Chinese Medicine for People with Lung Cancer: Treatment ... · Lung Cancer: Treatment Results " ... complementary and alternative medicine. ... Lung Cancer Survival With Herbal Medicine

Chinese Medicine for People with!Lung Cancer: Treatment Results "

Clinical Advocacy Conference, Commonweal 2012""Michael McCulloch, LAc MPH PhD"www.PineStreetFoundation.org""

Historical origins o  Chinese medicine developed within the context of

the social, political, and geographical milieu of the growth and development of China throughout its history.

o  Incorporation of newly discovered medicines from other parts of the world into the broader framework of the practice of medicine.

o  Examples include influences from Indian Ayurvedic medicine, Persian-‐‑Islamic influences via the Silk Road

www.pinestreetfoundation.org"

Philosophical origins o  Taoism: health is becoming harmonious with nature,

emphasizing the extra channels and Heart-‐‑Kidney connection

o  Buddhism: health means accepting who you are, emphasizing sedation and strategies and Heart-‐‑Spleen harmonization

o  Confucianism: health means knowing who you are relative to the social hierarchy, emphasizing tonic strategies and Liver-‐‑Spleen-‐‑Kidney harmonization


We conducted a survival study with 10-year follow-up of lung (n=235) & colon cancer (n=193) patients"

o  Retrospective medical record data"o  Diagnosis: biopsy/pathology reports, x-ray, CT"o  Patients treated at a Chinese medicine clinic, also

receiving care at regional oncology centers"o  Consecutive case series: all patients with lung or

colorectal cancers presenting between 1986 and 1993"o  Internal comparison: "

n  patients following treatment only during chemotherapy/radiation therapy (short-term), vs. "

n  those who continued (long-term)"o  External comparison: "

n  our cohort vs. "n  cancer registries (Kaiser Permanente & California Cancer

Registry)"

The evolution of this research approach

1st observational trial: King Nebuchadnezzar & Daniel

1st Cox regression survival paper

1st propensity score paper

1st MSM paper

2012 1997

1983 1972 6th Century BC

(Cox, 1972; Green & Benedetti, et al. 2003; Rosenbaum & Rubin, 1983; Robins 1997)"

Relevant case information

o  Western medical history of the present illness o  Laboratory results & pathology report o  Imaging reports o  Exercise history o  Dietary history o  Family history o  Seek to understand current & historical stresses o  Chinese medical history o  Pulse & diagnosis o  Review of symptoms and signs


3-‐‑week treatment timing Part 1: begins the day of chemotherapy infusion, and continues

through Day 3 n  potentiate chemotherapy effectiveness n  enhanced systemic drug delivery by improving circulation and

reducing muscle tension Part 2: days 4 through 11

n  help cleanse the system of toxic (but no longer therapeutically active) drug metabolites

n  help cleanse the lymphatic system Part 3: days 12 until the day of next chemotherapy infusion

n  systematically rebuild the immune system n  prepare the liver, kidneys and bone marrow for the next round of

chemotherapy


Treatment details"


Treatment groups"

Short-term tx lasting

duration of chemotherapy

/radiation"

Long-term continuing after chemotherapy/

radiation"

Total"

Lung Cancer" 54" 181" 235"Stage !II! 11! 22! 33!Stage !IIIA! 9! 66! 75!Stage !IIIB! 13! 71! 84!Stage !IV! 21! 22! 43!


Treatment history: patients & controls"

(Broffman & McCulloch, et al. Integrative Cancer Therapies, Aug 2011)"

Stage IV Lung Cancer: Herbs & Vitamins + Conventional therapy vs Conventional alone"

(PAM+V = Pan-Asian Medicine + Vitamins; KPNC = Kaiser Registry, CCR = California Cancer Registry)"

Median survival - 33 months: TCM + conventional, vs. 6 months: conventional alone

Stage IV Lung Cancer: how long should supportive care continue?"

(PAM+V = Pan-Asian Medicine + Vitamins; KPNC = Kaiser Registry, CCR = California Cancer Registry)"

Median survival - 33 months: long-term, vs. 10 months: short-term

Stage IV Lung Cancer: do herbs & vitamins !improve chemotherapy success?"

(PAM+V = Pan-Asian Medicine + Vitamins)"

12 Integrative Cancer Therapies XX(X)

Strengths of the Study

To our knowledge, this is the first use of causal inference using the MSM approach in cancer survival or in any CAM therapy. It is also the first use of the propensity score in any Chinese herbal therapy.

We intentionally used specific herbal and vitamin prod-ucts commonly available in the commercial markets and free of proprietary constraints. In this way, we hoped to maximize the accessibility and applicability of our treat-ment approach for clinicians and researchers.

We found consistency between the different multivariate analyses methods used: traditional Cox regression, MSM Cox regression, and propensity score Cox regression. Propensity score analysis was best able to detect a survival advantage, followed by MSMs.

Lead time (the delay between diagnosis and initiation of PAM+V treatment) averaged between 22 days and 28 days. This is comparable with what is known about delays in delivery of care to those with lung cancer in conventional oncology practice: delays attributable to the patient average 18 days, and delays attributable to the health system aver-age 62 days.44 To strengthen our inference, we conducted a sensitivity analysis in which we dropped all PAM+V-treated

patients with lead time greater than 60 days. We also con-ducted a conservative analysis where we excluded all KPNC external controls who survived for less than 60 days. In both these sensitivity analyses, we found differences of only a few percentage points in the HRs, which did not change our inferences.

Patients’ use of imagery, visualization, exercise, and Qi-Gong was an integral part of the treatment design, and they were encouraged to learn and practice these approaches as much as possible; these are the kinds of approaches stud-ied in whole systems research, where the emphasis is on the net effect of the holistic protocol design. Teasing apart the relative efficacy of each individual PAM+V component could be pursued in a future prospective study designed to answer this question. Holistic protocols like PAM+V can also be studied using an approach called pragmatic trials, which evaluate a therapy as it is used in normal practice (as compared with the more fixed and constrained approach used in most clinical trials).45

Limitations of the StudyThese are observational data, retrospectively gathered from medical records and cancer registry databases. There may

Figure 4. Lung cancer survival, showing all possible treatment combinations of PAM+V and radiotherapy, using California Cancer Registry patients as external controlsAbbreviation: PAM+V, Pan-Asian medicine + vitamins.

Stage IIIA Lung Cancer: do herbs & vitamins !improve radiation success?"

Stage IIIA Lung Cancer: do herbs & vitamins help surgery success?

10 Integrative Cancer Therapies XX(X)

Figure 2. Lung cancer survival, showing all possible treatment combinations of PAM+V and surgery, using California Cancer Registry patients as external controlsAbbreviation: PAM+V, Pan-Asian medicine + vitamins.

In Kaplan-Meier analysis, in stages II, IIIA, IIIB, and IV lung cancer, there was longer survival with long-term practitioner-guided PAM+V therapy compared with CAM use in the general population (Figure 6). In patients with stages IIIA, IIIB, and IV cancer, there was no difference in survival between short-term PAM+V users within the Pine Street cohort and CAM users in the general population, further reinforcing the benefit of long-term maintenance of adjunctive complementary therapies (although these find-ings on CAM use in the general population are prone to error because of misclassification bias arising from the way in which CAM use data were gathered by the California Cancer Registry (Figure 6).

Validity of External ControlsTo confirm the validity of external controls, we compared survival rates from our analysis among California Cancer Registry and Kaiser controls with those reported by other authors also using SEER data and found that they were comparable (Table 6). For example, in stage IIIB and IV patients treated with chemotherapy, median survival in

California Cancer Registry controls was 6.9 months and in Kaiser controls 6.1 months, compared with 6.8 months in other studies also using SEER data during the same time period.40

Crude Survival Rates: Stage IISurvival at 1 year was 95% in the long-term PAM+V group, 100% in the short-term PAM+V group, 64% in the Kaiser controls, and 67% in California Cancer Registry controls. Survival at 2 years was 93% in the long-term PAM+V group, 70% in the short-term PAM+V group, 50% in Kaiser controls, and 47% in California Cancer Registry controls. Survival at 5 years was 36% in both long-term and short-term PAM+V groups, 13% in Kaiser controls, and 22% in California Cancer Registry controls (Table 7).

Crude Survival Rates: Stage IIIASurvival at 1 year was 93% in the long-term PAM+V group, 70% in the short-term PAM+V group, 50% in Kaiser controls, and 47% in California Cancer Registry

McCulloch et al. 13

Figure 5. Survival in non-small-cell lung cancer, comparing TCM patients initially treated at PSC with those followed up at other CAM centersAbbreviations: PSC, Pine Street Clinic; CAM, complementary and alternative medicine.

have been unmeasured differences between patients choos-ing PAM+V versus those who did not, which could have additionally contributed to differences in survival. We did not have data that would allow us to control for possible confounding by socioeconomic status, which is associated with increased use of CAM,46 better access to conventional cancer therapy,47 and increased cancer survival.48

In the California Cancer Registry and Kaiser, we did not have available data on smoking, which is an important prognostic factor in lung cancer survival. Although some studies have shown that smoking history confers less favor-able survival in people diagnosed with lung cancer,49,50 oth-ers have shown no significant differences in survival,51 particularly in people with advanced disease.52 We did, however, have smoking history data available for those in the PAM+V cohort. This allowed us to include smoking as a variable in all our multivariate survival analyses compar-ing long-term versus short-term PAM+V treatment.

We did not have prospectively gathered data available for analysis and were therefore unable to account for time-dependent confounding, which is often present in longitudi-nal studies and capably handled by MSM analysis. Early

papers on the MSMs stated the assumption of no unob-served confounders, although this assumption is unverifi-able and has recently been called into question.53,54

We did not have data on CAM use by external controls in the Kaiser data. Nevertheless, even if the proportion of CAM use among Kaiser members was as high as the 26% to 30% reported in the literature,55 we anticipate that this would have biased our results toward the null and that the true survival benefit of PAM+V use may even be stronger than we estimated. To strengthen our inference, we also conducted a conservative analysis where we excluded all KPNC external controls who survived less than 2 months and found only a difference in the HR of a few percentage points (which caused no change in our inference).

The existing and newly developed conventional thera-pies for lung cancer, which were in use during the time span of data collection for this study, are known to have signifi-cant toxicities.56-58 Enhancing patient compliance with and tolerance of conventional therapies is an often-reported goal of many CAM treatment programs. We did not include that outcome as a part of the current study. Nevertheless, we are starting to see outcomes data on the contributions of

Study results: due to treatment center, or !the treatment itself?

1, 2 and 5-‐‑year survival rates: lung cancer

(PAM+V = Pan-Asian Medicine + Vitamins)"

Integrative Cancer TherapiesXX(X) 1 –20© The Author(s) 2011Reprints and permission: http://www. sagepub.com/journalsPermissions.navDOI: 10.1177/1534735411406439http://ict.sagepub.com

406439 ICTXXX10.1177/1534735411406439McCulloch et alIntegrative Cancer Therapies© The Author(s) 2011

Reprints and permission: http://www.sagepub.com/journalsPermissions.nav

1Pine Street Foundation, San Anselmo, CA, USA2University of California at Berkeley School of Public Health, Berkeley, CA, USA3Kaiser Permanente Northern California, Oakland, CA, USA4San Francisco Oncology Associates, San Francisco, CA, USA5Chinese Academy of Sciences, Beijing, China

Corresponding Author:Michael McCulloch, Pine Street Foundation, 124 Pine St, San Anselmo, CA, USA Email: [email protected]

Lung Cancer Survival With Herbal Medicine and Vitamins in a Whole-Systems Approach: Ten-Year Follow-up Data Analyzed With Marginal Structural Models and Propensity Score Methods

Michael McCulloch, LAc, MPH, PhD1,2, Michael Broffman, LAc1, Mark van der Laan, PhD2, Alan Hubbard, PhD2, Lawrence Kushi, DSc3, Alan Kramer, MD4, Jin Gao, MD, PhD5, and John M. Colford Jr, MD, PhD2

AbstractComplementary and alternative medicines are used by up to 48% of lung cancer patients but have seen little formal assessment of survival efficacy. In this 10-year retrospective survival study, the authors investigated Pan-Asian medicine + vitamins (PAM+V) therapy in a consecutive case series of all non-small-cell lung cancer patients (n = 239) presenting at a San Francisco Bay Area Chinese medicine center (Pine Street Clinic). They compared short-term treatment lasting the duration of chemotherapy/radiotherapy with long-term therapy continuing beyond conventional therapy. They also compared PAM+V plus conventional therapy with conventional therapy alone, using concurrent controls from the Kaiser Permanente Northern California and California Cancer Registries. They adjusted for confounding with Kaplan-Meier, Cox regression, and newer methods --propensity score and marginal structural models (MSMs), which when analyzing data from observational studies or clinical practice records can provide results comparable with randomized trials. Long-term use of PAM+V beyond completion of chemotherapy reduced stage IIIB deaths by 83% and stage IV by 72% compared with short-term use only for the duration of chemotherapy. Long-term PAM+V combined with conventional therapy reduced stage IIIA deaths by 46%, stage IIIB by 62%, and stage IV by 69% compared with conventional therapy alone. Survival rates for stage IV patients treated with PAM+V were 82% at 1 year, 68% at 2 years, and 14% at 5 years. PAM+V combined with conventional therapy improved survival in stages IIIA, IIIB, and IV, compared with conventional therapy alone. Prospective trials using PAM+V with conventional therapy for lung cancer patients are justified.

Keywordslung cancer, survival, Chinese herbal medicine, vitamins, propensity score, marginal structural models, chemotherapy, radiotherapy

Background

Lung cancer is the leading cause of cancer death in the United States, with 75% of cases being non-small-cell lung cancer.1,2 In 1988, when recruitment for the cohort described in the current study began, median survival with inoperable non-small-cell lung cancer was 6 months following etoposide/cisplatin chemotherapy and 8 months with added !- and "-interferons.3 Systemic therapies for advanced non-small-cell lung cancer have not substantially improved survival.

(Broffman & McCulloch, et al. Integrative Cancer Therapies, Aug 2011)"

This is a short section for the advocates & researchers here today…"

Long-term TCM + conventional treatment, vs. short-term TCM + conventional treatment"

www.pinestreetfoundation.org

Long-term TCM + conventional treatment, vs. conventional treatment alone (ca registry controls )"


Astragalus-Based Chinese Herbs and Platinum-BasedChemotherapy for Advanced Non–Small-Cell Lung Cancer:Meta-Analysis of Randomized TrialsMichael McCulloch, Caylie See, Xiao-juan Shu, Michael Broffman, Alan Kramer, Wei-yu Fan, Jin Gao,Whitney Lieb, Kane Shieh, and John M. Colford Jr

A B S T R A C T

PurposeSystemic treatments for advanced non–small-cell lung cancer have low efficacy and high toxicity.Some Chinese herbal medicines have been reported to increase chemotherapy efficacy andreduce toxicity. In particular, Astragalus has been shown to have immunologic benefits bystimulating macrophage and natural killer cell activity and inhibiting T-helper cell type 2 cytokines.Many published studies have assessed the use of Astragalus and other Chinese herbal medicinesin combination with chemotherapy. We sought to evaluate evidence from randomized trials thatAstragalus-based Chinese herbal medicine combined with platinum-based chemotherapy (versusplatinum-based chemotherapy alone) improves survival, increases tumor response, improvesperformance status, or reduces chemotherapy toxicity.

MethodsWe searched CBM, MEDLINE, TCMLARS, EMBASE, Cochrane Library, and CCRCT databases forstudies in any language. We grouped studies using the same herbal combinations for random-effects meta-analysis.

ResultsOf 1,305 potentially relevant publications, 34 randomized studies representing 2,815 patients metinclusion criteria. Twelve studies (n ! 940 patients) reported reduced risk of death at 12 months (riskratio [RR] ! 0.67; 95% CI, 0.52 to 0.87). Thirty studies (n ! 2,472) reported improved tumor responsedata (RR ! 1.34; 95% CI, 1.24 to 1.46). In subgroup analyses, Jin Fu Kang in two studies (n ! 221patients) reduced risk of death at 24 months (RR ! 0.58; 95% CI, 0.49 to 0.68) and in three studies(n ! 411) increased tumor response (RR ! 1.76; 95% CI, 1.23 to 2.53). Ai Di injection (four studies;n ! 257) stabilized or improved Karnofsky performance status (RR ! 1.28; 95% CI, 1.12 to 1.46).

ConclusionAstragalus-based Chinese herbal medicine may increase effectiveness of platinum-based chemo-therapy when combined with chemotherapy. These results require confirmation with rigorouslycontrolled trials.

J Clin Oncol 24:419-430. © 2006 by American Society of Clinical Oncology

INTRODUCTION

Lung cancer is the leading cause of cancer death inthe United States, accounting for 27% and 31% of allcancer deaths in women and men, respectively.1 Al-though lung cancer deaths in men have declinedsubstantially (from 92 in 100,000 in 1995, to 84 in100,000 in 2001), death rates in women only recentlybegan to stabilize in 1995 (at approximately 42 in100,000 between 1995 and 2001) after increasing fortwo decades between 4% and 6% per year.2 Lungcancer is now the leading cause of cancer death inwomen.1 Seventy-five percent of all lung cancer oc-currences are non–small-cell lung cancer.

Despite treatment advances, new systemictherapies for advanced non–small-cell lung cancerdeveloped in the last few decades continue to haveboth low efficacy and high toxicity. Meta-analyseshave shown that, compared with treatment withsurgery alone, adjuvant treatment with chemother-apy reduces the risk of death at 2 years by only13%3; adjuvant chemoradiotherapy reduces thatrisk by 14%4; adjuvant radiotherapy alone con-versely increases that risk by 21%.5,6 The additionof platinum-based drugs to standard chemother-apy protocols increased 12-month survival by 5%and tumor response by 62%, but with significantlyincreased hematologic toxicity, nephrotoxicity, and

From the University of California,Berkeley School of Public Health, Divi-sion of Epidemiology, Berkeley; SanFrancisco Oncology Associates; Insti-tute of Biophysics, Chinese Academyof Sciences, San Francisco, CA; PineStreet Foundation, San Anselmo; andInstitute of Information, China Academyof Traditional Chinese Medicine,Beijing, China.

Submitted July 29, 2005; acceptedOctober 12, 2005.

Authors’ disclosures of potential con-flicts of interest and author contribu-tions are found at the end of thisarticle.

Address reprint requests to JohnColford, MD, PhD, University of Califor-nia, Berkeley, 140 Warren Hall, MC7360, Berkeley, CA 94720; e-mail:[email protected].

© 2006 by American Society of ClinicalOncology

0732-183X/06/2403-419/$20.00

DOI: 10.1200/JCO.2005.03.6392

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

VOLUME 24 ! NUMBER 3 ! JANUARY 20 2006

419

Copyright © 2006 by the American Society of Clinical Oncology. All rights reserved. Downloaded from www.jco.org at CONS CALIFORNIA DIG LIB on January 18, 2006 .

Twelve studies (n = 940 patients): 33% improvement in 12 month survival (RR = 0.67; 95% CI, 0.52-0.87).

Thirty studies (n = 2,472): 34% improvement in tumor response (RR = 1.34; 95% CI, 1.24 - 1.46).

Chinese herbs combined with chemotherapy:"

Alternate Explanations for these Survival Differences"

o  Selection bias: are patients who are choosing CAM better off to begin with?"

o  Higher social and economic status: associated with less smoking, longer survival"

o  Self-efficacy (making better choices for yourself leads to better outcomes): difficult to measure retrospectively"

o  Informative censoring: did patients with worse prognosis not continue treatment? "

o  Residual confounding: other factors which contributed to the outcome?"


Growth in CAM use may be outpacing growth in pharmaceutical development

(Eisenberg, Davis et al. 1998; Nahin & Dahlhamer, et al. 2010; Stockwell, 2011)"

Annual new drug approvals (new chemical entities)"Annual drug R&D (U.S. billions)"Annual out-of-pocket spending on CAM (U.S. billions) "

Non-‐‑randomized studies of alternative medicines are essential!

Very few federally-‐‑funded randomized cancer trials happen…

(Source: PubMed systematic search, 1995-2010, NHS/NCI/NCCAM grants, all RCTs)"

Randomized trials can show inflated therapeutic benefit compared to real-world use"

o  In meta-analyses comparing RCTs to observational studies, RCTs showed exaggerated benefits in:"n  Antidepressants in major depressive disorder: a 5-fold

inflation of drug benefits (Naudet & Maria, et al. 2011)

n  Drugs to reduce bleeding during angioplasty: a 2-‐‑fold inflation of drug benefits (Centurión, 2010)

o  In a meta-analysis of 110 RCTs: Primary outcomes changed in 34% of trials, and secondary outcomes in 70%, between time of trial registration & publication. (Ewart & Lausen, 2009)!

o  Clinical trial protocols may exclude as many as 60% of patients who would otherwise be eligible for a therapy in community care practice. (Gandhi & Ameli, et al. 2005)!

Patient are reluctant to join randomized trials, limiting their feasibility for CAM"

o  Less than 3% of cancer patients will participate in randomized trials (Murthy & Krumholz, et al. Jama 2004) "

o  This may even be more so the case with CAM trials, because CAM therapies are so widely available."

o  Many CAM therapeutic approaches show positive data in observational studies, but RCTs are proceeding very slowly, and other questions may never be answered, or answerable, by RCTs."

o  Question: are randomized trials really the best way to evaluate CAM efficacy?"

RCTs" Observational studies"

Cost" Very high; also vulnerable to financial interest bias" Very low"

Selection bias" Overly selected patients" Selection bias in who

chooses CAM"

Feasibility" Patients recruitment for CAM trials difficult"

Very high (data already exist)"

Internal validity"

Less confounding by unmeasured variables."

Analysis relies more on breadth of data"

External validity"

Highly constrained clinical context"

More representative of how CAM is used in practice"

Observational (non-randomized) studies & RCTs: both have advantages & limitations "

Capabilities & unique features of Propensity Score analysis in observational data

o  Can provide near-‐‑randomized comparability between groups in observational studies (given enough variables that could contribute to the outcome).

o  Essential to reducing bias self-‐‑selected treatment seWing. o  Can identify true causal effects sometimes not found

through traditional association models o  A standardization tool, making groups comparable based

on probability of having been treated, given individual characteristics, such as age, gender, and other variables

o  Never before applied in studies of Chinese herbal medicine and cancer survival"

Rules, Guidelines & Capabilities

o  Consecutive case series: everyone case counted. o  Lag time: ruled out with sensitivity analysis. o  Propensity Score analysis: allow causal inference, and addresses selection bias."

o  Ideally suited to analyzing practice center data. o  Simple, elegant, sophisticated alternative at lower cost than randomized trials.


Gratitude"

o  Mark Renneker, Sandee Birdwell & Commonweal"o  Our co-authors: "

n  Michael Broffman LAc (Pine Street Foundation)"n  Mark van der Laan, PhD (University of California Berkeley) n  Alan Hubbard, PhD (University of California Berkeley) n  Lawrence Kushi, DSc (Kaiser Permanente Northern Calif.) n  Alan Kramer, MD (San Francisco Oncology Associates)"n  Donald I. Abrams, MD (San Francisco General Hospital,

University of California San Francisco) n  Jin Gao, MD, PhD (Chinese Academy of Sciences, Beijing) n  John M. Colford Jr, MD, PhD (University of California

Berkeley) o  California Cancer Registry"


Documents

Chinese Medicine for People with Lung Cancer: Treatment ... · Lung Cancer: Treatment Results " ... complementary and alternative medicine. ... Lung Cancer Survival With Herbal Medicine