scored by patients at home as a follow-up—here named sentinel—to improve relapse detection. Its performances were compared to those of a routine imaging follow-up. Methods Patients with lung cancer were prospectively recruited to weekly fill a form at home for self-assessing weight, fatigue, pain, appetite, cough, and breathlessness during at least 4 months. Each patient reported weight and assessed the severity of each symptom by grading it from 0 (no symptom) to 3 (major symptom). A score was retrospectively designed for discriminating patients with relapse from those without. Accuracy of relapse detection was then compared to values of the routine planned imaging. Results Forty-three patients were included in our center and recruited for 16 weeks or more follow-up during which at least one tumor imaging assessment was performed (CT scan or PET-CT). Forty-one completed the form weekly. Sensitivity, specificity, and positive and negative predictive values of sentinel were high (86, 93, 86 % and 93 vs 79, 96, 92, and 90 % for routine imaging—p =ns) and well correlated with relapse (pχ 2>0.001). Moreover, relapses were detectable with sentinel on average 6 weeks earlier than the planned imaging. F. Denis : A. Charron : E. Voog Jean Bernard Center/Victor Hugo Clinic, 9 rue Beauverger, Le Mans, France F. Denis (*) : L. Viger : C. Letellier CORIA—University of Rouen, Av. de l’Université, BP 12, 76801 Saint-Etienne du Rouvray cedex, France e-mail: [email protected] Conclusion This study suggests that a personalized cancer follow-up based on a weekly self-evaluation of six symptoms is feasible and may be accurate for earlier detection of lung cancer relapse, allowing integration in electronic devices for real-time patient outcome follow-up. Keywords Lung cancer . Follow-up . Supportive care . Personalized medicine . Early relapse detection Introduction Lung cancer is the first cause of cancer-induced mortality in the world and remains a poor prognosis [1, 2]. Although pretreatment imaging evaluations are well-defined for the diagnosis of lung carcinoma, very few studies were devoted to the follow-up of patients after the completion of a therapy or during maintenance therapy [3–5]. Moreover, there is no personalized follow-up, and there is no evidence yet that an expensive routine imaging-based follow-up may improve prognosis of patients who could relapse. There is no randomized trial result comparing intensive follow-up using CT scan and symptoms-only follow-up for relapse detection. Nevertheless, a Brazilian retrospective study compared a strict follow-up with frequent visits, imaging, and laboratory examinations in patients who underwent a complete resection of non-small cell lung cancer to a follow-up with infrequent visits that were scheduled mainly on the basis of patient's symptoms evaluated during visits at the hospital [6]. No difference in the survival outcome was noted, but symptom follow-up was found to be more cost-effective than routine imaging follow-up. Few relapses are indeed associated with curative intent in this cancer, and at least 75 % of them are symptomatic [7–9]. Some symptoms also appear to have prognostic value in determining clinical course and survival [10]. Support Care Cancer In our institution, from July 30, 2012 to September 30, 2012, a form designed for our “sentinel” follow-up was given to 43 consecutive symptomatic (or not) patients with surgical excision, complete response, or detectable but nonprogressive lung carcinoma. Patients receiving chemotherapy were excluded except if they received bevacizumab maintenance. An example of the form is shown in Fig. 1. Patient characteristics are reported in Table 1. Median age was 62 years (min, 42 years; max, 82 years). Fourteen patients had distant metastasis. Thirty-five patients received no treatment and eight were under a maintenance treatment by bevacizumab for metastatic disease during our study. Twenty-four patients had no detectable tumor by CT scan or PET-CT, and 19 had nonprogressive detectable tumors. Thirty-seven patients had tumor initial assessments by CT scan and six by PET-CT. Patients were asked to report weight and five symptoms, which were appetite loss, fatigue, pain, cough, and breathlessness, weekly. Words that were used for patient's self-assessment were “fatigue” (same word as in French) to describe asthenia and “breathlessness” (“essoufflement” in French) to describe dyspnea. All terms were clearly explained by a physician during the study entry visit. The five symptoms had to be graded the same day as the weight was recorded. These six items were reported in a form during at least 16 weeks. Each patient self-assessed the severity of symptoms by grading them from 0 (no symptom) to 3 (major symptoms). Weight loss was graded by the physician as follows: grade 0 for no weight loss, grade 1 for 1 kg loss since patient recruitment, grade 2 for 2 kg loss, and grade 3 for 3 kg loss or more. Data collection was prospectively performed. Physical examination was performed during follow-up, every 16 weeks or earlier if needed (due to a patient call, for instance). We also collected filled forms when planned PET-CT or CT scan was performed during routine follow-up, on average 16 weeks after the beginning of the study. PET-CT was systematically used when CT scan was positive and biopsy/cytology was performed when needed. PET-CT or other modalities was also used in symptomatic patients without CT scan abnormalities. In our institution, physical assessment and CT scan are repeated every 16 weeks for all patients during maintenance therapy or following combined radio-chemotherapy or following curative surgery for 2 years, then it is repeated every 6 months for 3 years. Due to the lack of a gold standard to follow-up patients with lung cancer, we choose to combine all examinations to serve as a reference. We then compared the efficiency of the common follow-up in our hospital to sentinel. Fig. 1 Example of a form filled by our patient. True negative case with the sentinel follow-up. This patient had stage 4 NSCLC and had a persistent complete response after chemotherapy. He received bevacizumab maintenance during this study. Stable symptoms were reported with “sentinel” during 20 weeks. No progression was observed with planned follow-up CT scan at 16 weeks. Self-graded symptoms were associated with colors to improve visual assessment by the physician Up to now, one of the most common strategies for a routine follow-up is to track the evolution of possible tumors by performing regular clinical assessments with or without routine imaging at few months interval. In the case of lung cancer, the most obvious symptoms are pain, breathlessness, coughs, fatigue, and appetite [11]. For numerous cancers, one of the most important parameters for the prognostic is the weight loss [12, 13]. The objective of the present study was therefore to test whether a personalized cancer follow-up based on a weekly self-evaluation of six symptoms was reliable and helpful for detecting cancer relapse. We thus designed a follow-up based on patients' ratings of symptoms—here designated by “sentinel”—for early relapse detection. Its performances were then compared to those of a routine planned follow-up imaging based on CT scan or PET-CT. Methods Support Care Cancer Table 1 Patient characteristics Characteristics Males/females Pathology Squamous cell Adenocarcinoma Small cell carcinoma Large cell carcinoma Initial Stage I/II IIIA IIIB IV Detectable disease at the beginning of the study Yes No Previous treatment Surgery Radiotherapy Concomitant radio-chemotherapy Chemotherapy Disease status at study entry Complete response after surgery Partial or complete response after radio-chemotherapy Stable disease after radio-chemotherapy Partial or complete response after palliative chemotherapy Stable disease after palliative chemotherapy Treatment ongoing None Maintenance therapy Planned imaging CT scan PET-CT N =43 38/5 15 20 4 4 3 21 2 14 19 24 5 2 22 14 5/5 19/22 3/22 8/14 6/14 35 8 37 6 The dynamics underlying symptoms were retrospectively investigated from the forms. The global score of the six clinical parameters (the five symptoms plus the weight grade) was computed for each week and for each patient (see Figs. 1 to 2, for examples). The sentinel returns retrospectively a positive relapse with the highest sensitivity (93 %) when at least one of the three following conditions was verified: 1. Three kilogram weight loss during at least 2 weeks 2. Two symptoms simultaneously equal to grade 3 during at least 1 week 3. A global score greater than or equal to 7 during at least 2 weeks These conditions were tested for detecting relapse only once the global score was less than 7 for 1 week. For instance, a patient returned a global score greater than 6 during the first 3 weeks after inclusion and less than 7 at the fourth week: this procedure was thus only applied starting from week 4. This procedure was retained after a trial and error approach. It allows detecting cancer relapse with the highest sensitivity, specificity, and positive and negative predictive values. Youden index and Q Yule coefficients were also computed for all types of relapse (locoregional or distant failure). Results were then compared to relapse detections obtained with the routine imaging follow-up and with the complementary PETCT or pathological/cytological assessments if needed. Brain MRI was only performed in the presence of neurologic symptoms and signs on physical examination. The Fisher exact test was used to compare sensitivity, specificity, and positive and negative predictive values between “sentinel” and routine imaging follow-up. χ 2 test was used in 2×2 tables to assess statistical association between the disease (relapsing or not) and the “sentinel” or imaging results. All tests were two-sided and “p” value was considered significant when less than 0.05. Before inclusion, all patients signed written informed consent and “Informatic and Liberty National Commission” form allowing data deletion according to patient's wish. The study followed guidelines of our institutional ethical committee. Results The study included 43 consecutive patients. Forty-one were compliant and filled exhaustively their form. Two patients forgot or refused to fill their form. Patients were followed up during at least 16 weeks (median time, 5 months), and all presented at least one tumor imaging after reference imaging assessment (which was performed at study initiation). Due to relapse-associated acute symptoms, one patient visited the oncologist earlier (4 weeks only after the beginning of the study) and a CT scan was thus performed. Note that “sentinel” detected the relapse because this patient reported grade 3 anorexia, grade 2 asthenia, and grade 3 pain caused by liver metastasis. Weight loss was scored with grade 2: this patient thus fulfilled condition II. Fourteen patients presented a tumor relapse/progression as determined by combining clinical imaging (CT scan and PETCT) and cytological/pathological examinations. All patients who relapsed (n =14) were symptomatic and 12 of them were positive according to “sentinel” (86 %). Two were positive for condition II alone (2 symptoms graded to 3), 4 were positive for condition III alone (global score ≥7 for at least 2 weeks), 1 was positive for both conditions I (3 kg of weight loss during 2 weeks) and II, 2 were positive for both conditions I and III, 2 were positive for conditions II and III, and 1 was positive for conditions I, II, and III. Routine imaging (CT scan for 33 evaluable patients and PET-CT for the others) did not allow detecting relapse in three patients. One patient had pleural Support Care Cancer Fig. 2 Example of a true positive “sentinel” detection, which was a false negative case with a routine imaging follow-up: this patient reported progressive weight loss and asthenia. Planned CT scan and PET-CT were negative. Lumbar puncture led to discover metastatic meningitis. Mild but detectable symptoms thus appeared 4 weeks before planned imaging infusion, which was stable as assessed by CT scans (at the inclusion in this protocol and 16 weeks later), but cough increased and pleural cytology became positive. The second patient presented an increase of his pain but CT scan (the routine imaging) did not show any tumor progression. Only a complementary PET-CT and a biopsy allowed detecting a cancer relapse. These two patients were detected using the sentinel follow-up. A third patient had no relapse detected with the routine imaging (CT scan and PET-CT were negative) but was positive according to sentinel: he had a meningeal carcinomatosis diagnosed using a brain MRI (Fig. 2). Sentinel results were then compared to routing imaging (CT scan or PET-CT) and/or cytology. We thus found retrospectively 12 true positive patients, 25 true negative patients, 2 false positive and 2 false negative patients (pχ 2 <0.001). For all true positive “sentinel” patients, symptoms were detectable on average 6 weeks before routine imaging (min, 1 week; max, 12 weeks). The two false negative patients returned by “sentinel” had symptoms. One had isolated superior cave syndrome 16 weeks after the study initiation caused by mediastinal relapse. The second false negative case corresponds to a patient presenting a grade 2 dyspnea and asthenia the week of the planned routine imaging. Symptoms just started to be self-assessed with increasing grades by the patient when the routine imaging was scheduled. He had pericardial metastasis and died 1 month later. This is one example for which the routine imaging was planned at the occurrence of symptoms: in such a case, sentinel would have detected this case 1 or 2 weeks later. Sensitivity, specificity, and positive and negative predictive values, Youden index, and Q Yule coefficient for evaluating sentinel results versus those obtained with a routine planned imaging are reported in Table 2. Sensitivity, specificity, and positive and negative predictive values were 86, 93, 86, and 93 % for “sentinel” and 79, 96, 92, and 90 % for planned imaging, respectively. There were no significant statistical difference (p =ns) between “sentinel” and the routine imaging follow-up for relapse detection. Patients identified as false positive (false negative) by sentinel were not the same as the patient identified as false positive (false negative) by routine imaging. We also calculated sensitivity, specificity, and positive and negative predictive values, Youden index, and Q Yule coefficient of “sentinel” for evaluable patients with (n =18) or without (n =23) detectable disease at the beginning of the study. The relationship between the disease (progression/relapse or not) and the “sentinel” assessment remains significant in both populations (pχ 2 <0.01 in patients without detectable disease and pχ 2 <0.001 in patients with initial detectable disease) as reported in Tables 3 and 4. Sentinel tended to be more accurate than imaging in patients having detectable disease than in patient without initial nondetectable disease but the difference was nonsignificant. Discussion To the best of our knowledge, this study is the first to test a personalized symptom-based follow-up in lung cancer. It suggests that weekly self-scored patient symptom dynamics may lead to a follow-up with an excellent compliance and completeness and may be very helpful to detect cancer relapse or tumor progression. A variety of assessment instruments have been created to assess and follow up cancer symptoms. However, there is no ideal instrument, and the wide variety of instruments reflects the different settings for symptom assessment as reported in a wide review by Kirkova and colleagues [14]. However, a recent study showed that realtime data collection of patient with cancer is feasible and allowed to monitor symptoms to assess toxicity and tumor response [15]. Our study showed that relapse detection may be performed using self-assessment of few symptoms which Support Care Cancer Table 2 Two by two tables and results for evaluable patients (n =41) with the sentinel and the routine imaging (CT scan or PET-CT) when compared with a relapse/progression detection using all modalities. Chisquared test indicates that there is a significant association between the two forms of assessment and the disease (relapse or no relapse) Relapse No relapse 12 2 11 3 2 25 1 26 Sentinel (%, CI 95) Routine imaging (%, CI 95) Sensitivity Specificity Positive predictive value 86 % (67–100) 93 % (83–100) 86 % (67–100) 79 % (57–100) 96 % (89–100) 92 % (77–100) Negative predictive value Youden Index Q Yule coefficient pχ 2 93 % (83–100) 0.78 0.97 <0.001 90 % (77–100) 0.75 0.98 <0.001 Sentinel positive Sentinel negative Imaging positive Imaging negative could be sent by the patients to the oncologist: relapse detection may thus be reliably observed almost in real time and, in average, earlier than routine imaging. Self-evaluated symptoms were weight, fatigue, pain, appetite, cough, and breathlessness. Fatigue mainly results from a lack of sleep, and weakness would have been more appropriate since it is more related to the lack of energy induced by the tumor growth. Our form to be filled up by the patients will thus be improved by replacing “fatigue” by “weakness”. “Breathlessness” is commonly induced by a physical effort. “Shortness of breath” is induced by a respiratory failure (as induced by a lung cancer, for instance) and would be more rigorous. Nevertheless, all our patients clearly defined what breathlessness is but may have some difficulties to recognize what “shortness of breath” is. This is why we choose to misuse “breathlessness.” We thus used an original approach by prospectively using self-evaluation forms weekly filled at home by the patients having lung carcinoma and high risk of relapse. A score Table 3 Two by two tables and results for evaluable patients without detectable disease (n = 23) (with and without maintenance therapy) at the beginning of the study. Chi-squared test indicates that there is a significant association between the two forms of assessment and the disease (relapse or no relapse) strongly associated with relapse was thus obtained. It can be integrated in electronic devices such as patient smartphone. In our population, we found that the sentinel score may be as reliable as a routine planned imaging follow-up. Moreover, on average, relapses detection (according to symptoms) were reported with “sentinel” 6 weeks before planned imaging thus suggesting that sentinel would allow more efficient treatment since it was initiated earlier than routine imaging follow-up. It is indeed important to note that all symptomatic relapsing patients but one have waited oncologist planned visit and imaging while symptoms began sometime many weeks earlier. This suggests that an earlier adapted oncological or symptomatic treatment could have been provided. The symptoms request substantial needs of supportive care, and numerous patients do not visit their physician, although symptoms may be severe when associated with relapse [16]. Earlier alert by an electronic version of sentinel would therefore help to prevent clinical deterioration of patient before initiating treatment. Relapse No relapse Sentinel positive 3 2 Sentinel negative Imaging positive Imaging negative 1 3 1 17 0 19 Sentinel (%, CI 95) Routine imaging (%, CI 95) 75 % (32–100) 89 % (75–100) 60 % (17–100) 94 % (83–100) 0.64 0.92 <0.01 75 % (32–100) 100 % 100 % 95 % (85–100) 0.75 1 <0.001 Sensitivity Specificity Positive predictive value Negative predictive value Youden Index Q Yule coefficient pχ 2 Support Care Cancer Table 4 Two by two tables and results for evaluable patient with detectable disease (n =18) with and without maintenance therapy at the beginning of the study. Chisquared test indicates that there is a significant association between the 2 forms of assessment and the disease (relapse or no relapse) Relapse No relapse 9 1 8 1 0 8 2 7 Sentinel (%, CI 95) Routine imaging (%, CI 95) Sensitivity Specificity Positive predictive value 90 % (71–100) 100 % 100 % 80 % (55–100) 88 % (66–100) 89 % (69–100) Negative predictive value Youden Index Q Yule coefficient pχ 2 89 % (69–100) 0.9 1 <0.001 78 % (51–100) 0.68 0.93 <0.01 Sentinel positive Sentinel negative Imaging positive Imaging negative Sentinel may also be useful to limit false positive alerts and may reduce the anxiety of patient due to slight symptoms because they would be aware that the physician is kept informed continuously about their global status. Symptomatic relapse (or progression) rate in our study (100 % of relapse) is consistent with other published data. In their study, Gilbert et al. showed that in 245 patients having earlier stages (1 to 2B) who followed up after operation, 80 among 111 patients who relapsed were symptomatic (72 %) and 67 % of relapses were diagnosed by a generalist physician [8]. Our population was heterogeneous since it combined patients with or without maintenance treatments. We choose to incorporate patients treated by maintenance bevacizumab due to the good tolerance of this treatment and because it does not interact with patient's relapse-induced symptoms. On the other hand, “sentinel” was not used in patients having more “aggressive” chemotherapy that would have induced symptoms perturbing “sentinel” results. The size of the cohort is small, but χ 2 test and Yule Q, coefficient that measure the link between the disease and “sentinel”, results are quite convincing even in the subgroups of patients with initial detectable or nondetectable tumors. Lung cancer is a disease for which intensive follow-up does not necessarily improve survival because there is often no effective therapy against a recurrence. This expectation is suggested by studies of follow-up in small cohorts of patients curatively resected or irradiated non-small cell lung carcinoma [3–6, 17]. Hence, patients with detectable but nonprogressive tumors were incorporated in our study because no documented standard for the surveillance of these patients were set in the NCCN, ACCP ASCO, or ESMO guidelines [18, 19]. We thus think that a personalized follow-up based on weekly selfassessed symptoms should be developed for this population in association with a routine imaging. A large randomized clinical trial conducted by the French Intergroup of Thoracic Oncology (IFCT 0302) is in progress in France to compare, in postoperative situations, a follow-up made of clinical and thoracic X-ray planned every 6 months, and a more intensive follow-up that adds CT scan and endoscopy to clinical examination every 6 months on survival. However, in this study, planned visits to oncologists occur only every 6 months, which thus provide only sparse data to detect tumor relapse. Compare to such a follow-up, clinical data as defined in sentinel could have been sent weekly to the oncologist by a smartphone for instance and thus treated in real time by him. This concept is already used in cardiology (by monitoring blood pressure), diabetology (by monitoring glycemia), and in nutrition care (by monitoring weight variation). Due to the good compliance provided by our patients, sentinel could have improved the efficacy of a routine imaging by avoiding many useless imaging. It could be useful too for individualizing patient's follow-up thus avoiding anxiety producing unnecessary and expensive imaging for nonsymptomatic and nonrelapsing patients. Reports of patients could appear subjective or nonspecific because patients assessed their symptoms themselves, and benign disease may cause symptoms close to those leading to conclude to a relapse. We only found two false positive patients in our study. One had simultaneously bronchitis and gastroenteritis, and the other had 3 weeks bronchitis. Subjectivity was limited by the patient weight, which is an objective measure and strongly related with relapse when associated with fluctuations of other symptoms. Moreover, our conditions are mainly based on the dynamics (including duration) of symptoms and not only on the values of grades at a given time. This real-time assessment of symptoms and their underlying dynamics by patient may be useful to avoid underestimation of symptoms by physician or overestimation by family caregivers as it appears to be in clinical practice [20]. Our study reveals a very strong agreement between patients' ratings of symptoms and tumor dynamics. This approach Support Care Cancer occurs to be in agreement with the new theoretical analysis of a chaotic cancer model describing the interactions between host and tumor cells [21]. In this model, the best variable to observe the cancer dynamics is sometimes the population size of host cells and not necessarily the population size of tumor. At patient body scale, this suggests that symptoms or weight loss, quite related to the behavior of host cells, could be sometimes better to observe tumor dynamics on host than observing the tumor itself. This assumption is well supported by the present study and others [12, 13]. Some studies suggest that symptom improvement could be a prognostic factor for survival in cancer patients undergoing palliative care. Sentinel could thus be used for that purpose [22]. Moreover, as symptoms are prevalent and severe among patients with cancer [23], clinical study seeking to evaluate the impact of treatment on patients (thus including measurement of symptoms) in real time are promising [15]. A prospective study is in progress to optimize our sentinel follow-up and to test if sentinel improves the routine imaging follow-up or not. This study is in progress and will also assess long-term compliance and satisfaction of patients and physicians using an electronic version of “sentinel” to report symptoms and weight changes over time using their smartphone or PC. Alerts are automatically transmitted to the oncologist. 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