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Keywords:

  • cancer;
  • chemotherapy;
  • deferred;
  • immediate;
  • metastatic

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Aim:  To examine the evidence of benefit in initiating immediate chemotherapy in patients with newly diagnosed asymptomatic metastatic incurable cancer, compared with delaying chemotherapy until symptomatic progression.

Methods:  Through an extensive review of published reports, we examined the biological, clinical, psychological and ethical background of the issue and reported on the available clinical trial evidence in a variety of tumor types.

Results:  Only a limited number of clinical trials have directly examined the role of immediate versus delayed chemotherapy in patients with incurable asymptomatic metastatic cancer. Small studies in mesothelioma, colorectal cancer, breast cancer, myeloma, and low-grade lymphoma suggest no survival benefit for the immediate initiation of chemotherapy. However, there was no evidence in other tumor types.

Conclusion:  The appropriate timing of chemotherapy initiation in an asymptomatic patient with metastatic cancer remains a substantial question in oncology. Many factors are likely to impact on the decision. However, little if any evidence demonstrates a clear advantage in the immediate initiation of chemotherapy in this setting.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. REFERENCES

For the symptomatic patient with incurable metastatic cancer, the initiation of chemotherapy may be a complex decision. Consideration must be given to the nature of the cancer itself, the symptoms associated with the cancer, the likelihood of benefit from treatment, the potential toxicity associated with therapy, and specific patient factors, including performance status, age and comorbidities.1 Further, patients themselves will address the question from a variety of philosophical frameworks.2

Over many decades, the role and effectiveness of palliative chemotherapy has been well defined. Studies of chemotherapy compared to best supportive care have documented tangible benefits, including symptom control, improved quality of life and survival benefits.3–11 Similarly, new chemotherapy agents have improved outcomes above and beyond previously used regimens in virtually all of the cancers we treat.9,12–19

The question of intervention with chemotherapy is more problematic in patients who are asymptomatic despite having metastatic disease. These patients may be diagnosed incidentally de novo or during routine follow-up after a previous diagnosis of localized cancer. This group of patients is enlarging given the widespread availability of radiological, biochemical and tumor marker testing.20–24 Presentation while asymptomatic varies with the type of cancer. Twenty-four percent of all hepatoma cases present with no symptoms, compared to 2% of patients with lung cancer, and 17% of patients with colorectal cancer.25–27

Patients enrolled in trials may vary in their disease, performance status, and comorbidities, and Table 1 documents a selection of recent pivotal phase III studies across a variety of tumor types. In the clinical trial setting, the proportion of patients in large studies who were performance status (PS) 0 (asymptomatic) ranges between 4 and 68%, with the proportion of patients with PS 0-1 (asymptomatic or mildly symptomatic) 82–99% for melanoma, prostate, colorectal, ovary and lung cancers.

Table 1.  Performance status at trial entry in selected randomised trials
DiseaseRegimenPS 0 (%)PS 1 (%)PS 0-1 (%)PS 2 (%)PS 3 (%)
  1. 5-FU, 5-fluorouracil; carbo, carboplatin; cis, cisplatin; D+E, docetaxel + estramustine; doc, docetaxel; DTIC, dacarbazine; ECF, epirubicin + cyclophosphamide + 5-fluorouracil; etop, etoposide; FA, folinic acid; FL, 5-flourouracil + folinic acid; FOLFOX, oxaliplatin + 5-fluorouracil + folinic acid; GBM, glioblastoma; gem, gemcitabine; IFL, irinotecan + 5-fluorouracil + folinic acid; irino, irinotecan; M+P, mitoxantrone + prednisolone; NA, not applicable; NSCLC, non-small-cell lung cancer; Pac, paclitaxel; PS, performance status; RT, radiotherapy; SCLC, stage small-cell lung cancer; Sx, surgery.

Colorectal16FOLFOX vs 5-FU/FA46449010NA
Prostate10M+P vs P45963288
Prostate14D+E vs M+PNANA8911NA
Colorectal15IFL vs FL5142837NA
Ovary17Platinum/Pac vs platinum6430946NA
GBM28Concurrent temozolamide/RT vs RT alone39498812NA
Gastro-esophageal29Perioperative ECF vs Sx alone6832100NANA
NSCLC30Cis/pac vs cis/gem vs cis/doc vs carbo/pac3064946NA
NSCLC4Vinorelbine18587624NA
SCLC31Cis/irino vs cis/etop12778911NA
Renal cell cancer32Sunitinib5446100NANA
Melanoma33Fotemustine vs DTIC6631991NA

Two alternative intervention strategies are commonly practiced in patients with asymptomatic metastatic incurable cancer: immediate chemotherapy and delayed chemotherapy. The latter is usually introduced at symptomatic progression of disease. We have conducted a review of published reports to examine if there were any objective data to recommend one approach over the other and to review the issues that may impact on the decision making process.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Searches of the following databases were undertaken: Medline, PubMed and The Cochrane Database of Randomized Controlled Trials. Search terms used included: “chemotherapy”, “metastatic”, “early”, “late”, “deferred”, “immediate”, “timing”, “active surveillance”“expectant”, “upfront”, “watchful waiting”, “observation”, “palliative”, and “asymptomatic”. “Immediate” treatment was defined as initiated as soon as metastatic disease was established by any means, and “delayed” treatment as initiated at the time of development of symptoms. Only studies that prospectively randomised asymptomatic patients to immediate versus delayed chemotherapy were identified. Subgroup analyzes of symptomatic versus asymptomatic patients in trials were not examined. The bibliographies of relevant articles were screened for the identification of additional articles. Abstracts from the American Society of Clinical Oncology annual meeting were examined (2000–06). Searches within mainstream oncology journals were undertaken, local experts were asked about relevant articles and oncology textbooks were examined.

Other relevant areas of interest, such as tumor biology, animal studies, patient preferences, and physician preferences were also examined.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. REFERENCES

A total of nine studies prospectively compared immediate versus delayed chemotherapy (Table 2). Only three were published in the last 10 years. Information was found regarding low-grade lymphoma, colorectal cancer, breast cancer and mesothelioma. A Cochrane Systemic Review examined myeloma. No studies were found regarding the treatment of prostate, pancreatic, esophageal, ovarian, stomach, germ cell, renal, head and neck, non-small-cell lung cancer carcinoma, hepatoma, glioma, sarcoma, or melanoma.

Table 2.  Phase III studies examining immediate versus delayed chemotherapy in patients with asymptomatic metastatic cancer
StudyTumor typenMedian follow-up (mo)Criteria for inclusionQOL% Delayed pts Rx with CT for progressionMedian time to CT in delayed group (mo)Median survival immediate group (mo)Median survival delayed group (mo)P-valueJudgement on treatment's effectiveness
  1. CT, chemotherapy; D-S, Durie-Salmon; LGL, low grade lymphoma; NE, not examined; NS, not started; OS, overall survival; QOL, quality of life; RR, response rate.

Young et al.34LGL10460Stage III or IV No symptomsNE44%34Not reachedNot reachedNSReasonable to wait
Brice et al.35LGL19345Stage II–IV No symptomsNE60%335 year survival 70%5 year survival 78%NSReasonable to wait
Ardeshna et al.36LGL309192Stage III or IV No symptomsNE73%31.280.470.80.84Reasonable to wait
Nordic Gastrointestinal Tumor Adjuvant Therapy Group37Colorectal183NSAsymptomaticNE57%5.9149<0.02Prolongs time to symptoms and OS
Ackland et al.38Colorectal16857AsymptomaticEqual70%4–613.011.00.49No OS or QOL benefit
O'Brien39Mesothelioma43NSStable symptomsEqual77%414100.1Trend to longer symptom free period and OS
Ahman et al.40Breast75NSStable disease No prior chemoNENE430.220.5NSImproved OS
CALGB 738241Breast157NSStable diseaseNENE526 (I) 29 (II)30NSImproved RR and response duration, no improved OS
ECOG 217442Breast34NSStable diseaseNENE6.141.340.40.5Equal
Hjorth et al.43Early stage myeloma5048Stage I (D-S)NENE124543NSDeferral reasonable in well-informed patients
Riccardi et al44Early stage myeloma7451Stage I (D-S)NENE11Not reachedNot reachedNSEqual
Riccardi et al.45Early stage myeloma14565Stage 1 (D-S)NENE1364710.64Deferring treatment reasonable

Low grade lymphoma

Three prospective randomized studies have examined the role of immediate versus delayed intervention in low-grade lymphoma. Young et al. randomized 104 patients to immediate aggressive combined modality Pro-MACE-MOPP (cyclophosphamide, etoposide, methotrexate, folinic acid, predinisolone, mustargen, vincristine and procarbazine) followed by radiotherapy (n = 43) or delayed chlorambucil on progression (n = 41).34 Fifteen patients initially screened were treated actively off-study. Forty-four percent of patients in the watch-and-wait arm crossed to the combined modality arm on symptomatic progression, at a median time of 34 months. There was no significant difference in overall survival between the two groups. Of note, the study had different treatments for the immediate versus delayed arms.

Brice et al. randomized 193 patients to no initial treatment, prednimustine (an ester of chlorambucil and prednisolone), or α-interferon.35 Response rates were 56% and 70% to the immediate and delayed treatments, respectively. No difference in overall survival time was found.

In a larger trial (n = 309) with a median follow-up of 16 years, Ardeshna et al. randomized patients to chlorambucil or observation until disease progression.36 Neither overall survival nor cause specific survival differed between the two groups, and 19 of the 151 patients randomized to observation were alive and had not received any chemotherapy.

Colorectal cancer

Two studies have examined the role of immediate versus delayed intervention in metastatic colorectal cancer. The Nordic Study examined 183 patients with asymptomatic colorectal cancer randomized to methotrexate, bolus 5-fluorouracil (5-FU) and rescue folinic acid for five courses, or to delayed chemotherapy when symptoms appeared.37 Only 57% of the patients in the delayed group ever received chemotherapy. There was a trend to improved overall survival with early treatment: the early group overall survival time was 14 months, compared to 6 months for the delayed group, P = 0.13 (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.51–1.03). The chemotherapy regimens used to treat the patients on the delayed intervention arm varied, and there was no quality of life data. The patients who were being observed were reviewed every 2 months in this trial, and some commentators have suggested that this relatively long period between reviews, in patients in whom a change in symptomatic status is crucial, may have contributed to the trend to a worse outcome for the delayed group.38

In a meta-analysis of two very similar randomized trials involving 168 patients with asymptomatic metastatic colorectal cancer, treated with either immediate or delayed 5-FU/folinic acid, there was no difference in median survival; the immediate chemotherapy having a median survival time of 13 months compared with 11 months in the delayed chemotherapy group (HR 1.15, 95% CI 0.79–1.72, P = 0.49), and no difference in progression free survival, 10.2 months (immediate) versus 10.8 months (delayed) (HR 1.08, 95% CI 0.71–1.64, P = 0.73).38 Quality of life was assessed by the European Organization for The Research and Treatment of Cancer (EORTC) QLQ-C30 tool, and one of the trials also used a range of other assessment tools. No significant quality of life differences were found in overall quality of life, or any component domain on any of the assessment tools.

Breast cancer

Three trials performed over 20 years ago, compared immediate chemotherapy postoophorectomy for advanced breast cancer with chemotherapy on progression.40–42,46,47 The 1977 Ahman et al. study randomized 75 premenopausal patients with advanced breast cancer who had undergone an oophorectomy to immediate chemotherapy (cyclophosphamide, 5-FU, and prednisolone) or the same chemotherapy on appearance of progressive metastatic disease.40 The study reports no statistically significant overall survival difference, but an improved progression free survival in the immediate treatment arm of 53 weeks versus 17 weeks in the delayed treatment arm (no details of statistical significance given). However, the clinical significance of this is uncertain in the setting of no overall survival benefit and no quality of life data.

Cancer and Leukemia Group B (CALGB) 7382 randomized 157 premenopausal women with metastatic breast cancer to immediate chemotherapy post oophorectomy (either cyclophosphamide alone or vincristine, prednisolone, cyclophosphamide, methotrexate and 5-FU, VPCMF), or VPCMF following progression.41 There were no differences in overall survival between the three groups.

ECOG 2174 randomized 34 premenopausal women who had responding or stable disease post oophorectomy at 12 weeks to immediate or delayed chemotherapy on progression.42 The purpose of the study was to examine whether the addition of chemotherapy to patients responding to oophorectomy prolonged remission duration, rather than to see whether observation until symptomatic progression was safe. There was no overall survival difference between the groups.

In none of these studies was the development of symptoms necessary to begin chemotherapy after a period of observation. The studies were not designed to specifically compare the effect of immediate versus delayed treatment. They employed as their control arm oophorectomy, which was an active treatment in a proportion of the patients in the study. Finally, because of the time of their design, they used chemotherapy now not regarded as standard, and because it was not available at the time the studies were performed, did not incorporate estrogen receptor testing.

Mesothelioma

One small trial examined this question in mesothelioma, comprising 43 patients with either no symptoms or stable symptoms over 4 weeks, randomized to immediate versus delayed treatment (mitomycin, vinblastine, and cisplatin) on symptomatic progression.39 Seventeen of the 22 patients in the delayed treatment arm received chemotherapy. The primary objective was median time to symptom progression from the study randomization. Symptom progression was defined as worsening of symptoms on symptom scoring, increased analgesia requirements, continued weight loss and poor appetite, deterioration in performance status, or preference for chemotherapy, assessed every 3 weeks. The time to symptom progression was 25 weeks in the early treatment group versus 10 weeks in the delayed treatment group (P = 0.1). Of the secondary objectives, there was no significant difference in overall survival (14 months [immediate group]versus 10 months [delayed group], P = 0.1) or quality of life. Quality of life was assessed again by the EORTC 30 tool, and there were no significant differences between early and delayed treatment arms.

Early stage multiple myeloma

The Cochrane Database Systemic Review found three trials with a total of 131 patients in both of the early and the deferred treatment groups.43–45,48 There was no difference in mortality or response rate. The data set was too small for both conclusions, and included sparse data on quality of life and toxicity.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. REFERENCES

The efficacy of chemotherapy in patients with metastatic incurable cancer is well established.49 Treatment objectives include symptom control, improved quality of life, prolongation of progression free survival and prolongation of overall survival. In symptomatic patients, the institution of chemotherapy remains complex, with many factors contributing to the decision making process. In the asymptomatic patient, the decision to institute chemotherapy may be even more difficult.

Timing of therapy

The timing of early intervention of anticancer therapies in patients has been shown to be of benefit in a variety of contexts. Early introduction of chest irradiation in the treatment of limited disease small-cell lung cancer is of benefit, providing an improved overall survival at 5 years (OR 0.64, 95% CI 0.44–0.92, P = 0.02), and a short period between the start of chemotherapy and the end of radiotherapy results in an improved survival.50,51 Similarly, early introduction of hormone therapy in advanced prostate cancer provides a survival benefit over delayed introduction.52

In contrast, there is no apparent benefit in the early use of irradiation in patients with low-grade glioma compared to delayed intervention, with no statistical difference in overall survival.53 In addition, the institution of palliative thoracic radiotherapy in the context of unresectable locally advanced non-small-cell lung cancer and minimal thoracic symptoms was found to be equally effective in overall survival, quality of life and lack of psychological distress when given immediately versus on symptomatic progression.54

Older studies have compared the use of immediate chemotherapy versus best support care and shown that chemotherapy can provide objective benefits, such as symptom control, improved quality of life and overall survival.3–11,49,55–60 These studies were not specific for asymptomatic patients and few studies have directly examined outcomes in patients who receive immediate intervention against delayed intervention.

Our review has demonstrated a paucity of data regarding the timing of intervention in patients with asymptomatic metastatic incurable cancer. Further, the studies examined are relatively old, represent outdated chemotherapy treatment strategies and are generally small and statistically underpowered. Only two assessed quality of life, a crucial component in this setting. Accrual was difficult in a number of the studies, and this parallels other trial experience where the option of less or delayed chemotherapy is offered.61 Despite this, oncologists are regularly confronted by the question, “When should I intervene with chemotherapy”?

Factors that may influence the decision regarding treatment initiation

Some hypothetical patient vignettes are instructive (Table 3). Two patients with asymptomatic metastatic colorectal cancer and two patients with hormone refractory prostate cancer are shown. Even with a simple “work-up” these patients clearly represent different challenges for their treating oncologists. The temptation to intervene immediately in the two younger patients with bulky, poorly differentiated disease is strong, despite the lack of symptoms. For these two patients there is an assumption that symptoms will arise in a short time. In contrast, there is a strong temptation not to intervene in the two older patients with low volume disease that may represent a more indolent cancer.

Table 3.  Patient vignettes (metastatic colorectal cancer and hormone refractory prostate cancer)
 Asymptomatic metastatic colorectal cancerAsymptomatic hormone refractory prostate cancer
  1. CEA, carcinoembryonic antigen; LDH, lactate dehydrogenase; PSADT, prostate specific antigen doubling time; ULN, upper limit of normal.

Age (years)50755075
Tumor differentiationPoorModerateGleason 9Gleason 7
MarkersRapidly rising CEA LDH > x3 ULNSlowly rising CEA LDH normalPSADT rapidPSADT slow
Volume of diseaseBulkySmallBulkySmall
Performance status0000
Immediate chemotherapy?YesNoYesNo

Table 4 lists a number of factors that may influence decisions regarding treatment initiation in patients with asymptomatic metastatic incurable cancer. These factors can be divided into cancer, treatment and patient related features. These shall be discussed in detail below, along with other factors that may influence the decision to treat immediately.

Table 4.  Factors in considering immediate versus delayed intervention in the asymptomatic patient
Patient factors
 Performance status
 Comorbidities
 Patient preferences
 Previous experience with chemotherapy
Tumor factors
 Natural history of the disease
 Significant tumor bulk
 Adverse pathological features
 Rapid change in tumor markers
 Involvement of critical structures
Treatment factors
 Multiplicity of treatment options
 Likelihood and extent of survival benefit
 Likelihood of quality of life benefit
 Toxicity
 Availability of clinical trials
 Availability of “non-toxic” targeted therapies

Clinical experience with different tumors

Some incurable cancers have a reputation for aggressive growth and rapid symptom onset. Such tumors include glioblastoma, extensive stage small-cell lung cancer, gastric, esophageal and pancreatic cancers. In contrast, other cancers such as lower grade glioma, prostate cancer and breast cancer may have more indolent natural histories. The treating clinician may treat immediately because of their understanding and knowledge of the cancers' aggressive biology. Further, delaying therapy may result in the risk that a patient may have a precipitous fall in performance status that may mitigate against later intervention.

As well as the distinction between the aggressiveness of different tumor types, there is also considerable biological heterogeneity within tumor types. That metastatic disease is diagnosed in an asymptomatic patient may suggest information regarding its biology. A tumor that is incidentally found on a screening chest X-ray, liver function tests, prostate specific antigen (PSA), or physical examination, or one that causes symptoms that are negligible or easily controlled, may have different biological behavior, respond to chemotherapy differently and have a wider range of potential survival times to one that is already causing ascites, pain, hypercalcaemia and significant fatigue.

Tumor bulk and site of disease may also influence treatment decisions. For example, bulky disease, such as that involving significant portions of the liver or lung, but not causing biochemical or symptomatic compromise may argue for earlier treatment. Similarly, involvement of critical structures such as invasion of mediastinal vessels, pericardium, or significant pleural effusion in a lung cancer, radiological evidence of early bowel obstruction in a colorectal cancer, or significant omental disease in other gastrointestinal cancers, may suggest earlier treatment.

Tumor markers

The availability of tumor markers such as PSA, CA-125 and carcinoembryonic agent contribute to the debate. Such tumor markers may indicate relapse and promote intervention despite a lack of symptoms or indeed, visible evidence of metastatic disease. For both the patient and clinician, a rising tumor marker may provide an impetus to treat with chemotherapy immediately rather than observe. The often cited “PSA-itis” is an example of anxiety associated with non-intervention in the face of a rising tumor marker. Klotz has called this significant anxiety patients experience “PSAdynia”.20,62 However, the time to symptomatic disease progression may be of significant duration. Smith et al. studied patients with hormone refractory prostate cancer (a rising PSA) but no evidence of metastatic disease (i.e. biochemical progression only).63 These patients had a median bone metastasis-free survival time of 30 months, although the time to symptomatic progression was not examined. Detectable tumor markers below the level at which clinical symptoms arise can complicate decisions about when treatment should be initiated.

Novel systemic therapies

The increasing availability of novel systemic therapies should also be included in this debate. The advent of well-tolerated, efficacious, molecular targeting oral medications may redefine our approach to patients with asymptomatic metastatic disease. For example, sunitinib in the treatment of renal cell cancer may alter the equation between toxicity and efficacy, compared to the previous use of immunotherapy agents such as interferon.32 In this instance, clinicians and patients may opt for earlier intervention, although the data for early versus delayed treatment initiation will be lacking.

Availability of clinical trials

One option for patients and clinicians is to use clinical “windows of opportunity” to test new therapies and delay the use of conventional therapies. For example, in men with hormone refractory prostate cancer, the timing of chemotherapy remains controversial. For some patients with a slowly rising PSA and small volume metastatic disease, delaying chemotherapy may be acceptable. For these patients, there is the option to enrol in clinical trials examining the use of novel therapies.

In 365 patients with previously untreated metastatic breast cancer, for example, Constanza et al. randomized patients with performance status 0–1 to immediate treatment with CAF (cyclophosphamide, adriamycin, and 5-FU), or initial treatment with one of five (then) experimental phase II agents (trimetrexate, melphalan, amonafide, carboplatin or elsamitrucin).64 Patients who received the experimental agents received up to four cycles of the agent before crossing over to the CAF treatment arm. There was no difference in the median survivals between the groups, although there was a trend towards patients with visceral metastases to have a poorer response rate on the phase II agent plus CAF arm, 37% versus 54% on the immediate CAF arm, P = 0.078. This trial did not explicitly measure the effect of observation until symptomatic progression, but did not find any harm associated with a period of (relatively) inactive therapy prior to commencing treatment, although patients with visceral disease may have a poorer response rate.

Patient preferences

The period following diagnosis and before treatment is stressful and decisions regarding treatment provoke significant anxiety for patients and their families.65,66 A number of studies have examined the hypothetical decision of patients with early stage disease, and members of the public without disease, in the situation of making a decision about chemotherapy should they develop incurable metastatic malignancy2,3,67–73 Age, the presence of dependents, toxicity of treatment, chance of benefit, understanding of their prognosis with and without treatment, and preference of the oncologist all affect patients' preferences.

Few studies have examined the question of preference for immediate versus delayed chemotherapy in the setting of asymptomatic disease. McQuellon asked 115 patients with early stage breast cancer about their treatment preferences in hypothetical scenarios of metastatic disease and found that 59–78% of women would prefer to initiate chemotherapy in the absence of symptoms, depending on the treatment scenario with which they were faced.2 Factors that were associated with a preference for treatment when asymptomatic were a better physical function and having previously received adjuvant chemotherapy.

The only study that looked prospectively at the preferences and decisions of patients with metastatic disease, rather than at hypothetical scenarios in patients who had early stage disease, or no cancer at all, is that reported by Koedoot et al.74 Sixty-eight percent of patients favored chemotherapy at baseline, and the majority of these patients had a very strong preference for chemotherapy. The patient's preference for chemotherapy before consultation with the oncologist was also a strong predictor for the patient's subsequent acceptance of it. Young age, an “information seeking” as opposed to a “deferring” decision-making style, and a preference for quantity of life as opposed to quality of life also predicted acceptance of palliative chemotherapy. It is possible that these factors may also influence the decision of early versus delayed chemotherapy, but this was not studied in this patient group.

Physician preferences

What do oncologists in practice think about this question, and how do they present the options to patients? Studies of the information given by oncologists discussing the options of immediate chemotherapy or observation showed that the option of observation was given explicitly to approximately half of the patients and explained extensively to only 27%.75

Twenty-three percent of the patients had the option of watchful waiting mentioned once and being told that the option involved “doing nothing”. In the same study less than half of the patients received information of disease related symptoms, prognosis and treatment related side-effects such as fatigue, vomiting and a declining condition.

A study of 697 oncologists providing an indication of their strength of preference for palliative chemotherapy versus watchful waiting by evaluating 16 vignettes of patients with incurable cancer found considerable variation in their preferences.76 Interestingly, the histological nature of the “metastatic cancer” was not specified in the vignettes. Age, the wish to be treated and a survival gain of ≥3 months were the strongest factors influencing the decision. The toxicity, likelihood of tumor response and a worse physical condition affected the decision to a lesser degree. Studies of clinicians from different specialties involved with cancer care have also found different preferences in clinicians for the use of palliative chemotherapy.77,78 Higher percentages of medical oncologists were optimistic about chemotherapy and recommended it for patients over the age of 70, than chest physicians, palliative physicians and radiation oncologists.

Other factors

There is limited data from preclinical studies that suggest early intervention is more effective than delayed intervention.79–81 This may relate to the development of resistant clones, increasing tumor hypoxia and reduced drug penetration as the tumor itself increases in size.82–85

Ethically, the interpretation of non-maleficence (doing no harm) could be applied to either the defence of early chemotherapy or the defence of delayed chemotherapy. Early chemotherapy saves the patient from the potential harm of being too unwell for chemotherapy, while delayed chemotherapy avoids toxic side-effects, given that there is no evidence of worse survival in treating on symptomatic progression. The principles of justice and informed consent mandate discussion with the patient and participation in the decision making process.86 This area is not addressed in the published reports.

General considerations in the clinic

A number of factors need to be considered as to whether to treat asymptomatic metastatic disease. First, immediate commencement of chemotherapy should not be an automatic response. Second, clinicians should reflect on patient, tumor and treatment factors (Table 4). In a patient who is asymptomatic and being observed, clinical review of symptoms, weight and performance status as well as a subtle sense of the patient's wellness may determine the appropriate timing of intervention. A rapid change in tumor markers or scan appearance may recommend early intervention.

Treatment options may also influence the decision. Clinicians may be reluctant to use chemotherapy in situations such as prostate cancer, when few effective second-line agents exist, compared with breast, lung or colon cancer, where effective second or third-line options are available. From a patient perspective, specific treatment opportunities may engender some enthusiasm to treat immediately. These include the availability of clinical trials, “non-toxic” targeted therapies and the knowledge that a multitude of interventions is available with the ever-expanding portfolio of therapeutic agents.

Is it possible to predict who should be treated immediately?

Is it possible to distinguish which patients need immediate intervention? In other circumstances, prognostic factors and prognostic indices provide information on who to treat and how. Online algorithms exist for assisting decisions about adjuvant therapy for breast cancer based on age, comorbidities, general health and tumor characteristics.87 Klotz suggests “active surveillance” of men with good risk early stage prostate cancer.88 In metastatic cancer, nomograms have been created to assess likely overall survival in prostate cancer and there is interest in the CA-125 area under the curve as a means of prognostication in ovarian cancer.89–91 Such examples may evolve to useful biological and clinical assessment tools that may augment sophisticated clinical judgment.

CONCLUSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Our review demonstrates a striking lack of data regarding the timing of chemotherapy in patients with asymptomatic metastatic incurable cancer. Despite this, oncologists are frequently confronted by this problem. Intuitively, we base intervention on a variety of cancer, patient and treatment related factors. In some instances we consider “pre-emptive” intervention in those patients in whom we believe symptomatic progression is likely to occur within a relatively short period of time. However, we have all observed patients with indolent disease who require no immediate intervention.

The most effective method of resolving this issue would be to conduct well-designed clinical trials comparing immediate versus delayed intervention. In the meantime, the decision to intervene immediately in this group of patients needs to be made on a disease-by-disease basis and on a patient-by-patient basis. The nature of malignancy, its course over time, patient comorbidities, and most importantly, the patient's preferences and understanding of the decisions involved are all factors that come into play when making this important decision.

ACKNOWLEDGMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. REFERENCES

We would like to thank Associate Professor Michael Green, and Associate Professor Martin Stockler for their reviews of this paper, and for their helpful input.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGMENTS
  9. REFERENCES
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